CAM 50115

Infliximab

Category:Prescription Drug   Last Reviewed:June 2021
Department(s):Medical Affairs   Next Review:June 2022
Original Date:June 2013    

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

For individuals with systemic juvenile idiopathic arthritis who receive infliximab, the evidence includes a small randomized controlled trial (RCT) with 60 children, several uncontrolled studies that have evaluated infliximab for individuals who have juvenile idiopathic arthritis, and case reports. Relevant outcomes are symptoms, change in disease status, health status measures, quality of life, and treatment-related morbidity. These studies did not differentiate populations based on the subtype of juvenile idiopathic arthritis. Two TNF-α inhibitor products have been approved by the Food and Drug Administration for polyarticular juvenile idiopathic arthritis. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with select rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors (e.g., 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 of a small number of RCTs for some conditions and multiple uncontrolled studies. Relevant outcomes are symptoms, change in disease status, health status measures, quality of life, and treatment-related morbidity. For most conditions, the results generally did not demonstrate any group differences. For some conditions (e.g., sarcoidosis, Sjögren syndrome), the few small RCTs available have not reported benefit. Uveitis is frequently a dominant feature of Behçet syndrome TNF-α inhibitor therapy other than infliximab has been approved by the Food and Drug Administration. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with vasculitides potentially treatable with TNF-α inhibitors (e.g., giant cell arteritis/ polymyalgia rheumatic, 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 systemicvasculitides and preliminary randomized trials. Relevant outcomes are symptoms, change in disease status, health status measures, quality of life, and treatment-related morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes. Evidence was contradictory for infliximab efficacy in antineutrophil cytoplasmic antibody-associated vasculitides and in large vessel vasculitides. There is limited high-quality data assessing for the use of infliximab for the systemic vasculitides (antineutrophil cytoplasmic antibody or non-antineutrophil cytoplasmic antibody subtypes). Cutaneous small vessel vasculitis has been reported as an adverse effect of TNF-α inhibitor therapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with nonrheumatic musculoskeletal conditions (e.g., arthritis [other than rheumatoid arthritis and psoriatic arthritis], sacroiliitis) or rheumatic joint disease refractory to tumor necrosis factor α inhibitors who receive infliximab off-label or intra-articular injection of infliximab, includes a systematic review, small RCTs and, nonrandomized studies. Relevant outcomes are symptoms, change in disease status, health status measures, quality of life, and treatment-related morbidity. None of the studies demonstrated a positive treatment effect. The evidence is insufficient to determine the effects of the technology on health outcomes.

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 FDA for infliximab and other TNF-α inhibitors (updated September 2018).

Table 1. FDA-Approved Indications for TNF-α Inhibitors

Conditions

Infliximab1,

Adalimumab2,

Certolizumab Pegol3,

Etanercept4,

Golimumab5,

Rheumatoid arthritis

Yes, with MTX and after CTF

Yes, alone or with MTX or DMARDs

Yes

Yes, alone or with MTX

Yes, with MTX

Juvenile idiopathic arthritis

No

Yes, with M-to-S polyarticular JIA for ages ≥2 y

Yes, for adults and children ≥6 y, after CTF

Yes, for polyarticular JIA at ages ≥2 y

No

Crohn disease

Yes, for adults and children ≥6 y, after CTF

Yes, for adults and children ≥6 y, after CTF

Yes, for adults, after conventional therapy failure

No

No

Ankylosing spondylitis

Yes

Yes

Yes

Yes

Yes

Psoriatic arthritis

Yes

Yes, alone or with DMARDs

Yes, for adults with active psoriatic arthritis

Yes, with MTX when responseto MTX alone is inadequate

Yes, alone or with MTX

Plaque psoriasis

Yes, when other systemic therapies are medically less appropriate

Yes, when other systemic therapies are medically less appropriate

Yes, for adults with M-to-S plaque psoriasis who are candidates for systemic therapy or phototherapy

Yes, for adults and children ≥4y who are candidates for systemic therapy or phototherapy

No

Ulcerative colitis

Yes, in adults and children ≥6 y, after CTF

Yes, after CTF

No

No

Yes, with inadequate response or intolerant to prior treatment or requiring continuous steroid therapy

Hidradenitis suppurativa

No

Yes, for adults with M-to-S disease

No

No

No

Noninfectious uveitis

No

Yes, for adults with intermediate, posterior, and panuveitis

No

Yes, for adults with intermediate, posterior, and panuveitis

No

CTF: conventional therapy failure; DMARD: disease-modifying antirheumatic drug; FDA: Food and Drug Administration; 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.

