Medical Policy      

Policy Num:      M5.001.010
Policy Name:    Infliximab (Remicade, Inflectra, Renflexis, Avsola and Unbranded Infliximab)
Policy ID:          [M5.001.010]  [Ac/MA/ M+/P+]  [5.01.15]

Last Review:      May 10, 2024
Next Review:      May 20, 2025
 

Related Policies: None

Infliximab (Remicade, Inflectra, Renflexis, Avsola and Unbranded Infliximab)

Summary

Description- Intro

Infliximab (Remicade) is a tumor necrosis factor α (TNF-α) blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. Infliximab is also being considered as an off-label treatment for systemic juvenile idiopathic arthritis, select rheumatic and autoimmune conditions, vasculitides, and nonrheumatic musculoskeletal conditions. This evidence review focuses on the off-label p indications.

Summary of Evidence- Intro

For individuals with systemic juvenile idiopathic arthritis who receive infliximab off-label, the evidence includes systematic reviews, an observational study, and case reports. Relevant outcomes are symptoms, change in disease status, health status measures, quality of life (QOL), and treatment-related morbidity. Systematic reviews note that studies do not differentiate populations based on the subtype of juvenile idiopathic arthritis. Evaluation of infliximab to treat systemic juvenile idiopathic arthritis is limited to case reports. The pathophysiology of this subtype of juvenile idiopathic arthritis does not predict a significant response to infliximab. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have select rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors (eg, sarcoidosis, systemic sclerosis, Sjögren syndrome, Kawasaki disease, primary sclerosing cholangitis, Behçet syndrome, and Behçet syndrome uveitis) who receive infliximab off-label, the evidence includes systematic reviews and/or meta-analyses of small randomized controlled trials (RCTs) and observational studies on these conditions, individual observational studies, RCTs, and a placebo-controlled trial that was terminated early. Relevant outcomes are symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. Results generally did not demonstrate any group differences. Overall, larger prospective RCTs are needed to further define the role of infliximab for the management of these conditions. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with vasculitides potentially treatable with TNF-α inhibitors (eg, giant cell arteritis/ polymyalgia rheumatica, granulomatosis with polyangiitis [Wegener granulomatosis], polyarteritis nodosa) who receive infliximab off-label, the evidence includes a systematic review of primarily uncontrolled, observational studies of biologic therapies for systemic vasculitides and preliminary randomized trials. Relevant outcomes are symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. Evidence was contradictory for infliximab efficacy in antineutrophil cytoplasmic antibody-associated vasculitides and in large vessel vasculitides. There are limited high-quality data assessing the use of infliximab for the systemic vasculitides. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with nonrheumatic musculoskeletal conditions (eg, arthritis [other than rheumatoid arthritis and psoriatic arthritis], sacroiliitis) or rheumatic joint disease refractory to TNF-α inhibitors who receive infliximab off-label or intra-articular injection of infliximab, the evidence includes a systematic review, small RCTs, and nonrandomized studies. Relevant outcomes are symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. None of the studies demonstrated a positive treatment effect. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals with Rheumatoid arthritis when used alone or in combination with methotrexate in patients with psoriatic arthritis to reduce signs and symptoms of active arthritis, inhibit progression of structural damage, and improve physical function. The evidence is sufficient to determine the effects of the technology on health outcomes.

For individuals with  Crohn’s disease < 6 years of age  To reduce the number of draining enterocutaneous and rectovaginal fistulas and maintain fistula closure in fistulizing Crohn’s disease (adult patients); OR • To reduce signs and symptoms and to induce and maintain clinical remission of moderately to severely active Crohn’s disease (adult and pediatric patients). The evidence is sufficient to determine the effects of the technology on health outcomes.

For individuals with  Ulcerative colitis  < 6 years of age  to reduce signs and symptoms and to induce and maintain clinical remission in patients with moderately to severely active ulcerative colitis who have had inadequate response to conventional treatment such as aminosalicylates, corticosteroids, or immunosuppressants unless unable to tolerate these drugs (adult and pediatric patients. The evidence is sufficient to determine the effects of the technology on health outcomes.

For individuals with Ankylosing spondylitis to reduce signs and symptoms in patients with active ankylosing spondylitis refractory to conventional therapies (inadequate symptom relief from other treatments such as NSAIDs, COX-2 inhibitors, or methotrexate, unless unable to take these drugs).The evidence is sufficient to determine the effects of the technology on health outcomes. 

For individuals with  Psoriatic arthritis  when used alone or in combination with methotrexate in patients with psoriatic arthritis to reduce signs and symptoms of active arthritis, inhibit progression of structural damage, and improve physical function. The evidence is sufficient to determine the effects of the technology on health outcomes.

For individuals with  Plaque psoriasis to treat adult patients with chronic severe plaque psoriasis (as evidenced by psoriatic plaques covering at least 10% of the body surface) who have failed prior treatment with psoralen-UVA or UVB light therapy, or conventional systemic therapies (methotrexate,cyclosporine, Soriatane), or patient has a contraindication to these treatments. The evidence is sufficient to determine the effects of the technology on health outcomes.

Additional Information

For individuals who have Behçet syndrome and Behçet syndrome uveitis potentially treatable with TNF-α inhibitors, further evidence generation is not anticipated due to the rarity of the conditions; especially for uveitis, which is recognized clinically as difficult to treat. Current clinical guidance supports the use of infliximab as an alternative with failure or intolerance of conventional therapy and biologic treatment.

OBJETIVE

The objective of this evidence review is to determine whether the off-label use of infliximab to treat various medical conditions (eg, systemic juvenile idiopathic arthritis, select rheumatic and autoimmune conditions, vasculitides, nonrheumatic musculoskeletal conditions) improves the net health outcome.

COVERAGE INDICATIONS, LIMITATIONS, AND/OR MEDICAL NECESSITY

This evidence review was created in February 2002 and has been updated with searches of the PubMed database. The most recent literature update was performed through January 20, 2022.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and ability to function including benefits and harms. Every clinical condition has specific outcomes that are important to patients and 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 technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 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. Randomized controlled trials 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.

Population Reference No. 1 

Systemic Juvenile Idiopathic Arthritis

Clinical Context and Therapy Purpose

The purpose of infliximab is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with systemic juvenile idiopathic arthritis (JIA) potentially treatable with tumor necrosis factor α (TNF-α) inhibitors.

The question addressed in this evidence review is Does the use of infliximab off-label to treat systemic JIA improve the net health outcome?

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

Populations

The relevant population of interest is individuals with JIA. Specifically, individuals with systemic JIA represent the least common subtype of JIA. Previously known as Still disease, systemic JIA presents with joint symptoms, fever, and rash in young children. The pathophysiology remains unclear, but it is thought to be auto-inflammatory. The inflammatory process underlying systemic JIA appears to be distinct from other categories of JIA, with a central role for both interleukin-1 (IL-1) and IL-6. Therapy targeted to IL-1 and IL-6 is part of guideline-directed treatment for systemic JIA. A subset of children with systemic JIA has been described to have a particularly refractory course, with persistent disease associated with a high risk of joint damage and severe growth impairment. Thus, the place in therapy for infliximab has been explored when other disease-modifying treatment has been unsuccessful.

