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MP 5.01.15 Infliximab

Medical Policy    
Section
Prescription Drugs
Original Policy Date
2/15/02
Last Review Status/Date
Reviewed with literature search/10:2013
Issue
10:2013
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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically. 


Description

Infliximab (Remicade® Centocor) is a tumor necrosis factor a (TNF-α) blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. Infliximab is administered via intravenous infusion.

Background

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

There are a number of TNF-α blocking agents; etanercept (Enbrel®, Amgen); adalimumab (Humira®, Abbott); certolizumab (Cimzia®, UCB) administered via subcutaneous injection and infliximab (Remicade® Centocor) administered via an intravenous (IV) infusion in the physician's office, outpatient setting, or infusion center. This policy focuses on infliximab that is administered in the physician's office and is thus typically adjudicated under the medical benefit.

The initial labeled indications for infliximab by the U.S. Food and Drug Administration (FDA) included treatment of rheumatoid arthritis, fistulizing Crohn's disease, and inducing remission in patients with moderately to severely active Crohn's disease that has had an inadequate response to conventional therapy. In 2002, the FDA approved an additional indication for maintaining clinical remission in Crohn’s disease. Maintenance therapy is designed to prevent disease flares in patients with quiescent disease; the drugs most commonly used are azathioprine and 6-mercaptopurine. This new, labeled indication markedly broadens the clinical indications for patients with Crohn's disease. In December 2004, the FDA approved infliximab for the treatment of ankylosing spondylitis, and in early 2005, the FDA approved infliximab for the treatment of psoriatic arthritis. In September 2005, the FDA approved infliximab for the treatment of “reducing signs and symptoms, achieving 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.” In May 2006, the FDA approved infliximab for use in pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. In September 2006, the FDA approved infliximab for patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate. The need for close monitoring and regular follow-up visits with a physician is noted in the FDA approval. In 2011, the FDA approved infliximab for use in pediatric patients ages 6 years and older for the treatment of ulcerative colitis. As of December 2008, infliximab-labeled indications were compared to those for TNF blocking agents adalimumab, certolizumab, and etanercept.

TNF

Blocking

Agent

Rheumatoid Arthritis

Juvenile Idiopathic Arthritis

Crohn’s Disease

Ankylosing Spondylitis

Psoriatic Arthritis

Plaque Psoriasis

Ulcerative Colitis

Infliximab

Yes

in combination with MTX

after treatment failure with conventional therapy

No indication

Yes

after treatment failure with conventional therapy

fistulizing CD

in children age 6 years and older

Yes

Yes

after treatment failure with conventional therapy

Yes

when other systemic therapies are medically less appropriate

Yes

after treatment failure with conventional therapy

in children age 6 years and older

Adalimumab

Yes

alone or in combination with MTX or DMARDs

Yes

ages 4 years and older

Yes

after treatment failure with conventional therapy and infliximab

Yes

Yes

in combination with DMARDs

Yes

when other systemic therapies are medically less appropriate

No indication

Certolizumab

Yes

No indication

Yes

after treatment failure with conventional therapy

No indication

No indication

No indication

No indication

Etanercept

Yes

alone or in combination with MTX

Yes

ages 2 years and older

No indication

Yes

Yes

in combination with MTX when response to MTX alone is inadequate

Yes

candidates for systemic therapy or phototherapy

No indication

Yes: agent has an approved indication; CD: Crohn’s disease; MTX: methotrexate; DMARDs: disease-modifying antirheumatic drugs.

On September 4, 2008, the FDA released an FDA Alert notifying healthcare professionals that histoplasmosis and other invasive fungal infections are not consistently recognized in patients taking tumor necrosis factor-α blockers (TNF blockers) certolizumab pegol (Cimzia), etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade). This situation has resulted in delays in appropriate treatment, sometimes resulting in death. The FDA will require the makers of the tumor necrosis factor-α blockers (TNF blockers) to further highlight the information about the risk of invasive fungal infections, such as histoplasmosis, in the Boxed Warning and Warnings sections of the drugs’ prescribing information and the Medication Guide for patients. The FDA will also require that the makers of the TNF blockers educate prescribers about this risk. Subsequently, in August 2009, the FDA added another Boxed Warning indicating there is an increased risk of lymphoma and other cancers associated with the use of TNF blockers in children and adolescents. In November 2011, the FDA began requiring TNF blocker manufacturers to perform additional safety surveillance, consisting of in-depth follow-up of reports of malignancy cases and expedited reporting of malignancy to the FDA (within 15 days of becoming aware of the report) for pediatric and young adult patients. Annual summaries and assessments of malignancies and TNF blocker utilization data will also be required by the FDA from the manufacturers.

In March 2013, the FDA issued further warnings and precautions regarding malignancies and concurrent administration of infliximab with other biological agents. (1) For Malignancies, under section 5.2, the FDA stated that “the incidence of malignancies including lymphoma was greater in Remicade-treated patients than in controls. Due to the risk of HSTCL [hepatosplenic T cell lymphoma] providers should carefully assess the risk/benefit, especially if the patient has Crohn’s disease (CD) or ulcerative colitis, is male, and is receiving azathioprine or 6-mercaptopurine treatment.” For Concurrent Administration with other Biological Therapeutics, under section 5.11, the FDA stated that “there is insufficient information regarding the concomitant use of Remicade with other biological therapeutics used to treat the same conditions as Remicade. The concomitant use of Remicade with these biologics is not recommended because of the possibility of an increased risk of infection.” (1)


Policy

Infliximab may be considered medically necessary as first-line therapy (i.e., initial treatment) 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*;

Infliximab may be considered medically necessary as second-line therapy (i.e., for use when first-line therapy fails or is not tolerated) for the following conditions:

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 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 antirheumatic 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.

Other uses of infliximab are considered investigational, including, but not limited to:

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


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 this may be assessed only on the basis of its medical necessity.

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


Rationale

This policy was originally created in 2002 and was updated with searches of the MEDLINE database. The most recent literature search was performed for the period of July 2012 through September 11, 2013. The following is a summary of the key literature to date.

Tumor Necrosis Factor Blocker Safety

In 2012, a meta-analysis of lymphoma risk from tumor necrosis factor (TNF) blocker treatment was published by Wong and colleagues. (2) The meta-analysis included 14 randomized controlled clinical trials (RCTs) and included 5,179 patients treated with TNF blockers and 2,306 controls. Lymphoma occurred in 11 patients treated with TNF blockers (0.21%), whereas 4 patients in the control groups (0.17%) developed hematolymphoid neoplasms; this was not statistically significant (p<0.05).

A 2011 meta-analysis of 74 RCTs of TNF blockers found cancer was diagnosed in 0.84% (130/15,418) of patients randomized to TNF blocker treatment, whereas, 0.64% (48/7486) of patients randomized to comparator groups were diagnosed with cancer. (3) However, this meta-analysis examined diagnosis of cancer in the short term, i.e., between the time period of starting TNF blocker treatment and 30 days after completed treatment. The need for long-term studies to further evaluate cancer risk with TNF treatment was noted. In a 2011 Cochrane meta-analysis and overview, 163 RCTs and 46 extension studies on biologics, totaling 61,964 patients, were evaluated for adverse effects. (4) There was no statistically significant difference between biologics and comparators in the rate of serious adverse events including infection, lymphoma and heart failure. However, risk of withdrawal was significantly higher with infliximab than control (odds ratio [OR]: 2.04, 95% confidence interval [CI]: 1.43-2.91; number needed to harm=12, 95% CI: 8-28). The need for long-term studies to further evaluate the safety of biologics was also noted.