FDA requires notification to prescribers of the risks of invasive fungal infections and monitoring for malignancies with use of TNF blockers. In addition, in March 2013, 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,

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 increasedrisk 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 vs adalimumab or etanercept. Data on long-term safety remain scarce.

Table 2. Systematic Reviews of Safety of Infliximab and TNF Inhibitors 

Study

Dates

Studies/Patients

Population

Design

Summary of Safety Results

Rungapiromnan et al (2017)8,

Up to 2016

38/18,024

Psoriasis

RCTs

No increase in risk of major cardiovascular AEs with TNF inhibitors (OR=0.67; 95% CI, 0.10 to 4.63)

Mocko et al (2016)6,

Up to 2016

7/4952

M-to-S ulcerative colitis

RCTs

  • No difference in AEs, SAEs, or infections between infliximab and other TNF inhibitors

Desai et al (2016)7,

Up to 2015

61/>104,000

Ankylosing spondylitis, IBD, JAI, plaque psoriasis, psoriatic arthritis, RA

RCTs, OBS

  • Risk of treatment discontinuation due to AEs higher with infliximab vsadalimumab or etanercept. Risk for serious infections higher with infliximab vs abatacept, adalimumab, or etanercept.
  • No differences in risk detected for mortality, malignancies, and herpes zoster

Ramiro et al (2014)9,;

EULAR guidelines

Up to 2013

49/>85,000

RA

Cohort, registry

  • TNF inhibitors associated with increased risk of serious infections, skin infections (including herpes zoster), and TB reactivation
  • No increase in overall cancer risk but lymphoma and non-melanoma skin cancer risk increased vsgeneral population
  • Increased risk of melanoma vs other DMARDs

Michaud et al (2014)10,

 

1990-2013

44/11,700

RA

RCTs

  • TNF inhibitors associated with increased risk of serious infection (OR=1.4; 95% CI, 1.1 to 1.8), treatment discontinuation due to AEs (OR=1.2; 95% CI, 1.1 to 1.4) vs placebo and/or traditional DMARDs
  • No significantly increased risk of malignancy

Lopez-Olivo et al (2012)11,

2000-2015

63/29,423

RA

RCTs

No statistically increased risk of malignancy vs DMARDs or placebo with at least 6 mo of treatment; however, risk increased for lymphoma (OR=2.1; 95% CI, 0.6 to 8.4) for TNF inhibitors vs controls

Moulis et al (2012)12,

1983-2010

33/7029

RA

RCTs

No statistically increased risk of malignancy vs DMARDs or placebo with up to 2 y of treatment; marginally increased risk of non-melanoma skin cancer (OR=1.9; 95% CI, 1.0 to 3.7)

Wong et al (2012)13,

2000-2009

14/7485

RA

RCTs

Increased risk of lymphoma (RD=1.3 lymphomas per 1000 person-years; 95% CI, -0.2 to 2.8; p=0.09)

Askling et al (2011)14,; EMA request

Up to 2010

74/22,904

Any disease condition

RCTs

For anti-TNF vs comparators (RR=1.0; 95% CI, 0.6 to 1.7 for cancers excluding non-melanoma skin cancer; RR=2.0; 95% CI, 1.1 to 4.0 for non-melanoma skin cancer)

Singh et al (2011)15,

Up to 2010

209/61,964

Any disease condition except HIV/AIDS

RCTs, CCTs, OLE

  • Higher rate of total AEs for biologics vs controls (OR=1.2; 95% CI, 1.1 to 1.3); increased risk of TB reactivation (OR=4.7; 95% CI, 1.2 to 18.6). Infliximab associated with higher risk of withdrawals due to AEs (OR=2.0; 95% CI, 1.4 to 2.9).
  • No increased rate of SAEs, serious infections, lymphoma, and congestive heart failure

AE: adverse event; CCT: controlled clinical trial; CI: confidence interval; DMARD: disease-modifying antirheumatic drug; EULAR: European League Against Rheumatism; EMA: European Medicines Agency; 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.

