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 response to 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 increased risk of malignancy, the literature is mixed; many recent meta-analyses have yet to demonstrate an increased risk overall, but some literature has indicated that TNF inhibitor therapy may increase the risk of developing skin cancer(s) and lymphoma. Two systematic reviews have compared safety among TNF inhibitors.^6,7 One reported no differences in adverse events between TNF inhibitors while the other found higher rates of adverse events and serious infections with infliximab 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 vs adalimumab 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 vs general 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 for non-preferred products there has been a trial and failure of ONE preferred therapy (Exceptions to the preferred therapy in the policy includes: pregnancy, breastfeeding, 17 years old and younger, members who previously attempted to switch agents and did not respond to therapy or had adverse event, and members whose disease is uncontrolled)..

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 methotrexate had better outcomes than those taking methotrexate alone 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 methotrexate groups, respectively. Inactive disease also continued for a longer duration in the infliximab group (mean, 26 weeks) than in the combination and methotrexate groups (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 systemic vasculitides 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 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.

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  

1. Food and Drug Administration (FDA). Highlights of Prescribing Information: Remicade (infliximab). 2015; https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/103772s5373lbl.pdf. Accessed September 22, 2018.
2. Food and Drug Administration (FDA). Highlight of Prescribing Information: Humira (adalimumab). 2017; https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125057s401lbl.pdf. Accessed September 22, 2018.
3. Food and Drug Administration (FDA). Highlights of Prescribing Information: Cimzia (certolizumab). 2017; https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125160s270lbl.pdf. Accessed September 22, 2018.
4. Food and Drug Administration (FDA). Highlights of Prescribing Information: Enbrel (etanercept). 2017; https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/103795s5551lbl.pdf. Accessed September 22, 2018.
5. Food and Drug Administration (FDA). Highlights of Prescribing Information: Simponi (golimumab). 2017; https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125289s133lbl.pdf. Accessed September 22, 2018.
6. Mocko P, Kawalec P, Pilc A. Safety profile of biologic drugs in the therapy of ulcerative colitis: a systematic review and network meta-analysis. Pharmacotherapy. Aug 2016;36(8):870-879. PMID 27312826
7. Desai RJ, Thaler KJ, Mahlknecht P, et al. Comparative risk of harm associated with the use of targeted immunomodulators: a systematic review. Arthritis Care Res (Hoboken). Aug 2016;68(8):1078-1088. PMID 26663412
8. Rungapiromnan W, Yiu ZZN, Warren RB, et al. Impact of biologic therapies on risk of major adverse cardiovascular events in patients with psoriasis: systematic review and meta-analysis of randomized controlled trials. Br J Dermatol. Apr 2017;176(4):890-901. PMID 27518205
9. Ramiro S, Gaujoux-Viala C, Nam JL, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. Mar 2014;73(3):529-535. PMID 24401994
10. Michaud TL, Rho YH, Shamliyan T, et al. The comparative safety of tumor necrosis factor inhibitors in rheumatoid arthritis: a meta-analysis update of 44 trials. Am J Med. Dec 2014;127(12):1208-1232. PMID 24950486
11. Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, et al. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA. Sep 05 2012;308(9):898-908. PMID 22948700
12. Moulis G, Sommet A, Bene J, et al. Cancer risk of anti-TNF-alpha at recommended doses in adult rheumatoid arthritis: a meta-analysis with intention to treat and per protocol analyses. PLoS One. Nov 2012;7(11):e48991. PMID 23155441
13. Wong AK, Kerkoutian S, Said J, et al. Risk of lymphoma in patients receiving antitumor necrosis factor therapy: a meta-analysis of published randomized controlled studies. Clin Rheumatol. Apr 2012;31(4):631-636. PMID 22147207
14. Askling J, Fahrbach K, Nordstrom B, et al. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf. Feb 2011;20(2):119-130. PMID 21254282
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
16. Kemper AR, Coeytaux R, Sanders GD, et al. Disease-Modifying Antirheumatic Drugs (DMARDs) in Children with Juvenile Idiopathic Arthritis (Comparative Effectiveness Review No. 28). Rockville, MD: Agency for Healthcare Research and Quality; 2011.
17. Shenoi S, Wallace CA. Tumor necrosis factor inhibitors in the management of juvenile idiopathic arthritis: an evidence-based review. Paediatr Drugs. Dec 1 2010;12(6):367-377. PMID 21028916
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
19. Tynjala P, Vahasalo P, Tarkiainen M, et al. Aggressive combination drug therapy in very early polyarticular juvenile idiopathic arthritis (ACUTE-JIA): a multicentre randomised open-label clinical trial. Ann Rheum Dis. Sep 2011;70(9):1605-1612. PMID 21623000
