Medical Policy

Policy Num:      05.001.029
Policy Name:    Nononcologic Uses of Rituximab
Policy ID:          [05.001.029]  [Ac / B / M+ / P+]  [5.01.24]

Last Review:       November 14, 2024
Next Review:      November 20, 2025

Related Policies:

05.001.016 Uses of Monoclonal Antibodies for the Treatment of Non-Hodgkin Lymphoma

Nononcologic Uses of Rituximab

SUMMARY

Rituximab is a monoclonal antibody against the CD20 antigen on B lymphocytes. Rituximab lyses pre-B and B lymphocytes and is successfully used to treat B-cell lymphoma. Rituximab has been used with increased frequency for nononcologic indications, particularly autoimmune diseases thought to be B-cell mediated.

Hematologic Disorders and Vasculitides

For individuals who have autoimmune hemolytic anemia-warm autoimmune hemolytic anemia and cold agglutinin syndrome-refractory to first-line therapy who receive rituximab, the evidence includes randomized controlled trials (RCTs) and observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Two RCTs have found that overall response rates were better with rituximab than a control condition at 1 year in patients with newly diagnosed warm autoimmune hemolytic anemia. Serious adverse events were higher with rituximab than corticosteroids (1 RCT) but lower than placebo (the other RCT). Response rates from observations studies have supported these findings and found lesser yet substantive response rates in patients with cold agglutinin syndrome. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have relapsed or refractory idiopathic thrombocytopenic purpura who receive rituximab, the evidence includes an RCT of second-line therapy and observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Rituximab as second-line treatment for adult thrombocytopenia trial failed to demonstrate improved outcomes with rituximab as second-line therapy in adults with idiopathic thrombocytopenic purpura. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have relapsed or refractory thrombotic thrombocytopenic purpura who receive rituximab, the evidence includes a nonrandomized trial (phase 2), a cohort study, and case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. These studies have provided consistent evidence of improved health outcomes. For example, a phase 2 trial reported substantially lower relapse rates than historical controls. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis) who receive rituximab, the evidence includes a single-center retrospective observational study and 3 case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Response and remission rates have generally been high, but treatment-related adverse events-some severe-have been reported. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input obtained in 2014 supported the use of rituximab in Churg-Strauss syndrome and in combination with corticosteroids as first-line treatment for severe (eg, organ-threatening) disease. Therefore, this indication may be considered medically necessary.

For individuals who have congenital or acquired hemophilia A with inhibitory antibodies, refractory to first-line therapy, who receive rituximab, the evidence includes a phase 2 trial, a cohort study, and case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Response rates have varied among reports (25% to 50%), depending on whether rituximab was administered as mono- or combination therapy; remission rates have generally been high. Treatment-related adverse events-some severe-have been reported. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have hepatitis C virus-associated cryoglobulinemic vasculitis who receive rituximab, the evidence includes 2 RCTs, a phase 2 nonrandomized trial, and observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The reported response rates in these studies are consistent with improved health outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Autoimmune-Related Connective Tissue Disorders

For individuals who have mixed connective tissue disease who receive rituximab, the evidence includes 2 case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. In one of the series, 3 of 5 patients with mixed connective tissue disease achieved partial remission with rituximab and, in the other, which focused on mixed connective tissue disease related to interstitial lung disease, there was no significant change in forced vital capacity at 1 or 2 years after initiating rituximab. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have multicentric Castleman disease (angiofollicular lymph node hyperplasia) who receive rituximab, the evidence includes 2 prospective and 3 retrospective cohort studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Although the evidence base consists of nonrandomized studies, rituximab has significantly improved overall survival and markedly reduced the incidence of non-Hodgkin lymphoma. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have primary Sjögren syndrome, refractory to first-line therapy, who receive rituximab, the evidence includes a large RCT (disease onset <10 years prior) and smaller observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The efficacy of rituximab has not been consistently demonstrated in this population. For example, a large (N=120) randomized trial showed no difference in response rates compared with placebo, and a small (N=41) nonrandomized trial showed statistically significant differences in response rates compared with disease-modifying antirheumatic drugs in previously treated patients. The incidence of adverse events did not appear to increase above that observed in other patient populations. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input obtained in 2014 supported the use of rituximab in the treatment-refractory primary Sjögren syndrome; therefore, this indication may be considered medically necessary.

For individuals who have systemic lupus erythematosus, refractory to first-line therapy, who receive rituximab, the evidence includes a large RCT and systematic reviews that also included observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The single RCT failed to show improved response rates at 1 year with rituximab add-on therapy. Cohort studies and case series of refractory patients have generally reported higher response rates than controlled studies. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input obtained in 2014 supported the use of rituximab in the treatment of refractory systemic lupus erythematosus. Treatment algorithms, developed based on scenarios reviewed by 13 systemic lupus erythematosus experts, generally concur with that clinical input.

For individuals who have lupus nephritis, refractory to first-line therapy, who receive rituximab, the evidence includes an RCT and noncomparative studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The single RCT did not show improved response rates at 1 year with rituximab add-on therapy. Noncomparative studies have reported complete and partial response rates of 30% to 40% and approximately 35%, respectively, in patients with mostly refractory disease. Adverse events occurred in approximately 20% of patients. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input obtained in 2014 supported the use of rituximab in the treatment of lupus nephritis.

For individuals who have systemic sclerosis, refractory to first-line therapy, who receive rituximab, the evidence includes observational studies and a small, unblinded trial. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Add-on rituximab therapy has generally improved skin symptoms and pulmonary function tests; adverse events, including sepsis deaths, occurred in 21% to 47% of patients. Long-term follow-up for efficacy and safety is limited. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical input obtained in 2014 supported the use of rituximab in systemic sclerosis considered refractory to first-line therapies supported rituximab as medically necessary.

Other Autoimmune-Related Conditions and Disorders

For individuals who have multiple sclerosis who receive rituximab, the evidence includes 2 RCTs, a registry study, and case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. One RCT in patients with relapsing-remitting multiple sclerosis showed reductions in the number of lesions detected by gadolinium-enhanced magnetic resonance imaging and at 24 and 48 weeks, and in clinical outcomes at 24-week follow-up. However, methodologic limitations restrict the conclusions drawn from these data. One well-designed RCT in patients with primary-progressive multiple sclerosis demonstrated no effect of rituximab on disease progression. A large registry study found that rituximab was associated with a relatively low rate of adverse events and relapses and little change in disability scores; this study lacked a comparison group. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have neuromyelitis optica (prevention relapse), refractory to first-line therapy, who receive rituximab, the evidence includes uncontrolled observational studies and systematic reviews. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. A 2016 systematic review of 46 uncontrolled studies found significant reductions in the relapse rate and Expanded Disability Status Scale scores after beginning treatment with rituximab. Based on adverse events reported, the safety of rituximab in neuromyelitis optica appeared comparable to the safety in other patient populations. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have refractory and nonrefractory myasthenia gravis who receive rituximab, the evidence includes observational studies and a systematic review. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. A systematic review found a significant reduction in a myasthenia gravis symptom score after beginning rituximab treatment and a relatively low rate of adverse events. A limitation of the studies was that adverse event reports were not available for all patients. An uncontrolled observational study found significantly better clinical outcomes in patients with anti-MuSK myasthenia who were treated with rituximab compared with those who did not receive rituximab. However, few controlled studies and no RCTs are available. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have idiopathic membranous nephropathy who receive rituximab, the evidence includes an RCT and observational studies. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. Rituximab may have moderate benefit in patients with idiopathic membranous nephropathy who have failed previous treatment with other immunosuppressive regimens or those with a moderate risk of progression who have not previously received immunosuppressive therapy. However, an RCT with longer follow-up is needed to confirm the benefits of rituximab and to determine the optimal schedule, dose, and long-term safety and efficacy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have minimal change in disease (adults and children) who receive rituximab, the evidence includes observational studies in adults and 2 RCTs and observational studies in children. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. Rituximab benefit children with nephrotic syndrome associated with minimal change disease. However, because of the risk of severe and potentially life-threatening complications, rituximab use should be restricted to children with frequent relapses and serious adverse events from their medications (because the long-term efficacy and safety of rituximab in this group of patients remain unclear). The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have  moderate to severe pemphigus vulgaris (off label indication) ¹⁹⁰  rituximab is an emerging therapy for many autoimmune diseases such as pemphigus and connective tissue diseases. In these cases, off-label alternative treatment remains an option, especially for recalcitrant and rapidly progressive cases, or when conventional therapy is contraindicated

Transplant-Related Conditions and Disorders

For individuals who have corticosteroid-refractory chronic graft-versus-host disease who receive rituximab, the evidence includes multiple cohort studies. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. Treatment with rituximab has demonstrated response rates in most patients, with sustainedresponse and steroid reduction or discontinuation in some. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have sensitization to human leukocyte antigen and are renal transplant candidates who receive rituximab, the evidence includes an RCT and cohort studies. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. An RCT comparing desensitization regimens with and without rituximab was terminated due to excess serious adverse events in the control arm. There may be a higher risk of polyomavirus BK virus infection. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are kidney transplant candidates who are receiving induction immunosuppressive therapy, the evidence includes cohort studies with historical controls and case series RCTs and systematic reviews. Although observed improvements in outcomes have suggested potential benefit with rituximab, data are retrospective or from small prospective studies. Dose-response studies and larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. For individuals who are heart transplant candidates who are receiving induction immunosuppressive therapy, the recommendation for the use of rituximab as part of a combination regimen is based on consensus reporting of case reports and expert opinion.

For individuals who have antibody-mediated rejection of a solid organ transplant who receive rituximab, the evidence includes cohort studies with historical controls and case series. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. Although observed improvements in outcomes have suggested potential benefit with rituximab, data are retrospective or from small prospective studies. Dose-response studies and larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have antibody-mediated rejection (AMBR)after pancreatic islet transplantation who receive rituximab, the evidence includes a case report. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes.

Additional Information

Clinical input obtained in 2014 supported the use of rituximab for the following off-label indications:

• Churg-Strauss syndrome and in combination with corticosteroids as first-line treatment for severe (eg, organ-threatening) disease;

• treatment-refractory primary Sjögren syndrome;

• refractory systemic lupus erythematosus (treatment algorithms, developed based on scenarios reviewed by 13 systemic lupus erythematosus experts, generally concur with that clinical input);

• lupus nephritis;

• systemic sclerosis considered refractory to first-line therapies.

Therefore, these indications may be considered medically necessary. Further details from clinical input are described in the Supplemental Information Section.

OBJECTIVE

The objective of this evidence review is to determine whether rituximab improves the net health outcome in patients with various autoimmune and nonautoimmune conditions.

POLICY STATEMENTS

Rituximab may be considered medically necessary for the following off-label indications:

•         the following autoimmune hemolytic anemias (AIHA):

   o    warm AIHA in glucocorticoid-refractory or glucocorticoid-dependent patients;

   o    cold agglutination syndrome;

•         thrombotic thrombocytopenic purpura in patients with refractory disease or relapse (ie, lack of response to plasma exchange therapy and glucocorticoids);

•         Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis):

    o    first-line treatment in combination with glucocorticoids for patients with severe (organ-threatening) disease;

    o    add-on therapy for treatment-refractory disease;

•         factor inhibitors in patients with hemophilia who are refractory to conventional first-line treatments (eg, immune tolerance induction, glucocorticoids with or without cyclophosphamide), preferably as add-on therapy

•         add-on therapy for patients with hepatitis C virus-associated cryoglobulinemic vasculitis who have:

   o    active disease resistant to antiviral drugs; or

   o    severe or life-threatening cryoglobulinemic vasculitis;

•         multicentric Castleman disease (first- or second-line therapy);

•         primary Sjögren syndrome that is refractory to glucocorticoids and other immunosuppressive agents;

•         add-on therapy for systemic lupus erythematosus refractory to standard first-line treatment;

•         add-on therapy for lupus nephritis refractory to standard first-line treatment regimens;

•         systemic sclerosis (scleroderma) in patients refractory to first-line treatment;

•         neuromyelitis optica for relapse prevention;

•         idiopathic membranous nephropathy;

•         glucocorticoid-refractory chronic graft-versus-host disease; and

•         desensitization of human leukocyte antigen-sensitized renal transplant candidates before transplantation.

•      Moderate to severe Pemphigus Vulgaris (PV) in adult patients

Rituximab is investigational for all other nononcologic uses, including but not limited to:

•         idiopathic thrombocytopenic purpura in patients who do not respond to first-line treatments;

•         paroxysmal cold hemoglobinuria;

•         mixed connective tissue disease;

•         multiple sclerosis;

•         treatment of myasthenia gravis;

•         treatment of minimal change disease;

•         prophylaxis for graft-versus-host disease;

•         induction immunosuppressive therapy for kidney transplantation;

•         induction immunosuppressive therapy for heart transplantation

•         treatment of antibody-mediated rejection in solid organ transplant recipients; and

•         treatment of antibody-mediated rejection after pancreatic islet transplantation.

POLICY GUIDELINES

Dosing

Rituximab should be administered by a health care professional with appropriate medical support to manage severe and potentially fatal infusion reactions (https://www.gene.com/download/pdf/rituxan_prescribing.pdf).

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Coding

Please see the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Triple-S Salud Preferred Drugs Determination 

For all FDA approved indications:

• First treatment of choice will be biosimilars Truxima and Ruxience.

In order to consider any other rituximab agents, patients must have:

• documented previous use and therapeutic failure to biosimilars Truxima and Ruxience.
• intolerance or contraindication to biosimilars Truxima and Ruxience.

BACKGROUND

Rituximab

Rituximab (Rituxan) is a chimeric murine-human monoclonal antibody directed against the CD20 surface antigen, which is expressed on pre-B and mature B lymphocytes. Rituximab induces lysis of normal and malignant CD20-expressing B cells; possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity.^1,

B cells are thought to play a role in the pathogenesis of rheumatoid arthritis and other autoimmune diseases by producing auto-antibodies and proinflammatory cytokines, and by activating T lymphocytes.^1, Rituximab reduces the number of B cells in the peripheral blood and in lymphoid tissues, thereby interrupting pathogenic processes of autoimmune diseases.

Rituximab is infused intravenously.

Adverse Events

Rituximab carries the following Boxed warnings^2,:

• Fatal infusion reactions within 24 hours of rituximab infusion; approximately 80% of fatal reactions occurred with the first infusion

• Severe mucocutaneous reactions, some with fatal outcomes

• Hepatitis B virus reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death

• Progressive multifocal leukoencephalopathy resulting in death

Labeled warnings and precautions include:

• Tumor lysis syndrome (for patients with hematologic malignancies)

• Infections

• Cardiac arrhythmias and angina

• Renal toxicity

• Bowel obstruction and perforation

• Not administering live virus vaccines before or during rituximab therapy

• Cytopenias

• Embryo-fetal toxicity

• Limited data on concomitant use with other biologic agents and disease-modifying antirheumatic drugs other than methotrexate in rheumatoid arthritis, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and pemphigus vulgaris

• Limited data on use in rheumatoid arthritis patients who have not had prior inadequate response to tumor necrosis factor antagonists

regulatory status

In 1997, rituximab (Rituxan^® [Biogen; Genentech]) was initially approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsed or refractory low-grade, CD20-positive, B-cell non-Hodgkin lymphoma (see evidence review 2.03.05). Subsequent indications approved by FDA are summarized Table 1.

Table 1. FDA Approved Indications for Rituximab

B-AL; B-cell acute leukemia; BL: Burkitt lymphoma; BLL: Burkitt-like lymphoma; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; CLL: chronic lymphocytic leukemia; CR: complete response; CVP: cyclophosphamide, vincristine, prednisone; DLBCL: diffuse large B-cell lymphoma; FC: fludarabine, cyclophosphamide; FDA: U.S. Food and Drug Administration; GPA: Granulomatosis with Polyangiitis;MPA: Microscopic Polyangiitis; MTX: methotrexate; NHL: non-Hodgkin lymphoma; PR: partial response; RA: rheumatoid arthritis; TNF: tumor necrosis factor.

Truxima (rituximab-abbs), Ruxience (rituximab-pvvr), and Riabni (rituximab-arrx) have been FDA-approved as biosimilar agents to Rituxan (rituximab), but these agents are only approved for adult patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, GPA (Wegener's Granulomatosis)/MPA, and RA. None of these agents are FDA-approved as an interchangeable biologic.

RATIONALE

This evidence review was created in October 2014 and has been updated with searches of the PubMed database. The most recent literature update was performed through August 22, 2024. .

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

This review focuses on the off-label nononcologic uses of rituximab.

Population Reference No. 1

Hematologic Disorders and Vasculitidies

Autoimmune Hemolytic Anemia

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have autoimmune hemolytic anemia (AIHA), warm AIHA and cold agglutinin syndrome, refractory to first-line therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with AIHA, warm AIHA and cold agglutinin syndrome, refractory to first-line therapy.

AIHA comprises direct Coombs-positive anemias, such as warm (80% of AIHA) and cold autoantibody types, as well as drug-induced AIHA. Warm AIHA is mediated by warm-reactive antibodies, primarily immunoglobulin G (IgG), that react optimally with human red blood cells in vitro at 37°C (98.6°F). Cold-reactive antibodies, primarily immunoglobulin (Ig)M, react maximally at 4°C (39°F). Cold AIHA, in turn, comprises cold agglutinin syndrome and paroxysmal cold hemoglobinuria. Warm and cold AIHA may be idiopathic (primary) or secondary, eg, to lymphoma or lymphoproliferative disorders.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat AIHA refractory to first-line therapy: glucocorticoids and splenectomy. Corticosteroids are the first-line treatment in warm AIHA but less effective in cold AIHA.^3,4,

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Warm Autoimmune Hemolytic Anemia

Systematic Reviews

A systematic review by Crowther et al (2011) assessing treatments for idiopathic warm AIHA in adults identified 3 studies (case series) on use of rituximab for refractory disease (N=42).^5, Overall response rate (ORR) was 93% (complete response [CR], 43%; partial response [PR], 50%). One study (2009) reported a relapse in 2 (15%) of 13 responders and severe sepsis in 1 (4%) of 27 rituximab-treated patients with a mean follow-up of 21 months.^6, Reviewers recommended rituximab 375 mg/m² weekly for 4 weeks or splenectomy for relapsed or refractory warm AIHA (level 2 recommendation [evidence suggests that benefits and risks are finely balanced or uncertain] based on level C evidence [case series]).

Randomized Controlled Trials

Michel et al (2017) randomized 32 patients with warm AIHA that were diagnosed and treated no more than 6 weeks before receiving rituximab (n=16) or placebo (n=16).^7, Patients received 2 infusions, 2 weeks apart (ie, days 1 and 15 after randomization), prior to which all patients were treated with methylprednisolone. The primary outcome was the ORRs (PR and CR) at 1 year. In an intention-to-treat analysis at 1 year, ORRs were 75% (95% confidence interval [CI], 47.6% to 92.7%) in the rituximab group and 31% (95% CI, 11% to 58.7%) in the placebo group; the difference between groups was statistically significant (p=.032). Eleven of 12 patients who responded in the rituximab group had a CR and all 5 patients in the placebo group who responded had a CR. Serious adverse events occurred in 4 patients in the rituximab group and 7 patients in the placebo group. Serious infections occurred in 2 patients in the rituximab group and 6 patients in the placebo group (p=.39). Patients were followed for 2 years, at which time 6 patients in the placebo group and none in the rituximab group had died (p=.017).

Birgens et al (2013) published a multicenter RCT of first-line rituximab in newly diagnosed patients with idiopathic or secondary warm AIHA.^8, Patients were randomized to rituximab (375 mg/m² weekly for 4 weeks) plus short-course (2 weeks followed by taper) prednisolone (n=32) or prednisolone alone (n=32). At 12 months, ORR was 75% in the rituximab group and 36% in the control group (p=.003). At 36 months, 70% of rituximab responders and 45% of control responders maintained CR or PR (p=.02). Serious adverse events occurred in 9 (28%) of 32 rituximab-treated patients and 5 (17%) of 32 controls (p=.12). These events included 5 serious infections in the rituximab group and 2 serious infections in controls (p=.16).

Cold Agglutinin Syndrome

Petz (2008) identified 11 case reports and case series of rituximab in cold agglutinin syndrome.^4, In 2 case series (n=47 patients), ORR was 62%. The median duration of response in 20 responders was 11 months, and no serious adverse events were reported in 20 rituximab-treated patients. Based on this evidence, Petz suggested rituximab as a treatment option for cold agglutinin syndrome, along with avoidance of cold and immunosuppressive drugs.

