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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/10:2014
Issue
10:2014
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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

 

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

There are a number of TNF-α blocking agents: etanercept (Enbrel®, Amgen), adalimumab (Humira®, Abbott), and certolizumab (Cimzia®, UCB) administered via subcutaneous injection; golimumab (Simponi®, Janssen Biotech) administered subcutaneously or intravenously; and infliximab (Remicade® Centocor) administered via an intravenous 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.

Regulatory Status

Initial FDA-labeled indications for infliximab included RA and fistulizing CD, and induction of remission in patients with moderately to severely active CD with an inadequate response to conventional therapy. In 2002, FDA approved an additional indication for maintenance of clinical remission in CD. Maintenance therapy is designed to prevent disease flares in patients with quiescent disease; drugs most commonly used are azathioprine and 6-mercaptopurine. This new, labeled indication markedly broadened the
clinical indications for patients with CD. In December 2004, FDA approved infliximab for the treatment of ankylosing spondylitis, and in early 2005, FDA approved infliximab for the treatment of psoriatic arthritis. In September 2005, 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, FDA approved infliximab for use in pediatric patients with moderately to severely active CD who have had an inadequate response to conventional therapy. In September 2006, FDA approved infliximab for patients with chronic severe (ie, 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 FDA approval. In 2011, FDA approved infliximab for use in pediatric patients ages 6 years and older for the treatment of ulcerative colitis (UC). As of August 2014, infliximab-labeled indications were compared with those for TNF blocking agents adalimumab, certolizumab, etanercept, and golimumab (see Table 1)

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

 

TNF Blocking Agent

Rheumatoid Arthritis

Juvenile Idiopathic Arthritis

Crohn Disease

Ankylosing Spondylitis

Psoriatic Arthritis

Plaque Psoriasis

Ulcerative Colitis

Infliximab

Yes
in combination with MTX

After conventional therapy treatment failure

No

Yes
After treatment failure with conventional therapy

Fistulizing CD

In children age ≥6y

Yes

 

Yes
When other systemic therapies are medically less appropriate

Yes
After conventional therapy treatment failure

In children age ≥6y

Adalimumab

Yes
Alone or in combination with MTX or DMARDs

Yes
Ages ≥4y

Yes
After treatment failure with conventional therapy

Yes

 Yes
Alone or in combination with DMARDs

Yes
When other systemic therapies are medically less appropriate

Yes
After treatment failure with conventional therapy

Certolizumab

Yes

No

Yes
After treatment failure with conventional therapy

Yes

Yes

No

No

Etanercept

Yes
Alone or in combination with MTX

Yes
Ages ≥2y

No

Yes

Yes
In combination with MTX when response to MTX alone is inadequate

Yes
Candidates for systemic therapy or phototherapy

No

Golimumab

Yes
In combination with MTX

No

No

Yes

Yes
Alone or in combination with MTX

No

Yes
With an inadequate response or intolerant to prior treatment or requiring continuous steroid therapy


CD: Crohn disease; DMARD: disease-modifying antirheumatic drug ; MTX: methotrexate ; Yes: agent has an approved indication.

On September 4, 2008, 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. FDA required manufacturers of TNF-α blockers to further highlight 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. FDA also required that manufacturers educate prescribers about this risk. Subsequently, in August 2009, 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, FDA began requiring TNF-blocker manufacturers to perform additional safety surveillance, comprising in-depth followup of reports of malignancy cases and expedited reporting of malignancy to FDA (within 15 days of becoming aware of the report) for pediatric and young adult patients. FDA also requires annual summaries and assessments of malignancies and TNF-blocker utilization data from the manufacturers.

In March 2013, FDA issued further warnings and precautions regarding malignancies and concurrent administration of infliximab with other biological agents. For malignancies, current prescribing information states, “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, current prescribing information states, “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 review was performed for the period through August 28, 2014. The following is a summary of the key literature to date.

