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 14, 2025
Next Review:     May 20, 2026
 

Related Policies: None

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

Summary

Description

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 group of indications.

Summary of Evidence 

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 who have Behçet syndrome and Behçet syndrome uveitis potentially treatable with TNF-α inhibitors, current clinical guidance supports the use of infliximab as an alternative with failure of or intolerance to conventional therapy and biologic treatment. Both conditions are rare and Behçet syndrome uveitis is recognized clinically as difficult to treat.

Additional Information

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.

OBJEcTIVE

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.

Policy Guidelines

Initial authorizations

1. Patient has had a trial and failure of an appropriate regimen of first-line therapy based on the indication for treatment:
   1. Moderate to Severe Rheumatoid Arthritis - DMARD therapy including concurrent use of two or three of the regimens below for at least 3 months or intolerance or a contraindication to use:
      1. Methotrexate 20mg weekly (GI intolerance requires trial of SC/IM methotrexate at 20mg weekly)
      2. Hydroxychloroquine titrated to 200-400mg daily
      3. Sulfasalazine titrated to 2,000mg-3,000mg daily
      4. Leflunomide 10-20mg daily
   2. Psoriatic Arthritis – First line therapy including concurrent use of the regimens below for at least 1 month:
      1. Continuous treatment with a NSAID at therapeutic doses; and,
      2. Methotrexate 20mg weekly (GI intolerance requires trial of SC/IM methotrexate at 20mg weekly)
   3. Plaque psoriasis – First-line therapy including concurrent use of two of the regimens below for at least 3 months or intolerance or a contraindication to use:
      1. Topical corticosteroid therapy
      2. Phototherapy: at least 20-30 treatments given 2-3 times weekly.
      3. Methotrexate 5mg-15mg weekly (GI intolerance requires trial of SC/IM methotrexate at 5mg-15mg weekly) in combination with folic acid supplementation
      4. Cyclosporine at a dose of at least 2.5 – 5 mg/kg/day until disease control achieved
      5. Acitretin at a dose of at least 25 mg daily
   4. Ankylosing Spondylitis – Use of first-line therapy including all of the regimens below:
      1. Continuous treatment with a NSAID at therapeutic doses for one month; and,
      2. For patients with only peripheral disease, local corticosteroid injections when the disease process permits; and,
      3. For patients with only peripheral disease, methotrexate 20mg for at least 3 months orSulfasalazine titrated to 2000mg to 3000mg daily for at least 3 months.
   5. Ulcerative Colitis –Use of at least two of the systemic regimens below for at least 12 weeks:
      1. Sulfasalazine 4-6 gram daily
      2. Mesalamine 2-4.8 gram daily
      3. Balsalazide 6.75 grams
      4. Corticosteroid regimens:
         1. Prednisone 40-60 mg daily
         2. Oral budesonide 9 mg daily
         3. Budesonide rectal; or
      5. Azathioprine 1.5-2.5 mg/kg daily
      6. 6-mercaptopurine 1-1.5 mg/kg daily
   6. Moderate to Severe Crohn’s Disease – Use of first-line therapy including one of the following:
      1. Treatment with any of the following corticosteroid regimens for two weeks has been ineffective or is contraindicated:
         1. Prednisone 40-60 mg daily
         2. Oral budesonide 9 mg daily
         3. Budesonide rectal; or
      2. Inability to taper off one of the corticosteroid regimens above; or
      3. Breakthrough disease while stabilized for at least 3 months on one of the following therapies:
         1. Azathioprine 2-3 mg/kg daily
         2. 6-mercaptopurine 1-1.5 mg/kg daily
         3. Methotrexate 20mg weekly (GI intolerance requires trial of SC/IM methotrexate at 20mg weekly)
   7. ​​​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
      1. has had an inadequate response with conventional therapy (i.e., systemic corticosteroids or immunosuppressive agents) OR
      2. has an intolerance or contraindication with conventional therapy OR
      3. if with uveitis has previously received a biologic indicated for uveitis.

Medication administration must occur at a clinic office or home-infusion setting unless medical necessity is met based on the criteria below, supported by medical documentation:

1. The patient has experienced a severe or life-threatening reaction with previous infusions of the same or similar products; or,
2. The patient has a medical condition that renders him or her unstable, exceptionally complex, immunocompromised or otherwise high-risk such that continued oversight in the current facility is required; or,
3. There are no alternative settings available to the patient as a result of both of the following:
   1. The patient is unable to use home-infusion services as documented by the physician, social worker, or infusion provider; and,
   2. The patient is unable to access alternative settings due to unreasonable distance [>30 miles] or other extenuating circumstances.
4. The prescribed regimen is within the FDA-approved dosing regimen. A current patient weight is required for all requests.
5. No other biologic agent will be used concurrently to treat this indication.