Ankylosing Spondylitis

In 2013, Machado and colleagues performed a meta-analysis of RCTs to evaluate the efficacy and safety of the various anti-TNF agents for the treatment of ankylosing spondylitis. (5) The primary outcome was the ASAS 20 response, which is defined by the Assessment of SpondyloArthritis international Society (ASAS) as a reduction by at least 20% and 10 units (visual analog scale from 0 to 100) in at least 3 of the following domains: patient global assessment lumbar pain, physical function, and inflammation (without a worsening of >20% and 10 units in the remaining fourth domain). Seven (of 18) trials included in this review (published through September 2012) assessed the effects of infliximab; 5 of infliximab with placebo, one of infliximab and methotrexate versus methotrexate and placebo, and one of infliximab versus etanercept. Under subgroup analyses, at 12/14 weeks, the golimumab presented the highest relative risk (RR): for ASAS 20 response (2.74, 95% CI: 1.78-4.22), followed by adalimumab (RR: 2.33; 95% CI: 1.45-3.74), etanercept (RR: 2.13; 95% CI: 1.75-2.58), and infliximab (RR: 1.82; 95% CI: 1.16-2.58). After 24 weeks, only one study of each anti-TNF agent remained in the meta-analysis and the highest RR was related to infliximab (RR: 3.18; 95% CI: 1.99-5.08), followed by etanercept (RR: 2.53; 95% CI: 1.80-3.57) and adalimumab (RR: 2.15; 95% CI: 0.96-4.83). The incidence of adverse events was not significantly different between the groups. (5)

Significantly higher rates for ASAS 20 response (as with other outcome measures) was also reported with anti-TNF agents compared to placebo in another meta-analysis published in 2013 by Ren and colleagues, with most adverse events in both treatment groups being of mild or moderate in severity. (6) It is important to consider the limitations of the included trials in both systematic reviews, especially in regard to investigating rare adverse events that were not the primary outcome of any study. These limitations are mainly the result of 3 factors: small sample sizes, short follow-up periods, and selection criteria that exclude patients with recent infections, a history of neoplasms, and significant comorbidities.

In 2012, Migliore and colleagues conducted a systematic review and Bayesian mixed treatment comparison of the effects of TNF-α blockers (infliximab, etanercept, and adalimumab) for the treatment of ankylosing spondylitis. (7) Included in the comparison were 3 randomized controlled trials (RCTs) that evaluated Assessment in Ankylosing Spondylitis (ASAS) response criteria. All 3 TNFs examined were found to be more effective than placebo in achieving ASAS 20. However, infliximab was found to have an approximately 7 times greater probability of treatment response (OR: 6.8) compared to etanercept (5 times; OR: 4.9) or adalimumab (4 times; OR: 4.4). Limitations to this analysis include few available studies, differences in study designs, and a fixed comparison model.

A 2007 systematic review examined the comparative clinical effectiveness and cost-effectiveness of adalimumab, etanercept, and infliximab for the treatment of ankylosing spondylitis. (8) Nine placebo-controlled RCTs were included in the review of clinical effects. These included 2 studies of adalimumab, 5 of etanercept, and 2 of infliximab in comparison with placebo (along with conventional management). No RCTs directly comparing anti-TNF-α agents were identified. Meta-analyses were conducted for data on ASAS (20%, 50%, and 70% improvement, respectively), mean change in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and mean change in Bath Ankylosing Spondylitis Functional Index (BASFI) at 12 weeks following initiation of anti-TNF-α therapy or placebo for all 3 drugs. Meta-analyses were also conducted at 24 weeks for etanercept and infliximab. Each meta-analysis of anti-TNF-α therapy demonstrated statistically significant advantages over placebo, although there was no significant difference between individual anti-TNF-α agents. At 12 weeks, ASAS 50% responses were 3.6-fold more likely with anti-TNF-α treatment than placebo. Compared with baseline, BASDAI scores were reduced by close to 2 points at 12 weeks. Functional scores (BASFI) were reduced at 12 weeks. Six full economic evaluations (2 peer-reviewed published papers, 4 abstracts) were included in the review. The conclusions among economic evaluations were mixed, although the balance of evidence indicates that over short timeframes anti-TNF-α therapies are unlikely to be considered cost-effective. The limitations of the clinical outcome data impose restrictions on the economic assessment of cost-effectiveness. Direct unbiased randomized controlled trial evidence is only available in the short term. Current assessment tools are limited and, at present, BASDAI and BASFI are the best available, although not designed for, or ideal for, use in economic evaluations. The review of the 3 models submitted to National Institute for Health and Clinical Excellence (NICE) identified a number of inherent flaws and errors. The incremental cost-effectiveness ratios (ICERs) of etanercept and adalimumab were roughly similar, falling below an assumed willingness-to-pay threshold of 30,000 pounds. The ICER for infliximab was in the range of 40,000–50,000 pounds per quality-adjusted life-year (QALY). The short-term (12-month) model developed by this report's authors confirmed the large front-loading of costs with a result that none of the 3 anti-TNF-α agents appears cost effective at the current acceptable threshold, with infliximab yielding much poorer economic results (57,000–120,000 pounds per QALY). The assumptions of the short-term model were used to explore the cost-effectiveness of the use of anti-TNF-α agents in the long term.

In conclusion, the review of clinical data related to the 3 drugs (including conventional treatment) compared with conventional treatment plus placebo indicates that in the short term (12–24 weeks), the 3 treatments (adalimumab, etanercept, and infliximab) are clinically effective in relation to assessment of ASAS, BASDAI, and BASFI. Indirect comparisons of treatments were limited and did not show a significant difference in effectiveness between the 3 agents. The short-term economic assessment indicates that none of the 3 anti-TNF-α agents is likely to be considered cost-effective at current acceptability thresholds, with infliximab consistently the least favorable option. (8)

Inflammatory Bowel Disease

In 2013, Costa and colleagues published a meta-analysis on the rates of hospitalizations and surgery in patients with inflammatory bowel disease treated with infliximab (Crohn’s disease [CD] and ulcerative colitis [UC]). (9) Twenty-seven eligible studies (published through May 2012) were included (9 RCTs and 18 observational studies). Overall, 1,912 patients were evaluated in these trials (1,076 with CD, and 836 with UC). Infliximab treatment was associated with a significant odds reduction of hospitalization risk in comparison to controls, both in RCTs (OR: 0.51; 95% CI: 0.40-0.65; I2 test for heterogeneity=0%) and observational studies (OR: 0.29; 95% CI: 0.19-0.43; I2=87%). The magnitude of this risk reduction was similar across patients with CD and UC. In patients with CD, the RCTs and observational findings on overall major surgery rate were consistent. Infliximab treatment was associated with a significant odds reduction of overall major surgery risk in comparison to controls, in both RCTs (OR: 0.31; 95% CI: 0.15-0.64; I2=0%) and observational studies (OR: 0.32; 95% CI: 0.21-0.49; I2=77%). In patients with UC, pooled results from RCTs and observational studies on overall major surgery rate were different. Infliximab treatment was associated with a significant 43% odds reduction of overall major surgery risk in RCTs (OR: 0.57; 95% CI: 0.37-0.88; I2=0%); on the other hand, a nonsignificant increase was found in pooled results from observational studies (OR: 1.43; 95% CI: 0.65-3.13; I2=76%). There were several limitations with this meta-analysis including potential selective reporting and failure to describe withdrawals (attrition bias) in the included RCTs, and presentation of unadjusted risk estimates in observational studies. In addition, there was significant heterogeneity in the findings from observational studies, and 3 (of 18) studies were published in abstract form. (9)