20. Katsicas MM, Russo RA. Use of infliximab in patients with systemic juvenile idiopathic arthritis refractory to etanercept. Clin Exp Rheumatol. Jul-Aug 2005;23(4):545-548. PMID 16095128
21. Billiau AD, Cornillie F, Wouters C. Infliximab for systemic onset juvenile idiopathic arthritis: experience in 3 children. J Rheumatol. May 2002;29(5):1111-1114. PMID 12022340
22. Arida A, Fragiadaki K, Giavri E, et al. Anti-TNF agents for Behcet's disease: analysis of published data on 369 patients. Semin Arthritis Rheum. Aug 2011;41(1):61-70. PMID 21168186
23. Hibi T, Hirohata S, Kikuchi H, et al. Infliximab therapy for intestinal, neurological, and vascular involvement in Behcet disease: Efficacy, safety, and pharmacokinetics in a multicenter, prospective, open-label, single-arm phase 3 study. Medicine (Baltimore). Jun 2016;95(24):e3863. PMID 27310969
24. Maneiro JR, Salgado E, Gomez-Reino JJ, et al. Efficacy and safety of TNF antagonists in sarcoidosis: data from the Spanish Registry of Biologics BIOBADASER and a systematic review. Semin Arthritis Rheum. Aug 2012;42(1):89-103. PMID 22387045
25. Judson MA, Baughman RP, Costabel U, et al. Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomised trial. Eur Respir J. Jun 2008;31(6):1189-1196. PMID 18256069
26. Loza MJ, Brodmerkel C, Du Bois RM, et al. Inflammatory profile and response to anti-tumor necrosis factor therapy in patients with chronic pulmonary sarcoidosis. Clin Vaccine Immunol. Jun 2011;18(6):931-939. PMID 21508170
27. Phumethum V, Jamal S, Johnson SR. Biologic therapy for systemic sclerosis: a systematic review. J Rheumatol. Feb 2011;38(2):289-296. PMID 21041277
28. Ramos-Casals M, Tzioufas AG, Stone JH, et al. Treatment of primary Sjogren syndrome: a systematic review. JAMA. Jul 28 2010;304(4):452-460. PMID 20664046
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
30. Burns JC, Mason WH, Hauger SB, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr. May 2005;146(5):662-667. PMID 15870671
31. Tremoulet AH, Jain S, Jaggi P, et al. Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double-blind, placebo-controlled trial. Lancet. May 17 2014;383(9930):1731-1738. PMID 24572997
32. Hommes DW, Erkelens W, Ponsioen C, et al. A double-blind, placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis. J Clin Gastroenterol. May-Jun 2008;42(5):522-526. PMID 18344886
33. Silva-Fernandez L, Loza E, Martinez-Taboada VM, et al. Biological therapy for systemic vasculitis: a systematic review. Semin Arthritis Rheum. Feb 2014;43(4):542-557. PMID 23978781
34. de Menthon M, Cohen P, Pagnoux C, et al. Infliximab or rituximab for refractory Wegener's granulomatosis: long-term follow up. A prospective randomised multicentre study on 17 patients. Clin Exp Rheumatol. Jan-Feb 2011;29(1 Suppl 64):S63-71. PMID 21586199
35. Hoffman GS, Cid MC, Rendt-Zagar KE, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med. May 1 2007;146(9):621-630. PMID 17470830
36. Visvanathan S, Rahman MU, Hoffman GS, et al. Tissue and serum markers of inflammation during the follow-up of patients with giant-cell arteritis--a prospective longitudinal study. Rheumatology (Oxford). Nov 2011;50(11):2061-2070. PMID 21873264
37. Salvarani C, Macchioni P, Manzini C, et al. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med. May 1 2007;146(9):631-639. PMID 17470831
38. Pimentel DC, El Abd O, Benyamin RM, et al. Anti-tumor necrosis factor antagonists in the treatment of low back pain and radiculopathy: a systematic review and meta-analysis. Pain Physician. Jan-Feb 2014;17(1):E27-44. PMID 24452656
39. Williams NH, Lewis R, Din NU, et al. A systematic review and meta-analysis of biological treatments targeting tumour necrosis factor alpha for sciatica. Eur Spine J. Sep 2013;22(9):1921-1935. PMID 23529742
40. Dirckx M, Groeneweg G, Wesseldijk F, et al. Report of a preliminary discontinued double-blind, randomized, placebo-controlled trial of the anti-TNF-alpha chimeric monoclonal antibody infliximab in complex regional pain syndrome. Pain Pract. Nov 2013;13(8):633-640. PMID 23692303
41. Barkham N, Keen HI, Coates LC, et al. Clinical and imaging efficacy of infliximab in HLA-B27-Positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum. Apr 2009;60(4):946-954. PMID 19333933
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
43. National Institute for Health and Care Excellence (NICE). TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis [TA383]. 2016; https://www.nice.org.uk/guidance/ta383. Accessed September 22, 2018.
44. Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol. May 2008;58(5):826-850. PMID 18423260
45. Rosenbach M, Hsu S, Korman NJ, et al. Treatment of erythrodermic psoriasis: from the medical board of the National Psoriasis Foundation. J Am Acad Dermatol. Apr 2010;62(4):655-662. PMID 19665821
46. Ringold S, Weiss PF, Beukelman T, et al. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. Oct 2013;65(10):2499-2512. PMID 24092554 

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 Blue Shield Association technology assessment program (TEC) and other nonaffiliated 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     

06/14/2022	Annual review, no change to policy intent, but, expansion of coverage statement regarding trial and failure of preferred therapy. No other changes.
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.