Inflectra (infliximab-dyyb) and Renflexis (infliximab-abda) – Coverage may be authorized when all of the following are met:

a. Medical necessity has been demonstrated based on all Remicade coverage criteria above, and 

b. Patient has tried and failed the following preferred anti-TNF agents:

c. Remicade, Enbrel, and Humira for Rheumatoid Arthritis, Psoriatic Arthritis, Plaque Psoriasis, or Ankylosing Spondylitis

d. Remicade and Humira for Crohn’s Disease or Ulcerative Colitis, and

e. Provider has documented a statement of medical necessity including rationale suggesting improved outcomes with Inflectra that could not be achieved with a preferred product.

Authorizations will be provided for one year.

Reauthorizations for biologic regimens of up to FDA-approved doses and frequencies

Renewals will be provided annually with provider attestation that they have seen the patient within the last fourteen months and the patient is benefiting from use of the medication. Initial approval is 60 days, renewals 6 months. 

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 22, 2025.

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 individuals 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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups ( eg, 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 ( eg, women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

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 individuals with systemic juvenile idiopathic arthritis (JIA) potentially treatable with tumor necrosis factor α (TNF-α) inhibitors.

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 interleukin-6 (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 individuals 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.^17, 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.^18,

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).^19, 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.^20,21,

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 juvenile idiopathic arthritis (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, quality of life (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 individuals with select rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors.

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.

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.^24,

Randomized Controlled Trials

Randomized trials of infliximab for Behcet syndrome are summarized in Tables 4 through 7. Moots et al (2024) published the results of a pragmatic, Bayesian design, RCT of infliximab or interferon alfa-2a in patients (N=79) with refractory Behcet syndrome.^25, All patients were biologic-naive. Most of the patients were White (British; 86%). The primary outcome was the Behcet Disease Activity Index (BDAI) score at 12 weeks. The mean difference in BDAI scores was 0.13 (80% credible interval, -0.19 to 0.46). Secondary outcomes were similar between groups. Steroid cessation was reported in 20% of patients who received infliximab and 44% of patients who received interferon alfa-2a.

Saadoun et al (2024) conducted a multicenter RCT that compared infliximab and cyclophosphamide in patients (N=52) with severe Behcet syndrome.^26, All patients had substantial vascular or neurological involvement. The primary outcome was complete response, which was defined as resolution of all baseline symptoms, normal C-reactive protein levels, and radiological remission and prednisone ≤0.1 mg/kg/day, measured at week 22. Results for the primary outcome showed that 81% of patients who received infliximab and 56% of patients who received cyclophosphamide achieved complete response at 22 weeks. Complete response was achieved in 73% of patients with vascular involvement and 60% with neurologic involvement. Relapse was observed in 1 patient who received infliximab and 4 patients who received cyclophosphamide.

Talarico et al (2024) conducted a multicenter RCT to evaluate the efficacy and safety of infliximab and adalimumab in patients (N=40) with mucocutaneous Behcet syndrome that was not responsive to traditional immunosuppressants.^27, Therapy was continued for 24 weeks and prior and concurrent therapy was allowed. Most of the patients were White (85.0%).The primary outcome was time to response, with response defined as remission of mucocutaneous manifestations. The median time to response was 42 days in the adalimumab group and 152 days in the infliximab group (p=.001). Response occurred in 64% of the infliximab group and 94% in the adalimumab group (p=.023). The risk of nonresponse was higher in the infliximab group (hazard ratio, 2.56; 95% CI, 1.22 to 5.26; p=.013).

Table 4. Summary of Key Randomized Controlled Trial Characteristics

Table 5. Summary of Key Randomized Controlled Trial Results

The purpose of the study limitations tables (see Tables 6 and 7) 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 6. Study Relevance Limitations

Table 7. Study Design and Conduct Limitations

Nonrandomized Studies

A single-arm prospective study performed at 21 institutions in Japan was published by Hibi et al (2016).^28, 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.