Tumor Necrosis Factor Blocker Safety

To inform the 2013 update of rheumatoid arthritis (RA) guidelines by the European League Against Rheumatism (EULAR), Ramiro et al conducted a systematic review of safety outcomes with conventional (eg, methotrexate, azathioprine) and biological (eg, tumor necrosis factor [TNF] inhibitors) treatments of
RA.(2) Literature was searched through March 2013, and 49 comparative cohort and registry studies of biological disease-modifying antirheumatic drugs (DMARDs) were included. Meta-analysis was not possible due to substantial heterogeneity in study designs, eg, varying confounders adjusted for in analysis. In comparison with conventional DMARDs, patients on TNF inhibitors had an increased risk of serious infections (7 studies with low-to-moderate risk of bias [total N=84,578]; range of adjusted hazard ratios [HRs], 1.1-1.8 [95% confidence intervals (CIs), 0.8 to 2.7]) and an increased risk of skin infections, including herpes zoster (4 studies with low-to-moderate risk of bias [total N=77,163]; range of adjusted HRs, 1.0-1.7 [95% CIs, 0.8 to 2.7]). One included study with moderate risk of bias (N=81) reported an increased risk of tuberculosis reactivation in comparison with the general population (adjusted HR=34.9 [95% CI, 8.9 to 137.2]), but the risk estimate is unstable as evidenced by the very wide confidence interval. For malignancy, overall cancer risk was not increased in comparison with patients taking conventional DMARDs or with the general population. Lymphoma risk was not increased in comparison with patients taking conventional DMARDs but was increased in comparison with the general population (3 studies with low-to-moderate risk of bias [total N=10,100]; range of adjusted HRs, 2.7-6.0 [95% CIs, 1.6 to 15.4]). One study with low risk of bias (N=10,878) reported an increased risk of melanoma in comparison with patients taking conventional DMARDs (adjusted HR=1.5 [95% CI, 1.1 to 2.5]). Nonmelanoma skin cancer risk was not increased in comparison with patients taking conventional DMARDs but was increased in comparison with the general population (1 study with low risk of bias [N=11,881]; adjusted HR=1.72 [95% CI, 1.43 to 2.04]). No new safety signals were identified.

These results align with a 2014 systematic review with meta-analysis of double-blind RCTs of TNF inhibitor treatment of RA conducted by the National Institutes of Health.(3) Literature was searched through May 2013; 44 RCTs were included (total N=11,700 receiving TNF inhibitor, 5008 receiving conventional
DMARDs, 893 receiving placebo). TNF-inhibitor treatment was associated with an increased risk of serious infection (odds ratio [OR], 1.42 [95% CI, 1.13 to 1.78];  =0%) and treatment discontinuation due to adverse events (OR=1.23 [95% CI, 1.06 to 1.43]; =31%) compared with placebo and/or conventional DMARD controls. For malignancy, no ORs reached statistical significance.

In 2012, Lop ez-Olivo et al published a meta-analysis evaluating the risk of developing any type of malignancy in patients with RA only and provided data on 9 approved anti-TNF agents (including infliximab).(4) In meta-analysis of 63 RCTs (published through July 2012), use of these agents for at least 6
months was not statistically associated with an increased risk of malignancy compared with other DMARDs or with placebo. Of 29,423 patients, 211 (0.7%) developed a malignancy during the trial (118 solid tumors, 48 skin cancers, 14 lymphomas, 5 hematologic nonlymphomas, 26 not specified). Another
meta-analysis of 33 RCTs by Moulis et al (2012) also did not find evidence for an increased cancer risk for 5 anti-TNF agents (including infliximab) in adult RA patients during up to 2 years of treatment.(5)

In 2012, Wong et al published a meta-analysis of lymphoma risk from TNF-inhibitor treatment.(6) Fourteen RCTs were included (total N=5179 patients treated with TNF blockers, 2306 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 diagnoses in 130 (0.84%) of 15,418 patients randomized to TNF-blocker treatment and 48 (0.64%) of 7486 patients randomized to comparator groups.(7) However, this meta-analysis examined cancer diagnosis in the short term, ie, the interval between initiation of 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.(8) 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 due to adverse events was significantly higher with infliximab than control
(OR=2.04; 95% CI, 1.43 to 2.91; number needed to harm, 12; 95% CI, 8 to 28). The need for long-term studies to further evaluate the safety of biologics also was noted.