Warm or Cold Autoimmune Hemolytic Anemia

Reynaud et al (2015) conducted a meta-analysis of 21 observational studies (N=409).^9, The pooled ORR was 73% (95% CI, 64% to 81%; 20 studies) with considerable heterogeneity (I²=60%); CR rate was 37% (95% CI, 26% to 49%; 20 studies), also accompanied by substantial heterogeneity (I²=72%). There was evidence of publication bias in the pooled ORR but not the CR. In cold agglutinin syndrome, the pooled ORR was 57% (95% CI, 47% to 99%; 6 studies). For warm AIHA , the pooled ORR was 79% (95% CI, 60% to 90%; 11 studies). These results supported the previously cited literature, with heterogeneity suggesting the potential to identify predictors of response (explored by the authors) using individual-level data. The potential publication bias suggests the pooled response rate (at least ORR) was biased upward.

Paroxysmal Cold Hemoglobinuria

Due to the generally self-limiting course and excellent prognosis of paroxysmal cold hemoglobinuria, rituximab is not considered a treatment option.

Section Summary: Autoimmune Hemolytic Anemia

Two RCTs have reported that ORRs were better with rituximab than a control condition at 1 year in patients with newly diagnosed warm AIHA. Serious adverse events were higher with rituximab than corticosteroids (1 RCT) but lower with rituximab than placebo (the other RCT). Response rates from observations studies have supported these findings and found lower yet substantive response rates in patients with cold agglutinin syndrome.

For individuals who have AIHA-warm AIHA and cold agglutinin syndrome-refractory to first-line therapy who receive rituximab, the evidence includes RCTs and observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Two RCTs have found that overall response rates were better with rituximab than a control condition at 1 year in patients with newly diagnosed warm AIHA. Serious adverse events were higher with rituximab than corticosteroids (1 RCT) but lower than placebo (the other RCT). Response rates from observations studies have supported these findings and found lesser yet substantive response rates in patients with cold agglutinin syndrome. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 2

Idiopathic Thrombocytopenic Purpura

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have relapsed or refractory idiopathic thrombocytopenic purpura (ITP) is to provide a treatment option that is an alternative to or an improvement on existing therapies. ITP is an acquired autoimmune disorder with no known cause, although it can co-occur with other autoimmune diseases.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with relapsed or refractory ITP.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to make decisions about relapsed or refractory ITP: glucocorticoids, intravenous immunoglobulins (IVIGs), and anti-Rho(D).

However, relapses are common within the first year, and splenectomy is often required. Rituximab has been investigated to delay or avoid splenectomy.^10,11,

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Auger et al (2012) conducted a meta-analysis of studies evaluating rituximab before splenectomy in adults with ITP.^10, Literature was searched through May 2011; 15 retrospective or prospective observational studies and 4 RCTs were included (N=368 nonsplenectomized patients). Publication bias was not detected. Thirteen studies dosed rituximab at 375 mg/m² weekly for 4 weeks; 6 studies used alternative regimens. Concomitant medications were not described. Median follow-up was 9 months (range, 2.3 to 65 months). Pooled ORR (platelet count, >50´10⁹/L) was 57% (95% CI, 48% to 65%; I²=49%; 20 studies), and 57% (95% CI, 35% to 76%; I²=79%) at 1 year (6 studies). In separate analyses, the CR rate (defined as platelet count either >150´10⁹/L or >100´10⁹/L) was 41% (95% CI, 33% to 50%; I²=51%; 19 studies) and 40% (95% CI, 31% to 49%; I²=0%) at 1 year (5 studies). In 36 responding patients, mean time to response and median duration of response were 6.3 weeks (95% CI, 2.8 to 9.9 weeks) and 49 weeks (range, 17 to 60 weeks), respectively. Adverse events and meta-analysis of RCT control arms were not reported.

Liang et al (2012) conducted a systematic review of studies evaluating rituximab for ITP in children.^12, Literature was searched through December 2011, and 30 case series or case reports were included (N=370). Publication bias was not detected. Median patient age was 8 years (range, 6 months to 19 years). Thirty-nine (11%) patients had a splenectomy. The most common rituximab dose (in 47% of patients) was 375 mg/m² weekly for 4 doses; concomitant medications were not described. Pooled ORR (platelet count, ≥30´10⁹/L with at least doubling of the platelet count, a standard response criterion) was 68% (95% CI, 58% to 77%; I²=68%), and pooled CR (platelet count, ≥100´10⁹/L) was 39% (95% CI, 30% to 49%; I²=57%). Median time to response was 3.0 weeks (interquartile range [IQR], 1.0 to 3.6 weeks) in 40 responders, and median duration of response was 12.8 months (IQR, 4.5 to 25.1 months). The incidence of grade 3 or 4 infection and grade 3 or 4 immediate hypersensitivity reaction or serum sickness was 4% each.

Randomized Controlled Trials

Two RCTs published after the systematic reviews examined rituximab in adults with newly diagnosed ITP. Gudbrandsdottir et al (2013) randomized 133 patients with newly diagnosed ITP to rituximab 375 mg/m² weekly for 4 weeks plus dexamethasone 40 mg daily for 4 days (n=62) or dexamethasone alone (n=72).^13, Patients had baseline platelet counts of 25´10⁹/L or less, or 50´10⁹/L or less with bleeding symptoms. Median follow-up was 2.5 years. The ORR (platelets count ≥50´10⁹/L) sustained at 6 months was 58% in the rituximab group and 37% in the control group (p=.02); at 12 months, sustained response rates were 53% and 33%, respectively (p<.05). Among responders, the median time to rescue treatment was not reached in the rituximab group and 7.4 months in the control group (p=.007). The median platelet count at the time of rescue treatment was 15´10⁹/L (IQR, 7 to 24 ´10⁹/L). Time to relapse also was longer in the rituximab group (p=.03). Serious adverse events occurred more commonly in the rituximab group (26%) than in the control group (11%; p=.04). Because the authors reported numbers of adverse events rather than patients who experienced adverse events, incidences could not be calculated.

Arnold et al (2012) reported on a feasibility study of rituximab in nonsplenectomized adults with newly diagnosed (47%) or relapsed (53%) ITP.^11, Sixty patients were randomized to rituximab 375 mg/m² weekly for 4 weeks (n=33) or placebo (n=27), both administered in combination with standard treatments (most commonly prednisone, dexamethasone, and IVIG). The primary efficacy outcome was a composite of any platelet count less than 50´10⁹/L, significant bleeding, or rescue treatment once standard treatment was stopped. At 6 months, the between-group difference of the composite end point was not statistically significant (64% rituximab vs 78% placebo; relative risk, 0.81; 95% CI, 0.59 to 1.11). Differences in overall (platelet count, ≥30´10⁹/L) or CR (platelet count, ≥100´10⁹/L) were not statistically significant at 6 or 12 months. Significant bleeding events occurred less commonly in the rituximab group (25%) than in the control group (35%). The number of infections (any grade) and serious adverse events were comparable between groups. Because numbers of adverse events rather than patients who experienced adverse events were reported, incidences could not be calculated.

Despite lack of clarity in the long-term durability of response, trials have suggested there is a potential initial benefit from rituximab in untreated patients; however, in practice, rituximab is generally reserved for treatment failures. Ghanima et al (2015) reported results from a multicenter, double-blind, placebo-controlled, randomized trial of rituximab as second-line therapy in adult ITP (the RITP trial).^14, Glucocorticoid-unresponsive patients (112 randomized, 3 refused treatment) were included from 14 centers in Norway, Tunisia, and France. Participants were unsplenectomized adults with platelet counts below 30´10⁹/L and had failed to respond to glucocorticoids or relapsed during dose tapering or after stopping. Patients were randomized to infusions of rituximab or saline (placebo); glucocorticoids were continued but tapered to maintain platelet counts (>20´10⁶/L). The initially specified primary end point was splenectomy within 1.5 years, but because of approval of thrombopoietin receptor agonists, it was revised to “treatment failure” defined by splenectomy after week 12 or meeting criteria for a splenectomy. The trial was powered to detect a reduction in primary end point occurrence from 70% to 40% or a hazard ratio (HR) of 2.57, with a potential 20% dropout rate. Overall response (OR) was defined as a platelet count of 30´10⁹/L or higher and CR as a platelet count of 100´10⁹/L or higher 4 weeks after drug administration (a doubling of platelet count was also required). Through 1.5 years, the OR was observed in 81% and 73% of the rituximab and placebo arms, respectively (p=.15), and CR in 58% and 50%, respectively (p=.12). Treatment failure occurred in 46% receiving rituximab and in 52% of the placebo arm (HR, 0.89; 95% CI, 0.55 to 1.45; p=.65). Splenectomies were performed in 8 (15%) receiving rituximab arm 14 (26%) receiving placebo (p=.12). However, rituximab-treated patients experienced a longer median time to relapse (36 weeks vs 7 weeks). One or more bleeding episodes occurred in 21 (38%) and 27 (50%) of the rituximab and placebo arms, respectively, but more severe episodes were observed with rituximab. Finally, the cumulative steroid dose did not differ between treatment arms (p=.33).

The well-conducted RITP trial failed to demonstrate improved outcomes with rituximab as second-line therapy in adults with ITP, despite generally more favorable outcomes with rituximab in the trial. In context, splenectomy achieves a sustained response in 60% to 70% of patients. Here, 24% of rituximab-treated and 14% of placebo-treated patients experienced sustained responses. Extended follow-up data were retrospectively collected for 72 (83%) patients out of the 84 patients who were not splenectomized during the initial RITP study; the median duration of follow-up was 72 months (IQR, 62 to 82).^15, The median duration of response was significantly longer in patients who received rituximab (8.2 months) versus placebo (1.8 months; p=.036). Among patients who achieved a CR in the RITP study (n=49), the median time to relapse was 17 months in the rituximab group versus 11 months in the placebo group (p=.55). Two years after the start of the RITP study, splenectomy was performed in 13 patients (17.2%) in the rituximab group and 22 patients (26.4%) in the placebo arm (p=.12). Five patients in the rituximab group and 6 in the placebo arms died during the study. Overall, these results did not support the use of rituximab in this setting.

Section Summary: Idiopathic Thrombocytopenic Purpura

Two systematic reviews in ITP of primarily observational studies (1 in children [median age, 8 years], 1 in adults) and 2 RCTs in adults investigated mostly nonsplenectomized patients. Overall and CR rates were approximately 57% and 40%, respectively, in adults, and 68% and 39% in children. Median response durations were approximately 1 year. For patients who initially achieve a CR, the median time to relapse was 17 months with rituximab and 11 months with placebo in an extended follow-up of patients from 1 RCT. Adverse event reporting was inconsistent; serious infections and hypersensitivity reactions occurred in 4% of 370 children included in the systematic review. A placebo-controlled randomized trial evaluating rituximab as second-line therapy did not demonstrate benefit compared with placebo.

For individuals who have relapsed or refractory ITP who receive rituximab, the evidence includes an RCT of second-line therapy and observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Rituximab as second-line treatment for adult thrombocytopenia trial failed to demonstrate improved outcomes with rituximab as second-line therapy in adults with ITP. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 3

Thrombotic Thrombocytopenic Purpura

Clinical Context and Therapy Purpose

The relevant population of interest is individuals with relapsed or refractory TTP. Refractory TTP, defined as progression of clinical symptoms during plasma exchange (PE) therapy, occurs in 10% to 20% of acquired TTP cases.^16,

TTP is a life-threatening condition characterized by microvascular thrombosis, thrombocytopenia, and microangiopathic hemolytic anemia leading to end-organ ischemia and infarction (commonly brain, heart, kidneys).^17, TTP is due to an acquired (95% of cases) or congenital (5% of cases) deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. In 38% to 95% of cases of idiopathic TTP, anti-ADAMTS13 neutralizing antibodies are present.^18, When ADAMTS13 is absent or depleted, large uncleaved von Willebrand factor multimers aggregate in high shear areas of the microvasculature, leading to thrombotic microangiopathy.^19,

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat relapsed or refractory TTP: glucocorticoids, PE, cyclosporine, cyclophosphamide, and vincristine.

The main treatment for TTP is PE and corticosteroids. For refractory TTP patients, increased PE and/or addition of cyclosporine are current treatment options.^18,

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review of 15 case series and 16 case reports (N=100) by Tun et al (2012) evaluated immune-mediated, relapsed or refractory TTP treated with rituximab.^17, Studies of secondary TTP and empirical rituximab treatment were excluded. In all studies, rituximab was dosed at 375 mg/m² weekly for a median of 4 doses (range, 1 to 8 doses). Ninety-eight (98%) patients achieved CR, defined as platelet recovery, lack of TTP-related symptoms, and no evidence of microangiopathic hemolytic anemia lasting more than 30 days. Two (2%) patients were considered nonresponders. During median follow-up of 13 months (range, 1 to 97 months), 9% of patients who achieved CR relapsed. Anti-ADAMTS13 antibody positivity and severe ADAMTS13 deficiency (enzyme activity, <10%) predicted response to rituximab (positive predictive value, 99% for both). Serious rituximab-related adverse events occurred in 3 (3%) patients: acute biventricular cardiogenic shock, sacral abscess, and abdominal abscess.

Nonrandomized Trials

Scully et al (2011) conducted a phase 2, multicenter, nonrandomized cohort in England.^20, Forty patients with anti-ADAMTS13 antibody-positive, new-onset (85%) or acute relapsed (15%) TTP were enrolled and compared with an age-, sex-, and ethnicity-matched historical control group of 40 patients. Enrolled patients received rituximab 375 mg/m² weekly for 4 weeks; 3 patients died, and 1 withdrew before receiving all 4 doses of rituximab. All patients and historical controls received PE at admission and then daily (or twice daily for new or progressive neurologic or cardiac symptoms; protocol maximum of 8 infusions) until remission, defined as sustained platelet count (>15´10⁹/L) for 2 consecutive days; corticosteroid (typically intravenous [IV] methylprednisolone 1 g/d) was given for 3 days. The primary efficacy outcome was the number of PE treatments to remission. Forty enrolled patients received a median of 16.5 (range, 4 to 34) PE treatments compared with 18 (range, 6 to 92) treatments in the historical control group (p=.5). Among secondary outcomes, there was no statistical difference between groups in the number of hospital admission days, but among patients who relapsed (4 in the rituximab group, 21 in the control group), median time to relapse (defined as readmission with thrombocytopenia <150´10⁹/L 30 days after discharge from an acute episode) was longer in rituximab-treated patients (27 months; range, 17 to 31 months) than in historical controls (18 months; range, 3 to 60 months). However, follow-up for rituximab and control groups was 12 and 49 months, respectively. Both incidences of infections and serious adverse events were similar between groups.

Scully et al (2007) also reported on a multicenter cohort study of 25 patients who had anti-ADAMTS13 antibody-positive acute relapsing (56%) or acute refractory (44%) TTP.^21, Patients received methylprednisolone daily for 3 days, daily PE until sustained platelet count (as previously defined), and rituximab 375 mg/m² immediately after PE weekly for 4 weeks. All 25 patients achieved clinical remission (defined as cessation of PE, sustained platelet count, and absence of clinical disease) within 1 to 3 weeks of treatment. During median follow-up of 10 months (range, 1 to 33 months), there were no relapses and no infectious complications.

Froissart et al (2012) conducted a single-arm trial in 22 adults with acute (n=6) or relapsed (n=16) TTP refractory to therapeutic PE.^17, Rituximab was administered in 4 infusions over 15 days. Patients were enrolled from a registry in the Reference Network for Thrombotic Microangiopathies (France). Outcomes were compared with a historical control group of 57 consecutive patients (from the same registry, all ADAMTS13-deficient) treated with vincristine with or without cyclophosphamide. Both current patients and historical controls were treated using defined protocols. There was 1 (4.5%) death in the rituximab group and 4 (7.0%) in 57 historical controls. Platelet count recovery (>150´10⁹/L) was observed in the 21 survivors (100%) versus 78% of historical controls; by day 35, all rituximab survivors had platelet count recovery versus 78% of controls, with shorter time to recovery in the rituximab group. No relapses were observed in rituximab-treated patients in the first year following treatment while 5 patients in the control group relapsed (p=.34). Adverse effects of rituximab were not recorded during follow-up. Implications of these results are limited primarily by a small sample size, lack of randomization, and treatment dates (historical controls treated between 2000 and 2005 vs rituximab group between 2005 and 2008). That said, the results are consistent with others suggesting potential benefit in refractory and relapsed TTP.

Section Summary: Thrombotic Thrombocytopenic Purpura

Studies assessing the use of rituximab for TTP have enrolled patients with acquired (anti-ADAMTS13 antibody-positive) TTP. No RCTs have been reported on the use of rituximab in relapsed or refractory TTP. Because the progressive disease is potentially life-threatening and because relapsed and refractory patients have few alternative treatment options, rituximab may be considered as a treatment option in this setting.

For individuals who have relapsed or refractoryTTPwho receive rituximab, the evidence includes a nonrandomized trial (phase 2), a cohort study, and case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. These studies have provided consistent evidence of improved health outcomes. For example, a phase 2 trial reported substantially lower relapse rates than historical controls. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 4

Churg-Strauss Syndrome (Eosinophilic Granulomatosis With Polyangiitis)

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis [EGPA]) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with Churg-Strauss syndrome (EGPA).

Churg-Strauss syndrome, also called EGPA, is an anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis characterized by peripheral and tissue eosinophilia, frequently affecting the lungs, in patients with asthma.^22, The disease is uncommon, with an estimated prevalence of 11 to 14 per million adults. Eosinophilic infiltration of the heart, lungs, and kidneys can lead to ventricular dysfunction, pulmonary hemorrhage, and renal failure, respectively; cardiac involvement is the leading cause of early death.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat Churg-Strauss syndrome: glucocorticoids, cyclophosphamide, azathioprine, and methotrexate.

Corticosteroids are used with or without cyclophosphamide, depending on disease severity. Azathioprine or methotrexate may be used as steroid-sparing agents. Because of its demonstrated efficacy in granulomatosis with polyangiitis and microscopic polyangiitis, rituximab has been used in patients with EGPA syndrome refractory to conventional immunosuppressant therapy.^23,

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review informing the 2022 update of the European Alliance of Associations for Rheumatology recommendations for the management of ANCA-associated vasculitis provided general findings related to treatments used for these conditions, including in EGPA.^24, Investigators included 26 articles on the treatment of EGPA. Of these, the studies that focused on rituximab included 1 RCT, 1 retrospective cohort study (Canzian et al, as described below), and 2 case series (including Thiel et al, described below). The details from the RCT by Terrier et al (2021) were limited, as the data has only been published as abstract data. It included 105 patients with newly diagnosed or relapsing EGPA and compared rituximab alone to rituximab plus cyclophosphamide. All patients received glucocorticoids. The authors found similar response rates (remission) in both groups. In summary, the authors concluded that moderate to high quality evidence suggests that rituximab can be used for remission induction in EGPA with adverse prognostic factors. No meta-analyses were performed due to heterogeneity between studies.

Retrospective Studies

Canzian et al (2021) published a retrospective European collaborative study in patients with EGPA who received treatment with biologics for refractory and/or relapsing disease.^25, Among the 147 patients in the study, 63 received rituximab, 51 received mepolizumab, and 33 received omalizumab. In patients receiving rituximab, the median Birmingham Vasculitis Activity Score (BVAS) decreased to 1 (IQR, 0 to 4.5) at 6 months and 0 (IQR, 0 to 2) at 12 months. The frequency of remission, PR, treatment failure, and stopping treatment due to adverse events with rituximab was 49%, 24%, 24%, and 3%, respectively. The frequency of remission, PR, treatment failure, and stopping treatment due to adverse events was 15%, 33%, 48%, and 4%, respectively, in the omalizumab group and 78%, 10%, 8%, and 4%, respectively, in the mepolizumab group.

Thiel et al (2017) published a retrospective single-center study with long-term follow-up comparing 14 patients who had EGPA and received rituximab with 14 matched patients who received cyclophosphamide.^26, In the rituximab group, the median total follow-up after remission induction was 48 months (IQR, 15 to 67.25 months), compared with 54.5 months (IQR, 28.5 to 112.5 months) in the cyclophosphamide group. In the rituximab group, all patients showed a response to treatment within 6 months of starting therapy; in the cyclophosphamide group, all patients responded to treatment within 9 months. In the rituximab group, 9 (64%) patients experienced partial remission, and 5 (36%) experienced complete remission. For the cyclophosphamide group, partial and complete remission were observed in 10 (71%) and 4 (29%) patients, respectively. The median BVAS dropped significantly in both groups from baseline to 6 and 12 months (p<.001); in rituximab-treated patients, median BVAS decreased to 4 (IQR, 2.5 to 6) at 6 months and to 2.5 (IQR, 0 to 4.5) at 12 months. In the cyclophosphamide group, BVAS decreased to 2.5 (IQR, 1.5 to 6) at 6 months and to 3 (IQR, 0 to 6) at 12 months. During the observation period after remission induction, 4 patients in the rituximab group had a relapse (3 minor, 1 major), compared with 6 patients in the cyclophosphamide group (5 minor, 1 major). There were greater declines in IgG and IgM serum concentrations after rituximab than cyclophosphamide treatment; however, no rituximab-related infections were observed.