Cheon et al (2023) published another single-arm prospective study evaluating the efficacy of infliximab in participants with moderate to severe active intestinal Behçet disease.^29, A total of 33 patients received induction therapy with infliximab 5 mg/kg IV at weeks 0, 2, 6, and every 8 weeks thereafter. The mean disease activity index for intestinal Behçet disease (DAIBD) score decreased from 90.8 at week 0 to 40.3 at week 8 (mean change, 50.5; 95% CI, 37.5 to 63.4; p<.001). From weeks 0 to 32, the mean change in DAIBD score after maintenance therapy (infliximab 5 mg/kg IV every 8 weeks) was also statistically significant (mean change, 61.5; 95% CI, 46.0 to 77.1; p<.001). At week 32, 92.3% of patients maintained a clinical response.

Kehribar et al (2021) performed a single-center, retrospective cohort study in Turkey that evaluated 19 patients with Behçet disease with parenchymal neurological involvement.^30, 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.

Hibi et al (2024) published the results of a multicenter, prospective, observational study of infliximab for Behcet disease and intestinal, neurological, or vascular symptoms (N=255).^31, No new safety concerns were identified, and serious adverse events occurred in 14.9% of patients. At 2 years of follow-up, 68.8% of patients with intestinal disease had improved, and 100% and 91.7% of patients with neurological and vascular symptoms, respectively, had not worsened. The study was conducted in Japan, so it is possible that results would be different in a U.S. population.

Neuro-Behçet Disease

Mohammed & Woldeamanuel (2023) conducted a systematic review and meta-analysis on the effectiveness of infliximab treatment in neuro-Behçet disease.^32, A total of 21 studies (N=64) were included between January 2000 and May 2020, comprised of 4 open-label non-randomized single-arm interventional studies, 1 prospective cohort study, 2 case series, and 14 case reports. Overall, 93.7% of individuals responded to infliximab (95% CI , 0.880 to 0.993). The authors conclude infliximab yields homogenous therapeutic effectiveness in treating refractory neuro-Behçet disease. Limitations for this analysis include the lack of RCTs, small sample sizes with no comparator groups, and a lack of a standardized scoring among studies to assess treatment response in neuro-Behçet disease.

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 8 to 11).^33,34, 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 one study. Both studies included small sample sizes (N range of 89 to 177), and may have been underpowered to detect a difference between groups. A smaller observational study (N=50) also found no difference between infliximab, adalimumab, and certolizumab in patients with Behcet syndrome and uveitis.^35, 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 8. Summary of Characteristics of Observational Comparative Studies for Behçet Syndrome Uveitis

Table 9. Summary of Results of Observational Comparative Studies for Behçet Syndrome Uveitis

Table 10. Study Relevance Limitations

Table 11. Study Design and Conduct Limitations

Alizadegan et al (2022) published an additional retrospective, single-center, single-arm study in Turkey that evaluated infliximab therapy in 35 patients with Behçet syndrome uveitis refractory to conventional immunomodulatory treatment.^36, The mean follow-up was 49.5 months. Results demonstrated that the mean frequency of recurrences during infliximab treatment decreased from 1.47 attacks per year to 0.31 attacks per year (p<.001). Visual acuity also improved significantly in the first month of infliximab treatment (p=.026). Partial response to treatment was achieved in 91.4% of cases.

Sarcoidosis

Maneiro et al (2012) conducted a systematic review of sarcoidosis treatment with TNF blockers.^37, 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.^38, 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. Mahmood et al (2024) conducted a systematic review and meta-analysis of TNF inhibitors for cardiac sarcoidosis (8 single-arm studies, N=154 patients).^39, Significant findings included increase in ejection fraction (p<.001) and lower prednisone doses at 6 and 12 months (both p<.001). The authors concluded that high quality randomized trials are needed.

Analyses from a previously published randomized trial of 138 patients with pulmonary sarcoidosis were reported by Judson et al (2008).^40, 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.^41, Sakkat et al (2022) retrospectively investigated the effectiveness of infliximab in 33 patients with refractory sarcoidosis from 3 centers in Canada and the United Kingdom.^42, The most common indications for infliximab were pulmonary disease (n=14) and cutaneous disease (n=12), and the proportion of treatment success in these populations was 91.7% (95% CI, 61.5 to 99.8) and 78.6% (95% CI, 49.2 to 95.3), respectively.