Ankylosing Spondylitis

In 2013, Machado et al performed a meta-analysis of RCTs to evaluate the efficacy and safety of the various anti-TNF agents for the treatment of ankylosing spondylitis.(9) The primary outcome was the Assessment of SpondyloArthritis international Society (ASAS) 20 response, which is defined by ASAS as
a reduction by at least 20% and 10 units (visual analog scale range, 0-100) 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 compared infliximab with placebo, 1 compared infliximab plus methotrexate (MTX) with placebo plus MTX, and 1 compared infliximab with etanercept. Under subgroup analyses, at 12/14 weeks, golimumab presented the highest
relative risk (RR) for ASAS 20 response (2.74; 95% CI, 1.78 to 4.22), followed by adalimumab (RR=2.33; 95% CI, 1.45 to 3.74), etanercept (RR=2.13; 95% CI, 1.75 to 2.58), and infliximab (RR=1.82; 95% CI, 1.16 to 2.58). After 24 weeks, only 1 study of each anti-TNF agent remained in the meta-analysis, and
infliximab had the highest RR (3.18; 95% CI, 1.99 to 5.08), followed by etanercept (RR=2.53; 95% CI, 1.80 to 3.57) and adalimumab (RR=2.15; 95% CI, 0.96 to 4.83). The incidence of adverse events was not significantly different between groups.(9)

Ren et al (2013) also reported a meta-analysis that showed significantly higher rates for ASAS 20 response (and other outcome measures) with anti-TNF agents compared with placebo.(10) Most adverse events in both treatment groups were mild or moderate in severity. 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.

Subsequent systematic reviews published in 2013 and 2014 confirmed that TNF inhibitors improve disease activity and functional capacity compared with placebo in patients with either ankylosing spondylitis or nonradiographic axial spondyloarthritis.(11,12)

In 2012, Migliore et al conducted a systematic review and Bayesian mixed treatment comparison of the effects of TNF-α blockers (infliximab, etanercept, adalimumab) for the treatment of ankylosing spondylitis.(13) Included in the comparison were 3 RCTs that evaluated ASAS response. 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 with 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.(14) Nine placebocontrolled 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 ASAS 20%, 50%, and 70% improvement, mean change in Bath Ankylosing Spondylitis Disease Activity Index
(BASDAI), and mean change in Bath Ankylosing Spondylitis Functional Index (BASFI) at 12 weeks after 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 with 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 indicated that over short timeframes, anti-TNFα therapies are unlikely to be considered cost-effective. Limitations of the clinical outcome data impose restrictions on the economic assessment of cost-effectiveness. Direct evidence from unbiased RCTs is available only for short-term outcomes. 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. A review of the 3 models submitted to the National Institute for Health and Clinical (now Care) Excellence 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. ICER for infliximab was 40,000 to 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). 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.

A 2006 publication reported positive results from intraarticular injections of infliximab for treatment of refractory inflammatory monoarthritis in 3 patients with ankylosing spondylitis.(15) In conclusion, review of clinical data related to the 3 drugs (plus conventional treatment) compared with placebo plus conventional treatment indicated that in the short term (12-24 weeks), the 3 treatments (adalimumab, etanercept, infliximab) are clinically effective in relation to assessment of ASAS, BASDAI, and BASFI. Indirect treatment comparisons were limited and did not show a significant difference in effectiveness between the 3 agents. Short-term economic assessment indicated 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.(14)