Related Policies
20484 Measurement of Serum Antibodies to Infliximab and Adalimumab 

Policy

REMICADE (infliximab)
INFLECTRA (infliximab-dyyb)
RENFLEXIS (infliximab-abda) 
AVSOLA (infliximab-axxq)

Coverage of these drugs is provided when the criteria below is met and there has been a trial and failure of preferred therapy.

Infliximab may be considered MEDICALLY NECESSARY for the following condition:

Fistulizing Crohn’s Disease

  • reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing Crohn’s disease*;

Rheumatoid Arthritis

  • in combination with methotrexate, reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis* in patients who have had inadequate response to one or more DMARDs (disease-modifying antirheumatic drugs ( i.e., methotrexate, sulfasalazine);

Crohn’s Disease

  • reducing signs and symptoms, inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy*; (i.e., sulfasalazine, mesalamine products, corticosteroids, 6-mercaptopurine, azathioprine, cyclosporine, methotrexate);

Ankylosing Spondylitis

  • reducing signs and symptoms in patients with active ankylosing spondylitis*; in patients who have not had an adequate response to TWO conventional therapy; (i.e., nonsteroidal anti-inflammatory drugs (NSAIDs), sulfasalazine, methotrexate);

Psoriatic Arthritis

  • reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with psoriatic arthritis who have had inadequate response to one or more DMARDs* (disease-modifying anti-rheumatic drugs (i.e., methotrexate, sulfasalazine);

Plaque Psoriasis

  • for the treatment of adult patients with chronic severe (i.e., extensive and /or disabling) plaque psoriasis who are candidates for systemic therapy and when topical therapies, other systemic therapies (i.e., methotrexate), and phototherapy are medically less appropriate*;

Ulcerative Colitis

  • for reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in patients with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy* (i.e., corticosteroids, azathioprine, 6-mercaptopurine).

*Indicates FDA-approved indication.

While there isn't clinical trial evidence to support the following medical diagnoses to be treated with infliximab, they will be considered a compendial use and may be allowed as MEDICALLY NECESSARY:

  • Behcet's Syndrome
  • Hidradenitis suppurativa
  • Juvenile idiopathic arthritis
  • Sarcoidosis AFTER:
    • Trial and failure, contraindication, or intolerance to corticosteroids (e.g., prednisone)
    • Trial and failure, contraindication, or intolerance to one immunosuppressant (e.g., methotrexate (Rheumatrex, Trexall), Cytoxan (cyclophosphamide), or Imuran (azathioprine))
  • Uveitis

Other uses of infliximab are considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY, including, but not limited to:

  • age-related macular degeneration;
  • alcoholic hepatitis;
  • arthritis (other than rheumatoid arthritis and psoriatic arthritis);
  • cancer cachexia;
  • depression;
  • diabetic macular edema;
  • endometriosis;
  • erythrodermic or exfoliative psoriasis;
  • giant cell arteritis;
  • graft-versus-host disease;
  • intra-articular injections;
  • Kawasaki syndrome;
  • polyarteritis nodosa;
  • polymyalgia rheumatica;
  • renal cell carcinoma;
  • sacroiliitis;
  • sclerosing cholangitis;
  • Sjogren syndrome;
  • systemic lupus erythematosus;
  • systemic necrotizing vasculitides
  • systemic sclerosis
  • Wegener’s granulomatosis.

CONTINUATION OF THERAPY

  • Documentation of positive clinical response to therapy for all diagnoses.
  • Documentation of positive clinical response to therapy as evidenced by ONE of the following for plaque psoriasis: 
    • Reduction of the body surface area (BSA) involvement from baseline 
    • Improvement in symptoms (e.g., pruritus, inflammation) from baseline

Biosimilars

  • Inflectra (infliximab-dyyb)
  • Renflexis (infliximab-abda)
  • Ixifi (infliximab-qbtx) 

Policy Guidelines
Infliximab is typically administered initially in a 3-dose induction regimen followed by maintenance therapy every 8 weeks in patients who respond. 

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all drugs approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational and thus, may only be assessed based on medical necessity.
 