In 2012, Lichtenstein and colleagues published a pooled analysis on the safety of long-term infliximab treatment, with/without concomitant immunomodulators, for CD and UC across 10 industry-sponsored studies. (10) These studies included 5 RCTs contributing data from patients who received intravenous infliximab 5 mg or 10 mg /kg (n=1,713; ± azathioprine) or placebo (n= 406; ± azathioprine). No significant increase in infections, serious infections, or malignancy with infliximab versus placebo was reported in patients with inflammatory bowel disease. For example, when expressed on the basis of incidence (95% CI) per 100 patient-years of follow-up, overlapping 95% confidence intervals indicated that the incidences of malignancies were similar in the placebo- and infliximab-treated patients with CD (1.61 (0.19-5.82) vs. 0.49 (0.18-1.06), respectively) and with UC (0.00-1.43) vs. 0.60 (0.20-1.40), respectively). (10)

Crohn’s Disease

In 2013, Rosenfeld and colleagues published a meta-analysis of studies comparing the rates of postoperative complications among CD patients treated with Infliximab therapy versus alternative therapies. (11) Data were extracted from 6 observational studies (published through October 2012) including 1,159 patients, among whom 413 complications were identified. The most common complications were wound infections, anastomotic leak and sepsis. There was no significant difference in the major complication rate (OR: 1.59; 95% CI: 0.89-2.86; p=0.15), minor complication rate (OR, 1.80; 95% CI: 0.87-3.71; p=0.11), reoperation rate (OR: 1.33; 95% CI: 0.55-3.20; p=0.52) or 30-day mortality rate (OR: 3.74; 95% CI: 0.56-25.16; p=0.13) between the infliximab and control groups. Key limitations of this meta-analysis included a high degree of heterogeneity in the analyses of major complication rates given the observational study designs. In addition, the included studies varied in terms of severity, location and duration of disease, as well as the type of surgical procedure, whether it looked at single or multiple surgical procedures and the method (laparoscopic or open) of surgery. (11)

In 2013, Yoshida and colleagues published a prospective, Japanese single-center, RCT to assess the efficacy of scheduled maintenance infliximab monotherapy to prevent postoperative CD recurrence. (12) Thirty-one CD patients who had undergone ileocolic resection within the past 4 weeks were randomly assigned to scheduled infliximab at 5 mg/kg intravenously every 8 weeks for 36 months (n=15) or without infliximab (control arm on conventional medication (if any), n=16). All patients were treated without immunomodulator or corticosteroid following surgery. The primary and secondary endpoints were remission rates at 12 and 36 months, defined as CD Activity Index (CDAI) ≤150, an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score <2, and C-reactive protein (CRP) <0.3 mg/dL. Additionally, endoscopic recurrences at 12 and 36 months were evaluated. At 12 and 36 months, 100%, and 93% of patients in the infliximab group were in remission (IOIBD <2), respectively vs. 69% and 56% in the control arm (p<0.03). Similarly, 87% and 87% of patients in the infliximab group maintained serological remission (CRP <0.3 mg/dL) versus 37.5% and 37.5% in the control arm (p<0.02). In addition, the infliximab group achieved higher endoscopic remission at 12 months, 79% versus 19% (p=0.004). However, in the Kaplan–Meier survival analysis the CDAI scores between the 2 arms were not significantly different either at 12 or at 36 months. No adverse events were observed. Future multicenter trials in larger cohorts of patients and over a longer time period need to be undertaken to confirm these findings. (12)

A 2011 systematic review of 11 RCTs of infliximab and adalimumab for the treatment of Crohn’s disease (CD) found both agents improved outcomes in moderate to severe and fistulizing Crohn’s disease compared to placebo. (13) A multicenter open-label randomized controlled trial (RCT) from Europe of 133 patients with active CD who had not been previously treated with corticosteroids, antimetabolites, or biological agents and who were assigned either early combined immunosuppression (infliximab plus either azathioprine or methotrexate) or conventional management (induction with corticosteroids and sequentially adding antimetabolites [azathioprine or methotrexate] and infliximab) with 2-year follow-up, found that early immunosuppression was more effective than conventional therapy for preventing disease progression. (14) At 26 weeks, 60% versus 36% of the early immunosuppression and conventional treatment groups were in remission (remission rates were statistically different at 1 year [62% and 42%, respectively] but not at 2 years). Corticosteroid, but not antimetabolite, usage was lower, and the median time to relapse was longer in the early immunosuppression group (329 days vs. 175 days). Safety profiles were similar, although the study was not powered to detect safety differences. In 2010, results of the randomized, double-blind SONIC trial were reported. (15) In the SONIC trial, 508 adult patients with moderate to severe Crohn’s disease received either infliximab monotherapy, azathioprine monotherapy, or a combination of these 2 drugs. At week 26, corticosteroid-free clinical remission was achieved in 56.8% (96/169) of combination therapy patients, 44.4% (75/169) of infliximab monotherapy patients (p=0.02), and 30.0% (51/170) of azathioprine monotherapy patients (comparison with combination therapy p<0.001; and comparison with infliximab p=0.006). At week 50, numerical trends were similar. Mucosal healing at week 26 had occurred in 43.9% (47/107) of combination therapy patients, 30.1% (28/93) of infliximab patients (p=0.06), and 16.5% (18/109) of azathioprine patients (comparison with combination therapy p<0.001, comparison with infliximab p=0.02).

A systematic review examined the evidence for the effectiveness of TNF-α blocking agents in the maintenance of remission in patients with CD refractory to conventional treatments, including corticosteroids and immunosuppressants. In the reviewed RCTs, patients older than 18 years with CD who had a clinical response or clinical remission with a TNF-α blocking agent, or patients with CD in remission but unable to wean corticosteroids, were randomized to maintenance of remission with a TNF-α blocking agent or placebo. Outcome measures reported in the primary studies included clinical remission, clinical response, and steroid-sparing effects. Nine studies met all inclusion criteria. Pooled results from 3 RCTs found that infliximab maintains clinical remission (risk ratio [RR]: 2.50; 95% CI: 1.64-3.80), clinical response (RR: 2.19; 95% CI: 1.27-3.75), fistula healing (RR: 1.87; 95% CI: 1.15-3.04) and has corticosteroid-sparing effects (RR: 3.13; 95% CI: 1.25-7.8), in patients with CD responsive to infliximab induction therapy. There is evidence from 2 randomized controlled trials that adalimumab maintains clinical remission to week 54 (RR: 3.28; 95% CI: 2.13-5.06), has higher rates of steroid-free remission at week 26 and week 56 versus placebo (6% placebo, versus 29% adalimumab), and is superior to placebo for maintenance of steroid-free remission to week 54 (RR: 4.24; 95% CI: 1.57-11.47). There was evidence from 1 randomized controlled trial comparing certolizumab pegol to placebo, which found certolizumab pegol to be effective for maintenance of clinical remission (RR: 1.68; 95% CI: 1.30-2.16) and clinical response (RR: 1.74; 95% CI: 1.41-2.13) to week 26.