Case Series

A small number of case series have been reported. Novikov et al (2016) reported data from 6 patients with moderately severe or severe relapsing disease refractory to conventional immunosuppression. ²⁷  A primary end point was complete or partial remission within 3 to 6 months after rituximab administration. The median duration of follow-up after the first rituximab dose was 10 months. Within 3 to 6 months, complete (4/6) or partial (2/6) remission was achieved in all patients.

Mohammad et al (2016) identified 20 men and 21 women treated with rituximab between 2003 and 2013 at 4 vasculitis centers: 15 (37%) with refractory, 21 (51%) with relapsing, and 5 (12%) with new-onset EGPA. ²⁸  At 1 year, remission was observed in 49% and partial remission in 39%; 31 adverse events occurred, including 6 severe infections requiring hospitalization.

Muñoz et al (2015) reported on the results of 27 rituximab-treated EGPA patients with refractory (n=20), relapsed (n=5), and newly diagnosed (n=2) disease.^28, Adverse events included infections (n=2), bronchospasm (n=2), and seminoma (n=1).

Thiel et al (2013) reported on a case series of 9 treatment-refractory patients who received rituximab add-on therapy. ^{30, ,} All patients responded (1 complete remission [BVAS=0 for ≥3 months and stable prednisone dose ≤7.5 mg daily], 8 partial remissions [BVAS >0]) after 1 cycle of rituximab with no relapses in 9 months of follow-up. Three patients who received preemptive retreatment (ie, not in response to relapse) were relapse-free for a median follow-up of 3 years. Five (55%) of 9 patients had minor respiratory infections. One patient who received a second (preemptive) course of rituximab developed a testicular seminoma 12 months after the first cycle (6 months after the second cycle).

Section Summary: Churg-Strauss Syndrome

Evidence for use of rituximab to treat Churg-Strauss syndrome includes case series primarily in treatment-refractory patients. Response and remission rates with rituximab were generally high. Treatment-related adverse events, some severe, have been reported. Treatment options are limited for patients refractory to conventional immunosuppressants, and because rituximab has demonstrated efficacy in other ANCA-associated vasculitis diseases (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA] ), rituximab has been considered for use an add-on therapy in patients with treatment-refractory Churg-Strauss syndrome.

For individuals who have Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis) who receive rituximab, the evidence includes a single-center retrospective observational study and 3 case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Response and remission rates have generally been high, but treatment-related adverse events-some severe-have been reported. The evidence is insufficient to determine the effects of the technology on health outcomes. .Medically necessary by clinical input.

Population Reference No. 5

Congenital or Acquired Hemophilia A and Inhibitory Antibodies

Clinical Context and Therapy Purpose

The purpose of rituximab in individuals who have congenital or acquired hemophilia A and inhibitory antibodies, refractory to first-line therapy, is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with congenital or acquired hemophilia A and inhibitory antibodies, refractory to first-line therapy.

Hemophilia is a coagulopathy characterized by reduced, absent, or nonfunctioning clotting factor VIII (FVIII; hemophilia A) or, less commonly, factor IX (hemophilia B). Treatment comprises replacement therapy with the missing or deficient clotting factor. Over time, antibodies to infused clotting factor develop in 20% to 30% of patients with severe hemophilia A and 2% to 5% of patients with hemophilia B.^31, If left untreated, antibody inhibitors eventually render replacement therapy ineffective.

Hemophilia is generally considered a genetic disorder but acquired hemophilia A is a rare autoimmune disease caused by acquired auto-antibodies against FVIII. Underlying medical conditions, such as autoimmune diseases, solid tumors, lymphoproliferative malignancies, or pregnancy, can be identified in approximately half of the patients.

Interventions

The therapy being considered is rituximab. Rituximab has been investigated as an alternative to immune tolerance induction (ITI) or for patients who are nonresponsive to ITI.^32,

Comparators

The following therapies are currently being used to treat congenital or acquired hemophilia A and inhibitory antibodies, refractory to first-line therapy: ITI and other immunosuppressants (eg, cyclophosphamide).

ITI is recommended first-line treatment of factor inhibitors in hemophilia.^33, ITI comprises increasing the dose and frequency of factor infusions until inhibitor is undetectable and FVIII levels normalize. The success rate is low (25%), and associated risks (eg, anaphylaxis, irreversible nephrotic syndrome) are significant. Immunosuppressive therapy with corticosteroids alone or in combination with cyclophosphamide is recommended for first-line inhibitor eradication.

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Congenital Hemophilia

Systematic Reviews

Laros-van Gorkom et al (2014) conducted a systematic review of immunosuppressants in congenital hemophilia.^34, Only case reports and cohort studies were identified. Cyclophosphamide (46 children, 39 adults) and rituximab (42 children, 23 patients) were the most commonly used drugs, with overall success rates of 40% to 44% and 40% to 63%, respectively. Three infections were reported with cyclophosphamide (3 severe sepsis) and 6 with rituximab.

Collins et al (2013) reviewed the literature on rituximab for the treatment of factor inhibitors in congenital hemophilia.^33, Several case reports in patients who failed conventional ITI reported mixed responses. A cohort study of 15 patients, refractory to first-line ITI showed improved response when rituximab was added to ITI rather used as monotherapy. But durable responses were uncommon (14%). In case reports and case series, rituximab plus ITI provided mixed results in patients with hemophilia B.

Franchini et al (2008) published a systematic review evaluating rituximab for congenital hemophilia with inhibitors.^35, A literature search identified 29 studies (case reports, case series; N=49). In most reports, rituximab was given after failure of several courses of conventional ITI. Half of the studies administered rituximab in combination with ITI or other immunosuppressive treatment (eg, plasmapheresis, immunoadsorption, immunosuppressive drugs), and half administered rituximab monotherapy. Analysis of individual patient data showed complete remission in 53% of patients. No serious rituximab-related adverse events were reported. In multivariate analysis, coadministration with FVIII, ITI was statistically associated with response (HR, 4.7; 95% CI, 1.6 to 13.7; p=.005), although the CI was wide, suggesting imprecision in the effect estimate, likely due to small numbers.

Nonrandomized Studies

Leissinger et al (2014) reported on the results from a phase 2 proof-of-concept trial of rituximab monotherapy to decrease amnestic FVIII antibody levels in patients with congenital hemophilia A.^35, Investigators planned to attain a sample size of 50, but, due to low accrual, closed enrollment after 16 patients (data and safety monitoring board decision). Four weekly doses of rituximab (375 mg/m²) were administered. A major response was seen in 3 (18.8%) patients, and 1 had a minor response through 22 weeks; 11 participants experienced serious adverse events. The authors concluded: “Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerization strategies.”

Acquired Hemophilia A

Huth-Kuhne et al (2009) reviewed the literature on rituximab for inhibitor eradication in acquired hemophilia A ^{32, ,} Uncontrolled studies and case reports usually administered rituximab in combination with other immunosuppressive treatments. Remission rates in 43 rituximab-treated patients (half first-line therapy, half second-line therapy) and 44 control patients treated with cyclophosphamide and corticosteroids (all first-line) were comparable.

Section Summary: Factor Inhibitors in Hemophilia

Rituximab for factor inhibitor eradication in congenital hemophilia and acquired hemophilia A has been studied in a small number of patients, primarily in case reports and cohort studies. In ITI-refractory patients with congenital hemophilia and factor inhibitor, remission rates between 40% and 63% have been reported in those who received rituximab alone or in combination with continued ITI. A comparative study in acquired hemophilia A did not find improved response rates in patients treated with rituximab alone or in combination compared with standard cyclophosphamide plus cyclosporine. Evidence does not support rituximab as an alternative to standard treatments for factor inhibitor eradication (ie, ITI in congenital hemophilia and immunosuppression with cyclophosphamide and corticosteroids in acquired hemophilia A). However, the evidence does suggest that patients who are refractory to these first-line treatments may benefit from rituximab without an increase in adverse events. Combination regimens may be preferred. Given the lack of treatment options in refractory patients and the serious, possibly fatal, outcomes if factor inhibitors are not eradicated, rituximab may be considered in this setting.

For individuals who have congenital or acquired hemophilia A with inhibitory antibodies, refractory to first-line therapy, who receive rituximab, the evidence includes a phase 2 trial, a cohort study, and case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Response rates have varied among reports (25% to 50%), depending on whether rituximab was administered as mono- or combination therapy; remission rates have generally been high. Treatment-related adverse events-some severe-have been reported. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 6

Hepatitis C Virus-Associated Cryoglobulinemic Vasculitis

Clinical Context and Therapy Purpose

The purpose of rituximab in individuals who have hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with HCV-associated cryoglobulinemic vasculitis.

Of 3 types of cryoglobulinemia, type 2 and type 3 may be called “mixed” due to the clonal expansion of more than 1 immunoglobulin class, commonly IgM and IgG. Type 1, in contrast, is characterized by a single monoclonal immunoglobulin. Eighty percent of mixed cryoglobulinemic vasculitis is associated with chronic HCV infection. Treatment of the underlying infection to achieve sustained viral response is the treatment of choice. For patients who do not achieve sustained viral response, corticosteroids and cytotoxic agents are alternative treatment options but may exacerbate underlying liver disease.^37,38,

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat HCV-associated cryoglobulinemic vasculitis: ITI and other immunosuppressants (eg, cyclophosphamide).

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Dammacco et al (2013)^38, and Puéchal and Guillevin (2013)^39, published reviews of HCV-associated cryoglobulinemic vasculitis. Previous treatment recommendations,^40, recently published RCTs,^41,42, and heterogeneous nonrandomized studies (that varied by design, HCV genotype, previous treatment, rituximab dose, concomitant therapy) (total N=377) reported response rates of approximately 80%, and led reviewers to draw the following conclusions^38,39,

• The choice of the most suitable treatment for a given patient should be based on the level of disease activity and the extent and severity of organ involvement.

  • For patients with mild-to-moderate disease activity, antiviral therapy was recommended as first-line treatment.

  • For patients with active disease resistant to antiviral agents, and for patients with severe (eg, leg ulcers, glomerulonephritis, peripheral neuropathy) or life-threatening cryoglobulinemic vasculitis, the addition of rituximab (or other B-cell-depleting monoclonal antibody) may slow or halt disease progression.

  • Pegylated interferon alfa may exacerbate some clinical features of cryoglobulinemic vasculitis, such as skin ulcers and peripheral neuropathy.

  • When rituximab is added, plasmapheresis and immunosuppressive therapy also should be added.

• Optimal rituximab dosing for vasculitis has not been determined. Most patients in studies received 4 weekly infusions of 375 mg/m².

• One gram dosing of rituximab may precipitate cryoglobulin.

• HCV load, which does not appear to be associated with detectable adverse events on the liver or with HCV reactivation, may increase during rituximab therapy.

• Viral load and liver function tests should be monitored at regular intervals during rituximab treatment.

More recently, Covic et al (2023) published a systematic review that continues to support the efficacy of rituximab in this setting, either alone or with antiviral therapy.^43,

Nonrandomized Studies

Visentini et al (2015) reported on the results from a phase 2 trial (EUDRACT) addressing rituximab dosing in mixed cryoglobulinemia.^44, Fifty-two patients with HCV-associated disease, either ineligible or intolerant of antivirals, were treated with low-dose rituximab (250 mg/m²´2). The response was evaluated at 3, 6, and 12 months and then compared with historical results from 19 published studies. A CR or PR was observed in 81% of patients by 3 months compared with 86% in 208 patients in prior studies treated with high-dose rituximab (375 mg/m² weekly for 4 weeks). Adverse events attributed to treatment were identified in 11.5% of patients compared with 19.9% in the high-dose studies. The investigators suggested this low-dose regimen may have similar efficacy to a high-dose regimen.

Section Summary: Hepatitis C Virus-Associated Cryoglobulinemic Vasculitis

Recent reviews have summarized the literature on rituximab for the treatment of HCV-associated cryoglobulinemic vasculitis. Across 2 RCTs and many observational studies (N=377), the median OR was approximately 80%. However, these studies were done before the advent of direct-acting antiviral treatment and pegylated interferon-free drug regimens for HCV infection. More effective antiviral treatments should improve outcomes (eg, virologic and immunologic responses, cure rate) of both HCV and associated vasculitis. However, for patients with antiviral-resistant active disease or with severe or life-threatening cryoglobulinemic vasculitis, rituximab in combination with current treatments may improve health outcomes. Viral load and liver function tests should be monitored during rituximab treatment. A phase 2 trial has suggested low-dose rituximab may have similar efficacy as high-dose treatment with fewer adverse events.

For individuals who have HCV-associated cryoglobulinemic vasculitis who receive rituximab, the evidence includes 2 RCTs, a phase 2 nonrandomized trial, and observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The reported response rates in these studies are consistent with improved health outcomes. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 7

Autoimmune-Related Connective Tissue Disorders

Mixed Connective Tissue Disease

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have mixed connective tissue disease (MCTD) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with MCTD.

MCTD has various features of systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis in the presence of increased anti-ribonucleoprotein (anti-RNP) antibodies. ^{45, ,} Although some have questioned whether MCTD is a distinct entity, associated human leukocyte antigen (HLA) class 2 alleles (HLA-DR4 and -DR1) are distinct from those associated with SLE, systemic sclerosis, and polymyositis/dermatomyositis. The most common clinical presentation- Raynaud syndrome, arthralgias, swollen hands, sausage-like fingers, and muscle weakness- appear in 90% of patients. More serious organ involvement can lead to pulmonary arterial hypertension, glomerulonephritis, gastrointestinal bleeding, and severe central nervous system involvement.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat MCTD: glucocorticoids. Common treatments include corticosteroids and cyclophosphamide.

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trial

Maher et al (2023) conducted a multicenter, randomized, double-blind, double-dummy study (RECITAL) comparing rituximab (n=51) to cyclophosphamide (n=50) in individuals with severe, progressive interstitial lung disease associated with scleroderma, idiopathic inflammatory myositis, or MCTD.^46, The study characteristics and results are detailed in Tables 2 and 3. Among the 16 participants with MCTD, 9 received rituximab and 7 received cyclophosphamide. For the primary outcome of change from baseline to week 24 in forced vital capacity (FVC), results in the overall cohort did not demonstrate a statistically significant difference between rituximab and cyclophosphamide (−40 ml; 95% CI, -153 to 74 ml; p=.49). The authors reported that the effects of both treatments were consistent across all 3 connective tissue disease subtypes, with the greatest benefit observed in participants with idiopathic inflammatory myositis and the least benefit in those with scleroderma; however, quantitative results for the subgroups were not provided. Notably, the trial was terminated early due to the COVID-19 pandemic and concerns about initiating immunosuppressive therapy during that time.

Table 2. Summary of Key RCT Characteristics

Abbreviations: IV: intravenous; RCT: randomized controlled trial; UK: United Kingdom.

Table 3. Summary of Key RCT Results

CI: confidence interval; FVC:forced vital capacity; HR: hazard ratio; RCT: randomized controlled trial.The purpose of the study limitations tables (see Tables 4 and 5) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement.

Table 4. Study Relevance Limitations

Abbreviations: MCTD: mixed connective tissue disease.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Table 5. Study Design and Conduct Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias; 5. Other.b Blinding key: 1. Participants or study staff not blinded; 2. Outcome assessors not blinded; 3. Outcome assessed by treating physician; 4. Other.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication; 4. Other.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials); 7. Other.e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference; 4. Other.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated; 5. Other.

Case Series

The evidence for rituximab to treat MCTD consists of small case series. A multicenter case series by Lepri et al (2016) included 44 patients with connective tissue disorders related to interstitial lung disease, 6 of whom had MCTD.^47, Patients received treatment with rituximab. In addition, they were treated with disease-modifying antirheumatic drugs (DMARDs) or immunosuppressants. The primary outcome, change in FVC at 1 year, did not change significantly from baseline to 1 year in the MCTD group (mean, 64.5% at baseline; 63.0% at 1 year; p=.6). There was a small, nonstatistically significant change in FVC at 2 years (mean, 61%; p=.80). Adverse events were not reported separately for the subset of patients with MCTD.

A case series by Jansson et al (2011) evaluated a retrospective cohort of 65 pediatric patients who had various autoimmune disorders.^48, Mean age at disease onset was 11 years; mean disease duration before rituximab treatment was 3 years. Patients were treated with rituximab and followed for at least 6 months. Five patients were considered to have an MCTD- 2 unclassified, 1 Sjögren syndrome, and 2 MCTD. One patient with MCTD died 3 months after starting rituximab, and this death was attributed to disease progression. Of the 4 remaining patients with an MCTD disorder, 3 attained partial remission, and 1 had disease progression. Adverse infusion-related events were reported in 12 (18%) of 65 patients but were not reported separately by disease type.

Section Summary: Mixed Connective Tissue Disease

Data from 1 RCT that was terminated early and included 16 patients with MCTD and 2 case series with 6 or fewer patients with MCTD are insufficient to determine the efficacy and safety of rituximab for the treatment of MCTD. In the RCT, results in the overall cohort, which included patients with interstitial lung disease related to scleroderma, idiopathic inflammatory myositis, or MCTD, demonstrated no statistically significant difference between rituximab and cyclophosphamide in the change in FVC from baseline to 24 weeks. In one of the series, 3 of 5 patients with MCTD achieved partial remission with rituximab; in the other, which focused on MCTD related interstitial lung disease, there was no significant change in FVC at 1 or 2 years after initiating rituximab.

Autoimmune-Related Connective Tissue Disorders

For individuals who have MCTD who receive rituximab, the evidence includes 2 case series. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. In one of the series, 3 of 5 patients with MCTD achieved partial remission with rituximab and, in the other, which focused on MCTD related to interstitial lung disease, there was no significant change in forced vital capacity at 1 or 2 years after initiating rituximab. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 8

Multicentric Castleman Disease

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have multicentric Castleman disease (angiofollicular lymph node hyperplasia) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with multicentric Castleman disease (angiofollicular lymph node hyperplasia).

Castleman disease (angiofollicular lymph node hyperplasia) is a rare lymphoproliferative disorder associated with human herpes virus-8 infection. Prevalence is increased among HIV-infected patients and associated with Kaposi sarcoma. Progression to lymphoma and mortality is high in these patients. Castleman disease has 2 distinct forms with characteristic findings on histologic examination: unicentric or localized (hyaline vascular histology), and multicentric (plasma cell infiltrate). The clinical presentation typically involves lymphadenopathy and multiorgan involvement with an aggressive course. In HIV-non-infected patients, multicentric Castleman disease typically presents after age 70 years. ^49,

Interventions

The therapy being considered is rituximab. Rituximab is considered an alternative therapy.^48,

Comparators

The following therapies are currently being used to treat multicentric Castleman disease: interleukin (IL)-6 inhibitors, chemotherapy, glucocorticoids, ganciclovir, valganciclovir, and other antiviral medications.

For HIV-infected patients, current guidelines suggest IV ganciclovir or oral valganciclovir for treatment of multicentric Castleman disease based on level C evidence. Other treatments include combination chemotherapy and tocilizumab, a monoclonal anti-IL 6 antibody.

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Reid et al (2012) reviewed the literature on rituximab in patients with HIV-related lymphoma and multicentric Castleman disease.^51, They identified 1 prospective and 2 retrospective cohort studies of patients with multicentric Castleman disease who were treated with rituximab (N=69). In the prospective study (N=21), median follow-up was 12 months (range, 1 to 49 months), and the estimated 2-year overall survival (OS) rate was 95%. Of 11 patients who had Kaposi sarcoma at baseline, progression occurred in 4 (36%). No grade 3 or 4 adverse events were reported. One retrospective study compared the incidence of subsequent non-Hodgkin lymphoma (NHL) in 33 rituximab-treated patients with the incidence in non-rituximab-treated patients. All rituximab-treated patients had received first-line chemotherapy (etoposide, vinblastine, anthracyclines). Three-year NHL incidence was 0.04% in the rituximab group compared with 23% in non-rituximab-treated patients. Median OS was 15.7 years and 5.2 years in the rituximab and control groups, respectively. Kaposi sarcoma recurred in 4 (27%) of 11 patients. Mild-to-moderate infections occurred in 27% of rituximab-treated patients.