Systemic Sclerosis (Scleroderma)

A systematic review by Phumethum et al (2011) evaluated 3 observational studies on biologics for systemic sclerosis.^43, 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 that anti-TNF agents did not demonstrate effectiveness in the treatment of Sjögren syndrome.^44, 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

Broderick et al (2024) conducted a review of intravenous immunoglobulin (IVIG) for the treatment of Kawasaki disease.^45, Four studies were reviewed comparing IVIG with infliximab as a secondary treatment for Kawasaki disease. There was no clear difference between IVIG and infliximab groups in the incidence of coronary artery abnormality (N=197; OR , 1.31; 95% CI , 0.46 to 3.74, P=.62) and incidence of adverse effects (N=201; OR , 1.13; 95% CI , 0.35 to 3.61; p=.84). Fewer individuals receiving infliximab required further (tertiary) treatment (N=199; OR , 3.99 ; 95% CI , 1.98 to 8.02 ; p<.001). The authors concluded that there was no clear evidence to support the effectiveness of IVIG compared to infliximab on the incidence of coronary artery abnormalities, adverse effects, duration of fever, length of hospital stay, acute coronary syndrome, or mortality due to a lack of statistical power in the data.

Wang et al (2024) conducted a systematic review and metanalysis of 14 randomized and non-randomized clinical trials (N=1257) to compare the efficacy of infliximab alone or in combination with IVIG to IVIG in the primary treatment of Kawasaki disease and retreatment in IVIG-resistant Kawasaki disease.^46, The primary outcome was effectiveness, defined as a response to study drug without a need for further treatments. In refractory Kawasaki disease, infliximab alone had a higher effectiveness rate (OR , 4.48; 95% CI , 2.67 to 7.52) compared to IVIG. In initial treatment of Kawasaki disease, infliximab with IVIG had a higher effectiveness rate (OR , 2.26; 95% CI , 1.02 to 5.01) compared to IVIG. There was no difference in coronary artery lesions or aneurysms between infliximab with IVIG versus IVIG in primary treatment or infliximab alone versus IVIG in retreatment. The reviewers concluded that, compared to standard treatment, infliximab alone is effective and safe for children with refractory Kawasaki disease, but there is limited efficacy for initial treatment of Kawasaki disease. Two noted limitations of this meta-analysis are that most studies were non-randomized with low level of evidence, and among the included RCTs, five were considered to have a high risk of bias.

Kabbaha et al (2022) performed a systematic review and meta-analysis of 4 RCTs (N=199) to compare infliximab versus intravenous immunoglobulins on the incidence of coronary artery aneurysms and treatment resistance in children with refractory Kawasaki disease.^47, The pooled risk ratio for treatment resistance in patients treated with infliximab was 0.40 (95% CI, 0.25 to 0.64). The risk ratio for the incidence of coronary artery aneurysms was 1.20 (95% CI, 0.54 to 2.63), for infusion reactions was 0.63 (95% CI, 0.18 to 2.22), and for infections was 0.55 (95% CI, 0.27 to 1.12). The overall certainty of the available evidence was rated very low for 3 RCTs and moderate for one RCT.

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 12 to 13).^48, The literature was searched through July 2019. No differences in coronary artery damage, coronary artery aneurysms, rate of non-response to 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).

Table 12. Comparison of Trials/Studies Included in Systematic Reviews & Meta-analyses

Table 13. Systematic Review and Meta-analyses Characteristics

Table 14. Results of Systematic Review and Meta-analyses of Tumor Necrosis Factor Inhibitors versus Placebo or Additional Treatment

Randomized Controlled Trials

A RCT by Burns et al (2021), which was completed in the US, 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.^50, 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.^67,

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. Small RCTs in patients with Behcet syndrome found that infliximab was more effective than cyclophosphamide, but not more effective than adalimumab. 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 tumor necrosis factor α (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. Small RCTs in patients with Behcet syndrome found that infliximab was more effective than cyclophosphamide, but not more effective than adalimumab. 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.

Behçet syndrome and Behçet syndrome uveitis

***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"

In 2014, the American Uveitis Society published expert panel recommendations on the use of biologic TNF-α blocking agents to treat ocular inflammatory diseases.^79, 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 disease, and for use of infliximab as first- or second-line treatment of acute flares of pre-existing Behcet disease

For individuals who have Behçet syndrome and Behçet syndrome uveitis potentially treatable with TNF-α inhibitors, current clinical guidance supports the use of infliximab as an alternative with failure of or intolerance to conventional therapy and biologic treatment. Both conditions are rare and Behçet syndrome uveitis is recognized clinically as difficult to treat.

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 individuals with selected vasculitides potentially treatable with TNF-α inhibitors.

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.^68, 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^69, 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.^70, 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.^71,

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.^72,

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 individuals with select nonrheumatic musculoskeletal and rheumatic conditions (via off-label use or intra-articular injection) potentially treatable with TNF-α inhibitors.