The authors concluded infliximab 5 mg/kg or 10 mg/kg, given every 8 weeks, is effective for the maintenance of remission and maintenance of fistula healing in patients who have responded to infliximab induction therapy. Adalimumab, 40 mg weekly or every other week, is effective for the maintenance of remission in patients who have responded to adalimumab induction therapy. Certolizumab pegol, 400 mg every 4 weeks, is effective for the maintenance of remission in patients who have responded to certolizumab induction therapy. No comparative trials have evaluated the relative efficacy of these agents. Adverse events are similar in the infliximab, adalimumab, and certolizumab groups compared with placebo, but study size and duration generally are insufficient to allow an adequate assessment of serious adverse events associated with long-term use. (16)

A review article examined the evidence base of both established treatments (such as enteral nutrition, corticosteroids, 5-aminosalicylates, and immunosuppressive agents) and emerging treatments (such as the anti-TNF-α agents, infliximab and adalimumab) used to induce and maintain remission in CD. The authors conclude exclusive enteral nutrition is recommended as the first-line of treatment for the induction of remission in pediatric CD. Corticosteroids are also effective for inducing remission but may be associated with significant adverse events. Patients with chronically active CD may benefit from immunosuppressive agents such as azathioprine and methotrexate. Infliximab is effective for inducing remission in patients who continue to have significant active disease, despite the use of conventional treatments. Adalimumab may be indicated for patients who develop a svere allergic reaction to infliximab or those who initially respond to infliximab but subsequently lose their response. Treatments that have been shown to be effective for the maintenance of remission include azathioprine, methotrexate, infliximab, and adalimumab. Recent evidence also suggests that long-term enteral nutritional supplementation with patients taking about half of their daily calorie requirements as enteral nutrition may be an effective strategy for the maintenance of remission in CD. (17)

A meta-analysis examined placebo-controlled trials to evaluate safety and efficacy of TNF antagonists for CD. The primary endpoints were clinical remission for luminal CD and fistula closure at greater than or equal to 2 consecutive visits. Ten studies evaluated anti-TNF treatment of fistulizing CD, involving 776 patients. In overall analysis, anti-TNF therapy was effective for fistula closure only in maintenance trials after open-label induction (mean difference, 16%; 95% CI: 8-25%; p<0.001). In 21 studies enrolling 5,356 individuals, anti-TNF therapy did not increase the risk of death, malignancy, or serious infection. The authors concluded infliximab, adalimumab, and certolizumab are effective in luminal CD. Efficacy of anti-TNF agents other than infliximab in treating fistulizing CD requires additional investigations. A longer duration of follow-up and a larger number of patients are required to better assess the safety profile of TNF antagonists in CD. (18)

A review article explored conventional and emerging treatments for CD and ulcerative colitis. The authors discuss 5-aminosalycylic acid agents (mesalamine, olsalazine), a mainstay in the treatment of both CD and ulcerative colitis. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy. Nonsystemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal ulcerative colitis, respectively, are also effective in mild-moderate disease. 6-mercaptopurine and its pro-drug azathioprine are steroid-sparing immunomodulators, effective in the maintenance of remission of both CD and ulcerative colitis, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the United States and Europe for the treatment of CD, and infliximab is also approved for the treatment of ulcerative colitis. (19) A systematic review and meta-analysis of infliximab treatment given preoperatively to patients with Crohn’s disease (CD) was published in 2012 by Kopylov et al. (20) This review found an increase in postoperative infections associated with preoperative infliximab and “a trend toward an increased risk of noninfectious and overall complications.” In another systematic review and meta-analysis in 2011, Ehteshami-Afshar and colleagues also found an increase in postoperative infections in patients using infliximab for inflammatory bowel disease. (21) Pouch-related complications, sepsis and thrombotic events were also more common in patients using infliximab. However, as the reviewers noted, patients receiving infliximab usually have more severe disease and have been refractory to other treatments, thereby, possibly being more susceptible to increased complications.

Several studies have reported on the use of infliximab for pediatric CD. In the REACH trial, 112 children, age 6-17 years, with severe CD [Pediatric Crohn's Disease Activity Index (PCDAI) score >30] that responded inadequately to standard therapy were given infliximab intravenous therapy. (22) Those patients that responded to infliximab therapy at 10 weeks were randomized to 5 mg/kg every 8 or 12 weeks. After 10 weeks of treatment, 88.4% (99/112) of patients responded to infliximab, and 58.9% (66/112) of patients reached clinical remission. After 54 weeks of treatment, clinical remission was achieved in more patients on an 8-week infliximab schedule than compared to a 12-week schedule (55.8% [29/52] vs. 23.5% [12/51], respectively). At 46 weeks, 60 patients continued infliximab treatment for 3 more years in the open-label extension trial. (23) Infliximab was effective in decreasing disease activity to no disease or mild disease in approximately 80% of patients. Serious infection occurred in 10% (6 patients).

In conclusion, the clinical data related to the use of TNF blocking agents in the treatment of CD indicates that infliximab, adalimumab, and certolizumab pegol are effective for the maintenance of remission in patients who have responded to induction therapy. The efficacy of anti-TNF agents, other than infliximab, in treating fistulizing CD requires additional investigation. Studies with longer duration of follow-up and larger number of patients are required to better assess the long-term safety profile of TNF antagonists in CD.

Ulcerative Colitis

The 2005 approval by the U.S. Food and Drug Administration (FDA) of infliximab for the treatment of ulcerative colitis (UC) was based in part on the results of ACT 1 and ACT 2 randomized studies. (24) These studies enrolled patients with disease refractory to at least 1 standard therapy, including corticosteroids, immunosuppressants, or mesalamine. Patients received infliximab or placebo infusions at 0, 2, and 6 weeks and then every 8 weeks thereafter. The ACT 1 trial continued infusions until week 46, with final evaluation at week 54. In contrast, the ACT 2 trial continued infusions until week 22, with final evaluation at week 30. The primary endpoint of both trials was induction of clinical response, while secondary endpoints included clinical remission. In both studies, the infliximab group had a significant improvement in both clinical response and clinical remission at all time points studied. Also, a significantly greater percentage of patients in the infliximab group were able to discontinue steroids while in clinical remission. Based on the results of these studies, the FDA gave infliximab priority review. In 2012, Reinisch and colleagues reported on the long-term extension trial on 229 patients from the ACT-1 and ACT-2 trials. (25) The safety profile during the extension trial was consistent with the original trials, and infliximab continued to be effective for up to 3 years. However, infliximab was discontinued in 70 (30.6%) patients due to adverse events, lack of efficacy, and other reasons.

In 2013, Chang and colleagues performed a meta-analysis to evaluate the outcomes of UC patients receiving infliximab or cyclosporine as rescue therapy in acute severe steroid-refractory exacerbations. (26) Six retrospective cohort studies (published through May 2012) describing 321 patients met the inclusion criteria. The meta-analysis did not show significant differences between infliximab and cyclosporine in the 3-month colectomy rate (odds ratio (OR): 0.86; 95% CI: 0.31-2.41, p=0.775), in the 12-month colectomy rate (OR: 0.60; 95% CI: 0.19-1.89, p=0.381), in adverse drug reactions (OR 0.76; 95% CI: 0.34-1.70; p=0.508), and in postoperative complications (OR: 1.66; 95% CI: 0.26-10.50; p=0.591). Several limitations need to be acknowledged in this meta-analysis, including study populations being uncontrolled and potentially heterogeneous, discrepancies in the dosage and serum levels of cyclosporine used across studies, and the accrual period of these studies ranging from 1993 to 2011, a period that has seen major advancement in the use of laparoscopic surgical techniques and devices, which may a major impact on the overall management of these patients and contributed to their operative outcomes. (26)

In 2012, Yang and colleagues performed a meta-analysis of observational studies (published through August 2012) to determine the relationship between preoperative infliximab use and early postoperative complications in UC patients undergoing abdominal surgery. (27) A total of 13 studies involving 2,933 patients were included in this meta-analysis. There was no significant association between infliximab therapy preoperatively and total (OR: 1.09; 95% CI: 0.87-1.37, p=0.47), infectious (OR: 1.10; 95% CI: 0.51-2.38, p=0.81) and noninfectious (OR: 1.10; 95% CI: 0.76-1.59, p=0.61) postoperative complications, respectively. A significantly decreased risk for infectious complications was reported with infliximab use within 12 weeks prior to surgery (OR: 0.43; 95% CI: 0.22-0.83, p=0.01). No publication bias was observed across studies. However, significant heterogeneity was observed when combining these studies with regard to the infectious complications. (27)

In a 2011 systematic review of pediatric ulcerative colitis treatment, data from 6 studies on infliximab, consisting of 126 pediatric patients, yielded a short-term pooled response of 75% (95% CI: 67-83%) with a 1-year pooled response of 64% (95% CI: 56-72%). (28) The FDA approval of infliximab for pediatric use in 2011 was based on data from a Phase 3 randomized, multicenter, open-label study of moderately to severely active ulcerative colitis patients aged 6-17 years. (29) Patients in the study were refractory or unable to tolerate standard therapy with 6-mercaptopurine, azathioprine, corticosteroids, or 5-aminosalicylate. In this study, 73% (44/60) of patients responded to infliximab at 8 weeks. Adverse events were similar to infliximab use in adult populations. In a 2010 prospective multicenter study, children with severe ulcerative colitis were treated with infliximab after failed intravenous corticosteroids. (30) Twenty-five out of 33 patients responded to infliximab, which was considered to be effective,

Additional, reviews of infliximab for the treatment of ulcerative colitis were published in 2009 and 2010. (31, 32) The reviews found infliximab treatment is appropriate for acute exacerbations of severely active ulcerative colitis when cyclosporine is not appropriate or contraindicated.