Based on benefits or contract language, infliximab may be considered either a pharmacy or medical benefit.

Rationale

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

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

Systemic Juvenile Idiopathic Arthritis
Clinical Context and Test 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).

The question addressed in this evidence review is: Does the use of infliximab to treat systemic JIA improve the net health outcome.

The following PICOTS were used to select literature to inform this review.

Patients
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 secretion of proinflammatory cytokines (e.g., tumor necrosis factor α [TNF-α]interleukin-1, interleukin-6) in systemic JIA creates targets for biologic therapy.Infliximab, as well as another TNF-α inhibitor (etanercept), are labeled for use in the polyarticular form of JIA.

Interventions
The therapy being considered is infliximab.

Comparators
Comparators of interest include other nonbiologic therapies, other TNF-αinhibitors (e.g., etanercept, adalimumab), and interleukin-1 and interleukin-6 inhibitors. Treatment of patients with JIAtypically includes a regiment of corticosteroids and anti-inflammatory drugs.

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

Timing
Follow-up assessment of the treatment effect of infliximab should be made at 6, 13, and 26 weeks.

Setting
Patients with systemic JIA are actively managed by rheumatologists, pediatricians, and primary care physicians in an outpatient clinical setting.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

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 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 the Food and Drug Administration (FDA) approval for this indication.17,

Randomized Controlled Trials
Ruperto et al. (2010) reported on an open-label extension trial of infliximab for JIA in 78 children.18, However, this study was limited by the high number of patients who discontinued infliximab treatment (42 [58%] patients) for various reasons. Of the remaining 36 patients, 40% achieved American College of Rheumatology Pediatric 50 response criteria at week 204, whereas 33% achieved American College of Rheumatology Pediatric 70 during this time period. Thirteen percent of patients achieved inactive disease status.

In a report of a multicenter, 54-week, randomized, open-label trial of JIA (N=60) by Tynjala et al. (2011), patients taking infliximab plus methotrexatehad better outcomes than those taking methotrexatealone or in combination with sulfasalazine and hydroxychloroquine.19, In patients taking infliximab, all 19 achieved American College of Rheumatology Pediatric 75 compared with 13 (65%) of 20 on combination treatment and 10 (50%) of 20 on methotrexate. Thirteen (68%) of patients taking infliximab achieved inactive disease status compared with 8 (40%) and 5 (25%) in the combination and methotrexategroups, respectively. Inactive disease also continued for a longer duration in the infliximab group (mean, 26 weeks) than in the combination and methotrexategroups (mean, 13 weeks and 6 weeks).

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
The evidence for infliximab in patients who have JIA includes systematic reviews, an RCT with 60 children, and uncontrolled studies. These studies do not differentiate study populations based on the subtype of JIA. There are 2 FDA-approved TNF-α inhibitor products for polyarticular JIA. Evaluation of infliximab to treat systemic JIA is limited to case reports.

Select rheumatic or autoimmune conditions
Clinical Context and Test Purpose
The purpose of infliximab off-label 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 and autoimmune conditions improve the net health outcome?

The following PICOTS were used to select literature to inform this review.

Patients
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 a corticosteroid therapy, other TNF-α inhibitors, and other biologic DMARDs.

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

Timing
Follow-up assessment of the treatment effect of infliximab for select rheumatic and autoimmune conditions should be through 24 weeks.

Setting
Patients with other rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors are actively managed by rheumatologists, condition-specific specialists, and primary care physicians in an outpatient clinical setting.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Behçet Disease
An evidence-based review by Arida et al. (2011) suggested that there may be a role for biologics in the treatment of Behçet disease.22, A single-arm prospective study performed at 21 institutions in Japan was published by Hibi et al. (2016).23, Eighteen participants diagnosed with complete or incomplete Behçet disease, neurologic Behçet, or vascular Behçet disease 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. Further study and the implementation of additional RCTs are needed.

Uveitis is frequently a dominant feature of Behçet syndrome. It is typically bilateral and episodic, often involves the entire uveal tract (pan uveitis), and may not resolve completely between episodes. TNF-α inhibitor therapy other than infliximab has been approved by the FDA.