Interventions

The therapy being considered is off-label use of infliximab.

Comparators

Comparators of interest include other nonbiologic therapies, other TNF-α inhibitors (eg, etanercept, adalimumab), and IL-1 and IL-6 inhibitors. Treatment of patients with JIA typically includes a regimen of corticosteroids and anti-inflammatory drugs.

Outcomes

The general outcomes of interest are a change in symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. Follow-up assessment of the treatment effect of infliximab should be made at 6, 13, and 26 weeks.

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 long-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

Most of the published literature on the use of infliximab for the treatment of JIA has not distinguished between the disease subtypes. Kemper et al (2011) conducted a comparative effectiveness review for the Agency for Healthcare Quality on the use of disease-modifying antirheumatic drugs (DMARDs) for children with JIA.^16, Reviewers found that evidence on biologic DMARDs was limited, although symptom improvement was reported. Heterogeneity of studies and outcome reporting, as well as varied categories of JIA, made meaningful comparisons of DMARDs difficult.

An evidence-based review by Shenoi and Wallace (2010) noted that infliximab is frequently used to treat JIA in clinical practice, despite not having U.S. Food and Drug Administration (FDA) approval for this indication.^17,

Observational Studies

Yue et al (2021) conducted a retrospective cohort study that evaluated the effectiveness and persistence of TNF inhibitors versus non-TNF inhibitors among newly diagnosed JIA patients (which included 6 of the 7 disease subtypes).^18, Persistence was defined as the duration from treatment initiation to discontinuation. There were 667 patients included and 614 patients who received TNF inhibitor therapy, with 18 of those patients (2.9%) receiving infliximab. After the first course of therapy, a second course of treatment was identified if the prescription was discontinued for any reason. In first-course therapy, treatment persistence was significantly longer among children receiving etanercept than among other agents, including infliximab (p=.007); there was no difference among persistence in second-course therapy. Discontinuation rates were similar across TNF inhibitors. The clinical Juvenile Disease Activity Score (cJADAS) reduction of TNF inhibitor users was significantly greater (6.6, 95% confidence interval [CI] 5.7 to 7.5) compared with non-TNF inhibitor users (3.0, 95% CI 1.5 to 4.6, p<.0001) at 6 months.

Case Series

The literature on the use of infliximab to treat systemic JIA is limited to case reports in children refractory to first-line treatment or other biologic products.^19,20,

Section Summary: Systemic Juvenile Idiopathic Arthritis

For individuals with systemic JIA who receive infliximab off-label, the evidence includes systematic reviews, an observational study, and case reports. Systematic reviews note that studies do not differentiate populations based on the subtype of JIA. Evaluation of infliximab to treat systemic JIA is limited to case reports. The pathophysiology of this subtype of JIA does not predict a significant response to infliximab.

For individuals with systemic JIA who receive infliximab off-label, the evidence includes systematic reviews, an observational study, and case reports. Relevant outcomes are symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. Systematic reviews note that studies do not differentiate populations based on the subtype of JIA. Evaluation of infliximab to treat systemic JIA is limited to case reports. The pathophysiology of this subtype of JIA does not predict a significant response to infliximab. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2 

Select Rheumatic or Autoimmune Conditions

The purpose of infliximab is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with select rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors.

The question addressed in this evidence review is: Does the use of off-label infliximab for the treatment of select rheumatic or autoimmune conditions improve the net health outcome?

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

Populations

The relevant population of interest is individuals with various treatment-refractory rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors. For this review, the following conditions are considered: Behçet syndrome, Behçet syndrome uveitis, sarcoidosis, systemic sclerosis, Sjögren syndrome, Kawasaki disease, and primary sclerosing cholangitis.

Interventions

The therapy being considered is off-label use of infliximab.

Comparators

Comparators of interest include other medications for the condition such as corticosteroid therapy, other TNF-α inhibitors, and other biologic DMARDs.

Outcomes

The general outcomes of interest are a resolution of symptoms, change in disease status, health status measures (Table 3), QOL, and treatment-related morbidity. Follow-up assessment of the treatment effect of infliximab for select rheumatic and autoimmune conditions should be through 24 weeks.

Table 3. Health Status Measures for Select Rheumatoid Arthritis Conditions

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 long-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

Behçet Syndrome

An evidence-based review by Arida et al (2011) suggested that there may be a role for biologics in the treatment of Behçet syndrome.^23, A single-arm prospective study performed at 21 institutions in Japan was published by Hibi et al (2016).^24, Eighteen participants diagnosed with complete or incomplete Behçet syndrome, neurologic Behçet, or vascular Behçet syndrome were enrolled. They received intravenous (IV) infliximab 5 mg/kg at weeks 0, 2, and 6, and every 8 weeks thereafter until week 46. Eleven (61%) of the 18 were complete responders at weeks 14 and 30. Scarring or healing of the principal ulcer was observed in 80% of the participants. Infections occurred in 11 participants. Kehribar et al (2021) performed a single-center, retrospective cohort study in Turkey that evaluated 19 patients with Behçet's disease with parenchymal neurological involvement. ^25,Patients received infliximab treatment for an average of 32.3 months; there were 11 (58%) patients that achieved remission and 7 (37%) patients that achieved disease stability. In addition, these 18 patients in remission or stable disease had no new attacks of genital ulcers occur, but 4 patients did have a recurrence of oral ulcers. Further study and the implementation of additional RCTs are needed.

Behçet Syndrome Uveitis

Uveitis is frequently a dominant feature of Behçet syndrome. It is typically bilateral and episodic, often involves the entire uveal tract (panuveitis), and may not resolve completely between episodes. Two observational studies have compared ocular outcomes in patients with Behçet syndrome uveitis treated with infliximab or adalimumab (Tables 4 to 7).^26,27, In general, results showed no difference between groups; however, adalimumab was associated with significantly higher visual acuity at last follow-up compared to infliximab in 1 study. Both studies included small sample sizes (N range of 89 to 177), and may have been underpowered to detect a difference between groups. Larger prospective, RCTs are needed to determine whether infliximab is an effective treatment option for Behçet syndrome uveitis. Of note, adalimumab is currently the only TNF-α inhibitor therapy that has been approved by the FDA for the treatment of noninfectious uveitis.

Table 4. Summary of Characteristics of Observational Comparative Studies for Behçet Syndrome Uveitis

BS: Behçet syndrome; IV: intravenous; N/A: not applicable; NR: not reported; SC: subcutaneous.

Table 5. Summary of Results of Observational Comparative Studies for Behçet Syndrome Uveitis

SD: standard deviation.a. Value at 12 months.b. Reported as best-corrected visual acuity. Visual acuity was also significantly improved with adalimumab versus infliximab at 1, 3, and 6 months. c N includes patients with Behçet syndrome; patients with sarcoidosis are not described. d Follow-up described as occurring "at last visit"; mean duration of treatment was significantly longer for infliximab (73.5 ± 45.3 months) versus adalimumab (12.3 ± 8.4); p<.001.