An earlier systematic review by Mylona et al (2008) identified 25 case series and case reports of HIV-infected patients with multicentric Castleman disease (N=84; 20 [24%] pre-highly active antiretroviral therapy, 64 [76%] post-highly active antiretroviral therapy).^49, Seven (9%) of 75 patients for whom treatment data were available received rituximab as first-line (n=2) or second-line (n=5) therapy. CRs occurred in 5 (81%) patients.

Prospective and Retrospective Studies

Rasmussen et al (2023) conducted a retrospective analysis of 99 patients (73 HIV-positive and 26 HIV-negative) with multicentric Castleman disease who received rituximab-based therapy as a first or second-line treatment.^52, After a median follow-up period of 51 months, 59 patients (62%) maintained persistent remission. Disease progression was observed in 34% of the HIV-positive patients (24 out of 70) and 48% of the HIV-negative patients (12 out of 25). The median time to disease progression was 101 months. The 2-year and 5-year progression-free survival (PFS) rates were 75.8% and 54.4%, respectively. Of the 25 patients who experienced a first relapse, 19 underwent a second round of 4 rituximab infusions, resulting in remission in all cases.

Gerard et al (2012) reported on a prospective cohort of 113 HIV-infected patients who had multicentric Castleman disease.^53, The authors compared the incidence of subsequent NHL in rituximab-treated (n=48) with that in non-rituximab-treated (n=65) patients. At a mean follow-up of 4.2 years, annual NHL incidence was 0.004% (4.2 per 1000 person-years) in the rituximab group and 7% (69.6 per 1000 person-years) in the control group (HR, 0.09; 95% CI, 0.01 to 0.70). Two- and 5-year OS rates were 93% (95% CI, 80% to 98%) and 90% (95% CI, 76% to 96%), respectively, in the rituximab group, and 68% (95% CI, 54% to 79%) and 47% (95% CI, 32% to 61%), respectively, in the control group. Ten Kaposi sarcoma exacerbations and 1 newly diagnosed Kaposi sarcoma were observed in 9 patients after rituximab therapy. Among 36 rituximab responders, multicentric Castleman disease recurred in 8 (22%) after a median of 10.5 months.

Hoffmann et al (2011) retrospectively reviewed 23 rituximab-treated and 29 non-rituximab-treated HIV-infected patients who had multicentric Castleman disease.^54, At a mean follow-up of 2.3 years, the mean estimated OS was not reached in the rituximab group and was 5.1 years in the control group (p=.03).

Case Series

Gliga et al (2021) reported outcomes for 9 male patients with HIV-associated Castleman disease who received rituximab.^55, Some patients received additional pharmacologic therapies or splenectomy in addition to rituximab therapy. Resolution of symptoms was observed in 6 patients and relapse occurred in 4 patients. The survival rate was 87.5% after 1 year (8 of 9 patients) and 71.4% after 3 years (5 of 7 patients).

A case report by Shin et al (2011) assessed the use of rituximab to treat multicentric Castleman disease in an HIV-uninfected patient.^56, Complete remission was achieved after 4 cycles of rituximab and followed by 4 months of corticosteroid maintenance therapy. Recurrence was not detected during more than 4 years of follow-up.

Section Summary: Multicentric Castleman Disease

Evidence for rituximab in multicentric Castleman disease comes almost exclusively from the HIV literature, which reflects the epidemiology of the disease. Prospective and retrospective cohort studies have reported markedly reduced incidence of subsequent NHL and substantially improved OS rates (≥93% at 2 years in 2 studies; 90% at 5 years in 1 study) in rituximab-treated patients compared with non-rituximab-treated unmatched controls. Progression or emergence of Kaposi sarcoma is an associated risk of rituximab treatment, with Kaposi sarcoma recurrence in approximately 30% of patients. No studies comparing rituximab with currently suggested first-line treatments (ganciclovir, valganciclovir) were identified. However, given the low-quality evidence supporting this recommendation and aggressive course of multicentric Castleman disease, effective treatment with rituximab may outweigh its associated risks. Therefore, rituximab may be considered for multicentric Castleman disease in the first- or second-line setting.

For individuals who have multicentric Castleman disease (angiofollicular lymph node hyperplasia) who receive rituximab, the evidence includes 2 prospective and 3 retrospective cohort studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Although the evidence base consists of nonrandomized studies, rituximab has significantly improved overall survival and markedly reduced the incidence of non-Hodgkin lymphoma. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 9

Primary Sjögren Syndrome

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have primary Sjögren syndrome, refractory to first-line therapy, is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with Sjögren syndrome.

Sjögren syndrome is an autoimmune disorder characterized by lymphocytic infiltration and progressive destruction of the exocrine glands of the body, specifically the salivary and lacrimal glands, which cause xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Extraglandular disease leads to vaginal dryness, chronic bronchitis, and dry skin, and may affect the kidneys, blood vessels, liver, pancreas, peripheral nervous system (distal axonal sensorimotor neuropathy), and central nervous system. Sjögren syndrome often accompanies other autoimmune disorders, such as rheumatoid arthritis and lupus. The condition is most common in women older than 40 years.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat Sjögren syndrome: methotrexate, hydroxychloroquine, infliximab, etanercept, azathioprine, mycophenolate mofetil (MMF), cyclophosphamide, and glucocorticoids.

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Doolan et al (2021) published a systematic review of 34 case reports, 8 case series, and 1 pilot study, which evaluated pharmacological strategies for the management of Sjögren syndrome with childhood-onset.^57, Authors' concluded that very low-quality data generally support rituximab for patients with Sjögren syndrome with mucosa-associated lymphoid tissue lymphoma and renal and nervous system complications.

Souzaet al (2016) published a systematic review of RCTs published to December 2015 that included trials enrolling adults with an established primary Sjögren syndrome diagnosis and that compared rituximab with other drugs or placebo as controls.^58, Four studies met eligibility criteria, 3 with low risk of bias and 1 with uncertain risk of bias. The total number of participants was 276 (145 rituximab, 131 placebo). Reviewers evaluated multiple outcomes such as lacrimal gland function, salivary gland function, fatigue improvement, and adverse events. They found no significant differences using the Schirmer test (the test determines whether the eye produces enough tears to keep it moist) between the groups at week 24. A significant difference between groups was reported for salivary flow rate. Reviewers concluded that treatment with a single rituximab course can improve salivary flow.

Ramos-Casals et al (2010) published a systematic review of treatments for primary Sjögren syndrome.^59, Literature was searched through April 2010, and 2 small RCTs (n=47 patients) plus several uncontrolled studies were identified. The RCTs compared rituximab with placebo for symptoms of xerostomia and fatigue. Statistically significant improvements in primary end points were not achieved with rituximab 1000 mg biweekly for 2 doses, although other symptoms (eg, dry eye) showed significant improvements. Uncontrolled studies have shown improvements in extraglandular features, such as vasculitis, neuropathy, and glomerulonephritis.

Randomized Controlled Trials

A blinded RCT by Devauchelle-Pensec et al (2014) assigned 120 patients with primary Sjögren syndrome and at least 1 extraglandular manifestation to rituximab 1000 mg weekly for 2 doses or placebo, and assessed response in global disease, pain, fatigue, and dryness at 24 weeks.^60, Mean baseline European Sjögren’s Syndrome Disease Activity Index (ESSDAI) score was 10 (ESSDAI scoring range, 0 [no symptoms] to 49 [high disease activity]). Baseline corticosteroids (30% of patients) and methotrexate (20% of patients) were discontinued 4 weeks before trial entry. Based on prespecified response criteria (≥30 mm improvement in 2 of 4 symptom visual analog scales at week 24), a statistically significant between-group difference was not observed. A statistically significant difference in the proportion of responders was observed at 6 weeks and in the reduction of fatigue at 6 and 16 weeks, both favoring rituximab. Serious infection occurred in 3% of rituximab-treated patients and 9% of controls, but overall serious adverse events occurred more commonly in rituximab-treated patients (21% vs 14% control). Infusion reactions occurred in 8% of rituximab-treated patients and 2% of controls.

Nonrandomized Studies

In a nonrandomized study, Carubbi et al (2013) compared rituximab (6 courses at 6-month intervals of rituximab 1000 mg biweekly for 2 doses; n=19) with conventional DMARDs (hydroxychloroquine, methotrexate, or cyclosporine; n=22) in patients with early-onset primary Sjögren syndrome.^61, A minimum ESSDAI score of 6 was required for study entry (median, 20; range, 6 to 41). Median disease duration was 14 months (range, 6 to 21 months). DMARDs and corticosteroids were discontinued at least 6 months before baseline, except for patients with severe extraglandular manifestations needing ongoing treatment, with no change in dosage allowed. At 24 weeks, the mean reduction from baseline ESSDAI score was significantly greater with rituximab than with DMARD therapy, and this difference was maintained through 120 weeks of follow-up.

Gottenberg et al (2013) updated a report on the French Autoimmunity and Rituximab registry.^62, Of 78 enrolled patients, 74 (95%) had systemic involvement of disease. At a median follow-up of 35 months, statistically significant reductions in corticosteroid usage and in ESSDAI scores were observed, and physician-assessed improvements after 1 cycle of rituximab were reported in 60% of patients. Improvements in both central and peripheral neuropathy were observed. Half of the patients required rituximab retreatment. Infusion reactions and delayed serum sickness-like disease leading to discontinuation of rituximab occurred in 5 (6%) patients. Three serious infections (1.3/100 patient-years) and 2 cancer-related deaths occurred.

Mekinian et al (2012) published 2 registry studies evaluating patients with primary Sjögren syndrome and involvement of the central^63, or peripheral nervous system.^64, Patients were drawn from the French Autoimmunity and Rituximab registry, a prospective cohort study of rituximab in autoimmune diseases. Of 11 patients with central nervous system involvement (eg, multiple sclerosis [MS]-like symptoms [n=6], cognitive dysfunction [n=3]), only 1 patient with cyclophosphamide-refractory transverse myelitis reported improvement in the ability to walk, and 1 patient with anxiety and depression reported subjective improvement. Of 17 patients with peripheral nervous system involvement (sensorimotor neuropathy [n=11], sensory neuropathy [n=4], multineuritis [n=2]), physician-assessed neurologic improvements occurred in 11 (65%) patients at 3 months and persisted in 9 (53%) patients at 6 months. Statistically significant improvements in objective measures (Rankin Scale scoring range, a 0 [no symptoms] to 6 [dead]; ESSDAI) were observed at 3, 6, and 9 months. Physician-assessed improvements at 3 months and change in ESSDAI scores at 6 months were statistically greater in patients with cryoglobulinemia and/or vasculitis.

Section Summary: Primary Sjögren Syndrome

Patients with primary Sjögren syndrome who require more than symptomatic treatment for severe glandular or extraglandular disease are generally treated with corticosteroids and immunosuppressive drugs. Rituximab has been studied in a small number of patients in randomized and nonrandomized trials and observational studies. The efficacy of rituximab has not been consistently demonstrated. For example, a large randomized trial (N=120) showed no difference in response compared with placebo in patients who had disease onset less than 10 years prior, and a small nonrandomized trial (N=41) showed statistically significant differences in response rates compared with DMARDs in previously treated patients. The incidence of adverse events did not appear to be increased above that observed in other patient populations. Given the limited treatment options and potentially serious outcomes, including death, for patients with refractory disease, rituximab has been considered for these patients. Well-designed randomized trials comparing rituximab with alternative treatments for first- and second-line therapy of primary Sjögren syndrome are needed.

For individuals who have primary Sjögren syndrome, refractory to first-line therapy, who receive rituximab, the evidence includes a large RCT (disease onset <10 years prior) and smaller observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The efficacy of rituximab has not been consistently demonstrated in this population. For example, a large (N=120) randomized trial showed no difference in response rates compared with placebo, and a small (N=41) nonrandomized trial showed statistically significant differences in response rates compared with disease-modifying antirheumatic drugs in previously treated patients. The incidence of adverse events did not appear to increase above that observed in other patient populations. The evidence is insufficient to determine the effects of the technology on health outcomes. .Medically necessary by clinical input.

Population Reference No. 10

Systemic Lupus Erythematosus

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have SLE, refractory to first-line therapy, is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with SLE, refractory to first-line therapy.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat SLE refractory to first-line therapy: methotrexate, hydroxychloroquine, belimumab, etanercept, azathioprine, MMF, cyclophosphamide, cyclosporine, and glucocorticoids.

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles and apply to all indications discussed herein:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

A systematic review by Borba et al (2014)^65, examined several biologics and included only 2 rituximab trials (EXPLORER, LUNAR), which are described next. Three systematic reviews that included the EXPLORER trial are summarized in Table 6. They are comprised of mostly prospective and retrospective cohort studies and case series. Most patients had refractory SLE. Rituximab dosing regimens and definitions of response, flare, and relapse varied across studies. Duxbury et al (2013) observed that this heterogeneity contributed to the “discrepancy in the perceived efficacy of rituximab between controlled [studies, which generally reported lower response rates] and observational studies [which generally reported higher response rates].”^66,

Table 6. Systematic Reviews Assessing Rituximab for Systemic Lupus Erythematosus

CR: complete response; PR: partial response; RCT: randomized controlled trial; TTR: median time to relapse.a In rituximab-treated patients.b A post hoc analysis of the RCT is not counted as a separate study here.c Included EXPLORER, LUNAR, and a Spanish-language RCT by Andrade-Ortega et al (2010)69, that found no difference between rituximab and cyclophosphamide in 19 patients with severe systemic lupus erythematosus.

Randomized Controlled Trials

Merrill et al (2010) reported on the EXPLORER (Exploratory Phase 2/3 SLE Evaluation of Rituximab) double-blind, RCT, which enrolled patients with moderate-to-severe extrarenal lupus despite background immunosuppressive therapy.^70, Patients (N=257) were randomized 2:1 to IV rituximab 1000 mg at weeks 1, 3, 24, and 26 or placebo in combination with prednisolone and either azathioprine, MMF, or methotrexate. At 1-year follow-up, there was no statistically significant between-group difference in clinical response as defined by improvement in British Isles Lupus Assessment Group (BILAG) index (BILAG measures overall and organ-specific disease activity on a scale from A [severe] to E [unaffected]). Seventy percent of the rituximab group and 72% of the placebo group had no clinical response; major clinical response (improvement from BILAG A to BILAG C in all organs at 24 weeks and maintenance of this response without moderate or severe flare to week 52) was achieved by 12% and 16% of the rituximab and placebo groups, respectively. In a prespecified subgroup analysis, African American or Hispanic patients (n=96) who received rituximab achieved more major and PR (14% and 20%, respectively) than those in the placebo group (9% and 6%, respectively; p=.041). However, because there was no correction for multiple comparisons, these results require replication. Safety and tolerability were similar in both groups.

Merrill et al (2011) also reported a post hoc analysis using alternative definitions of flare in the 72% (n=185) of patients who achieved low disease activity (BILAG C or better) at any point before week 52.^71, When mild (BILAG A) flares alone were examined, rituximab reduced the risk of a subsequent BILAG A flare and the mean annualized rate of BILAG A flares.

As suggested in a letter by Rudnicka et al (2010) about the EXPLORE trial, the stringent end point used (improvement to BILAG C in all organs) might have been unrealistic.^72, Based on observational data, rituximab appears to improve renal and musculoskeletal symptoms more than neurologic, cutaneous, and cytopenic symptoms in SLE patients; organ-specific improvements might have been informative end points. Similarly, the change in corticosteroid dose might have demonstrated a steroid-sparing effect with rituximab. Additionally, possible differences in dosages of background immunosuppressive therapies (not reported) might have biased results.

Section Summary: Systemic Lupus Erythematosus

Evidence for rituximab in patients with refractory SLE includes a large RCT that did not show improved response rates at 1 year with rituximab add-on therapy. Systematic reviews that selected mostly cohort studies and case series of refractory patients generally reported higher response rates (25% to 91% ORs) than controlled studies. Rates of serious adverse events and severe adverse events, mostly infections and infusion or allergic reactions, were 7% to 13%.

For individuals who have SLE, refractory to first-line therapy, who receive rituximab, the evidence includes a large RCT and systematic reviews that also included observational studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The single RCT failed to show improved response rates at 1 year with rituximab add-on therapy. Cohort studies and case series of refractory patients have generally reported higher response rates than controlled studies. The evidence is insufficient to determine the effects of the technology on health outcomes. Medically necessary by clinical input.

Population Reference No. 11

Lupus Nephritis

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have lupus nephritis, refractory to first-line therapies, is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with lupus nephritis, refractory to first-line therapies.

Lupus nephritis is among the most serious complications of SLE. It occurs in approximately half of SLE patients and is associated with a poor prognosis. ^73,

Interventions

The therapy being considered is rituximab

Comparators

The following therapies are currently being used to treat lupus nephritis: glucocorticoids, cyclophosphamide, MMF, cyclosporine, tacrolimus, and belimumab.

Treatment regimens including cyclophosphamide or MMF are administered with corticosteroids. Response rates at 1 year are 50% to 80%, but they are often only PRs ^73,

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Estimated 5-year survival among patients with International Society of Nephrology/Renal Pathology Society class IV (diffuse) lupus nephritis is 80% and among all SLE patients, 86%^74,; 5% to 10% of lupus nephritis patients will progress to end-stage renal disease at 10 years.^75,

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Comparative Studies

Randomized Controlled Trials

Rituximab has been compared to placebo in the 2012 double-blind LUNAR (Lupus Nephritis Assessment with Rituximab) RCT - 1 of the RCTs identified in the systematic review described below.^73, As reported by Rovin et al (2012), LUNAR was a randomized, double-blind, placebo-controlled phase 3 trial evaluating rituximab plus MMF and corticosteroids as initial therapy for proliferative lupus nephritis. The trial included 144 patients 16 to 75 years of age, who had histologic evidence of class III or IV lupus nephritis on biopsy within 12 months before randomization. Patients were randomized to IV rituximab 1000 mg at weeks 1, 3, 24, and 26 or placebo in combination with MMF and prednisone. The primary efficacy end point, superior overall (CR or PR) renal response rate at 1 year with rituximab, was not reached (57% [26% CR, 31% PR] in the rituximab group vs 46% [31% CR, 15% PR] in the placebo group; p=.18). The incidence of serious adverse events did not differ statistically between groups. An accompanying editorial by Lightstone (2012) observed that the trial was powered to detect a 20% increase in complete renal response and a 5% increase in partial renal response; it was underpowered to detect a difference comprising mainly PRs.^74,

Cohort Studies

A prospective cohort study compared the safety and efficacy of an intensified B-cell depletion induction therapy (IBCDT), without an immunosuppressive maintenance regimen, to the standard of care in biopsy-proven lupus nephritis.^76, Thirty patients were administered IBCDT (4 weekly rituximab 375 mg/m² doses and 2 more doses after 1 and 2 months; 2 infusions of 10 mg/kg cyclophosphamide, and 3 methylprednisolone pulses), followed by oral prednisone (tapered to 5 mg/day by the third month), and were matched to 30 controls (20 received 3 methylprednisolone pulse days followed by oral prednisone and MMF 2 to 3 g/day, whereas 10 were given cyclophosphamide). In the control group, MMF (1 to 2 g/daily) or azathioprine (1 to 2 mg/kg/day) were given for > 3 years as maintenance therapy. Refractory disease was noted for 20% of enrolled patients. At 12 months, complete renal remission was observed in 93% of patients receiving IBCDT, 62.7% receiving MMF, and 75% receiving cyclophosphamide (p=.03 for the comparison between IBCDT and MMF or cyclophosphamide). The mean follow-up after treatment was 44.5 months, 48.6 months, and 45.3 months for IBCDT, MMF, and cyclophosphamide groups, respectively. The mean (± IQR) time to flare was 57.9 (± 32.44) months in the IBCDT, 57.3 (± 37.52) months in the MMF, and 51.67 (± 62.64) months in the cyclophosphamide groups, respectively. No severe adverse events were observed in the IBCDT group, and no severe infections were reported during the follow-up.

RItuximab 1.9 g (total dose) has also been compared to high- and low-dose cyclophosphamide (5.1 g and 3 g total dose, respectively) and MMF 2.2 g/day in a retrospective cohort study in 222 patients with biopsy-proven lupus nephritis.^77, At 6 months, renal response was highest with rituximab (90.9%) and high-dose cyclophosphamide (90.3%) compared with low-dose cyclophosphamide (73%) or MMF (72%). Rates of serious adverse events requiring hospital admission were 9.1% for rituximab, 7.7% for low-dose cyclophosphamide, 6.6% for MMF, and 4.4% for high-dose cyclophosphamide (p=.78). Infections were the most common adverse events , and rates ranged from 14.7% for MMF to 27.3% for rituximab (p=.58). However, this study provides inadequate information to assess net health benefit as it was short-term and did not measure overall clinical response using a validated assessment instrument.