Sarcoidosis
Maneiro et al. (2012) conducted a systematic review of sarcoidosis treatment with TNF blockers.24, Reviewers found insufficient evidence to support the use of TNF blockers for the treatment of sarcoidosis.

Analyses from a previously published randomized trial of 138 patients with pulmonary sarcoidosis were reported by Judson et al. (2008).25, 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.26,

Systemic Sclerosis (Scleroderma)
A systematic review by Phumethum et al. (2011) evaluated 3 observational studies on biologics for systemic sclerosis.27, 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.28, Included in the review were 2 placebo-controlled trials of infliximab and etanercept, and 2 trials of fewer than 30 patients. In 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
Preliminary studies have investigated infliximab for the treatment of refractory Kawasaki disease.29,30. Tremoulet et al. (2014) conducted a phase 3, double-blind RCT in 196 children (age, 4 weeks to 17 years) with active (fever ≥38°C) Kawasaki disease.31, Patients were randomized 1:1 to a single dose of infliximab or placebo administered before IV immunoglobulin therapy. There was no statistical between-group difference in the primary outcome (immunoglobulin resistance) defined as return or persistence of fever (11% both groups, p=0.81). The observed reductions (noted at week 2) in fever duration, serum inflammatory markers, and left anterior descending coronary artery dimension did not persist to week 5.

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.32,

Section Summary: Select Rheumatic or Autoimmune Conditions
Individuals with various treatment-refractory rheumatic or autoimmune conditions are potentially treatable with TNF-α inhibitors. The evidence for the following conditions: Behçet syndrome, Behçet syndrome uveitis, sarcoidosis, systemic sclerosis, Sjögren syndrome, Kawasaki disease, and primary sclerosing cholangitis, consists of systematic reviews of small RCTs in these conditions. Results generally did not demonstrate any group differences. Uveitis is frequently a dominant feature of Behçet syndrome. It is typically bilateral and episodic, often involves the entire uveal tract (pan uveitis), and may not resolve completely between episodes. TNF-α inhibitor therapy other than infliximab has been approved by the FDA for noninfectious uveitis.

VASCULITIDES
Clinical Context and Test Purpose
The purpose of infliximab off-label 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 the off-label infliximab for the treatment of selected vasculitides improve net health outcomes?

The following PICOTS were used to select literature to inform this review.

Patients
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 rheumatics, 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 (e.g., corticosteroid therapy), other TNF-α inhibitors, and other biologic DMARDs.

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

Timing
Follow-up assessment of the treatment effect of infliximab for select vasculitides should be through 24 weeks.

Setting
Patients with other rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors are actively managed by rheumatologists, condition-specific specialists, and primary care physicians in an outpatient clinical setting.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

Systematic Reviews
Silva-Fernandez et al. (2014) conducted a systematic review of biologic therapies for systemic vasculitides.33, 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, an 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 granulomatosis34, 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.35, 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.36,

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.37,

Section Summary: Vasculitides
There is limited high-quality data assessing for the use of infliximab for the systemic vasculitides (antineutrophil cytoplasmic antibody or non-antineutrophil cytoplasmic antibody subtypes). Cutaneous small vessel vasculitis has been reported as an adverse effect of TNF-α inhibitor therapy

OTHER NONRheumatic MUSCULOSKELETAL and rheumatic CONDITIONS
Clinical Context and Test Purpose
The purpose of infliximab off-label or intra-articular injection 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 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 PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with joint pain and symptoms caused by select nonrheumatic musculoskeletal (e.g., 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 (e.g., corticosteroid therapy), other TNF-αinhibitors, and other biologic DMARDs.

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

Timing
Follow-up assessment of the treatment effect of infliximab for select musculoskeletal conditions should be through 24 weeks.

Setting
Patients with musculoskeletal conditions potentially treatable with TNF-α inhibitors are actively managed by rheumatologists, condition-specific specialists, and primary care physicians in an outpatient clinical setting.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
  • Studies with duplicative or overlapping populations were excluded.

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 treatment of these conditions.38,39.

Randomized Controlled Trials
A placebo-controlled randomized trial by Dirckx et al. (2013), who assessed 13 patients with complex regional pain syndrome, found statistically significant reductions in quality of life in patients who received infliximab.40,

Preliminary studies have investigated infliximab for the treatment of sacroiliitis.41,

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), who evaluated 23 patients (41 total intra-articular injections: 20 infliximab and 21 methylprednisolone).42, In this trial, improvements were greater with methylprednisolone.