Table 6. Study Relevance Limitations

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 for treatment 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. Not CONSORT reporting of harms; 4. Not established and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported.e. Follow-Up key: 1. Not sufficient duration for benefits; 2. Not sufficient duration for harms.

Table 7. 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.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.

Sarcoidosis

Maneiro et al (2012) conducted a systematic review of sarcoidosis treatment with TNF blockers.^28, Reviewers found insufficient evidence to support the use of TNF blockers for the treatment of sarcoidosis. Gallegos et al (2021) conducted a systematic review of non-steroidal treatment of cardiac sarcoidosis, including infliximab.^29, The reviewers concluded that steroids remain the cornerstone of anti-inflammatory management in patients with cardiac sarcoidosis until more robust clinical trials around non-steroidal treatments are published.

Analyses from a previously published randomized trial of 138 patients with pulmonary sarcoidosis were reported by Judson et al (2008).^30, Patients received infliximab or placebo for 24 weeks. An outcome metric designed for the study, the Physician Organ Severity Tool, summarized the involvement of 17 extrapulmonary organs. Although a statistical improvement in group mean score was noted at 24 weeks with infliximab, the outcome metric had not been clinically validated, and its relation to clinical outcomes was unknown. In a 2011 publication from the same authors, levels of inflammatory serum proteins were reduced in 134 sarcoidosis patients who received infliximab in the original trial.^31,

Systemic Sclerosis (Scleroderma)

A systematic review by Phumethum et al (2011) evaluated 3 observational studies on biologics for systemic sclerosis.^32, Infliximab and etanercept treatment reduced inflammatory arthritis and improved disability scores on the disability index of the Health Assessment Questionnaire. Reviewers recommended conducting larger, long-term studies to understand the role of biologics for the treatment of scleroderma.

Sjögren Syndrome

A systematic review by Ramos-Casals et al (2010) found anti-TNF agents did not demonstrate effectiveness in the treatment of Sjögren syndrome.^33, Included in the review were 2 placebo-controlled trials of infliximab and etanercept, and 2 trials of fewer than 30 patients evaluating rituximab. In the placebo-controlled trials, anti-TNF agents did not reduce joint pain, fatigue, or dryness, as measured by a composite visual analog scale, and reviewers concluded these agents were not clinically effective.

Kawasaki Disease

Systematic Reviews

Lu et al (2021) performed a systematic review and meta-analysis of 16 studies (N=429), including RCTs and observational studies (case-control and single arm), to assess the efficacy of infliximab for treatment of Kawasaki disease (Tables 8 to 10).^34, The literature was searched through July 2019. No differences in coronary artery damage, coronary artery aneurysms, rate of non-response to intravenous immunoglobulin (IVIG), or hospital length of stay were found when comparing infliximab (with or without IVIG) to IVIG or polyethylene glycol-treated human immunoglobulin alone (Table 10); adverse events occurred less frequently in patients treated with infliximab (with or without IVIG) compared to those in the IVIG or polyethylene glycol-treated human immunoglobulin groups (relative risk [RR], 0.811; 95% CI , 0.674 to 0.977). Seven single-arm studies (N=115) found that administration of infliximab was associated with significant reductions in coronary artery aneurysm (effect size, 0.15; 95% CI, 0.02 to 0.28) and adverse events (effect size, 0.156; 95% CI, 0.122 to 0.190).

Yamaji et al (2019) conducted a systematic review and meta-analysis of 5 RCTs (N=494) comparing TNF-α inhibitors to placebo or additional treatment with IVIG in children with Kawasaki disease (see Tables below); 4 of the 5 RCTs (n=293) included assessed infliximab and 1 RCT (n=201) assessed etanercept.^35, The literature was searched through September 2018. Pooled results from the meta-analysis found that overall, treatment with TNF-α inhibitors including infliximab led to significant reductions in the development of treatment resistance and infusion reactions, but no difference in the incidence of coronary artery abnormalities or infections. The quality of evidence was determined to be low for all outcomes.

Table 8. Comparison of Trials/Studies Included in Systematic Reviews & Meta-analyses

a. One study from this meta-analysis is not included in table due to lack of availability in Pubmed.

Table 9. Systematic Review and Meta-analyses Characteristics

NR: not reported; RCT: randomized controlled trial

Table 10. Results of Systematic Review and Meta-analyses of Tumor Necrosis Factor Inhibitors versus Placebo or Additional Treatment

CI: confidence interval; IVIG: intravenous immunoglobulin; LOS: length of stay; RR: relative risk; WMD: weighted mean difference.

Randomized Controlled Trials

A RCT by Burns et al (2021) compared infliximab versus a second infusion of IVIG in children with IVIG resistant Kawasaki disease and persistent or recurrent fever 36 hours to 7 days after completion of their initial IVIG infusion. ^52,The primary outcome measured was resolution of fever at 24 hours after initiation of study treatment, either infliximab (n=54) or second infusion of IVIG (n=49). Forty (77%) of 52 patients in the infliximab group met the primary outcome as did 25 (51%) of 49 patients in the second IVIG infusion group (odds ratio [OR] 0.31, 95% CI 0.13 to 0.73; p=.0076). There were 31 patients (n=9 in the infliximab group; n=22 in the second IVIG group) with fever beyond 24 hours that received crossover treatment (p=.0024).

Primary Sclerosing Cholangitis

A small placebo-controlled trial by Hommes et al (2008) assessing the use of infliximab for primary sclerosing cholangitis (n=24) was terminated early due to lack of treatment effect at interim analysis.^53,

Section Summary: Select Rheumatic or Autoimmune Conditions

For individuals who have select rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors (eg, Behçet syndrome, Behçet syndrome uveitis, sarcoidosis, systemic sclerosis, Sjögren syndrome, Kawasaki disease, primary sclerosing cholangitis) who receive infliximab off-label, the evidence includes systematic reviews and/or meta-analyses of small RCTs and observational studies on these conditions, individual observational studies, RCTs,and a placebo-controlled trial that was terminated early. Results generally did not demonstrate any group differences. Overall, larger prospective RCTs are needed to further define the role of infliximab for management of these conditions.

For individuals who have select rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors (eg, sarcoidosis, systemic sclerosis, Sjögren syndrome, Kawasaki disease, primary sclerosing cholangitis, Behçet syndrome, and Behçet syndrome uveitis) who receive infliximab off-label, the evidence includes systematic reviews and/or meta-analyses of small RCTs and observational studies on these conditions, individual observational studies, RCTs, and a placebo-controlled trial that was terminated early. Relevant outcomes are symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. Results generally did not demonstrate any group differences. Overall, larger prospective RCTs are needed to further define the role of infliximab for the management of these conditions. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

**For individuals who have Behçet syndrome and Behçet syndrome uveitis potentially treatable with TNF-α inhibitors, further evidence generation is not anticipated due to the rarity of the conditions; especially for uveitis, which is recognized clinically as difficult to treat. Current clinical guidance supports the use of infliximab as an alternative with failure or intolerance of conventional therapy and biologic treatment.  Medically Necessary only for Behçet syndrome and Behçet syndrome uveitis.  Considered investigational other e.g. sarcoidosis, systemic sclerosis, Sjögren syndrome, Kawasaki disease, primary sclerosing cholangitis.