Noncomparative Studies

Systematic Reviews

A systematic review by Weidenbusch et al (2013) evaluated the use of rituximab in refractory lupus nephritis and included 9 prospective comparative studies, 9 retrospective studies, and 8 case series and case reports (N=300).^78, Thirty-nine percent of patients had class IV nephritis, but 30% were unclassified. Rituximab dosing and use as an alternative or add-on therapy (to cyclophosphamide, MMF, azathioprine, or methotrexate) varied across studies; the most common dosing regimen was 375 mg/m² weekly for 4 weeks. Mean follow-up was 60 weeks (range, 12 to 120 weeks). Rituximab induced a complete, partial, or no response (using American College of Rheumatology and European League Against Rheumatism standard definitions in most studies) in 40%, 34%, and 26% of cases, respectively. Complete responses and any responses (complete or partial) were most frequent in patients with class III (focal) lupus nephritis and least frequent in patients with class V (membranous) lupus nephritis.

Case Series

Diaz-Lagares et al (2012) reported on pooled results from the UK-BIOGEAS Registry and published European studies.^79, The UK-BIOGEAS Registry was jointly developed in the U.K. and Spain to evaluate the use of rituximab in lupus nephritis. Among a total of 164 patients (99 Registry patients, 65 patients in published studies), most (57%) had class IV lupus nephritis. Rituximab was administered in combination with corticosteroids in 99% of patients and with immunosuppressive agents (cyclophosphamide or MMF) in 76% of patients. Half of the patients were refractory to standard treatment, 42% were treated for disease flare, and 8% were treated at first presentation of lupus nephritis. At 6 and 12 months, respectively, renal response rates (using standard definitions) were 27% and 30% for CR, 40% and 37% for PR, and 33% at both time points for no response, respectively. Overall (complete or partial) responses were more common in patients with class III lupus nephritis than in patients with class IV or V lupus nephritis (p=.007 and.03, respectively). Two (1%) patients developed severe infusion reactions. Twenty (12%) patients had 21 infections, most commonly respiratory infections (n=7). Six (4%) patients developed neutropenia (3 [2%] febrile neutropenia) after rituximab administration. Three (2%) patients developed posterior reversible leukoencephalopathy.

Section Summary: Lupus Nephritis

Evidence on the use of rituximab to treat refractory lupus nephritis includes an RCT that did not show improved ORRs at 1 year with rituximab add-on therapy; however, this trial might have been underpowered to show an improvement in PR. Findings from prospective and retrospective cohorts suggest that rituximab may improve renal response compared to low-dose cyclophosphamide and MMF on the short-term, but the overall clinical response was not reported. Summaries of noncomparative studies reported CR and PR rates of 30% to 40% and approximately 35%, respectively, in patients with mostly refractory disease. Adverse events occurred in approximately 20% of patients. For some patients with refractory lupus nephritis, add-on rituximab may improve health outcomes. However, because serious adverse events were observed in these patients (severe infections, febrile neutropenia, posterior reversible leukoencephalopathy), the risk-benefit profile of rituximab is improved when used after the failure of standard treatment regimens.

For individuals who have lupus nephritis, refractory to first-line therapy, who receive rituximab, the evidence includes an RCT and noncomparative studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. The single RCT did not show improved response rates at 1 year with rituximab add-on therapy. Noncomparative studies have reported complete and partial response rates of 30% to 40% and approximately 35%, respectively, in patients with mostly refractory disease. Adverse events occurred in approximately 20% of patients. The evidence is insufficient to determine the effects of the technology on health outcomes.Medically necessary by clinical input.

Population Reference No. 12

Systemic Sclerosis

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have systemic sclerosis (scleroderma), refractory to first-line therapy, is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with systemic sclerosis, refractory to first-line therapy.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to make decisions about systemic sclerosis: MMF, cyclophosphamide, and cyclosporine.

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Phumethum et al (2011) reviewed the literature on biologic therapies to improve inflammatory arthritis, disability (as assessed by the Health Assessment Questionnaire Disability Index), and skin symptoms in patients with systemic sclerosis.^80, Literature was searched in early 2010; 6 studies of rituximab (1 controlled trial^81, [reviewed next], 3 cohort studies, 3 case reports; N=39) were identified. No study reported improvements in the Health Assessment Questionnaire Disability Index scores, and resolution of joint pain was reported in a single patient. Improvements in skin score were observed in some rituximab-treated patients, but the effect size was smaller than in the control arm of the RCT. Incidences of infusion reactions and respiratory tract infections were 47% and 29%, respectively, in 1 study each. Reviewers concluded, “Adequately powered trials are needed to evaluate the efficacy, and longitudinal studies are needed to evaluate the long-term safety of these agents in SSc [systemic sclerosis].”

Similar conclusions were reached by McQueen and Solanki (2015)^82, in a review that included studies identified by Phumethum (excluding case reports) and the Jordan observational results (summarized below)-“if RTX [rituximab] were to be used today, it should either be in the context of a clinical trial or in specialized centres to ensure that outcome data are carefully collected and available to the international rheumatology research community.”

Likewise, a systematic review by Macrea et al (2023) that included 3 studies on the use of rituximab in patients with systemic sclerosis-associated interstitial lung disease, 2 of which are summarized below (Elhai et al 2019 and Daoussis et al 2010), concluded that "the quality of evidence for study outcomes was considered to be very low" and "additional research on treatment with rituximab is imperative."^83,

Nonrandomized Studies

The best evidence on using rituximab to treat systemic sclerosis comes from a cohort study by Elhai et al (2019) of 2-year follow-up data (median) on 254 patients with primarily lung involvement (58%) from the European Scleroderma Trial and Research (EUSTAR) network.^84, Rituximab-treated patients were propensity-score matched with 9575 non-rituximab-treated controls on 15 covariates, including various demographic and disease characteristics such as cutaneous form, disease duration, presence of antinuclear and/or ancentromere antibodies, follow-up duration, and immunosuppressive therapy. Rituximab regimens varied by center, but the most common dose for each infusion of was 1000 mg. Concomitant therapies included steroids, methotrexate, azathioprine, MMF, and cyclophosphamide. Mean decrease in Modified Rodnan Skin Score was -8 in 25 rituximab-treated patients and -4.9 in the control group (p<.0001). More patients treated with rituximab were able to decrease or stop steroids (25.3 vs 18.0 events per 100 person-years; odds ratio, 2.34; 95% CI, 1.56 to 3.53). But, similar numbers of patients in the rituximab and control groups had a decrease in mean FVC > 10% (6.5 vs 6.6 events per 100 person-years; odds ratio, 1.03; 95% CI, 0.55 to 1.94). Severe side effects occurred in 14% of rituximab-treated patients, which led to discontinuation in 9%. A total of 6 deaths occurred (2%), 2 of which were rated as possibly-related – respiratory insufficiencies in the context of lung carcinoma. The rituximab-treatment improvements in skin fibrosis in this study are consistent with a previous smaller and shorter-term EUSTAR study by Jordan et al (2015).[73]

Jordan et al (2015) conducted a multicenter case-control study of patients with scleroderma enrolled in the European Scleroderma Trial and Research database.^85, Sixty-three rituximab-treated patients were matched with non-rituximab-treated controls on scleroderma subtype (diffuse or limited), baseline FVC, baseline Modified Rodnan Skin Score, disease duration, follow-up duration, and immunosuppressive therapy. Fifty-six percent of patients had severe diffuse scleroderma. The most frequent dose of IV rituximab was 1000 mg weekly for 2 weeks. Immunosuppressive therapies included prednisone, methotrexate, azathioprine, MMF, and cyclophosphamide. Median follow-up was 7 months (IQR, 4 to 9 months). Mean improvement in Modified Rodnan Skin Score was 24.0 percentage points in 25 rituximab-treated patients and 7.7 percentage points in matched controls (p=.03). Treatment effect exceeded an anchor-based minimally important difference of 5.3 percentage points reported by Khanna et al (2006).^86, Mean FVC as reported by Jordan et al increased 0.4 percentage points in 9 rituximab-treated patients and decreased 7.7 percentage points in matched controls (p=.02). Mean standard deviation (SD) improvement in diffusing capacity of carbon monoxide did not differ statistically between groups (3.7 percentage points in the rituximab group vs 6.2 percentage points in the control group; p=.9). Infections occurred in 21% of rituximab-treated patients, and serum sickness/hypersensitivity reaction in 4%. The authors concluded that rituximab reduced skin and lung fibrosis in patients with systemic sclerosis compared with matched-control systemic sclerosis patients not receiving rituximab but confirmatory results would be needed in phase 3 RCTs.

Yilmaz et al (2021) retrospectively compared the effectiveness of cyclophosphamide and rituximab in patients with relapsed systemic sclerosis with interstitial lung disease.^87, Prior immunosuppressive therapies included corticosteroids, methotrexate, azathioprine, and MMF amongst others. In the cyclophosphamide group, it was observed that there was a significant increase from baseline in FVC percentage after 3, 9, 12, and 15 months of treatment (p=.003; p=.03; p=.004; and p=.002, respectively). In the rituximab group, there was no statistically significant change from baseline in FVC percentage at any time point (p>.05 at 3, 9, 12, and 15 months).

Daoussis et al (2010) assigned (by birth date) 14 patients with diffuse scleroderma to standard treatment plus 2 cycles of rituximab (375 mg/m² weekly for 4 doses) 6 months apart (n=8) or standard treatment alone (n=6).^81, Assignments were unblinded. Standard treatments included prednisone, bosentan, MMF, and cyclophosphamide. Statistically significant improvements in pulmonary function tests, but not in skin symptoms, were observed with rituximab compared with the control treatment. At 1-year follow-up, the median FVC increased 10.3 percentage points (IQR, 6.2 to 18.7) in the rituximab group and decreased 5.0 percentage points (IQR, 4.1 to 11.6; p=.002) in the control group. The median diffusing capacity of carbon monoxide increased 19.5 percentage points (IQR, 3.7 to 30.8) in the rituximab group and decreased 7.5 percentage points (IQR, 1.4 to 26.6) in the control group (p=.023). Median improvement in Modified Rodnan Skin Score was 39.3 percentage points (IQR, 27.3 to 65.0) in the rituximab group and 20.8 percentage points (IQR, 10.8 to 39.3) in the control group (p=.06).

Case Series

Several case series and case reports have described improvements in pulmonary function or decline in rates of progression in patients with interstitial lung disease^88,89,90,91, and improvements in skin symptoms^91,92, with add-on rituximab (N=25). All but 1 treatment-naive patient was refractory to standard immunosuppressive therapy. Serious adverse events occurred in 7 (28%) patients, including 2 deaths due to sepsis. Two reports described a benefit with rituximab cycles administered at 6-month intervals.^88,93, In a small retrospective study of 25 chronic connective tissue disease-associated interstitial lung disease, Chartrand et al (2015) found that rituximab was not associated with changes in percent FVC change or corticosteroid-sparing effects.^94,

Section Summary: Systemic Sclerosis

Evidence for rituximab in treatment-refractory systemic sclerosis includes observational studies and a small, unblinded trial. Add-on rituximab consistently improved skin symptoms but not pulmonary function tests; adverse events, including deaths, occurred in 21% to 47% of patients. Long-term follow-up for efficacy and safety is limited to 2 years However, second-line treatment options are limited, and the consequences of progressive disease may be life-threatening.

For individuals who have systemic sclerosis, refractory to first-line therapy, who receive rituximab, the evidence includes observational studies and a small, unblinded trial. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Add-on rituximab therapy has generally improved skin symptoms and pulmonary function tests; adverse events, including sepsis deaths, occurred in 21% to 47% of patients. Long-term follow-up for efficacy and safety is limited. The evidence is insufficient to determine the effects of the technology on health outcomes.Medically necessary by clinical input.

Population Reference No. 13

Other Autoimmune-Related Conditions and Disorders

Multiple Sclerosis

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have MS is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with MS.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat MS: interferons, glatiramer acetate, teriflunomide, fingolimod, dimethyl fumarate, alemtuzumab, mitoxantrone, and natalizumab.

Outcomes

The general outcomes of interest are symptoms, functional outcomes, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Controlled Studies: Comparison to Placebo

A Cochrane review by Filippini et al (2022) included 5 RCTs (Cheshmavar 2021 [summarized below]; Etemadifar 2019; Hauser 2008 [summarized below]; Hawker 2009 [summarized below]; and Komori 2016) and several observational studies.^95, Etemadifar et al (2019) compared rituximab to cyclophosphamide in patients with secondary progressive multiple sclerosis (SPMS) and Komori et al (2016) compared intrathecal and IV administration of rituximab for patients with SPMS; neither study evaluated relevant comparators and is therefore not reviewed further. The heterogeneity of study populations did not allow for pooling of data for the majority of outcomes evaluated in this Cochrane review and authors made the following conclusions: "For preventing relapses in relapsing MS, rituximab as 'first choice' and as 'switching' may compare favourably with a wide range of approved DMTs [disease-modifying treatments]. A protective effect of rituximab against disability worsening is uncertain. There is limited information to determine the effect of rituximab for progressive MS."

A Cochrane review by He et al (2013)^96, identified 1 RCT evaluating use of rituximab in relapsing-remitting multiple sclerosis (RRMS).^97, The phase 2, double-blind, placebo-controlled Helping to Evaluate Rituxan in Relapsing-Remitting Multiple Sclerosis (HERMES) trial, reported by Hauser et al (2008), enrolled 104 adults (age range, 18 to 55 years) with RRMS, at least 1 relapse during the preceding year, and an Expanded Disability Status Scale (EDSS) score of 0 to 5.0 (median, 2.5, indicating mild disability) at trial entry.^97, Patients were randomized 2:1 to 2 doses of IV rituximab 1000 mg 2 weeks apart or placebo. The primary efficacy end point was the total number of gadolinium-enhancing lesions on serial T1-weighted magnetic resonance imaging (MRI) brain scans (markers of acute inflammatory changes) at weeks 12, 16, 20, and 24. Planned follow-up was 48 weeks; 92% of patients completed 24 weeks of follow-up while 76% completed 48 weeks. Withdrawals were greater in the placebo group (40% vs 16% in the rituximab group). Patients who withdrew without having a relapse were considered to be relapse-free. The primary end point showed a statistically significant reduction in the rituximab group (p<.001) as did the number of new gadolinium-enhancing lesions over the same interval (p<.001). Fewer patients in the rituximab group than in the placebo group relapsed within 24 weeks (34% vs 15% placebo; p=.02) and at 48 weeks (20% vs 40% placebo; p=.04). Annualized relapse rates (ARRs) differed statistically at week 24 (0.4 [90% CI, 0.2 to 0.6] for rituximab vs 0.8 [90% CI, 0.5 to 1.3] for placebo), but not at week 48 (0.4 [90% CI, 0.2 to 0.6] for rituximab vs 0.7 [90% CI, 0.5 to 1.1] for placebo). Disability progression was not assessed.

More patients in the rituximab group (78%) than in the placebo group (40%) had adverse events within 24 hours after the first infusion (eg, chills, headache, nausea, pyrexia). Most (93%) were mild or moderate. The most common infection-associated adverse events (>10% in the rituximab group) were nasopharyngitis (20% vs 17% placebo), upper respiratory tract infections (19% vs 17%), urinary tract infections (15% vs 9%), and sinusitis (13% vs 9%). Trial limitations included a high and disproportionate number of withdrawals, lack of sensitivity analyses, and short duration of follow-up. Lack of a disability progression outcome (eg, change in EDSS score) would be considered a shortcoming in light of evidence that MRI changes and relapse rates are poor predictors of long-term disability.^98,99,

Castillo-Trivino et al (2013) reviewed studies of rituximab for relapsing and progressive forms of MS.^100, They identified 4 studies, including the HERMES trial in patients with RRMS (previously described^97,), a second RCT which was conducted in patients with primary-progressive MS (PPMS),^101, and 2 small cohort studies in RRMS (n=56 patients).^102,103, The RCT, known as the Study to Evaluate the Safety and Efficacy of Rituximab in Adults with Primary Progressive Multiple Sclerosis (OLYMPUS) trial, was double-blind, placebo-controlled and enrolled 439 adults (age range, 18 to 65 years) with PPMS for at least 1 year who had EDSS scores ranging from 2.0 to 6.5 (median, 5.0 [moderate-to-severe disability with impairment of daily activities]). Patients with a history of relapse were excluded. Patients were randomized 2:1 to 2 doses of IV rituximab 1000 mg 2 days apart every 6 months for 4 courses (8 doses). The primary end point was time to confirmed disease progression, defined as an increase in EDSS score of 1.0 point or more (≥0.5 points if baseline EDSS scores were >5.5 points) sustained for at least 12 weeks. Planned follow-up was 96 weeks for efficacy and 122 weeks for safety. Eighty-three percent of patients completed 96 weeks, and 77% completed 122 weeks of follow-up. Time to disease progression did not differ statistically between the rituximab and placebo groups (HR, 0.77; 95% CI, 0.55 to 1.09; p=.144). At 96 weeks, the increase in T2 lesion volume on MRI brain scan (a marker of past disease activity) was lower in the rituximab group than in the placebo group (p<.001). The incidence of grade 3 or higher adverse events was 40% in the rituximab group and 38% in the placebo group. Serious infections occurred in 5% and in less than 1% of the rituximab and placebo groups, respectively. Incidences of infusion-associated adverse events within 24 hours of the first dose were 67% and 23% in the rituximab and placebo groups, respectively. Most incidences were mild-to-moderate.

Controlled Studies: Comparison to Natalizumab

Scotti et al (2018) compared rituximab to natalizumab in 28 pairs of propensity-matched patients with RRMS using data from the MS registry of the Neurocenter of Southern Switzerland.^104, Rituximab was generally infused at 1000 mg on days 1 and 15, followed by a maintenance regimen of infusions at 9 months and at every 6 months thereafter for a median of 1.5 years (range, 0.5 to 8.3 years). The natalizumab regimen was not described. Time to "evidence of disease activity" was similar for rituximab compared with natalizumab (HR, 1.64; 95% CI, 0.46 ± 5.85, p=.44). A limitation of this study is that it did not report a comparison of rituximab to natalizumab on adverse effects.

Controlled Studies: Comparison to Glatiramer Acetate

Cheshmavar et al (2020) compared rituximab to glatiramer acetate in 84 Iranian patients with SPMS.^105, In the rituximab group (n=37), patients received rituximab 1000 mg IV once to start and then every 6 months; in the glatiramer acetate group (n=36), patients received 40 mg of glatiramer acetate 3 times/week subcutaneously. After 12 months, the mean (SD) EDSS score increased from 3.05 (1.01) to 4.14 (0.91) in the rituximab group (p<.001) and from 3.22 (1.20) to 4.60 (0.67) in the glatiramer acetate group (p<.001). No statistically significant difference was observed in EDSS between the 2 treatment groups (p=.071).

Controlled Studies: Comparison to Dimethyl Fumarate

Svenningsson et al (2022) compared ritiximab to dimethly fumarate in 200 Swedish patients with RRMS or clinically isolated syndrome in the RIFUND-MS trial.^106, Patients were randomized to rituximab 1000 mg followed by 500 mg every 6 months (n=100) or oral dimethyl fumarate 240 mg twice daily (n=100). After 24 months of follow-up, 3 (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial (defined as subacute onset of new or worsening neurological symptoms compatible with MS with a duration of more than 24 hours and preceded by at least 30 days of clinical stability), corresponding to a risk ratio of 0.19 (95% CI, 0.06 to 0.62; p=.0060).

Uncontrolled Studies: Systematic Reviews of Case Series

A 2019 systematic review by Hu et al evaluated 15 mostly case series studies that included a total of 946 patients with RRMS treated with rituximab.^107, It included all the most recently published case series studies, such as by Alcala et al (2018),^108, Yamout et al (2018),^109, and Scotti et al (2018).^104, Following rituximab, mean ARRs decreased by 0.80 (95% CI, 0.45 to 1.15) and the mean EDSS score decreased by 0.46 (95% CI, 0.05 to 0.87). However, between-study heterogeneity was high (I²: 61% to 69%), suggesting instability in the results. Although there were no serious adverse events, 29.6% of patients taking rituximab had at least 1 mild-to-moderate adverse event.