Juvenile Idiopathic Arthritis

In August 2011, the Agency for Healthcare Research and Quality (AHRQ) published a Comparative Effectiveness Review of disease-modifying anti-rheumatic drugs (DMARDs) for children with juvenile idiopathic arthritis (JIA). (33) The review found available evidence on biologic DMARDs is limited although symptom improvement has been reported. Heterogeneous studies and reporting of outcomes, as well as varied categories of JIA make meaningful comparisons of DMARDs difficult. Additionally, many questions remain regarding the safety of DMARDs in children, especially since there is a risk of malignancy, particularly lymphoma, with the use of TNF-α blocking agents.

Ruperto and colleagues reported on an open-label extension trial of infliximab for juvenile idiopathic arthritis in 78 children. (34) However, this study is limited by the high number of patients who discontinued infliximab treatment (42 patients) for various reasons. Of the remaining 36 patients, 40% achieved American College of Rheumatology (ACR)-Pedi 50 response criteria at week 204, whereas 33% achieved ACR-Pedi 70 during this time period. Inactive disease status was achieved in 13% of patients.

In a 2011 report of a multicenter, 54-week, randomized, open-label trial of 60 patients with juvenile idiopathic arthritis, by Tynjala, et al, infliximab plus methotrexate was found to result in better outcomes than methotrexate alone or in a combination of methotrexate, sulfasalazine, and hydroxychloroquine. (35) In patients receiving TNF, 100% (19/19) achieved ACR-Pedi 75 compared to 65% (13/20) on combination treatment and 50% (10/20) on methotrexate. Inactive disease status was achieved in 13 TNF patients versus 8 and 5 in the combination and methotrexate groups, respectively. Inactive disease also continued for a longer duration in the TNF group compared to the combination and methotrexate groups (mean 26 weeks versus 13 weeks and 6 weeks, respectively). A 2010 evidence-based review notes that infliximab is frequently used to treat JIA in clinical practice, despite not having FDA approval for this indication. (36)

Plaque Psoriasis and Psoriatic Arthritis

In 2012, the Agency for Healthcare Research and Quality (AHRQ) published a comparative effectiveness review to examine the benefits and harms of anti-TNF/biologic systemic agents compared with nonbiologic systemic agents or phototherapy in patients with chronic plaque psoriasis. (37) In total, 5 RCTs (n=1,227) and 4 observational studies (n=1,066) published through June 2012 were included in the AHRQ review. These studies directly compared either a systemic biologic agent with a systemic nonbiologic agent or phototherapy and reported at least one outcome of interest. Five RCTs (2 good, 2 fair, and one poor quality) and 2 fair-quality observational studies evaluated the comparative effectiveness of systemic biologic agents and systemic nonbiologic agents. The comparisons made included adalimumab, etanercept, infliximab, and ustekinumab versus methotrexate and etanercept versus acitretin. The comparative effectiveness of these therapies with regard to final health outcomes other than health-related quality of life (HRQOL) could not be determined because of a lack of evaluation in the included literature. When comparing infliximab with methotrexate, HRQOL was improved in patients taking infliximab, based on a single RCT (low strength of evidence). There was insufficient evidence to evaluate myocardial infarction and diabetes mellitus, and no other final health outcomes were reported. The evidence base for the comparative safety of systemic biologic agents and systemic nonbiologic agents or phototherapy was sparse. Overall, 5 RCTs (2 good, 2 fair, and one poor quality) and 2 observational studies (both fair quality) directly compared biologics with nonbiologics and reported at least one adverse outcome of interest; there were no studies which directly compared infliximab with other biologics/agents in the evaluation of harms. Additional RCTs or large observational studies and registries that directly compare individual drugs/interventions across these agents are needed to further examine the benefits and harms of these agents for treatment in patients with chronic plaque psoriasis. These trials should be adequately powered to assess final health outcomes that are important to decision makers, such as mortality, major adverse cardiovascular events, and psychological outcomes. Future analyses using indirect comparisons may also help supplement lack of direct comparative data. (37)

In 2013, 2 systematic reviews were published to assess the effectiveness and safety of anti-TNF agents in the treatment of psoriatic arthritis. These reviews reported no significant differences in effectiveness and overall adverse reactions between the available anti-TNF agents in patients with psoriatic arthritis. (38, 39)

In 2012, the Agency for Healthcare Research and Quality (AHRQ) issued an update of its 2007 report on drug therapy for adult psoriatic arthritis. (40) The review found available evidence on biologic DMARDs is limited, although symptom improvement has been reported. The reviewers noted firm conclusions could not be drawn about the comparative efficacy, effectiveness, functional status, health-related quality of life, or tolerability of DMARDs, including infliximab.

In 2011, a systematic review of infliximab, etanercept or adalimumab for psoriasis concluded each of these 3 agents was effective in reducing skin disease and joint symptoms. (41) Synthesis of the evidence found infliximab was more effective in improving skin and joint outcomes over etanercept and adalimumab. In another 2011 systematic review and meta-analysis, the risk of infections and lymphoma from TNF blocker treatment for psoriatic disease was examined from 20 studies. The risk of overall infection was odds ratio (OR): 1.18 (95% CI: 1.05-1.33). The risk of serious infection was OR: 0.70 (95% CI: 0.40-1.21). Malignancy OR was 1.48 (95% CI: 0.71-3.09).

RCTs comparing the effectiveness of TNF-α blocking agents for psoriatic arthritis are lacking. Migliore and colleagues conducted a mixed treatment comparison analysis of etanercept, infliximab, and adalimumab and found the greatest American College of Rheumatology (ACR) 20 response compared to placebo occurred with etanercept. (42) In a systematic review and meta-analysis in 2012, Reich and colleagues compared biologics available in Europe for the treatment of moderate to severe psoriasis in adults. (43) Included in the analysis were 4 RCTs on infliximab. Using Bayesian methods to estimate comparative effectiveness, the highest predicted mean probability of response occurred with infliximab at psoriasis area and severity index (PASI) levels 50 (93%), 75 (80%), and 90 (54%), followed by ustekinumab 90 mg, ustekinumab 45 mg, adalimumab, etanercept and efalizumab. In another 2012 systematic review and meta-analysis, Lucka et al. found infliximab and ustekinumab were most effective over a 24-week treatment period followed by adalimumab and etanercept. (44) The effectiveness of infliximab, adalimumab, and etanercept decreased after 24 weeks. However, these analyses are limited by the use of indirect comparisons.