*Clinical Input: “The use of infliximab may be considered medically necessary for the treatment of Behçet syndrome and Behçet syndrome uveitis when: patient is 18 years of age or older AND has had an inadequate response with conventional therapy (i.e., systemic corticosteroids or immunosuppressive agents) OR has an intolerance or contraindication with conventional therapy OR if with uveitis has previously received a biologic indicated for uveitis"

Population Reference No. 3 

Vasculitides

The purpose of infliximab is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with selected vasculitides potentially treatable with TNF-α inhibitors.

The question addressed in this evidence review is: Does the use of off-label infliximab for the treatment of selected vasculitides improve net health outcomes?

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

Populations

The relevant population of interest is individuals with select treatment-refractory vasculitides potentially treatable with TNF-α inhibitors. For this review, the following conditions were considered: giant cell arteritis/polymyalgia rheumatica, granulomatosis with polyangiitis (Wegener granulomatosis), and polyarteritis nodosa.

Interventions

The therapy being considered is off-label use of infliximab.

Comparators

Comparators of interest include other medications for the condition (eg, corticosteroid therapy), other TNF-α inhibitors, and other biologic DMARDs.

Outcomes

The general outcomes of interest are a resolution of symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. Follow-up assessment of the treatment effect of infliximab for select vasculitides should be through 24 weeks.

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 long-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

Silva-Fernandez et al (2014) conducted a systematic review of biologic therapies for systemic vasculitides.^54, Literature was searched through April 2013. Of 80 selected studies, 29 primarily uncontrolled, observational studies assessed TNF inhibitors (infliximab, etanercept, adalimumab, golimumab). Evidence was contradictory for infliximab efficacy in antineutrophil cytoplasmic antibody-associated vasculitides (granulomatosis with polyangiitis and microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis) and in large vessel vasculitides (giant cell arteritis, Takayasu arteritis).

Randomized Controlled Trials

Preliminary studies have investigated infliximab for the treatment of Wegener granulomatosis^55, and other vasculitides. A placebo-controlled trial of 44 patients with giant cell arteritis by Hoffman et al (2007) was terminated early due to lack of treatment effect for clinical outcomes at the interim analysis.^56, In a subsequent analysis by Visvanathan et al (2011), serum inflammatory biomarkers and markers of vascular remodeling on temporal artery biopsy did not differ between groups.^57,

A small placebo-controlled trial by Salvarani et al (2007), which evaluated infliximab for polymyalgia (n=51), did not show clinical benefit for the proposed outcomes.^58,

Section Summary: Vasculitides

For individuals with vasculitides potentially treatable with TNF-α inhibitors (eg, giant cell arteritis/ polymyalgia rheumatica, granulomatosis with polyangiitis [Wegener granulomatosis], polyarteritis nodosa) who receive infliximab off-label, the evidence includes a systematic review of primarily uncontrolled, observational studies of biologic therapies for systemic vasculitides and preliminary randomized trials. Evidence was contradictory for infliximab efficacy in antineutrophil cytoplasmic antibody-associated vasculitides and in large vessel vasculitides. There is limited high-quality data assessing the use of infliximab for the systemic vasculitides.

For individuals with vasculitides potentially treatable with TNF-α inhibitors (eg, giant cell arteritis/polymyalgia rheumatica, granulomatosis with polyangiitis [Wegener granulomatosis], polyarteritis nodosa) who receive infliximab off-label, the evidence includes a systematic review of primarily uncontrolled, observational studies of biologic therapies for systemic vasculitides and preliminary randomized trials. Relevant outcomes are symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. Evidence was contradictory for infliximab efficacy in antineutrophil cytoplasmic antibody-associated vasculitides and in large vessel vasculitides. There are limited high-quality data assessing the use of infliximab for the systemic vasculitides. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4 

Other Nonrheumatic Musculoskeletal and Rheumatic Conditions

The purpose of infliximab is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with select nonrheumatic musculoskeletal and rheumatic conditions (via off-label use or intra-articular injection) potentially treatable with TNF-α inhibitors.

The question addressed in this evidence review is: Does the use of off-label infliximab or intra-articular injection of infliximab for the treatment of select nonrheumatic musculoskeletal and rheumatic conditions improve net health outcomes?

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

Populations

The relevant population of interest is individuals with joint pain and symptoms caused by select nonrheumatic musculoskeletal (eg, osteoarthritis, radiculopathies, sacroiliitis) and rheumatic conditions. In addition, some patients with rheumatic joint conditions do not achieve pain and symptom control with IV infliximab for whom intra-articular injection of infliximab has been proposed.

Interventions

The therapy being considered is off-label use of IV infliximab or intra-articular injection of infliximab.

Comparators

Comparators of interest include other medications (eg, corticosteroid therapy), other TNF-α inhibitors, and other biologic DMARDs.

Outcomes

The general outcomes of interest are a resolution of symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. Follow-up assessment of the treatment effect of infliximab for select musculoskeletal conditions should be through 24 weeks.

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 long-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

Infliximab and other TNF inhibitors have been investigated for the treatment of various musculoskeletal pain syndromes. Two systematic reviews of low back pain with radiculopathy (sciatica) found insufficient evidence to conclude that TNF inhibitors were safe or effective for the treatment of these conditions.^59,60,

Randomized Controlled Trials

A placebo-controlled randomized trial by Dirckx et al (2013) that assessed 13 patients with complex regional pain syndrome found statistically significant reductions in QOL in patients who received infliximab.^61,

Preliminary studies have investigated infliximab for the treatment of sacroiliitis.^62,

Intra-articular injections of infliximab were not effective in treating chronic or recurrent gonarthritis in a randomized crossover study by van den Bijl et al (2009) that reported on 23 patients (41 total intra-articular injections: 20 infliximab and 21 methylprednisolone).^63, In this trial, improvements were greater with methylprednisolone.

Section Summary: Nonrheumatic Musculoskeletal and Rheumatic Conditions

For individuals with nonrheumatic musculoskeletal conditions (eg, arthritis [other than rheumatoid arthritis and psoriatic arthritis], sacroiliitis) or rheumatic joint disease refractory to TNF-α inhibitors who receive infliximab off-label or intra-articular injection of infliximab, the evidence includes a systematic review, small RCTs, and nonrandomized studies. None of the studies demonstrated a positive treatment effect.