The best case series evidence comes from the study by Salzer et al (2016), which, to date has reported on the largest number of patients- 822 rituximab-treated MS patients in a Swedish registry.^110, Of these, 557 patients had RRMS, 198 had SPMS, and 67 had PPMS. About 80% of patients had previously used other disease-modulated drugs; for about 20%, rituximab was their first disease-modulated drug. The mean follow-up was 23 months, and the mean duration of treatment with rituximab was 22 months. Patients were generally treated with a single IV infusion of rituximab 500 or 1000 mg every 6 to 12 months; in some cases, patients were given a higher dose after initial treatment (ie, 1000 to 2000 mg, divided into 2 infusions). A total of 59 MS relapses were identified in the database, with ARRs of 0.044 for RRMS, 0.038 for SPMS, and 0.015 for PPMS. The median EDSS score remained the same in patients with RRMS (p=.42), increased 0.5 points in patients with SPMS (p=.20), and increased 1.0 points in patients with PPMS (p=.25). At baseline, 26.2% of patients had contrast-enhancing lesions on MRI, and 4.6% of patients had contrast-enhancing lesions after treatment initiation. Contrast-enhanced lesions were most common in the first 6 months of treatment. Infusion reactions occurred in 7.8% of infusions. Of these, 159 adverse events were grade 1, 72 were grade 2, and 3 were grade 3. This study lacked a placebo or comparison group.

Section Summary: Multiple Sclerosis

Four RCTs have evaluated rituximab in patients with MS. One RCT in patients with RRMS showed improvements using MRI and in clinical outcomes at 24-week follow-up. The second RCT, also in patients with RRMS, demonstrated lower rates of relapse with rituximab at 24 months. The third RCT was conducted in patients with PPMS, and demonstrated no effect of rituximab on disease progression. A fourth smaller RCT (n=84) found that rituximab did not affect EDSS in patients with SPMS. A large registry study found a relatively low rate of adverse events and relapses and little change in disability scores; this study lacked a comparison group. Overall, methodologic limitations restrict the conclusions that can be based on available data.

Other Autoimmune-Related Conditions and Disorders

For individuals who have multiple sclerosis who receive rituximab, the evidence includes 2 RCTs, a registry study, and case series. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. One RCT in patients with relapsing-remitting multiple sclerosis showed reductions in the number of lesions detected by gadolinium-enhanced magnetic resonance imaging and at 24 and 48 weeks, and in clinical outcomes at 24-week follow-up. However, methodologic limitations restrict the conclusions drawn from these data. One well-designed RCT in patients with primary-progressive multiple sclerosis demonstrated no effect of rituximab on disease progression. A large registry study found that rituximab was associated with a relatively low rate of adverse events and relapses and little change in disability scores; this study lacked a comparison group. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 14

Neuromyelitis Optica

Clinical Context and Therapy Purpose

The purpose of rituximab in individuals who have neuromyelitis optica (NMO), refractory to first-line therapy, is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with NMO refractory to first-line therapy.

NMO is a rare autoimmune inflammatory disorder that selectively affects the spinal cord and optic nerves; clinical presentation is characterized by severe optic neuritis that can lead to blindness and transverse myelitis that can lead to paralysis. The clinical course typically is more severe than in MS, and often fatal,^111, and treatments may differ.^112,113, An autoantibody to aquaporin-4 (AQP4), a water channel found in high concentrations at the blood-brain barrier, is included in NMO diagnostic criteria.^114,115

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat NMO: azathioprine, MMF, methotrexate, mitoxantrone, and glucocorticoids.

Immunosuppression with azathioprine or MMF is common for relapse prevention. Rituximab is being studied for relapse prevention in NMO.

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity.

Curative treatment does not currently exist; treatment goals are relapse remission, relapse prevention, and symptom relief.^112,

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Rituximab treatment for patients with NMO has been evaluated in a systematic review and meta-analysis published by Gao et al (2019) of 26 mostly small retrospective uncontrolled studies and a meta-analysis by Magdalena et al (2022) consisting of 11 more recently published studies (Table 7).^117,

In Gao et al, review eligibility criteria was broad, allowing for inclusion of studies of all-comers with NMO. The 2 main variables evaluated were the ARR and/or EDSS. The meta-analysis found that rituximab reduces the relapse frequency and improves disability in most patients (Table 8). Meta-analysis findings were most heavily weighted (28%) by the largest (N=100) and longest-term (57 months of follow-up) study by Kim et al (2015), which reported an EDSS weighted mean difference of -1.00 (95% CI, -1.37 to -0.63).^118, Heterogeneity was moderate in the EDSS analysis, but a meta-regression that explored potential causes found no significant correlation with age of onset, duration of disease, follow-up time, dose of infusion and AQP4-IgG serostatus. Among patients with adverse reactions (Table 8), they were severe in 12 patients (2%); with the most common event being severe pneumonia (0.87%). Five patients died (0.87%) from causes including pneumonia (N=2), urogenital infection and thrombosis (N=1), bone marrow transplantation (N=1), and cardiac and respiratory failure due to very extensive myelitis reaching the medulla oblongata (N=1). It was not reported whether the deaths were likely to be treatment-related. Findings from this review by Gao et al (2019) are consistent with a smaller review from 2016 by Damato et al (N=438),^119, which also reported a significant reduction in the EDSS score after treatment (mean reduction, 0.64; 95% CI, -1.18 to -0.10).

In Magdalena et al (2022), the efficacy and safety of rituximab were compared to azathioprine and MMF.^120, The analysis included 1086 patients. Fewer patients treated with rituximab versus azathioprine experienced at least 1 relapse (odds ratio, 0.28; 95% CI, 0.13 to 0.58); the difference between rituximab and MMF did not reach statistical significance (odds ratio, 0.67; 95% CI, 0.38 to 1.16). Furthermore, the hazard rate for relapse was significantly reduced with rituximab compared with azathioprine (0.51; 95% CI, 0.35 to 0.75) and MMF (0.62; 95% CI, 0.41 to 0.94). In general, patients in the rituximab group experienced fewer side effects compared with other agents.

Table 7. Systematic Reviews Assessing Rituximab for Neuromyelitis Optica

MMF: mycophenolate mofetil; NMO: neuromyelitis optica; NR: not reported; RCT: randomized controlled trial.

Table 8. Results of Systematic Reviews Assessing Rituximab for Neuromyelitis Optica

CI: confidence interval; EDSS: Expanded Disability Status Scale; MMF: mycophenolate mofetil; NA: not applicable; NR: not reported; OR: odds ratio.

Controlled Studies: Neuromyelitis Optica

Compared to other available treatments, rituximab has favorable effects based on an RCT.^121, Nikoo et al (2017) randomized 40 patients with a relapsing-remitting course of NMO spectrum disorder to IV rituximab 1 g, followed by a second dose 2 weeks later, and then every 6 months and 46 to oral azathioprine 50 mg/day, which was increased to 2 to 3 mg/kg/day (with oral prednisolone as adjunctive therapy). At 6 years, mean disease duration was similar in both groups. But, mean EDSS score (3.33 vs 2.38; p=.014) and mean ARR (1.30 vs 1.02; p=.023) were significantly greater in the rituximab group, indicating more active disease at baseline. Follow-up was 12 months. Patients in the rituximab group had significantly better outcomes in terms of proportion who became relapse-free (78.8% vs 54.3%; p=.033) and EDSS score reduction (-0.98 vs -0.49; p<.001). There were no between-groups differences in proportions of patients with adverse events.

Uncontrolled Studies: Neuromyelitis Optica

Rituximab had similar effects in an earlier nonrandomized study by Radaelli et al (2016) that was not included in the systematic reviews by Gao et al or Magdalena et al for unclear reasons. Radaelli et al (2016) reported on the results of a prospective observational study of 21 patients with NMO or NMO spectrum of disorders who underwent at least 1 cycle of rituximab and were followed for at least 2 years.^122, At a mean follow-up of 48 months, the ARR decreased from 2.0 to 0.16 (p<.01) and EDSS scores decreased from 5.5 to 4.0 (p<.013). Twelve (57%) patients remained disease free during the follow-up period.

Section Summary: Neuromyelitis Optica

The evidence base for use of rituximab to prevent relapse in NMO is comprised of an RCT, an uncontrolled observational study, and a few systematic reviews. A 2019 systematic review of 26 mostly uncontrolled studies found significant reductions in the relapse rate and EDSS score after beginning treatment with rituximab; similar trends with respect to relapse rates were found in a 2022 systematic review of 11 more recently published studies. An RCT and an observational cohort study have suggested rituximab is as, or possibly more, effective than other agents in preventing relapse. Based on adverse events reported, the safety of rituximab in NMO appeared comparable to the safety in other patient populations.

For individuals who have neuromyelitis optica (prevention relapse), refractory to first-line therapy, who receive rituximab, the evidence includes uncontrolled observational studies and systematic reviews. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. A 2016 systematic review of 46 uncontrolled studies found significant reductions in the relapse rate and Expanded Disability Status Scale scores after beginning treatment with rituximab. Based on adverse events reported, the safety of rituximab in neuromyelitis optica appeared comparable to the safety in other patient populations. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 15

Myasthenia Gravis

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have refractory and nonrefractory myasthenia gravis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with refractory and nonrefractory myasthenia gravis.

Myasthenia gravis is a chronic autoimmune disorder that affects the neuromuscular junction resulting in varying degrees of muscular weakness. The normal communication of nerve impulses involves nerve endings releasing acetylcholine, a neurotransmitter at the neuromuscular junction, which normally binds with acetylcholine receptors that activate and result in a muscle contraction. For individuals with myasthenia gravis, this cholinergic communication is disrupted by antibodies.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat myasthenia gravis: immunotherapies.

Outcomes

The general outcomes of interest are change in disease status, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Tandan et al (2017) published a systematic review of studies on rituximab treatment of myasthenia gravis.^123, Forty-seven articles were identified, of which 38 were case reports. Nineteen studies were case series with at least 2 patients; there were no controlled studies. Data on response to rituximab were available for 168 patients. Patients received a mean of 6.8 infusions of rituximab. The mean number of relapses after rituximab in 100 patients was 0.4. The mean quantitative myasthenia gravis score was 16.8 before rituximab treatment and 8.7 after treatment. Many of the selected publications did not report adverse events. With a median follow-up of 17 months, adverse events were identified in 15 (14%) of 105 patients who had available data.

Zhao et al (2022) published a systematic review of studies on rituximab treatment of refractory myasthenia gravis.^124, A total of 24 studies involving 417 patients were included in a meta-analysis. The dose regimen of rituximab therapy varied amongst studies, but the majority of patients received routine induction doses (375 mg/m²) weekly for 4 consecutive weeks or 1 gram twice (2 weeks apart). The primary outcomes were the proportion of patients achieving minimal manifestation status (MMS) or better and quantitative myasthenia gravis (QMG) score change from baseline. Results demonstrated that 64% (95% CI, 49% to 77%) of patients achieved MMS or better, and the estimated reduction in QMG score was 1.55 (95% CI, 0.88 to 2.22). Approximately 20% of patients experienced adverse events, most of which were mild to moderate.

Comparative Nonrandomized Studies

A study by Hehir et al (2017), which was not included in the Tandan systematic review (described above), was a prospective blinded nonrandomized comparative study in patients with anti-muscle-specific kinase antibody (MuSK) myasthenia gravis.^125, Twenty-four patients were treated with rituximab and 31 received standard care without rituximab treatment. The primary outcome was the Myasthenia Gravis Status and Treatment Intensity (MGSTI) score. MGSTI scores range from level 0 (complete stable remission; no immunotherapy) to level 6 (symptomatic and requiring hospitalization). The authors defined a beneficial clinical outcome as an MGSTI score of level 2 or better. Level 2 was defined as having minimal manifestations/pharmacologic remissions with a low dose of dual therapy. A secondary outcome was an MGSTI score of level 1 or better (minimal manifestations/pharmacologic remissions with a low dose of oral monotherapy). Fifty-eight percent of patients in the rituximab arm had a successful clinical outcome (ie, MGSTI score of level 2 or higher) compared with 16% of controls; the difference between groups was statistically significant (p=.002). The median time to achieve an MGSTI score of level 2 or better for patients in the rituximab arm was 54 months. In addition, 54% of patients in the rituximab arm achieved the more stringent outcome of MGSTI score of level 1 or better at the final evaluation compared with 26% in the control arm (p=.003).

Brauner et al (2020) published a retrospective cohort study subsequent to the systematic review by Tandan et al (2017).^126, Rituximab was compared to conventional immunosuppressant therapy in a community sample of 50 patients with new-onset myasthenia gravis from Karolinska University Hospital in Stockholm. The primary outcome was time to remission. Median time to remission was significantly shorter with rituximab therapy (7 vs 11 months: HR, 2.97; 95% CI, 1.43 to 6.18). Discontinuations due to adverse events were significantly lower with rituximab (3% vs 46%; p<.001).

Nelke et al (2022) published a retrospective study comparing rituximab (n=57) and eculizumab (n=20) in patients with refractory anti-acetylcholine receptor antibody (anti-AChR-ab)-mediated myasthenia gravis.^127, Change in the QMG score was defined as the primary outcome. After 12 months of treatment, eculizumab-treated patients demonstrated a significantly greater benefit from treatment as compared with rituximab patients (QMG for rituximab was 11.2 [SD 7.3] vs 8.4 [SD 6.1] for eculizumab; p=.021). Similar trends were seen at 24 months (QMG for rituximab was 11.2 [SD 6.4] vs 9.6 [SD 8.5] for eculizumab; p<.001).

Section Summary: Myasthenia Gravis

Evidence for rituximab in treatment-refractory myasthenia gravis is comprised of systematic reviews of uncontrolled studies and small comparative observational studies. Two systematic reviews found a significant reduction in a myasthenia gravis symptom score after beginning rituximab treatment and a relatively low rate of adverse events. However, adverse event reports were not available for all patients. A prospective blinded nonrandomized comparative study found significantly better clinical outcomes in patients with anti-MuSK myasthenia gravis treated using rituximab compared with those who did not receive rituximab. A retrospective comparative study found significantly better clinical outcomes for rituximab versus conventional immunosuppressant therapy in patients with new-onset myasthenia gravis. Lastly, a retrospective study in patients with refractory myasthenia gravis demonstrated improved outcomes with eculizumab over rituximab. Currently, no randomized trials have assessed use of rituximab for this indication.

For individuals who have refractory and nonrefractory myasthenia gravis who receive rituximab, the evidence includes observational studies and a systematic review. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. A systematic review found a significant reduction in a myasthenia gravis symptom score after beginning rituximab treatment and a relatively low rate of adverse events. A limitation of the studies was that adverse event reports were not available for all patients. An uncontrolled observational study found significantly better clinical outcomes in patients with anti-MuSK myasthenia who were treated with rituximab compared with those who did not receive rituximab. However, few controlled studies and no RCTs are available. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 16

Idiopathic Membranous Nephropathy

Clinical Context and Therapy Purpose

The purpose of rituximab in individuals who have idiopathic membranous nephropathy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with idiopathic membranous nephropathy.

Membranous nephropathy involves the abnormal thickening of the glomerular basement membrane and is a leading cause of nephrotic syndrome. Most membranous nephropathy cases occur from unknown causes, and secondary membranous nephropathy may result from other predisposing diseases, infection, or medical therapy.

Interventions

The therapy being considered is rituximab. Rituximab has been evaluated in patients with idiopathic membranous nephropathy who have failed previous treatment with other immunosuppressive regimens or those with a moderate risk of progression who have not previously received immunosuppressive therapy.

Comparators

The following therapies are currently being used to treat idiopathic membranous nephropathy: immunomodulators.

In many cases, conservative treatment with renin-angiotensin system blockade is provided. Immunomodulatory therapies (eg, alkylating agents, calcineurin inhibitors, corticosteroids) are used to treat individuals who are unresponsive to conservative therapy.

Outcomes

The general outcomes of interest are change in disease status, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

For the comparison to supportive therapy, in an unblinded trial by Dahan et al (2017), 75 patients with persistent proteinuria (>3.5 g/d) were randomized to rituximab (n=37) or no rituximab (n=38).^128, At 6 months, there was no significant difference in the primary composite end point of complete (<500 mg/d) or partial (<3.5 g/d with ≥50% reduction vs baseline) remission of proteinuria between patients treated with (35%) or without rituximab (21%). The lack of benefit was attributed in part to the short duration of the trial. In the posttrial observational phase that followed patients for an additional 12 months, the rate of complete or partial remission was higher among patients treated with rituximab (65% vs 34%). In addition, patients treated with rituximab had lower proteinuria (2195 mg/g vs 4701 mg/g) and higher serum albumin (3.2 g/dL vs 2.7 g/dL) levels.

Three open-label, randomized trials compared rituximab to other immunosuppressive therapies (see Tables 9 and 10 for key characteristics and results). The MENTOR trial (Membranous Nephropathy Trial of Rituxumab) evaluated whether rituximab was noninferior to cyclosporine in patients with primary membranous nephropathy on the primary outcome of 24-month complete or partial remission.^129, The STARMEN (Sequential Treatment with Tacrolimus and Rituximab Versus Alternating Corticosteroids and Cyclophosphamide in PMN) trial compared a cyclic alternating treatment of corticosteroids and cyclophosphamide with a sequential treatment of tacrolimus and rituximab in the induction and maintenance of nephrotic syndrome remission for up to 24 months.^130, The RI-CYCLO (Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy) trial compared a cyclic alternating treatment of corticosteroids and cyclophosphamide to rituximab with a primary outcome of complete remission of proteinuria at 12 months.^131, Limitations related to each study's relevancy, design, and conduct are presented in Tables 11 and 12.

Table 9. Summary of Key Characteristics of RCTs Assessing Rituximab for Idiopathic Membranous Nephropathy

eGFR: estimated glomerular filtration rate measured in ml/min/1.73 m2; IV=intravenous; MENTOR: Membranous Nephropathy Trial of Rituxumab; NR: not reported; RCT: randomized controlled trial; RI-CYCLO: Rituximab versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy; STARMEN: Sequential Treatment with Tacrolimus and Rituximab Versus Alternating Corticosteroids and Cyclophosphamide in PMN.

Table 10. Summary of Results of RCTs Assessing Rituximab for Idiopathic Membranous Nephropathy

CI: confidence interval; KDQOL-SF: modified Kidney Disease Quality of Life Short Form; NR: not reported; RCT: randomized controlled trial; RR: relative risk; SD: standard deviation. a The primary outcome in Fernández-Juárez (2021) and Fervenza (2019) was complete or partial remission at 24 months. The primary outcome in Scolari (2021) was complete remission of proteinuria at 12 months.  b Subset of patients in complete or partial remissionc Mean difference

Table 11. Study Relevance Limitations of RCTs Assessing Rituximab for Idiopathic Membranous Nephropathy

RCT: randomized controlled trial.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 12. Study Design and Conduct Limitations of RCTs Assessing Rituximab for Idiopathic Membranous Nephropathy

RCT: randomized controlled trial.The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Observational Studies

Findings from the RCTs above are consistent with those of other observational studies, which have demonstrated a maximal reduction in proteinuria at 18 to 24 months after treatment with rituximab.^132,133, A multicentric prospective study by Moroni et al (2017) evaluated 34 patients with idiopathic membranous nephropathy and nephrotic syndrome who received rituximab once (n=18) or twice (n=16).^134, Rituximab was the first-line therapy for 19 (56%) and the second-line for 15 (44%) patients. At 12 months, 5 (14.7%) patients achieved CR, 10 (29.4%) PR, and 19 (55.8%) no response. At 24 months, 2 nonresponders achieved PR and 2 responders relapsed. Authors concluded that low-dose rituximab resulted in remission in less than 50% of patients with idiopathic membranous nephropathy. Higher rituximab doses and longer treatment regimens were suggested to induce and maintain a response. Additionally, large RCTs would be needed to establish the optimal schedule, dose, and long-term safety and efficacy.

Section Summary: Idiopathic Membranous Nephropathy

Evidence for rituximab in the treatment of idiopathic membranous nephropathy includes 4 RCTs and multiple observational studies. Rituximab may have moderate benefit in patients with idiopathic membranous nephropathy who have failed previous treatment with other immunosuppressive regimens or those with a moderate risk of progression who have not previously received immunosuppressive therapy. For the comparison of rituximab to other immunosuppressive therapies, 3 open-label, randomized trials are available. The MENTOR trial found that rituximab was both noninferior and superior to cyclosporine at 24-months on the primary outcome of 24-month complete or partial remission. The 2 treatments were comparable with regard to quality of life and adverse events measures. The STARMEN trial found that sequential tacrolimus-rituximab therapy was inferior to a cyclical corticosteroid-cyclophosphamide regimen for the induction of remission at 24 months in patients with primary membranous nephropathy at a high risk of progression; the incidence of adverse events was comparable between treatments. Lastly, the RI-CYCLO trial found no signal of more benefit or less harm with rituximab versus a cyclic corticosteroid-cyclophosphamide regimen in patients with membranous nephropathy.