The infliximab multinational psoriatic arthritis controlled trial (IMPACT) was a randomized study of infliximab as a treatment of psoriatic arthritis. (45) A secondary outcome focused on improvements in dermatologic manifestations of psoriasis. A total of 104 patients with psoriatic arthritis participated in this randomized, placebo-controlled and blinded study. Of these, only 39 had significant psoriatic skin lesions, as evidenced by a PASI score of equal to or greater than 2.5. (The maximum PASI score is 72. The score reflects lesional erythema, scaling, and thickness in 4 anatomic areas.) Patients received infliximab or placebo at 0, 2, 6, and 14 weeks. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab every 8 weeks through week 50, while patients randomized to infliximab continued to receive active treatment. Changes in the PASI score were analyzed for the 39 patients with skin lesions; 68% of infliximab patients achieved improvement of equal to or greater than 75% in the PASI score at week 16 compared to none in the placebo group. However, interpretation of these results is limited. The sample size was only 39 patients. In addition, patients were recruited to this trial based on arthritic manifestations with previous failure of one or more disease-modifying anti-rheumatic drugs (DMARDs). In contrast, it is not known whether previous therapies had been successful in controlling dermatologic manifestations of psoriasis.

Gottlieb and colleagues reported on a larger trial of 249 patients with severe plaque psoriasis who were randomized to receive an infusion of 1 of 2 different doses of infliximab or placebo at 0, 2, and 6 weeks. (46) In contrast to the IMPACT study, which enrolled patients with a PASI score of equal to or greater than 2.5, this study was limited to patients with a PASI score of 12 or greater and with psoriatic plaques covering at least 10% of their body surface. The primary endpoint was the proportion of patients who achieved at least 75% improvement in the PASI score from baseline at week 10. At week 10, 72% of patients treated with infliximab (3 mg/kg) and 88% of patients treated with infliximab (5 mg/kg) achieved a 75% or greater improvement from baseline in the PASI score, compared to 6% in the placebo group (p<0.001). While no studies directly compared various agents, these positive results were considered similar to that associated with cyclosporine, better than that associated with etanercept (another anti-TNF), and better than other topical agents. Results from this larger trial demonstrated that infliximab is an effective alternative in patients with moderately severe psoriasis who meet study criteria.

In 2010, Atteno and colleagues reported on a randomized trial of 100 patients treated with infliximab, etanercept, or adalimumab for psoriatic arthritis. (47) All 3 agents were effective in controlling signs and symptoms of psoriatic arthritis at 12 months.

In 2012, Baranauskaite et al. reported on a randomized, open-label study comparing infliximab with methotrexate to infliximab alone in 115 patients with psoriatic arthritis in the RESPOND study. (48) Infliximab with methotrexate resulted in greater improvements in outcomes and disease suppression than methotrexate alone. In the intention-to-treat analysis at 16 weeks, 44 of 51 patients (86.3%) achieved an American College of Rheumatology (ACR) 20 response on infliximab with methotrexate versus 32 of 48 patients (66.7%) in the methotrexate only group. (p=0.021). ACR 50 and ACR 70 responses were also significantly greater in the combination treatment group. Improvements in PASI scores were also statistically significantly greater at each time point in the combination treatment group. The mean reduction in PASI score by 16 weeks was 93.3% in the combination group and 67.4% in the methotrexate only group (p=0.0029). While adverse events were higher in the combination group, most adverse events were considered to be mild to moderate. Barker and colleagues reported on a randomized, open-label study of infliximab versus methotrexate in 868 methotrexate-naïve patients with moderate-to-severe plaque psoriasis in the RESTORE1 study. (49) At 16 weeks, significantly more patients achieved PASI 75 in the infliximab-treated group (508/653, 78%) than the methotrexate group (90/215, 42%; p<0·001).

Rheumatoid Arthritis

Many studies have been published demonstrating that TNF blockers, including infliximab, are more effective than placebo for the treatment of rheumatoid arthritis (RA). In 2013, Callhoff and colleagues published a meta-analysis to estimate the impact of biologic agents on physical function in patients with RA. (50) Thirty-five RCTs were included in the analysis, 10 with DMARD-naive patients and 25 with DMARD IRs. These studies’ 43 biologic treatment arms were included in the analysis. Among the 43 treatment arms, there were 5 with abatacept, 15 with adalimumab, 3 with certolizumab, 7 with etanercept, 4 with golimumab, 5 with infliximab and 4 with rituximab. Overall, biologics led to a greater improvement of physical function than that of nonbiologic DMARDs, with a standardized mean difference of the Health Assessment Questionnaire of 0.44 (95% CI: 0.38-0.50). There were no significant differences between individual biologics in both groups. (50)

In 2012, Lopez-Olivo and colleagues published a meta-analysis evaluating the risk of developing any type of malignancy in patients with RA only and providing data on 9 approved anti-TNF agents (including infliximab). (51) The use of these agents among RA patients included in a pooled analysis of 63 RCTs (published through July 2012) of at least 6 months’ duration was not significantly associated with an increased risk of malignancy compared with other DMARDs or with placebo. Of the 29,423 patients, 211 developed a malignancy during the trial (118 solid tumors, 48 skin cancers, 14 lymphomas, 5 hematologic nonlymphomas, and 26 not specified). Another meta-analysis of 33 RCTs published in 2012 by Moulis and colleagues similarly did not find any evidence for an increased cancer risk for 5 anti-TNF agents (including infliximab) in adult RA patients during up to 2 years of treatment. (52)

In April 2012, the Agency for Healthcare Research and Quality (AHRQ) published an update to its 2007 Comparative Effectiveness Review on RA drug therapy and found comparative studies on biologic DMARDs are limited. (53) While there are many observational comparative studies and mixed treatment comparisons (MTCs), studies have not provided sufficient evidence to determine appropriate strategies for use of biologic DMARDs, such as infliximab, including when to begin biologic DMARDs and in what drug therapy combinations. Superiority of any biologic DMARD over others could not be determined due to the lack of head-to-head trials comparing biologic DMARDs. Only one head-to-head randomized controlled trial by Schiff and colleagues was identified for the AHRQ review. (54) In this trial, in which abatacept and infliximab were compared to placebo, disease activity decreased more with abatacept, but remission was not significant at 1 year, as measured by the Disease Activity Score (DAS). The other 7 trials included in the AHRQ review on biologic DMARDs were not randomized. Efficacy appeared to be similar among biologic DMARDs, except for anakinra, which was found to be less effective. Additionally, etanercept may result in greater treatment outcome improvements in disease activity, but the evidence was considered to be of low strength, which limits interpretation of the MTC meta-analysis. Tolerability of biologic DMARDs was similar overall; however, cohort studies reported heart failure risk increased with biologic DMARDS, including infliximab.

In 2 systematic reviews and meta-analyses in 2012 (Gallego-Galisteo and Aaltonen), no TNF blocker produced superior outcomes in the treatment of RA. (21, 55) In Aaltonen et al., TNF blockers were found to have comparable outcomes to methotrexate, but when used together, outcomes were superior to when methotrexate or TNF blockers were used alone. (55)

In another 2012 systematic review by Schmitz and colleagues comparing TNF blockers for the treatment of RA using a Bayesian MTC, etanercept and certolizumab were estimated to be more efficacious than infliximab. (56) Additionally, adalimumab, certolizumab, etanercept and golimumab resulted in better Health Assessment Questionnaire outcomes than infliximab. The authors noted limitations in interpreting results with the MTC approach. A similar 2011 review by Turkstra et al., using an MTC approach, suggests etanercept and certolizumab may be more effective than abatacept, adalimumab, anakinra, golimumab, infliximab, rituximab, and tocilizumab for RA treatment. (57)

A systematic review by Malottki et al., in 2011, discussed adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of RA after failed treatment with a TNF blocker. (58) The reviewers found the evidence suggested rituximab and abatacept were more effective than supportive care. However, data on clinical effectiveness and comparisons of these TNF blockers is limited. Additionally, the benefits of using an alternative TNF blocker after failed first TNF blocker are uncertain.

In 2009, a review of 6 Cochrane reviews, including data from 4 studies on infliximab, was conducted to compare the safety and efficacy of abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab for RA. (59) Based on indirect comparisons, all of the biologics were similarly efficacious on the primary outcome measure of American College of Rheumatology 50 score, except for 3 comparisons with anakinra.