For individuals with nonrheumatic musculoskeletal conditions (eg, arthritis [other than rheumatoid arthritis and psoriatic arthritis], sacroiliitis) or rheumatic joint disease refractory to TNF-α inhibitors who receive infliximab off-label or intra-articular injection of infliximab, the evidence includes a systematic review, small RCTs, and nonrandomized studies. Relevant outcomes are symptoms, change in disease status, health status measures, QOL, and treatment-related morbidity. None of the studies demonstrated a positive treatment effect. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5

In a double-blind, placebo-controlled, phase III clinical trial, Maini and colleagues (1999) examined if infliximab would provide additional clinical benefit to patients who had active RA despite receiving methotrexate.  A total of 428 patients who had active RA and had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomized to placebo (n = 88) or one of four regimens of infliximab at weeks 0, 2, and 6.  Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for greater than or equal to 6 months, range 10 to 35 mg/wk).  Patients were assessed every 4 weeks for 30 weeks.  At 30 weeks, the American College of Rheumatology (ACR)-20 response criteria, representing a 20 % improvement from baseline, were achieved in 53, 50, 58, and 52 % of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20 % of patients receiving placebo plus methotrexate (p < 0.001 for each of the four infliximab regimens versus placebo).  A 50 % improvement was achieved in 29, 27, 26, and 31 % of infliximab plus methotrexate in the same treatment groups, compared with 5 % of patients on placebo plus methotrexate (p < 0.001).  Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group.  The authors concluded that during 30 weeks, treatment with infliximab plus methotrexate was more effective than methotrexate alone in patients with active RA not previously responding to methotrexate.

The protocol in the study by Maini et al (1999) pre-specified that pharmacokinetic data would be analyzed in the first 200 subjects.  However, the number of subjects with human anti-chimeric antibodies (HACA) formation was not stated.  Because of the murine component of the antibody, patients receiving infliximab can develop HACA that are associated with an increased rate of infusion reactions.  Pharmacokinetic measurements were actually performed in 197 patients and results were consistent with the previously defined half-life of 8 to 12 days.  It should be noted that HACA formation could not be measured in patients receiving infliximab since the drug interferes with the assay.  However, 27 patients who discontinued treatment before 30 weeks were tested for HACA formation, and 3 patients (11 %) tested positive for HACA (2 with a titer of 1/10 and 1 with a titer of 1/40).  The rate of HACA formation in patients with Crohn's disease (CD) treated with infliximab is reported to be 13 %, but this rate appears to be less if a patient is on concurrent immunosuppressive therapy (Hanauer, 1999; Sanborn and Hanauer, 2002).  It is unclear whether serum infliximab levels may decline more rapidly in the presence of HACA resulting in reduced effectiveness of infliximab therapy. 

St Clair et al (2002) examined the relationship between serum concentrations of infliximab and clinical improvement from RA following infliximab treatment.  Multiple blood samples were obtained from each of 428 subjects with active RA who were enrolled in a multi-center, randomized, double-blind, placebo-controlled trial (ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy]) evaluating the safety and effectiveness of infliximab therapy.  Serum levels of infliximab were measured by enzyme-linked immunosorbent assay.  Dose-response trends were analyzed using generalized logistic regression techniques.  Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial.  At week 54, 26 % of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab, a significantly greater proportion than in the other 3 treatment groups (p < 0.001).  Increased magnitude of ACR response (measured by the ACR-N, a continuous measure of clinical improvement derived from the ACR-20 criteria) and greater reduction from baseline in serum C-reactive protein level were both associated with higher trough serum concentrations of infliximab (p < 0.001), as was less progression of radiographical joint damage (p = 0.004), providing support for a dose-response relationship.  Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab than increasing the dose by 100 mg.  The authors concluded that these results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks.

In the study by St. Clair et al (2002), the relatively low proportion of ACR-50 responders in patients receiving 3mg/kg every 8 weeks may be due to inadequate exposure to infliximab during the course of therapy.  The trough serum levels of infliximab at 54 weeks varied more than 100-fold in this group suggesting marked differences among patients in exposure to infliximab.  The basis for this individual variability is unclear, but HACA and/or metabolic differences may offer some explanations.  However, it is unlikely that HACA are the sole reason for the rapid clearance of serum infliximab in this group of patients.  After completion of the study, HACA were detected in 25 patients (8.5 %) with analyzable samples.  These antibodies were distributed across all infliximab-treated groups.  The appropriate serum samples were available for measuring HACA in 19 of 21 patients from the group that received 3mg/kg every 8 weeks; and this group of patients had undetectable trough levels of infliximab.  Of these 19 subjects, only 6 were HACA-positive, and 2 had inconclusive results.  Therefore, metabolic factors probably are responsible for the rapid clearance of infliximab in some patients.

The relationship between clinical improvement and trough serum levels of infliximab bears clinical implications.  Although there was a trend towards a slightly higher proportion of serious side effects in the group receiving 3mg/kg every 4 weeks compared with the group receiving 3mg/kg every 8 weeks (16 % versus 11 %), this incidence was no higher than that observed in the placebo-controlled group (21 %).  Presently, there is a lack of evidence to identify which patients might benefit from a dose increase based on any clinical, laboratory, or radiographical factors.  Additionally, the relationship between trough serum levels of infliximab and clinical improvement is imprecise.  At 54 weeks, 6 (21 %) of the 28 patients in the study attained ACR-50 or better despite trough serum infliximab levels of less than 0.1 ug/ml.  Thus, trough serum levels of infliximab are not, by themselves reliable predictors of treatment response.  St Clair et al (2002) stated that they would not advocate the routine measurement of serum infliximab levels for this reasons.  It should also be noted that poor or lack of response to infliximab therapy may be the result of a particular disease characteristics (e.g., joint inflammation not primarily driven by TNF-alpha) or other host factors that preclude an adequate response to treatment.

Rheumatoid arthritis (RA) is an autoimmune disease that most commonly affects the wrists, fingers, knees, feet, and ankle joints symmetrically. o Treatment options for RA include: glucocorticoids (most often used for short-term management of flares), disease-modifying anti-rheumatic drugs (DMARDs): hydroxychloroquine, leflunomide, methotrexate, minocycline, and sulfasalazine; and biologic agents [non-TNF: abatacept (Orencia®), rituximab (Rituxan®), tocilizumab (Actemra®); anti-TNF: Humira, entanercept (Enbrel®), Remicade, Cimzia, and golimumab (Simponi®)].

Population Reference No. 6

Active Crohn’s Disease The safety and efficacy of single and multiple doses of REMICADE were assessed in 2 randomized, double-blind, placebo-controlled clinical studies in 653 patients with moderate to severely active Crohn’s disease [Crohn’s Disease Activity Index (CDAI) ≥220 and ≤400] with an inadequate response to prior conventional therapies. Concomitant stable doses of aminosalicylates, corticosteroids and/or immunomodulatory agents were permitted and 92% of patients continued to receive at least one of these medications. In the single-dose trial of 108 patients, 16% (4/25) of placebo patients achieved a clinical response (decrease in CDAI ≥70 points) at Week 4 vs. 81% (22/27) of patients receiving 5 mg/kg REMICADE (p<0.001, two-sided, Fisher’s Exact test). Additionally, 4% (1/25) of placebo patients and 48% (13/27) of patients receiving 5 mg/kg REMICADE achieved clinical remission (CDAI<150) at Week 4. In a multidose trial (ACCENT I [Study Crohn’s I]), 545 patients received 5 mg/kg at Week 0 and were then randomized to one of three treatment groups; the placebo maintenance group received placebo at Weeks 2 and 6, and then every 8 weeks; the 5 mg/kg maintenance group received 5 mg/kg at Weeks 2 and 6, and then every 8 weeks; and the 10 mg/kg maintenance group received 5 mg/kg at Weeks 2 and 6, and then 10 mg/kg every 8 weeks. Patients in response at Week 2 were randomized and analyzed separately from those not in response at Week 2. Corticosteroid taper was permitted after Week 6. At Week 2, 57% (311/545) of patients were in clinical response. At Week 30, a significantly greater proportion of these patients in the 5 mg/kg and 10 mg/kg maintenance groups achieved clinical remission compared to patients in the placebo maintenance group (Table 3). REMICADE® (infliximab) REMICADE® (infliximab) 11 Additionally, a significantly greater proportion of patients in the 5 mg/kg and 10 mg/kg REMICADE maintenance groups were in clinical remission and were able to discontinue corticosteroid use compared to patients in the placebo maintenance group at Week 54