Section Summary: Nonrheumatic Musculoskeletal and Rheumatic Conditions
The evidence on off-label infliximab for individuals who have other nonrheumatic musculoskeletal and refractory rheumatic conditions potentially treatable with TNF-α inhibitors includes a systematic review, small RCTs and, nonrandomized studies. None of the studies demonstrated a positive treatment effect.

Summary of Evidence
For individuals with systemic JIA who receive infliximab, the evidence includes a small RCT with 60 children, several uncontrolled studies that have evaluated infliximab for individuals who have JIA, and case reports. Relevant outcomes are symptoms, change in disease status, health status measures, quality of life, and treatment-related morbidity. These studies did not differentiate populations based on the subtype of JIA. Two TNF-α inhibitor products have been approved by the Food and Drug Administration for polyarticular JIA. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with select rheumatic or autoimmune conditions potentially treatable with TNF-α inhibitors (e.g., 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 of a small number of RCTs for some conditions and multiple uncontrolled studies. Relevant outcomes are symptoms, change in disease status, health status measures, quality of life, and treatment-related morbidity. For most conditions, the results generally did not demonstrate any group differences. For some conditions (e.g., sarcoidosis, Sjögren syndrome), the few small RCTs available have not reported benefit. Uveitis is frequently a dominant feature of Behçet syndrome TNF-α inhibitor therapy other than infliximab has been approved by the Food and Drug Administration. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with vasculitides potentially treatable with TNF-α inhibitors (e.g., giant cell arteritis/ polymyalgia rheumatic, 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 systemicvasculitides and preliminary randomized trials. Relevant outcomes are symptoms, change in disease status, health status measures, quality of life, and treatment-related morbidity. The evidence is insufficient to determine the effects of the technology on health outcomes. Evidence was contradictory for infliximab efficacy in antineutrophil cytoplasmic antibody-associated vasculitides and in large vessel vasculitides. There is limited high-quality data assessing for the use of infliximab for the systemic vasculitides (antineutrophil cytoplasmic antibody or non-antineutrophil cytoplasmic antibody subtypes). Cutaneous small vessel vasculitis has been reported as an adverse effect of TNF-α inhibitor therapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with nonrheumatic musculoskeletal conditions (e.g., arthritis [other than rheumatoid arthritis and psoriatic arthritis], sacroiliitis) or rheumatic joint disease refractory to TNF-α inhibitorswho receive infliximab off-label or intra-articular injection of infliximab, includes a systematic review, small RCTs and, nonrandomized studies. Relevant outcomes are symptoms, change in disease status, health status measures, quality of life, and treatment-related morbidity. None of the studies demonstrated a positive treatment effect. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements
National Institute for Health and Care Excellence
The National Institute for Health and Care Excellence (2016) published guidance on tumor necrosis factor α (TNF-α) inhibitors for ankylosing spondylitis and nonradiographic axial spondyloarthritis.43, The Institute recommended TNF-α inhibitors as options, when within their marketing authorizations, for adults with ankylosing spondylitis or nonradiographic axial spondyloarthritis who have failed nonsteroidal anti-inflammatory drugs.

Plaque Psoriasis and Psoriatic Arthritis
American Academy of Dermatology
The American Academy of Dermatology (2008) released guidelines on the management of psoriasis and psoriatic arthritis.44, These guidelines addressed the treatment of adult and childhood psoriasis and psoriatic arthritis, including biologics. The guidelines gave a strength of evidence grade of A for the use of the following TNF inhibitors: adalimumab, etanercept, and infliximab.

National Psoriasis Foundation
These recommendations indicated infliximab and cyclosporine were first-line agents that act rapidly for treatment of this indication. However, the availability of data on the treatment of erythrodermic psoriasis was limited, and the need for further study noted.

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.46, 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 TNF-α inhibitor therapy in refractory cases.

Vasculidites
An American College of Rheumatology guideline for the treatment and management of vasculitis is at the project plan stage with final publication anticipated in late 2019 or early 2020.