A 2008 meta-analysis of 12 randomized, controlled clinical trials suggested a clear benefit of anti-TNF agents over placebo or methotrexate in the treatment of rheumatoid arthritis (RA). (60) Patients with late disease appeared to have higher response, irrespective of the anti-TNF agent used, than patients with intermediate to early disease. Although there were no head-to head trials, the authors concluded that infliximab, etanercept, and adalimumab have similar overall efficacy in RA.

In March 2007, the Canadian Agency for Drugs and Technologies in Health issued an HTA Technology Report, “Infliximab and Etanercept in Rheumatoid Arthritis; Systematic Review of Long-term Clinical Effectiveness, Safety, and Cost-Effectiveness.” (61) The authors concluded infliximab and etanercept used concomitantly with methotrexate have moderate efficacy in the long-term treatment of active RA that is resistant to conventional therapy. The short-term (less than 12 months) safety profile was found acceptable. The long-term safety remains a concern. The economic review shows that costs per quality-adjusted life year (QALY) are high (greater than $100,000 for a QALY), surpassing the generally accepted thresholds for cost-effectiveness. The results suggest that infliximab with methotrexate, and etanercept with methotrexate are only cost-effective as second-line therapies after failure with traditional disease-modifying antirheumatic drugs (DMARDs).

Several studies have addressed dose escalation of infliximab for RA. Two studies found better treatment response after increasing infliximab dosage up to 10 mg/kg. (62, 63) Adverse events were not significantly different in one study. (63) However, Pavelka and colleagues found treatment efficacy did not improve and toxicity increased moderately after increasing infliximab dosage to 5 mg/kg. (64)

In 2012, van Vollenhoven and colleagues reported on the 2-year results of the randomized, nonblinded Swefot trial (Swedish Pharmacotherapy), which compared conventional combination treatment for RA to treatment with infliximab in 258 patients refractory to methotrexate. (65) Treatment response was not significantly different clinically between groups at 18 and 24 months and radiographically between groups at 18 months. However, the treatment group that received infliximab had less radiologic disease progression at 24 months (4·00 [standard deviation, SD: 10·0] vs. mean 7·23 [12·72]; p=0·009).

Sarcoidosis

An analysis from a previously published randomized trial of 138 patients with pulmonary sarcoidosis was published. The observed treatment benefit in extrapulmonary sarcoidosis patients receiving infliximab for 24 weeks was reported as an improvement in extrapulmonary Physician Organ Severity Tool, a metric designed for the present study that summarizes the involvement of 17 organs. While a statistical improvement in group-mean score was noted at 24 weeks, this measure has not been clinically validated, and its relationship to clinical outcomes is unknown. The accompanying editorial concluded that “a routine role for infliximab has not been established by these data.” (66, 67) In a subsequent publication from the same authors, levels of inflammatory serum proteins were reduced in 134 sarcoidosis patients compared to 50 controls. (68) The authors noted the need for further studies. Maneiro and colleagues conducted a systematic review of sarcoidosis treatment with TNF blockers. (69) The authors found insufficient evidence to support the use of TNF blockers in the treatment of sarcoidosis.

Scleroderma (Systemic Sclerosis)

A 2011 systematic review evaluated 3 studies on biologic agents for systemic sclerosis. (70) Infliximab and etanercept treatment resulted in improved inflammatory arthritis and disability scores on the Health Assessment Questionnaire Disability Index. The reviewers noted the need for larger, long-term studies to understand the role of biologics in treatment of scleroderma.

Sjögren Syndrome

A 2010 systematic review found anti-TNF agents have not demonstrated effectiveness in the treatment of Sjögren syndrome. (71) Included in the review were 2 placebo-controlled studies of infliximab and etanercept and 2 trials of fewer than 30 patients. The placebo-controlled studies did not improve joint pain, fatigue, or dryness, as measured by a composite visual analog scale, and the authors concluded these agents were not clinically effective.

Uveitis

In 2013, Cordero-Coma and colleagues published a systematic review regarding the use of anti-TNF agents for managing uveitis patients. (72) A total of 54 studies (published through October 2011) were included in this review. The evidence base for infliximab consisted of 4 open trials, one cross-sectional study, 12 prospective studies, and 33 retrospective studies and/or case series. A total of 517 patients who met all inclusion criteria were included in this systematic review. Based on the review of the evidence, the investigators rated the level of evidence for infliximab for the treatment of noninfectious immune-mediated uveitis as level 2b (findings based on extrapolation from individual cohort study, or low-quality randomized controlled trials). This review, however, has several limitations, including poor study design, heterogeneity of the study variables, lack of standardized methods to assess treatment efficacy for uveitis and variable treatment outcome measures. (72)

Four small studies (n=10 to 13 treated with infliximab) of both multiple etiology uveitis and Behcet’s uveitis were published. No control groups were included in these studies, which ranged in follow-up duration from 12–36 months. Visual acuity, inflammation, and episodes of recurrent severe uveitis were the outcomes of interest. For the 2 prospective open-label trials, 3 of 10 (30%) patients were free of recurrence at 24 months, and 7 of 12 (58%) patients were free of recurrence at 36 months. (73, 74) These small studies are promising; yet without control groups, they do not provide enough to determine impact on clinical outcomes.

Other Uses

In addition to its labeled uses, infliximab is being studied in treatment-refractory inflammatory diseases and other varied indications. The discussion here will include only publications reporting the use of infliximab or other TNF-α blocking agents in 10 or more patients.

Two systematic reviews were published in 2013 to evaluate the evidence base for the use of anti-TNF agents in hidradenitis suppurativa; based on data from observational studies, moderate to good response rates were observed in over 80% of the patients treated with infliximab. (75, 76) However, the quality of evidence overall, was of low quality and differed between the agents, making direct comparisons difficult.

Studies, which should be viewed as preliminary, are being reported on use of infliximab for treatment of refractory Kawasaki syndrome, (77, 78) sacroiliitis, (79) severe alcoholic hepatitis, (80) systemic lupus erythematosus, (81) Wegener’s granulomatosis, (82) and diabetic macular edema. (83) In addition, a publication reported on positive results from intra-articular injections of infliximab for treatment of refractory inflammatory monoarthritis in patients with ankylosing spondylitis. (84)

Other publications suggested potentially useful indications. One is a case series of refractory systemic necrotizing vasculitides, where, over 35 months of follow-up, 11 of 15 patients entered remission and 5 of 15 patients achieved sustained remission (>6 months). However, 10 patients relapsed after a median of 13 months. (85) One report of 2 Phase II trials of infliximab as a treatment for refractory renal cell carcinoma (n=18 treated with 10 mg/kg, n=19 treated with 5 mg/kg) showed partial response or stable disease, with 61% of those receiving the higher dose showing stable disease with a median duration of 7.7 months. One death due to infection was reported as well. (86)

A number of placebo-controlled trials of infliximab were conducted for other indications such as polymyalgia rheumatica (n=51), giant cell arteritis (n=44), endometriosis (n=21), sclerosing colangitis (n=24), pancreatic cancer cachexia (n=89), non-small-cell lung cancer‒related weight loss (n=61), depression, and graft-versus-host disease. (87-97) None of these trials showed a clinical benefit of infliximab in their stated outcomes. While small sample sizes may account for some lack of reported effect due to study power, 2 studies [giant cell arteritis, (88, 94) sclerosing colangitis (90)] were terminated early due to lack of treatment effect at interim analysis. Other studies reported negative results as well. Infliximab was not effective in the treatment of age-related macular degeneration in an unmasked, pilot, randomized, single-center Phase I/II study. (98) Intra-articular injections of infliximab were not effective in treating chronic or recurrent gonarthritis in a randomly assigned, crossover study of 23 patients (41 total intra-articular injections: 20 infliximab and 21 methylprednisolone). (99) In this study, improvements were greater with methylprednisolone. Additionally, infliximab did not improve clinical outcomes in a prospective longitudinal study of 44 patients with giant-cell arteritis. (94)

An evidence-based review suggests there may be a role for biologic drugs for the treatment of Behcet’s disease. (100) Three systematic reviews also suggest a role for infliximab in the treatment of hidradenitis suppurativa. (101-103) However, there is a need for randomized controlled trials and further study for these indications.