Crohn’s disease (CD) is a chronic inflammatory disorder that is characterized by focal, asymmetric, transmural, and granulomatous inflammation which primarily affects the gastrointestinal tract. o Therapeutic recommendations are individualized and depend on disease location, severity, and complications present. Treatment options for CD include: glucocorticoids (conventional steroids and budesonide), immunosuppressants (azathioprine, mercaptopurine, methotrexate), 5- aminosalicylates (5-ASA), and biologic agents [infliximab (Remicade®), adalimumab (Humira®), natalizumab (Tysabri®), certolizumab (Cimzia®), and vedolizumab (EntyvioTM)].

Population Reference No. 7

Conventional treatment options for patients with severe corticosteroid-refractory ulcerative colitis include intravenous cyclosporine, which is frequently limited by toxicity, or colectomy.  Studies have shown that infliximab, improves clinical, endoscopic, and histologic outcomes in patients with severely active ulcerative colitis refractory to conventional therapy, allowing corticosteroid sparing and reducing the need for colectomy.  This is consistent with scientific observations that suggest a central role for TNF in the inflammatory cascade.  Two phase III randomized, placebo-controlled clinical trials have demonstrated efficacy of infliximab in inducing and maintaining clinical response and remission of refractory moderate to severe ulcerative colitis (Rutgeerts et al, 2005; Sandborn et al, 2005).  In these clinical trials, subjects with moderate-to-severe ulcerative colitis that was refractory to at least one standard therapy were randomly assigned to infliximab in doses of 5 mg per kg or 10 mg per kg, or to placebo.  In 1 clinical trial involving 364 subjects with moderate-to-severe ulcerative colitis (Sandborn et al, 2005), 62 % of subjects in the 10-mg group and 69 % of subjects in the 5-mg group had a clinical response at 8 weeks, compared to 37 % of subjects in the placebo group (p < 0.001 for both).  At that time, 32 % of subjects in the 10 mg group and 39 % of subjects in the 5 mg group were in clinical remission, versus 15 % of subjects in the placebo group (p = 0.002 and p < 0.001, respectively).  By 30 weeks, 51 % of the 10-mg group and 52 % of the 5-mg group achieved clinical response versus 30 % of placebo-treated subjects (p = 0.002 and p < 0.001).  At that time, 37 % of the 10-mg group and 34 % of the 5-mg group were in clinical remission, versus 16 % of the placebo group (p < 0.001 and p = 0.001).

In a 2nd clinical trial involving 364 subjects with moderate-to-severe ulcerative colitis (Sandborn et al, 2005), 69 % of subjects in the 10-mg group and 65 % of subjects in the 5-mg group had a clinical response at 8 weeks, compared to 29 % of subjects in the placebo group (p < 0.001 for both).  At that time, 28 % of subject in the 10-mg group and 34 % of subjects in the 5-mg group were in clinical remission, versus 6 % of subjects in the placebo group (p < 0.001 for both).  By 30 weeks, 60 % of subjects in the 10-mg group and 47 % of subjects in the 5-mg group had a clinical response, compared to  26 % of subjects receiving placebo (p < 0.001 for both).  At that time, 36 % of subjects in the 10-mg group and 26 % of subjects in the 5-mg group were in clinical remission, compared to 11 % in the placebo group (p < 0.001 and p = 0.003).

On September 23, 2011, the FDA approved infliximab to treat moderately to severely active ulcerative colitis in children older than 6 years who have had inadequate response to conventional therapy.

Additional studies are needed to evaluate the optimal timing and duration of infliximab therapy, the utility of adjuvant medical treatments during infliximab therapy, and the long-term safety and comparative efficacy of the various treatments for ulcerative colitis to better define the role of infliximab in the treatment of this condition.  Other TNF antagonists for ulcerative colitis in various phases of investigation include the monoclonal antibody CDP 571, the fusion peptide etanercept, the phosphodiesterase inhibitor oxpentifylline, and thalidomide.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) that causes long-lasting inflammation and ulcers (sores) in the digestive tract. o Treatment options for UC include: glucocorticoids (conventional steroids and budesonide), immunosuppressants (azathioprine, mercaptopurine, methotrexate), 5- aminosalicylates (5-ASA), and biologic agents (Remicade, Humira, Tysabri, Cimzia, and Entyvio).

Population Reference No. 8

Ankylosing Spondylitis (AS) belongs to a group of chronic rheumatic diseases affecting the bones and joints connecting the spine and pelvis known asspondyloarthritis. o Treatment options include NSAIDs, corticosteroids, DMARDs, and anti-TNF biologic agents. Antiinflammatory agents such as NSAIDs may be used to reduce swelling; however, they do not affect disease progression. DMARDs (sulfasalazine and methotrexate) have not been proven effective for the treatment of axial disease. Anti- TNF agents (Enbrel, Humira, Remicade, Cimzia or Simponi) target the pathophysiologic mechanism of AS and have been shown to be beneficial and effective.

Two published randomized controlled trials have reported on significant reductions in disease activity in patients with ankylosing spondylitis and other spondyloarthropathies who were treated with infliximab.  Spondyloarthropathy (literally arthritis of the spine) may be associated with ankylosing spondylitis, Reiter's syndrome, reactive arthritis, psoriatic arthritis, and inflammatory bowel disease, or may be idiopathic (undifferentiated spondyloarthropathy).  Van den Bosch et al (2002) reported on a 12-week long clinical study involving forty patients with active spondyloarthropathy who were randomly assigned to receive an intravenous loading dose (weeks 0, 2, and 6) of 5 mg/kg infliximab or placebo.  Both patient and physician global assessments of disease activity on a visual analog scale improved significantly in the infliximab group compared with the baseline value, with no improvement in the placebo group.  As early as week 2 and sustained up to week 12, there was a highly statistically significant difference between the values for these 2 endpoints in the infliximab versus the placebo group.  In most of the other assessments of disease activity (laboratory measures, assessments of specific peripheral and/or axial disease), significant improvements were observed in the infliximab group compared with the baseline value and compared with placebo.  There was 1 severe drug-related adverse event, in which a patient developed disseminated tuberculosis.