For individuals who have idiopathic membranous nephropathy who receive rituximab, the evidence includes an RCT and observational studies. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. Rituximab may have moderate benefit in patients with idiopathic membranous nephropathy who have failed previous treatment with other immunosuppressive regimens or those with a moderate risk of progression who have not previously received immunosuppressive therapy. However, an RCT with longer follow-up is needed to confirm the benefits of rituximab and to determine the optimal schedule, dose, and long-term safety and efficacy. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 17

Minimal Change Disease

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have minimal change disease is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant populations of interest are adults and children with minimal change disease.

Interventions

The therapy being considered is rituximab. Rituximab has been used to treat various glomerulopathies, including those associated with minimal change disease in adults and children.

Comparators

The following therapies are currently being used to treat minimal change disease: immunosuppressants.

Outcomes

The general outcomes of interest are change in disease status, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Adults

Systematic Review

A systematic review of 7 prospective cohort studies, 10 retrospective cohort studies, and 4 case series evaluated rituximab in adults with frequent-relapsing or steroid-dependent nephrotic syndrome, including minimal change disease (N=382).^135, Studies of patients with steroid-resistant nephrotic syndrome were excluded, as rituximab does not appear to be effective in these patients. The median follow-up duration was 12 to 43 months. Studies were performed in the United States (2 studies), Europe (13 studies), and Asia (6 studies). Most studies reported on rituximab used in biopsy-proven minimal change disease (14 studies), followed by use in comorbid minimal change disease and focal and segmental glomerulosclerosis (6 studies) and in focal and segmental glomerulosclerosis (1 study). The primary outcomes were the rates of complete remission and relapse. The pooled rate of complete remission after rituximab treatment was 84.2% (95% CI, 67.7% to 96.3%; 13 studies); a subgroup analysis by histologic diagnosis found that minimal change disease had a much higher complete remission rate compared with focal and segmental glomerulosclerosis (91.6% vs 43%). The pooled rate of relapse after rituximab treatment was 27.4% (95% CI, 20.7% to 34.5%; 20 studies); a subgroup analysis by histologic diagnosis found similar results in patients with minimal change disease (27.6%) and focal and segmental glomerulosclerosis (29.8%). Rituximab was well tolerated with no new safety signals.

Observational Study

Ma et al (2023) retrospectively investigated the use of rituximab in patients with refractory nephrotic syndrome, including patients who were steroid-dependent, steroid-resistant, steroid-intolerant, and frequently relapsing.^136, The enrolled patients were divided into 2 groups based on their pathological patterns: 20 patients had podocytopathy (including minimal change disease [n=15] and focal segmental glomerulosclerosis [n=5]), and 26 patients had membranous nephropathy. In the podocytopathy group, 19 out of 20 patients (95.0%) achieved remission at 6 and 12 months (17 patients achieved complete remission and 2 patients achieved partial remission); the median time to first complete remission in this group was 1 month. Relapse occurred in 2 patients in the podocytopathy group; they received additional steroid treatment and subsequently achieved complete remission.

Heybeli et al (2021) retrospectively investigated second-line treatments in 76 adults with frequently-relapsing/steroid-dependent minimal change disease.^137, The following treatments were investigated: rituximab (n=13), MMF (n=12), calcineurin inhibitors (n=26), and cyclophosphamide (n=16). The median time to relapse after the second-line treatment was 66 months with rituximab versus 28 months with non-rituximab therapies (p=.170).

Children

Steroid resistant nephrotic syndrome

Systematic Review

Jellouli et al (2018) published a systematic review^138, of primarily small retrospective case series (N=226) assessing efficacy and safety of rituximab in children with steroid-resistant nephrotic syndrome. After a mean of 3.1 rituximab administrations, 89 children achieved remission (46.4%). However, sustained remission varied widely across studies, from 18% to 93.7%. Serious adverse events were observed in 5 children (2.2%), including 1 case each of agranulocytosis concomitant with upper respiratory infection, severe pneumonia from the influenza H1N1 virus, rapid progression of renal failure, and pancolitis and 3 cases of cardiomyopathy.

Steroid dependent nephrotic syndrome

Randomized Controlled Trials

Rituximab has been evaluated in 3 RCTs in children with steroid-dependent nephrotic syndrome. In the first trial, Ravani et al (2015) compared prednisone alone with prednisone plus a single dose of rituximab.^139, At 3-month follow-up, proteinuria was 42% lower in the prednisone plus rituximab group. In addition, all but 1 patient in the prednisone alone group relapsed within 6 months whereas the median time to relapse in the prednisone plus rituximab group was 18 months. However, because of the risk of severe and potentially life-threatening complications and because the long-term efficacy and safety of rituximab in this patient group remain unclear, rituximab use should be restricted to children with frequent relapses and serious adverse events from their medications.

In the second trial, Iijima et al (2014) reported on 48 children with frequently relapsing or with steroid-dependent (mean accumulated prednisolone dose, 18 to 19 mg/m²) nephrotic syndrome who were randomized to rituximab (375 mg/m²) or placebo for 4 weeks.^140, At 1-year follow-up, the primary end point of median relapse-free duration was longer with rituximab (267 days) than with placebo (101 days). The relapse rate was lower in the rituximab group (1.54 vs 4.17 relapses per person-year), as was the daily prednisolone dose (8.4 mg/m²vs 21 mg/m²). However, the effects were not maintained and, by the end of year 1, 17 (71%) of 24 patients who received rituximab relapsed (vs 23 [96%] of 24 who received placebo), and, by 19 months, all patients had relapsed.

A third trial was published in 2018 by Boumediene et al (NEPHRUTIX trial, NCT01268033)^141, that reported on 23 children who were highly steroid/calcineurin inhibitor and/or MMF-dependent and in remission for frequently relapsing nephrotic syndrome. At 6 months following randomization to rituximab or placebo (2 infusions at 1 week-interval) and discontinuation/tapering of MMF/calcineurin inhibitor, 90% of patients in the rituximab group maintained remission, while 100% of patients in the placebo group relapsed. Although promising, as the trial by Iijima et al (2014) demonstrated, demonstration of the durability of effects in larger and longer-term studies are still needed.

Case Series

A subsequent case series study by Hoseini et al (2018)^142, in 43 children with steroid- and cyclosporine-resistant or steroid- and cyclosporine-dependent noncongenital nephrotic syndrome, provided 2-year follow-up, data which is longer than in the RCTs. Although relapse rate was not reported, side effects were monitored. After 375 mg/m2/week, for 4 weeks, side effects reported included leukopenia in 2, alopecia in 1, and eosinophilia in 1.

Section Summary: Minimal Change Disease

Evidence for rituximab in the treatment of minimal change disease includes a systematic review and 2 observational studies in adults, and 3 RCTs and a case series with 2 years of follow-up in children. Rituximab may provide benefit in children with nephrotic syndrome associated with minimal change disease. However, because of the risk of severe and potentially life-threatening complications, rituximab use should be restricted to children with frequent relapses and serious adverse events from their medications, because the long-term efficacy and safety of rituximab in this group of patients remain unclear. Observational studies have suggested that rituximab may be an effective therapy in adults with frequently relapsing or glucocorticoid-dependent minimal change disease.

For individuals who have minimal change in disease (adults and children) who receive rituximab, the evidence includes observational studies in adults and 2 RCTs and observational studies in children. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. Rituximab benefit children with nephrotic syndrome associated with minimal change disease. However, because of the risk of severe and potentially life-threatening complications, rituximab use should be restricted to children with frequent relapses and serious adverse events from their medications (because the long-term efficacy and safety of rituximab in this group of patients remain unclear). The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 18

Transplant-Related Conditions and Disorders

Glucocorticoid-Refractory Chronic Graft-Versus-Host Disease

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have glucocorticoid-refractory chronic graft-versus-host disease (GVHD) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with glucocorticoid-refractory chronic GVHD.

Chronic GVHD, historically defined as occurring more than 100 days after transplant,^143, is the primary cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation.^144,

Interventions

The therapy being considered is rituximab, primarily for steroid-refractory chronic GVHD.

Comparators

The following therapies are currently being used to treat glucocorticoid-refractory chronic GVHD: MMF, cyclophosphamide, and cyclosporine.

Outcomes

The general outcomes of interest are change in disease status, quality of life, and treatment-related morbidity.

Approximately half of the patients respond to first-line treatment (systemic corticosteroid with or without a calcineurin inhibitor), but treatment options for steroid-refractory disease are limited, and the prognosis is poor.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Kharfan-Dabaja et al (2009) published a systematic review and meta-analysis of 7 cohort studies (N=111) assessing rituximab in chronic GVHD.^145, Three studies were prospective, and 4 were retrospective. Pooled ORR was 66% (95% CI, 57% to 74%). Indication-specific response rates were 13% to 100% for skin, 0% to 83% for oral mucosa, 0% to 66% for liver, and 0% to 38% for lung. Common adverse events were infusion reactions or infectious complications.

Nonrandomized Studies

Two studies examined prophylactic rituximab for the prevention of chronic GVHD after allogeneic hematopoietic cell transplantation. Cutler et al (2013) administered rituximab 375 mg/m² at 100 days and 3, 6, 9, and 12 months after nonmyeloablative or myeloablative transplantation of HLA-matched related (48%) or unrelated (58%) donor cells (N=65).^146, The most common diagnoses were acute myeloid leukemia and myelodysplastic syndromes. Systemic immunosuppressants were tapered per institutional standards. Thirty-two (49%) patients received all 4 rituximab infusions (median, 3); the most common reasons for not completing the treatment course were the development of GVHD and relapse. All patients had at least 2 years of follow-up (median, 2 years). Cumulative incidence of chronic GVHD and of steroid-requiring chronic GVHD were 48% and 31%, respectively; in a contemporaneous control cohort of 68 patients who declined study participation, corresponding incidences were 60% (p=.1 vs treatment cohort) and 49% (p=.015), respectively. Estimated 4-year relapse (34%) and nonrelapse mortality (5%) might have been unreliable due to low patient numbers at follow-up, which was not reported. The 2-year cumulative incidence of grade 3 or higher infections was 15%; 1 of 2 lethal infections was considered possibly related to rituximab.

Arai et al (2012) administered rituximab 375 mg/m² on posttransplantation days 56, 63, 70, and 77 to 35 patients who had high-risk chronic lymphocytic leukemia (n=22) or mantle cell lymphoma (n=13).^147, Patients received reduced-intensity conditioning with total lymphoid irradiation and antithymocyte globulin. Transplants were from matched related (n=19) or unrelated (n=16) donors. Systemic immunosuppressants were tapered and discontinued during rituximab treatment. Median follow-up for patients seen at the study center was 4 years. The incidence of acute GVHD was 6%, the cumulative incidence of chronic GVHD was 20%, and nonrelapse mortality was 3%. The 4-year OS rate was 73% for patients with chronic lymphocytic leukemia and 69% for patients with mantle cell lymphoma. Rituximab-related neutropenia (<500/mL) developed in 40% of patients, with febrile neutropenia and infection in 1 patient. Fifteen (43%) patients had severe grade 3 infections within 1 year of transplant; none were fatal.

Kim et al^148, (2010) published a multicenter, phase 2 cohort study of 37 patients with steroid-refractory chronic GVHD diagnosed according to National Institute of Health criteria.^149, Most transplants used myeloablative conditioning regimens (78%) and unrelated donor cells. Patients received rituximab 375 mg/m² weekly for 4 weeks and then monthly for 4 months; 29 patients completed treatment (4 dropped out, 4 died), and 22 completed 8 additional months of follow-up (2 dropped out, 5 died). Thirty-two (86%) patients had any response (complete or partial) at any time during the study; the median time to response was 29 days (range, 0 to 252 days). Twenty-one (57%) patients, maintained response for 1 year, of whom 6 discontinued and 15 reduced steroid therapy. Response rates were higher for skin, oral mucosa, and musculoskeletal symptoms (response rates, 71% to 100%) than for other organs (eg, 9% for lung involvement). Most treatment failures were due to infectious complications or relapse of the primary disease.

Section Summary: Graft-Versus-Host Disease

Rituximab for treatment of steroid-refractory chronic GVHD has been examined in cohort studies, which have shown responses in most patients, with sustained responses and steroid reductions or discontinuations in some. Because treatment options for patients with steroid-refractory GVHD are limited, rituximab may be considered in this setting.

The evidence for rituximab prophylaxis for GVHD includes 2 small cohort studies, 1 of which contained a contemporaneous control group. Although results suggested that rituximab may reduce the incidence of GVHD, replication in larger controlled trials are needed. Due to the risk of serious adverse events with rituximab, improved health outcomes in the prophylactic setting cannot be assumed.

Transplant-Related Conditions and Disorders

For individuals who have corticosteroid-refractory chronic GVHD who receive rituximab, the evidence includes multiple cohort studies. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. Treatment with rituximab has demonstrated response rates in most patients, with sustainedresponse and steroid reduction or discontinuation in some. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 19

Human Leukocyte Antigen Sensitization Before Kidney Transplant

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who are sensitized to HLA and are renal transplant candidates is to provide a treatment option that is an alternative to or an improvement on existing therapies.

Patients who are HLA-sensitized have broadly reactive alloantibodies (eg, due to previous pregnancy, transfusion of blood or blood products, or transplantation). HLA-sensitized patients are difficult to match for donor organs because of the high risks of hyperacute rejection and graft loss with cross-matched organs (ie, positive for reactive antigens). Panel reactive antibody assays define the level of HLA sensitization and are used to optimize the identification of compatible donors.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals sensitized to HLA and renal transplant candidates.

Patients who are HLA-sensitized have broadly reactive alloantibodies (eg, due to previous pregnancy, transfusion of blood or blood products, or transplantation). HLA-sensitized patients are difficult to match for donor organs because of the high risks of hyperacute rejection and graft loss with cross-matched organs (ie, positive for reactive antigens). Panel reactive antibody assays define the level of HLA sensitization and are used to optimize the identification of compatible donors.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat renal transplant candidates sensitized to HLA: IVIGs.

Some transplant centers employ desensitization protocols to overcome HLA sensitization. Protocols commonly use low-dose IVIG with PE or high-dose IVIG. ^150,

Outcomes

The general outcomes of interest are change in disease status, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Zhao et al (2014) conducted a meta-analysis of rituximab-containing induction regimens in HLA-sensitized kidney transplant recipients. .^151,  Literature was searched through July 2013, and 7 comparative studies (N=589) were identified. Studies varied by design (retrospective or prospective), sample size (40 to 144 patients), induction regimens, rituximab dosing, and whether rituximab was an add-on or alternative therapy. While statistical heterogeneity was low, overall study quality was very low; no prospective, randomized trials were included. In meta-analysis of 5 studies, acute antibody-mediated rejection (ABMR) occurred less in patients treated with rituximab (n=182) than in controls (n=212) (odds ratio, 0.52; 95% CI, 0.28 to 0.98; p=.04; I²=0%). Meta-analysis of 4 studies showed increased graft survival at 1 year in rituximab-treated patients (n=165) than in controls (n=183) (odds ratio, 3.02; 95% CI, 1.14 to 8.02; p=.03; I²=18%).

Randomized Controlled Trials

Vo et al (2014) planned to conduct a double-blind controlled trial of 90 HLA-sensitized, deceased donor, renal transplant recipients randomized to pretransplant desensitization with IVIG plus rituximab or IVIG plus placebo.^150, Of 15 patients enrolled, 13 underwent transplantation. However, after 5 serious events were observed in 7 patients randomized to placebo (ABMR in 3 patients, graft loss in 2 patients), the trial was halted. No ABMR or graft loss occurred in 6 rituximab-treated patients. Mean serum creatinine levels at 6 and 12 months were 1.7 mg/dL and 2.0 mg/dL, respectively, in 2 patients in the placebo group who had surviving allografts, and 1.1 mg/dL at both time points for patients who received rituximab. Although groups were similar at the time of transplantation for panel reactive antibody and donor-specific alloantibody levels, 1 (17%) of 6 patients randomized to rituximab had undergone previous transplant compared with 5 (70%) of 7 patients randomized to placebo.

Cohort Studies

Vo et al (2008, 2010, 2013) also reported on 3 other cohort studies of induction immunosuppression with rituximab plus IVIG in HLA-sensitized renal transplant recipients (N=200).^152,153,154, Patient and graft survival was 100% and 94% at 12 months; 95% and 84% at 24 months; and 95% and 88% (deceased donor transplants) at 48 months, all respectively. Mean serum creatinine levels at 12, 24, and 36 months were 1.5 mg/dL, 1.3 mg/dL, and 1.3 mg/dL, respectively. By comparison, the estimated 3-year survival of a contemporaneous cohort of 3754 highly sensitized (panel reactive antibody >80%) patients with end-stage renal disease who were wait-listed for transplants and remained on dialysis was 79%.

Opportunistic infection with polyomavirus BK (BKV) occurs in 10% to 20% of kidney transplants and can cause nephropathy, rejection, and graft dysfunction and failure. Barbosa et al (2014) compared 2 cohorts of kidney transplant recipients (63% deceased donor) for the posttransplant emergence of BKV.^155, One cohort (n=187) comprised HLA-sensitized patients who underwent pretransplant desensitization with IVIG plus rituximab; the other cohort (n=284) comprised non-HLA-sensitized patients. More patients in the desensitized group received lymphocyte-depleting immunosuppression induction (ie, with antithymocyte globulin or alemtuzumab; 78%) than in the nondesensitized group (38%). At 2 years posttransplant, BKV viremia occurred in 20% of desensitized patients and 10% of nondesensitized patients. Patient survival, graft survival, and incidence of BKV-associated nephropathy did not differ statistically between groups.

Section Summary: Human Leukocyte Antigen Sensitization Before Kidney Transplant

Several cohort studies and a systematic review in HLA-sensitized individuals have demonstrated good patient and graft survival with rituximab desensitization 1 to 3 years after transplant. An RCT comparing desensitization regimens with and without rituximab was terminated due to excess serious adverse events in the control arm, and 1 study reported no increase in BKV-associated nephropathy at 2-year follow-up. This evidence has suggested that health outcomes are improved with rituximab desensitization regimens in sensitized renal transplant candidates.

For individuals who have sensitization to HLA and are renal transplant candidates who receive rituximab, the evidence includes an RCT and cohort studies. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. An RCT comparing desensitization regimens with and without rituximab was terminated due to excess serious adverse events in the control arm. There may be a higher risk of polyomavirus BK virus infection. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Population Reference No. 20

Induction Immunosuppressive Therapy in Heart or Kidney Transplant

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have heart or kidney transplant receiving induction immunosuppressive therapy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with heart or kidney transplant receiving induction immunosuppressive therapy.

Antibodies other than anti-HLA antibodies that are circulating in the planned transplant recipient may cause damage to the donor organ. Antibody-mediated injury to allografts comprises ABMR, ABMR without complement deposition, antibody-mediated endarteritis, and accelerated arteriosclerosis of allografts.^156, Induction immunosuppressive regimens initiated before, at the time of, or immediately after transplantation, mute T-cell responses to antigen presentation reduces acute rejection.^157,

Interventions

The therapy being considered is rituximab as part of a combination induction regimen that typically includes plasmapheresis and IVIG therapy such as antithymocyte globulin recessive agents.

Comparators

The following therapies are currently being used to treat patients with heart or kidney transplant who are receiving induction immunosuppressive therapy: immunosuppressive antibodies, basiliximab, and alemtuzumab.

Outcomes

The general outcomes of interest are change in disease status, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Randomized Controlled Trials

Van den Hoogen et al (2015) conducted an RCT of 280 renal transplant patients.^158, Participants were randomized to rituximab (375 mg/m²) or placebo during surgery; maintenance immunosuppression included tacrolimus, MMF, and glucocorticoids. Acute rejection at 6 months occurred in 16.7% (23/138) of rituximab-treated patients and 21.2% (30/142) in the placebo arm (p=.25). Through 24 months there were similar rates of malignancies infections in both arms.