The placebo-controlled studies reporting minimal or no benefit of infliximab treatment in a variety of inflammatory diseases where epidemiologic evidence had suggested benefits are especially sobering, given the drug’s toxicities. Well-designed, comparative studies are imperative.

Ongoing Clinical Trials

A search of online site ClinicalTrials.gov identified at least 13 open, Phase III and IV studies addressing infliximab. These include studies on ulcerative colitis, Crohn’s disease, inflammatory bowel disease, rheumatoid arthritis, psoriasis, spondyloarthropathies, and Kawasaki disease.

Summary

Infliximab (Remicade® Centocor) is a tumor necrosis factor (TNF) a blocking agent approved by the U.S. Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and ulcerative colitis. Infliximab is administered via intravenous infusion.

In summary, head-to-head comparative trials that have evaluated the relative efficacy of the TNF blocking agents in the treatment of the various conditions are limited. However, the literature, which includes several systematic reviews, does consider the TNF blocking agents primarily infliximab, adalimumab, and etanercept to have similar efficacy in rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. For the maintenance of Crohn’s disease remission, the TNF blocking agents infliximab, adalimumab, and certolizumab are considered to have clinical efficacy. Infliximab has the additional approved indication for fistula healing. Adalimumab and etanercept are both administered subcutaneously, which may be more advantageous to the intravenous administration of infliximab.

Given the lack of comparative trials and randomized controlled trials for agents across conditions, the evidence does not definitively demonstrate that clinical outcomes are equivalent for the various TNF blocking agents. The policy statements that infliximab may be considered medically necessary remain unchanged.

The use of infliximab is considered investigational in all other indications, as listed in the policy statements, as the available evidence is preliminary or not in support of the use of infliximab for these conditions.

Practice Guidelines and Position Statements

The American College of Rheumatology’s (ACR) 2011 Model Biologics Policy indicates infliximab may be used off-label for the following indications: undifferentiated polyarthritis, undifferentiated spondyloarthropathy, sarcoidosis, myositis, Behcet’s disease, uveitis, adult-onset Still’s disease, reactive arthritis, juvenile idiopathic arthritis, and autoinflammatory diseases. (104) The ACR also recommends dose escalation of infliximab to 10 mg/kg in patients with rheumatoid arthritis or Crohn’s disease that does not completely respond to induction dosage.

In 2011, the World Congress of Gastroenterology issued the London Position Statement on biologics for inflammatory bowel disease. (105) Infliximab is considered appropriate for the treatment of Crohn’s disease after surgical drainage of any sepsis when the disease is steroid-refractory, steroid-dependent, or complex fistulizing. Infliximab is also considered appropriate for moderate or severe, refractory ulcerative colitis. The position statement also indicates TNF blocker dose adjustments may be appropriate when there is decrease or loss of response to treatment with biologics. Data on when TNF blocker treatment can be discontinued is noted to be insufficient.

A 2010 task force of the National Psoriasis Foundation developed consensus treatment recommendations for erythrodermic or exfoliative psoriasis. (106) These recommendations indicate infliximab and cyclosporine are first-line agents that act rapidly for treatment of this indication. However, the availability of data on the treatment of erythrodermic psoriasis is limited, and the need for further studies is noted.

In March 2006, the American Gastroenterological Association Institute released a medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease on behalf of the American Gastroenterological Association (AGA). (107) These recommendations are intended for adult patients and are based on the interpretation and assimilation of scientifically valid research. The ideal was to provide evidence based on prospective, randomized placebo-controlled trials; however, when this was not possible, the use of experts’ consensus was used. The recommendation for infliximab is for the treatment of patients with inflammatory and fistulizing Crohn’s disease (CD) that failed to respond to other therapies. In October 2006, the FDA approved expanding the indications for infliximab to include 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.

In May 2008, the American Academy of Dermatology released guidelines for the management of psoriasis and psoriatic arthritis. These guidelines address the treatment of both adult and childhood psoriasis and psoriatic arthritis including biologics. (108)

References:

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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 
ICD-10-CM (effective 10/1/15) 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
  M06.811-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 10/1/15)   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 

Index

Ankylosing Spondylitis, Infliximab Therapy
Crohn’s Disease, Infliximab Therapy
Infliximab
Psoriatic Arthritis, Infliximab Therapy
Remicade
Spondyloarthropathy, Infliximab Therapy


Policy History

Date Action Reason
02/15/02 Add to Prescription section New policy
10/08/02 Replace policy Policy revised: new FDA-labeled indication for maintenance therapy for Crohn's disease noted; updated references for other off-label indications
07/17/03 Replace policy Policy revised: infliximab for ankylosing spondylitis now considered medically necessary. Policy updated with reference to TEC Assessment, additional references added. Treatment of psoriatic arthritis will be addressed in the next revision, scheduled for 3.2003
12/17/03 Replace policy Policy updated; policy statement revised to state that treatment of psoriatic arthritis may be considered medically necessary, and supporting discussion and references added
11/9/04 Replace policy Policy updated with literature review for the period of July 2003 through September 2004; policy statement unchanged. References updated and renumbered
09/27/05 Replace policy Policy revised; new FDA-labeled indications noted; policy statement revised to indicate treatment of acute ulcerative colitis and psoriasis is considered medically necessary. All new references added
12/14/05 Replace policy – coding update only CPT coding updated
06/14/07 Replace policy Policy updated with literature search through April 2007; policy statements updated to reflect FDA approval in severe psoriasis. Reference numbers 5 and 6 added.
<07/10/08 Replace policy  Policy updated with literature search through June 2008, reference numbers 7-21 added. "OFf-label use" removed from policy title and FDA-approved uses added to policy. No changes in policy statements for off-label uses which are considered investigational
1/08/09 Replace policy  Policy updated with literature search through November 2008, reference numbers 1-4 and 11-33 added and other references renumbered. “Off-label use” removed from policy title. FDA-approved uses for TNF blocking agents infliximab; adalimumab, certolizumab and etanercept added to policy. Policy statement revised to indicate Behcet syndrome uveitis, juvenile idiopathic arthritis-associated uveitis, sarcoidosis, Sjogren syndrome, and other off-label uses are considered investigational.
12/08/11 Replace policy Policy updated with literature search through October 2011, reference numbers 1-3, 6-8, 10-12, 15-25, 27, 32-33, 37-39, 42-48, 54-67 added; other references deleted or renumbered. The following indications were added to the investigational policy status: age-related macular degeneration, alcoholic hepatitis, Behcet syndrome, depression, diabetic macular edema, erythrodermic or exfoliative psoriasis, intra-articular injections, graft-versus-host disease, juvenile idiopathic arthritis, sacroiliitis, systemic lupus erythematosus, systemic sclerosis, Wegener’s granulomatosis.
9/13/12 Replace policy Policy updated with literature search, reference numbers 1, 4, 13-14, 18, 24, 28, 30-32, 36-40, 50, 54, 76, 82-84 added. Hidradenitis suppurativa added to the investigational policy status; the remainder of the policy statements is unchanged.
10/10/13 Replace policy Policy updated with literature search through September 11, 2013, references 1, 5, 6, 9-12, 26, 27, 37-39, 50-52, 72, 75, 76, and 97 added. No change in policy statements.