Braun et al (2002) reported the results of a 12-week randomized placebo-controlled clinical trial involving 35 patients with active ankylosing spondylitis treated with intravenous 5 mg/kg infliximab infusion (at weeks 0, 2 and 6) and 35 patients assigned to placebo.  Eighteen (53 %) of 34 patients on infliximab had a regression of disease activity at week 12 of at least 50 % compared with 3 (9 %) of 35 on placebo (difference 44 % (95 % confidence interval [CI]: 23 to 61, p < 0.0001).  Function and quality of life also improved significantly on infliximab but not on placebo (p < 0.0001 and p < 0.0001, respectively).  The investigators reported that treatment with infliximab was generally well-tolerated, but 3 patients had to stop treatment because of systemic tuberculosis, allergic granulomatosis of the lung, or mild leucopenia.

These randomized controlled trials confirm the findings of an open label study of infliximab in 21 patients with active spondyloarthropathy who received a maintenance regimen of 5 mg/kg infliximab every 14 weeks, 19 of whom were followed for 1 year (Kruithof et al, 2002).  The investigators reported that, after each re-treatment a sustained significant decrease of all disease manifestations was observed.  Before re-treatment, symptoms recurred in 3/19 (16 %) at week 20, in 13/19 (68 %) at week 34, and in 15/19 (79 %) at week 48.  Twelve minor infectious episodes were observed in this cohort.

Ankylosing Spondylitis (AS) belongs to a group of chronic rheumatic diseases affecting the bones and joints connecting the spine and pelvis known asspondyloarthritis. o Treatment options include NSAIDs, corticosteroids, DMARDs, and anti-TNF biologic agents. Antiinflammatory agents such as NSAIDs may be used to reduce swelling; however, they do not affect disease progression. DMARDs (sulfasalazine and methotrexate) have not been proven effective for the treatment of axial disease. Anti- TNF agents (Enbrel, Humira, Remicade, Cimzia or Simponi) target the pathophysiologic mechanism of AS and have been shown to be beneficial and effective.

Population Reference No. 9

Safety and efficacy of REMICADE were assessed in a multicenter, double-blind, placebo-controlled study in 200 adult patients with active psoriatic arthritis despite DMARD or NSAID therapy (≥5 swollen joints and ≥5 tender joints) with 1 or more of the following subtypes: arthritis involving DIP joints (n=49), arthritis mutilans (n=3), asymmetric peripheral arthritis (n=40), polyarticular arthritis (n=100), and spondylitis with peripheral arthritis (n=8). Patients also had plaque psoriasis with a qualifying target lesion ≥2 cm in diameter. Forty-six percent of patients continued on stable doses of methotrexate (≤25 mg/week). During the 24-week double-blind phase, patients received either 5 mg/kg REMICADE or placebo at Weeks 0, 2, 6, 14, and 22 (100 patients in each group). At Week 16, placebo patients with <10% improvement from baseline in both swollen and tender joint counts were switched to REMICADE induction (early escape). At Week 24, all placebo-treated patients crossed over to REMICADE induction. Dosing continued for all patients through Week 46.

Psoriatic Arthritis (PsA) is a chronic inflammatory disease often associated with psoriasis. Psoriasis is an autoimmune disease affecting the skin, resulting in scaly red and whitepatches. o Treatment options include NSAIDS, DMARDs, and anti-TNF biologic agents. If PsA does not respond to the initial treatment [NSAIDs, DMARDs (sulfasalazine, methotrexate, cyclosporine, and leflunomide)] as monotherapy, combination therapy may be used. Hydroxychloroquine should be avoided due to exacerbation of psoriasis. Anti-TNF agents may be utilized when initial treatment has been ineffective. Anti-TNF agents approved for PsA include: Humira, Enbrel, Remicade, Cimzia andSimponi.

Population Reference No. 10

The safety and efficacy of REMICADE were assessed in 3 randomized, doubleblind, placebo-controlled studies in patients 18 years of age and older with chronic, stable plaque psoriasis involving ≥10% BSA, a minimum PASI score of 12, and who were candidates for systemic therapy or phototherapy. Patients with guttate, pustular, or erythrodermic psoriasis were excluded from these studies. No concomitant anti-psoriatic therapies were allowed during the study, with the exception of low-potency topical corticosteroids on the face and groin after Week 10 of study initiation.

Study I (EXPRESS) evaluated 378 patients who received placebo or REMICADE at a dose of 5 mg/kg at Weeks 0, 2, and 6 (induction therapy), followed by maintenance therapy every 8 weeks. At Week 24, the placebo group crossed over to REMICADE induction therapy (5 mg/kg), followed by maintenance therapy every 8 weeks. Patients originally randomized to REMICADE continued to receive REMICADE 5 mg/kg every 8 weeks through Week 46. Across all treatment groups, the median baseline PASI score was 21 and the baseline Static Physician Global Assessment (sPGA) score ranged from moderate (52% of patients) to marked (36%) to severe (2%). In addition, 75% of patients had a BSA >20%. Seventy-one percent of patients previously received systemic therapy, and 82% received phototherapy. Study II (EXPRESS II) evaluated 835 patients who received placebo or REMICADE at doses of 3 mg/kg or 5 mg/kg at Weeks 0, 2, and 6 (induction therapy). At Week 14, within each REMICADE dose group, patients were randomized to either scheduled (every 8 weeks) or as needed (PRN) maintenance treatment through Week 46. At Week 16, the placebo group crossed over to REMICADE induction therapy (5 mg/kg), followed by maintenance therapy every 8 weeks. Across all treatment groups, the median baseline PASI score was 18, and 63% of patients had a BSA >20%. Fifty-five percent of patients previously received systemic therapy, and 64% received a phototherapy.

Study III (SPIRIT) evaluated 249 patients who had previously received either psoralen plus ultraviolet A treatment (PUVA) or other systemic therapy for their psoriasis. These patients were randomized to receive either placebo or REMICADE at doses of 3 mg/kg or 5 mg/kg at Weeks 0, 2, and 6. At Week 26, patients with a sPGA score of moderate or worse (greater than or equal to 3 on a scale of 0 to 5) received an additional dose of the randomized treatment. Across all treatment groups, the median baseline PASI score was 19, and the baseline sPGA score ranged from moderate (62% of patients) to marked (22%) to severe (3%). In addition, 75% of patients had a BSA >20%. Of the enrolled patients, 114 (46%) received the Week 26 additional dose. In Studies I, II and III, the primary endpoint was the proportion of patients who achieved a reduction in score of at least 75% from baseline at Week 10 by the PASI (PASI 75).

In Study I and Study III, another evaluated outcome included the proportion of patients who achieved a score of “cleared” or “minimal” by the sPGA. The sPGA is a 6-category scale ranging from “5 = severe” to “0 = cleared” indicating the physician’s overall assessment of the psoriasis severity focusing on induration, erythema, and scaling. Treatment success, defined as “cleared” or “minimal,” consisted of none or minimal elevation in plaque, up to faint red coloration in erythema, and none or minimal fine scale over <5% of the plaque. Study II also evaluated the proportion of patients who achieved a score of “clear” or “excellent” by the relative Physician’s Global Assessment (rPGA). The rPGA is a 6-category scale ranging from “6 = worse” to “1 = clear” that was assessed relative to baseline. Overall lesions were graded with consideration to the percent of body involvement as well as overall induration, scaling, and erythema. Treatment success, defined as “clear” or “excellent,” consisted of some residual pinkness or pigmentation to marked improvement (nearly normal skin texture; some erythema may be present).  