U.S. Preventive Service Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing or unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials 

NCT Number Trial Name Planned Enrollment Completion Date
Ongoing 
NCT02363738 A Multisite, Fixed Dose, Randomized, Double-Blind, Placebo-Controlled 12-Week Study Evaluating the Efficacy, Safety, and Tolerability of Adjunctive Infliximab for the Treatment of Bipolar I/II Depression  60  Apr 2018 (ongoing) 
NCT02356445

Outcome of Use of Cytotoxic Drugs for Inflammatory Lung Diseases
(Sarcoidosis and will include infliximab)

2,000 Dec 2018
NCT01485055 Infliximab and Basiliximab for Treatment of Steroid Refractory Acute Graft Versus Host Disease 44 Dec 2018
NCT03065244 KIDCARE (Kawasaki Disease Comparative Effectiveness Trial) 250 Sep 2020

NCT: national clinical trial.

References  

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  15. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. Feb 16 2011(2):CD008794. PMID 21328309
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  18. Ruperto N, Lovell DJ, Cuttica R, et al. Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension. Ann Rheum Dis. Apr 2010;69(4):718-722. PMID 20237125
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  29. Burns JC, Best BM, Mejias A, et al. Infliximab treatment of intravenous immunoglobulin-resistant Kawasaki disease. J Pediatr. Dec 2008;153(6):833-838. PMID 18672254
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  42. van der Bijl AE, Teng YK, van Oosterhout M, et al. Efficacy of intraarticular infliximab in patients with chronic or recurrent gonarthritis: a clinical randomized trial. Arthritis Rheum. Jul 15 2009;61(7):974-978. PMID 19565559
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Coding Section

Codes Number Description
CPT 96365 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
  96366 Each additional hour (list separately in addition to code for primary procedure)
ICD-9 Procedure    
ICD-9 Diagnosis 555.0-555.9 Regional enteritis code range (includes Crohn’s disease)
  556.0-556.9 Ulcerative colitis code range
  696.0 Psoriatic arthropathy
  696.1 Other psoriasis
  714.0 Rheumatoid arthritis
  720.0-720.9 Ankylosing spondylitis and other inflammatory spondyloarthropathies, code range
HCPCS J1745 Injection, infliximab, 10 mg
  Q5103  Injection, infliximab-dyyb, biosimilar, (inflectra), 10 mg   
  Q5104  Injection, infliximab-abda, biosimilar, (renflexis), 10 mg   
  Q5121 (effective 7/1/2020)  Injection, infliximab-axxq, biosimilar, (AVSOLA), 10 mg 
ICD-10-CM (effective 10/01/15) K50.00-K50.919 Crohn’s disease code range
  K51.00-K51.919 Ulcerative colitis code range
  K52.81 Eosinophilic gastritis or gastroenteritis
  K52.9 Noninfective gastroenteritis and colitis unspecified
  L40.50-L40.59 Arthropathic psoriasis code range
  L40.8 Other psoriasis
  M06.80-M06.89 Other specified rheumatoid arthritis code range
  M06.9 Rheumatoid arthritis unspecified
  M45.0-M45.9 Ankylosing spondylitis code range
ICD-10-PCS (effective 10/01/15)   ICD-10-PCS codes are only for use on inpatient services. There is no specific ICD-10-PCS code for this procedure.
Type of Service Prescription Drug  
Place of Service Outpatient  

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

06/21/2021 

Annual review, no change to policy intent 

05/14/2021 

Interim review to add Coverage of these drugs is provided when the criteria is met and there has been a trial and failure of preferred therapy, update drug list and coding. 

06/18/2020 

Annual review. Updating policy for specificity in relation to sarcoidosis, continuation of therapy and biosimilars. 

06/17/2020 

Updated coding. Added Code Q5121 to be effective 7/1/2020. No other changes. 

06/12/2019 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

06/13/2018 

Annual review, no change to policy intent. 

06/19/2017

Annual review, adding a compendial use list to the policy, updating the list of investigational uses in the policy. Also updating background, description, regulatory status, rationale and references. 

07/18/2016 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

06/30/2015 

Annual review, no change to policy intent. Updating background, description, rationale and references. Adding regulatory status and coding. 

06/10/2014

Annual review. Added related policy, updated background, rationale and references. No change to policy intent.


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