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 individuals 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.^73,74,

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.^75,

Preliminary studies have investigated infliximab for the treatment of sacroiliitis.^76,

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).^77, 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

Rheumatoid arthritis

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

With non - fistulizing Crohn’s disease > 6 years of age

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

With Ulcerative colitis > 6 years of age

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

With  Ankylosing spondylitis

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

Psoriatic Arthritis (PsA)

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

Psoriasis

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

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

Population Reference No. 12

With Fistulizing CD in children aged 6 years or older

Population Reference No. 13

With JIA with sacroiliitis, enthesitis, or uveitis

Population Reference No. 14

With Noninfectious uveitis

Population Reference No. 15

With Polyarticular and oligoarticular JIA

Population Reference No. 16

With RA without methotrexate

Population Reference No. 17

With Sarcoidosis

Population Reference No. 18

With Immune Checkpoint Inhibitor-Related Toxicities

Population Reference No. 19

With Hematopoietic Cell Transplantation

Population Reference No. 20

With Relapsing Polychondritis

Relapsing polychondritis (RP) is a rare and potentially fatal autoimmune disease that provokes an inappropriate immune response that destroys the cartilage of the ears, larynx and nose. The response can also affect structures in the cardiovascular system, peripheral joints, skin, middle and inner ear, and central nervous system. As a very rare disease, there are not many randomized trials or placebo-controlled studies conducted for patients with this disease. Other systemic diseases that share clinical characteristics with RP are granulomatosis with polyangiitis, rheumatoid arthritis, syphilis, reactive arthritis due to ocular involvement and sarcoidosis. In cases were there is life or organ threatening disease and there is resistance to initial therapy, or has not responded adequately to the combination of either cyclophosphamide, azathioprine or MTX with high dose oral glucocorticoids; the use of biological agents (TNF inhibitors as infliximab, or tocilizumab) resulted in the highest frequency of responses (60 to 70%) in a 14 year retrospective cohort of 41 patients exposed to 105 biologics. 

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 (Humira®; Abbott), and certolizumab pegol (Cimzia®; UCB) are administered via subcutaneous injection; golimumab (Simponi®; Janssen Biotech and Simponi® Aria; Janssen Biotech) is administered subcutaneously (Simponi) or intravenously (Simponi Aria); 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.

Regulatory Status

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

Table 1. Food and Drug Administration-Approved Indications for Tumor Necrosis Factor-α Inhibitors

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 Remicade 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)

• October 2023, Zymfentra™ (infliximab-dyyb; Celltrion)

Safety

Systematic reviews have focused on evaluating the safety of TNF inhibitors. Summaries of the findings are shown in Table 2. Tumor necrosis factor 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.^7,8, 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

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 2021 update of the 2011 and 2013 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis focused on systemic juvenile idiopathic arthritis.^78, 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 other biological disease-modifying antirheumatic drugs (DMARDs), including tumor necrosis factor (TNF)-α inhibitor therapy, in refractory cases.

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.^79, 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 disease, and for use of infliximab as first- or second-line treatment of acute flares of pre-existing Behcet disease.

Kawasaki Disease

In 2021, the American College of Rheumatology released a guideline for the treatment of Kawasaki disease.^80, For patients with acute Kawasaki disease who are at high risk of intravenous immune globulin (IVIG) resistance or developing coronary artery aneurysms, using IVIG with other nonglucocorticoid immunomodulatory immunosuppressive agents (such as infliximab, anakinra, or cyclosporine ) as initial therapy is conditionally recommended over treatment with IVIG alone. The guideline states that the addition of the nonglucocorticoid immunosuppressive agents may improve outcomes in acute disease and may also improve cardiac outcomes.

Vasculitides

In 2021, the American College of Rheumatology released a guideline for the treatment and management of vasculitis.^81, 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 15.

Table 15. Summary of Key Trials

References

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48. Jone PN, Anderson MS, Mulvahill MJ, et al. Infliximab Plus Intravenous Immunoglobulin (IVIG) Versus IVIG Alone as Initial Therapy in Children With Kawasaki Disease Presenting With Coronary Artery Lesions: Is Dual Therapy More Effective?. Pediatr Infect Dis J. Oct 2018; 37(10): 976-980. PMID 29461447
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50. Mori M, Hara T, Kikuchi M, et al. Infliximab versus intravenous immunoglobulin for refractory Kawasaki disease: a phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial. Sci Rep. Jan 31 2018; 8(1): 1994. PMID 29386515
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