Psoriasis is a complex autoimmune inflammatory disease that occurs in genetically susceptible individuals and presents with the development of inflammatory plaques on the skin. o Treatment options include: phototherapy or photochemotherapy, DMARDs: cyclosporine, methotrexate, and acitretin. Anti-TNF agents may be utilized when initial treatment has been ineffective. Anti-TNF agents approved for plaque psoriasis include: Humira, Enbrel, and Remicade.

Population Reference No. 11

Individuals: With Crohn's disease (CD) in adults including fistulizing disease

Population Reference No. 12

Individuals:  With Fistulizing CD in children aged 6 years or older

Population Reference No. 13

Individuals:  With JIA with sacroiliitis, enthesitis, or uveitis

Population Reference No. 14

Individuals:  With Noninfectious uveitis

Population Reference No. 15

Individuals:  With Polyarticular and oligoarticular JIA

Population Reference No. 16

Individuals:  With RA without methotrexate

Population Reference No. 17

Individuals:  With Sarcoidosis

Population Reference No. 18

Individuals: With Immune Checkpoint Inhibitor-Related Toxicities

Population Reference No. 19

Individuals: With Hematopoietic Cell Transplantation

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.

Avsola and Renflexis are considered preferred agents. In order to use any other infliximab agents (Remicade, unbranded infliximab, Inflectra or any other), patients must have documented previous use and therapeutic failure, intolerance or contraindication to preferred agents Avsola and Renflexis.

Background

Tumor necrosis factor (TNF) is a cytokine produced by macrophages and T cells. Its name is based on the original observation 25 years ago that TNF killed tumor cells in vitro. Further research has revealed that TNF has a broad spectrum of biologic activities; in particular, it is a key mediator of inflammation and is produced in response to infection and immunologic injury.

There are a number of TNF-α blocking agents: etanercept (Enbrel; Amgen), adalimumab (HumiraÒ; Abbott), and certolizumab pegol (Cimzia; UCB) are administered via subcutaneous injection; golimumab (Simponi; Janssen Biotech) is administered subcutaneously or intravenously; and infliximab (Remicade; Janssen Biotech) is administered via an intravenous infusion in the physician's office, outpatient setting, or infusion center.

This evidence review focuses on the off-label uses of infliximab for various medical conditions and diagnoses.

The Food and Drug Administration (FDA) has approved or is reviewing biosimilar products for several TNF-α blocking agents. This evidence review does not evaluate biosimilar products.

Regulatory Status

Table 1 summarizes indications approved by the Food and Drug Administration (FDA) for infliximab and other TNF-α inhibitors.

Table 1. FDA-Approved Indications for Tumor Necrosis Factor-α Inhibitors

CTF: conventional therapy failure; DMARD: disease-modifying antirheumatic drug; FDA: U.S. Food and Drug Administration; JIA: juvenile idiopathic arthritis; M-to-S: moderate-to-severe; MTX: methotrexate; No: agent is not an approved indication; TNF: tumor necrosis factor; Yes: agent is an approved indication.

None of the TNF-α inhibitors described in Table 1 have been approved for intra-articular administration. The FDA requires notification to prescribers of the risks of invasive fungal infections and monitoring for malignancies with the use of TNF blockers. In addition, in March 2013, the FDA issued warnings and precautions against concurrent administration of infliximab with other biologic agents. For concurrent administration with other biologic therapeutics, current prescribing information states: “The concomitant use of Infliximab with these biologics is not recommended because of the possibility of an increased risk of infection.”^1,

The FDA has approved or is reviewing biosimilar products for several TNF-α blocking agents. This evidence review does not evaluate biosimilar products.

The following biosimilars of infliximab have been approved by the FDA for the treatment of Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis:

• June 2016, Inflectra (infliximab-dyyb; Celltrion)

• April 2017, Renflexis (infliximab-abda; Samsung Bioepsis/Merck)

• December 2017, Ixifi (infliximab-qbtx; Pfizer)

• December 2019, Avsola (infliximab-axxq; Amgen)

Safety

Systematic reviews have focused on evaluating the safety of TNF inhibitors. Summaries of the findings are shown in Table 2. TNF inhibitors are associated with several adverse events. In general, systematic reviews have shown an increased risk of infections, including herpes zoster, tuberculosis, and opportunistic infections. Regarding the increased risk of malignancy, the literature is mixed; many recent meta-analyses have yet to demonstrate an increased risk overall, but some literature has indicated that TNF inhibitor therapy may increase the risk of developing skin cancer(s) and lymphoma. Two systematic reviews have compared safety among TNF inhibitors.^6,7, One reported no differences in adverse events between TNF inhibitors, while the other found higher rates of adverse events and serious infections with infliximab versus adalimumab or etanercept. Data on long-term safety remain scarce.

Table 2. Systematic Reviews of Safety of Infliximab and Tumor Necrosis Factor Inhibitors

AE: adverse event; CCT: controlled clinical trial; CI: confidence interval; DMARD: disease-modifying antirheumatic drug; EMA: European Medicines Agency; EULAR: European League Against Rheumatism; IBD: inflammatory bowel disease; JIA: juvenile idiopathic arthritis; M-to-S: moderate-to-severe; OBS: observational; OLE: open-label extension study; OR: odds ratio; RA: rheumatoid arthritis; RCT: randomized controlled trial; RD: rate difference; RR: relative risk; SAE: serious adverse event: TB: tuberculosis; TNF: tumor necrosis factor.

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.

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.

Juvenile Idiopathic Arthritis

A 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis focused on systemic juvenile idiopathic arthritis.^64, The update highlighted the central role of cytokines in the inflammatory process for this condition and treatment targeting interleukin-1 and interleukin-6. Recommendations were made for the use of tumor necrosis factor (TNF)-α inhibitor therapy in refractory cases. There is an anticipated update to these recommendations in 2022.

Treatment-refractory Rheumatic or Autoimmune Conditions

Behçet Syndrome Uveitis

In 2014, the American Uveitis Society published expert panel recommendations on the use of biologic TNF -α blocking agents to treat ocular inflammatory diseases.^65, The summary includes a strong recommendation to consider use of infliximab or adalimumab (based on good quality and moderate-quality evidence, respectively) as a corticosteroid-sparing option for first- or second-line treatment of patients with ophthalmic manifestations of Behcet's disease, and for use of infliximab as first- or second-line treatment of acute flares of pre-existing Behcet's disease.

Vasculitides

In 2021, the American College of Rheumatology released a guideline for the treatment and management of vasculitis.^66, There were no recommendations made for the use of TNF-α inhibitor therapy. 

U.S. Preventive Service 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 ongoing and unpublished trials that might influence this review are listed in Table 11.

Table 11. Summary of Key Trials

NCT: national clinical trial.

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