Tyden et al (2009) conducted a multicenter, double-blind, RCT comparing induction immunosuppressive regimens with and without rituximab in 136 kidney transplant recipients.^159, Patients were randomized to a single infusion of rituximab (n=68) or placebo (n=68) within 24 hours before transplantation. All patients also received steroids, tacrolimus, and MMF. At 6 months after transplant, there were no statistically significant between-group differences in treatment failures (10 rituximab vs 14 placebo; p=.348), rejection episodes (8 rituximab vs 12 placebo; p=.317), mean creatinine clearance (67 mL/min rituximab vs 66 mL/min placebo), or incidence of infections. At 3-year follow-up, 8 (12%) of rituximab-treated patients and no placebo-treated patients had died (p=.006). Deaths were due to fungal pneumonia (n=1), lung cancer (n=1), and cardiac arrests (n=6). Pretreatment history of cardiovascular disease was similar between groups.

Case Series

The approach to alloantibody sensitization that includes rituximab as part of a combination regimen for heart transplant candidates and recipients has been developed based on expert opinion and consensus review of case reports in the absence of RCTs.^160,161,

Section Summary: Heart or Kidney Transplant Receiving Induction Immunosuppressive Therapy

For individuals who are kidney transplant candidates who are receiving induction immunosuppressive therapy, the evidence includes RCTs. The RCTs found no signal of more benefit or less harm with rituximab versus placebo as an add-on to maintenance immunosuppressive regimens. Dose-response studies and larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. For individuals who are heart transplant candidates who are receiving induction immunosuppressive therapy, the recommendation for the use of rituximab as part of a combination regimen is based on consensus reporting of case reports and expert opinion.

For individuals who are kidney transplant candidates who are receiving induction immunosuppressive therapy, the evidence includes RCTs. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. The RCTs found no signal of more benefit or less harm with rituximab versus placebo as an add-on to maintenance immunosuppression. Dose-response studies and larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. For individuals who are heart transplant candidates who are receiving induction immunosuppressive therapy, the recommendation for the use of rituximab as part of a combination regimen is based on consensus reporting of case reports and expert opinion. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 21

Acute Antibody-Mediated Rejection of a Solid Organ Transplant

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have ABMR of a solid organ transplant is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with ABMR of a solid organ transplant.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat patients with ABMR of a solid organ transplant: immunosuppression, plasmapheresis or PE, IVIGs, corticosteroids, and antilymphocyte antibodies.

Outcomes

The general outcomes of interest are change in disease status, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Systematic Reviews

Roberts et al (2012) conducted a systematic review of acute ABMR treatments of kidney transplant recipients.^162, Two published, low-quality studies of rituximab were identified (N=78). The studies used historical controls and were rated to be of very low quality. Most patients in both studies received deceased donor allografts. Graft failure occurred in 3 (8%) of 28 rituximab-treated patients and 14 (35%) of 40 controls.

Randomized Controlled Trials

Sautenet et al (2016) reported on the results of a phase 3 (N=38), multicenter, double-blind, placebo-controlled trial in biopsy-proven ABMR patients randomized to rituximab (n=19) or placebo (n=19) at day 5.^163, All patients received PE, IVIG, and corticosteroids. The primary end point was a composite of graft loss or no improvement in renal function at day 12. There was no difference in the proportion of patients achieving the primary end point (53% for rituximab vs 58% for placebo; p>.05). Authors acknowledged that the trial was underpowered to detect a significant difference between groups.

Zarkhin et al (2008) reported on an open-label RCT of 20 consecutive pediatric patients (age range, 2 to 23 years; mean, 14 years) who had biopsy-proven acute rejection with infiltrating B-cell clusters after a kidney transplant.^164, Patients (N=20) were randomized evenly to standard immunosuppressive treatment (pulse steroid and/or antithymocyte globulin) or standard treatment plus rituximab weekly for 4 doses. All patients completed rituximab dosing without serious adverse events through 12 months of follow-up. Statistically significant improvements in creatinine clearance levels were seen in the rituximab group compared with the control group at 6 and 12 months after treatment (p=.026 for trend).

Retrospective Studies

Neuhaus et al (2021) reported on a retrospective study that described the management of ABMR in adult lung transplant recipients (N=55) who received treatment with rabbit antithymocyte globulin, bortezomib, rituximab, IVIG, and/or PE.^165, The most commonly used regimen consisted of IVIG/PE/rituximab (49.1%; n=27). In all, 28 patients with positive donor-specific antibodies received a combination of IVIG/PE/rituximab for ABMR treatment. Of these patients, 86% (n=24) had a reduction in donor-specific antibodies. Death was reported in 2 patients who received IVIG/PE/rituximab and 1 patient who received IVIG/PE/rituximab/rabbit antithymocyte globulin.

Ravichandran et al (2013) reported on a retrospective case review of 33 cardiac recipients who had clinical suspicion of rejection (signs or symptoms of heart failure and/or hemodynamic compromise), complement component 4 staining on endomyocardial biopsy, and absence of grade 2R or greater cellular rejection.^166, Thirteen patients received rituximab, and 20 did not. Immunosuppressive regimens varied; all patients received steroids. All rituximab-treated (100%) patients and 80% of controls survived at least 1 week. At year 3, patient survival was 75% in the rituximab group and 29% in the control group (p=.009). Infections and rehospitalizations occurred in 4 (31%) and 8 (65%) of 13 rituximab-treated patients and in 2 (10%) and 7 (35%) of 20 controls, respectively.

Section Summary: Acute Antibody-Mediated Rejection of a Solid Organ Transplant

Evidence for rituximab induction to prevent acute ABMR includes a meta-analysis of 5 very low-quality trials and 1 RCT. Although the meta-analysis reported reduced ABMR and improved graft survival compared with controls, trial quality was very low. One RCT demonstrated higher mortality in the rituximab group at 3-year follow-up. A second RCT found no beneficial effect on biopsy-proven rejection. Rituximab has not been shown to improve health outcomes when used for induction immunosuppression in kidney transplant recipients.

Small numbers of heart, kidney, and lung transplant recipients with ABMR have been treated with rituximab in comparative and noncomparative studies. Although observed improvements in outcomes would suggest potential benefit with rituximab, data are retrospective or from small prospective studies.

For individuals who have ABMR of a solid organ transplant who receive rituximab, the evidence includes cohort studies with historical controls and case series. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. Although observed improvements in outcomes have suggested potential benefit with rituximab, data are retrospective or from small prospective studies. Dose-response studies and larger RCTs with longer follow-up are needed to demonstrate improved health outcomes. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 22

Acute Antibody-Mediated Rejection After Pancreatic Islet Transplantation

Clinical Context and Therapy Purpose

The purpose of rituximab in patients who have ABMR after pancreatic islet cell transplantation is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with ABMR after pancreatic islet cell transplantation.

Autoimmune destruction of insulin-secreting islet beta-cells causes type 1 diabetes.^167, ABMR after pancreatic transplantation is less common than cell-mediated rejection, but when it occurs, pancreatic islet cells appear to be particularly susceptible to injury.^168, Pancreatic islet transplantation is used in patients who have type 1 diabetes complicated by recurrent severe hypoglycemic episodes, and insulin independence is restored in 44% of patients.^169, However, graft function commonly declines over time, which is thought to be due in part to allograft rejection. Immunosuppression management after islet transplantation is not standardized.

Interventions

The therapy being considered is rituximab.

Comparators

The following therapies are currently being used to treat ABMR after pancreatic islet cell transplantation: corticosteroids.

Outcomes

The general outcomes of interest are change in disease status, quality of life, and treatment-related morbidity.

Study Selection Criteria

Methodologically credible studies were selected using the following principles :

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Case Series

In a case series of 18 patients reported by Torrealba et al (2008), 1 patient received rituximab plus IV corticosteroid, IVIG, and plasmapheresis for ABMR after simultaneous pancreas and kidney transplantation.^170, This patient subsequently required chronic insulin therapy for blood glucose control. As reported by Vendram et al (2010) and Melcher et al (2006), 3 patients with type 1 diabetes who underwent simultaneous pancreas and kidney transplantation and developed ABMR received single doses of rituximab 375 mg/m² in combination with T-cell-directed therapies (thymoglobulin and daclizumab, an anti-CD25 monoclonal antibody)^171, or IVIG and plasmapheresis.^172, Two patients in the first group remained insulin-independent for 36 months and 12 months, respectively, and the patient in the second series remained insulin-independent for 10 months of follow-up.

Section Summary: Pancreatic Islet Transplantation

Comparative studies evaluating the use of rituximab for ABMR after pancreas transplantation were not identified. Dose-response studies and larger RCTs with longer follow-up are needed to demonstrate improved health outcomes with rituximab treatment of ABMR.

For individuals who have ABMR after pancreatic islet transplantation who receive rituximab, the evidence includes a case report. Relevant outcomes are change in disease status, quality of life, and treatment-related morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes.

Population Reference No. 23

For individuals who have  moderate to severe pemphigus vulgaris (off label indication)  rituximab is an emerging therapy for many autoimmune diseases such as pemphigus and connective tissue diseases. In these cases, off-label alternative treatment remains an option, especially for recalcitrant and rapidly progressive cases, or when conventional therapy is contraindicated.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2014 Input

In response to requests, input was received from 9 physician specialty societies (16 reviewers) and 1 academic medical center while this policy was under review in 2014. Overall, input supported the policy statements as written. Exceptions included Churg-Strauss syndrome (most reviewers considered rituximab medically necessary and supported first-line use [induction therapy] for severe disease) and acquired thrombotic thrombocytopenic purpura (reviewers were split). Other suggested indications were chronic inflammatory demyelinating polyneuropathy, immunoglobulin M-related demyelinating neuropathies, myasthenia gravis, Lambert-Eaton myasthenic syndrome, ABO incompatible organ/tissue grafts, and post-solid organ transplant membranous nephropathy.

PRACTICE GUIDELINES AND POSITION STATEMENTS

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Neurology

In 2018, the American Academy of Neurology (AAN) updated its guidelines on disease-modifying therapies for adults with multiple sclerosis (MS); these guidelines were reaffirmed in 2021.^173, For patients with relapse-remitting MS, rituximab was judged to be likely more effective than placebo regarding the decreased risk of relapse at 1 year, as well as the decreased volume of T2 lesions from baseline to week 36, with a moderate confidence in the evidence (1 class II study). However, the evidence on the efficacy of rituximab in decreased annualized relapse rates at 1 year compared with placebo was insufficient (very low confidence in the evidence). The evidence is also insufficient regarding adverse event-related withdrawal and infection-associated serious adverse events following rituximab versus placebo (very low confidence in the evidence). For patients with progressive MS, rituximab was not found to be more effective than placebo in reducing the risk of disease progression over 2 years (low confidence in the evidence). Overall, the AAN recommended that clinicians counsel patients considering rituximab or other immunosuppressive agents regarding treatment risks (level B recommendation).

American College of Rheumatology

In 2012, the American College of Rheumatology (ACR) published evidence-based consensus guidelines on the treatment of lupus nephritis.^169, A task force panel voted that, in some cases, rituximab can be used in patients whose nephritis fails to improve or worsens after 6 months of 1 induction therapy, or after the patient has failed both cyclophosphamide and mycophenolate mofetil treatments (level C evidence, based on consensus, expert opinion, or case series). The guidelines are currently being updated and anticipated in the first half of 2025.^170,

In 2020, the ACR published guidelines for the management of pulmonary disease in patients with Sjögren syndrome.^171, The following recommendations were made regarding the use of rituximab in this setting:

• "If initial treatment with MMF [mycophenolate mofetil] or azathioprine is insufficient or not tolerated in Sjögren’s patients with interstitial lung disease (ILD) who are symptomatic and in whom pulmonary function tests (PFTs) or high-resolution CT [computed tomography] (HRCT) demonstrated moderate-severe impairment, subsequent second-line maintenance drugs may include rituximab and calcineurin inhibitors, cyclosporine, or tacrolimus." (Strength of Evidence: low; Strength of Recommendation: weak)

• "In a Sjögren’s patient with ILD who has acute or subacute hypoxic respiratory failure requiring hospitalization, despite initial therapies, rituximab or cyclophosphamide should be considered in addition to high-dose corticosteroids." (Strength of Evidence: low; Strength of Recommendation: moderate)

An updated guideline covering recommendations for all ILDs is set to be published  in 2023. ^{177, ,} Rituximab was conditionally recommended for patients with systemic autoimmune rheumatic disease-ILD as a first-line treatment option and for those with progression despite first-line ILD treatment. Rituximab was also conditionally recommended for patients with rapidly progressive systemic autoimmune rheumatic disease-ILD.

The 2021 ACR/Vasculitis Foundation guideline for the management of antineutrophil cytoplasmic antibody-associated vasculitis recommends rituximab in the setting of severe granulomatosis with polyangiitis and microscopic polyangiitis, but not specifically eosinophilic granulomatosis with polyangiitis.  ^178,

American Society of Hematology

In 2011, the American Society of Hematology (ASH) published evidence-based guidelines on immune thrombocytopenia (ITP).^179, Neunert et al (2019) published an update to these guidelines in 2019. ^180, Current recommendations regarding rituximab therapy are as follows:

• "In adults with newly diagnosed ITP, the ASH guideline panel suggests corticosteroids alone rather than rituximab and corticosteroids for initial therapy (conditional recommendation based on very low certainty in the evidence of effects)"

• "In adults with ITP lasting ≥ 3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests rituximab rather than splenectomy (conditional recommendation based on very low certainty in the evidence of effects)"

• "In adults with ITP lasting ≥ 3 months who are corticosteroid-dependent or have no response to corticosteroids, the ASH guideline panel suggests a TPO-RA [thrombopoietin receptor agonist] rather than rituximab (conditional recommendation based on very low certainty in the evidence of effects)"

• "In children with ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL [health-related quality of life] and do not respond to first-line treatment, the ASH guideline panel suggests the use of TPO-RAs rather than rituximab (conditional recommendation based on very low certainty in the evidence of effects)"

• "In children with ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL and do not respond to first-line treatment, the ASH guideline panel suggests rituximab rather than splenectomy (conditional recommendation based on very low certainty in the evidence of effects)."

American Thoracic Society

In 2023, the American Thoracic Society (ATS) published guidelines for the treatment of systemic sclerosis-associated ILD (SSc-ILD).^181, The authors provided a conditional recommendation for the use of rituximab (among other immunosuppressants) based on very low-quality evidence. Authors also noted that: "Further research is needed to determine the most optimal timing for the use of rituximab in the disease course of SSc-ILD (eg, in patients with an initial diagnosis of SSc-ILD vs. in stable SSc-ILD vs. progressive SSc-ILD)."

International Society of Heart and Lung Transplantation

In 2010, the International Society of Heart and Lung Transplantation (ISHLT) published evidence-based consensus guidelines on the care of heart transplant recipients.^160, These guidelines were updated in 2022.^182, Per the updated guidelines, rituximab was recommended for:

• desensitization therapy in human leukocyte antigen-sensitized heart transplant candidates (class 2b recommendation, usefulness/efficacy is less well-established; level C evidence, based on expert consensus);

• in combination treatments for antibody-mediated rejection (class 2a recommendation, weight of evidence/opinion favors usefulness/efficacy; level C evidence).

• preoperatively if isohemagglutinin titers >1:32 or added post operatively in cases of increasing isohemagglutinin levels (class 2a recommendation, weight of evidence/opinion favors usefulness/efficacy; level C evidence)

The guidelines also stated that at this time, routine rituximab induction cannot be recommended in non-sensitized cardiac transplant recipients.

In 2018, the ISHLT published a consensus document on the management of antibodies in heart transplantation. Rituximab was suggested as a treatment option for sensitized patients awaiting heart transplantation.^183,

International Society on Thrombosis and Haemostasis

In 2020, the International Society on Thrombosis and Haemostasis (ISTH) published guidelines for the treatment of thrombotic thrombocytopenic purpura (TTP).^184, The following recommendations were made regarding the use of rituximab in immune-mediated TTP (iTTP):

• "For patients with iTTP experiencing their first acute event, the panel suggests the addition of rituximab thrombotic thrombocytopenic purpurato corticosteroids and therapeutic plasma exchange (TPE) over corticosteroids and TPE alone. (A conditional recommendation in the context of very low certainty evidence.)"

• "For patients with iTTP experiencing a relapse, the panel suggests the addition of rituximab to corticosteroids and TPE over corticosteroids and TPE alone. (A conditional recommendation in the context of very low certainty evidence.)"

• "For patients with iTTP who are in remission, but still have low plasma ADAMTS13 activity with no clinical signs/symptoms, the panel suggests the use of rituximab over nonuse of rituximab for prophylaxis. (A conditional recommendation in the context of very low certainty evidence.)"

Kidney Disease and Improving Global Outcomes

The Kidney Disease and Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases was published in October 2021.^185, The guideline made the following relevant recommendations for glomerular diseases:

Membranous nephropathy

• "For patients with MN [membranous nephropathy] and at least one risk factor for disease progression, we recommend using rituximab or cyclophosphamide and alternate month glucocorticoids for 6 months, or CNI [calcineurin inhibitor]-based therapy for ≥6 months, with the choice of treatment depending on the risk estimate."

Nephrotic syndrome

• "For children with frequently relapsing nephrotic syndrome who develop serious glucocorticoid-related adverse effects and for all children with steroid-dependent nephrotic syndrome, we recommend that glucocorticoid-sparing agents be prescribed, rather than no treatment or continuation with glucocorticoid treatment alone...Patients should ideally be in remission with glucocorticoids prior to the initiation of glucocorticoid sparing agents such as oral cyclophosphamide, levamisole, mycophenolate mofetil (MMF), rituximab, or calcineurin inhibitors (CNIs). Coadministration of glucocorticoids is recommended for ≥2 weeks following initiation of glucocorticoid-sparing treatment... Choosing the most appropriate glucocorticoid-sparing agent from among oral cyclophosphamide, levamisole, MMF, rituximab, and CNI is a decision that requires careful consideration of specific patient related issues such as resources, adherence, adverse effects, and patient preferences. Oral cyclophosphamide and levamisole may be preferable glucocorticoid-sparing therapies in frequently relapsing nephrotic syndrome. MMF, rituximab, CNIs, and to a lesser extent, oral cyclophosphamide may be preferable to glucocorticoid-sparing therapies in children with steroid-dependent nephrotic syndrome."

Minimal change disease

• "We recommend cyclophosphamide, rituximab, CNIs, or mycophenolic acid analogs (MPAA) for the treatment of frequently relapsing/steroid-dependent MCD [minimal change disease], rather than prednisone alone or no treatment."

A KDIGO guideline for the management of lupus nephritis was published in January 2024.^186, The guideline made the following practice point: "Rituximab may be considered for patients with persistent disease activity or inadequate response to initial standard-of-care therapy." In this setting, the treatment algorithm recommended adding rituximab to other biologic therapies.

A KDIGO guideline for the management of ANCA-associated vasculitis (AAV) was published in March 2024.^187, The following recommendations were provided:

• "We recommend that glucocorticoids in combination with rituximab or cyclophosphamide be used as initial treatment of new-onset AAV."
  • Rituximab was noted to be preferred over cyclophosphamide for induction therapy in AAV in the following populations: children and adolescents; premenopausal women and men concerned about fertility; frail older adults; those requiring glucocorticoid sparing; relapsing disease; and PR3-ANCA-associated disease.
• "We recommend maintenance therapy with either rituximab, or azathioprine and low-dose glucocorticoids after induction of remission."
  • Rituximab was noted to be preferred over azathioprine for maintenance therapy in AAV in the following populations: relapsing disease; PR3-ANCA-associated disease; frail older adults; those requiring glucocorticoid sparing; and azathioprine allergy.
• "Patients with relapsing disease should be reinduced, preferably with rituximab."
• "Refractory disease can be treated by an increase in glucocorticoids (intravenous or oral), by the addition of rituximab if cyclophosphamide induction had been used previously, or vice versa."

Myasthenia Gravis Foundation of America

In 2020, a multinational Task Force appointed by the Myasthenia Gravis Foundation of America published updated recommendations for the management of myasthenia gravis.^188, The following recommendations were made regarding the use of rituximab:

• "Rituximab should be considered as an early therapeutic option in patients with muscle-specific kinase antibody-positive (MuSK-Ab+) MG [myasthenia gravis] who have an unsatisfactory response to initial immunotherapy."

• "The efficacy of rituximab in refractory acetylcholine receptor-positive (AChR-Ab+) MG is uncertain. It is an option if patients fail or do not tolerate other immunosuppressive (IS) agents"

National Institute for Health and Care Excellence

In 2022, NICE updated its guidance on the management of MS in primary and secondary care (NG220).^189, The guidance did not include rituximab.

U.S. Preventive Services Task Force Recommendations

Not applicable.

mEDICARE NATIONAL COVERAGE

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 9.

able 13. Summary of Key Trials

 NCT: national clinical trial.a Industry sponsored or co-sponsored.

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