Inflammatory Bowel Disease

In 2013, Costa et al published a meta-analysis on the rates of hospitalizations and surgery in patients with inflammatory bowel disease (Crohn disease [CD], ulcerative colitis [UC]) treated with infliximab.(16) Twenty-seven eligible studies (published through May 2012) were included (9 RCTs, 18 observational studies). Overall, 1912 patients were evaluated in these trials (1076 with CD, 836 with UC). Infliximab treatment was associated with a significant odds reduction of hospitalization risk in comparison with controls, both in RCTs (OR=0.51; 95% CI, 0.40 to 0.65; I²  test for heterogeneity, 0%) and observational studies (OR=0.29; 95% CI, 0.19 to 0.43; =87%). The magnitude of this risk reduction was similar across patients with CD and UC. In patients with CD, RCTs and observational findings on overall major surgery rate were consistent. Infliximab was associated with a significant odds reduction of overall major surgery risk in
comparison with controls, in both RCTs (OR=0.31; 95% CI, 0.15 to 0.64; =0%) and observational studies (OR=0.32; 95% CI, 0.21 to 0.49; =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 to 0.88; =0%), but a nonsignificant increase was found in pooled results from observational studies (OR=1.43; 95% CI, 0.65 to 3.13; =76%). Limitations of this meta-analysis included 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 (17%) of 18 studies were published in abstract form.(16)

In 2012, Lichtenstein et al 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.(17) These studies included 5 RCTs contributing data from patients who received intravenous infliximab 5 mg
or 10 mg/kg (n=1713; ± 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 per 100 patientyears
of follow-up, overlapping 95% CIs indicated that incidences of malignancies were similar in placebo- and infliximab-treated patients who had CD (1.61 [95% CI, 0.19 to 5.82] vs 0.49 [95% CI, 0.18 to 1.06], respectively) or UC (0.00 [95% CI, 0.00 to 1.43] vs 0.60 [95% CI, 0.20 to 1.40], respectively).(17)

Crohn Disease

In 2013, Rosenfeld et al published a meta-analysis of studies comparing rates of postoperative complications among CD patients treated with infliximab versus alternative therapies.(18) Data were extracted from 6 observational studies (published through October 2012) including 1159 patients, among whom 413 complications were identified. The most common complications were wound infections, anastomotic leak, and sepsis. There was no statistically significant difference in major complication rate (OR=1.59; 95% CI, 0.89 to 2.86; p=0.15), minor complication rate (OR=1.80; 95% CI, 0.87 to 3.71; p=0.11), reoperation rate (OR=1.33; 95% CI, 0.55 to 3.20; p=0.52) or 30-day mortality rate (OR=3.74; 95% CI, 0.56 to 25.16; p=0.13) between infliximab and control groups. A key limitation of this metaanalysis was considerable heterogeneity in analyses of major complication rates given the observational study designs; included studies varied in terms of severity, location, and duration of disease, type of surgical procedure, number of surgical procedures included (ie, single or multiple), and surgical method (laparoscopic or open).(18)

A 2014 systematic review with network meta-analysis concluded that TNF inhibitors are effective for induction and maintenance of response and remission in the treatment of CD and found of clinical superiority among TNF inhibitors.(19)

In 2013, Yoshida et al published a prospective, Japanese single-center, RCT to assess the efficacy of scheduled maintenance infliximab monotherapy to prevent postoperative CD recurrence.(20) 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 no infliximab (control arm on conventional medication, if any; n=16). All patients were treated without immunomodulator or corticosteroid after surgery. Primary and secondary end points were remission rates at 12 and 36 months, defined as Crohn’s Disease Activity Index (CDAI) of 150 or less, an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score less than 2, and C-reactive protein (CRP) less than 0.3 mg/dL. Additionally, endoscopic recurrences at 12 and 36 months were evaluated. At 12 and 36 months, respectively, 100% and 93% of patients in the infliximab group were in remission (IOIBD <2), versus 69% and 56% in the control arm (p<0.03). Similarly, 87% and 87% of patients in the infliximab group maintained serologic remission (CRP <0.3 mg/dL) versus 37.5% and 37.5% in the control arm (p<0.02). Additionally, the infliximab group achieved higher endoscopic remission at 12 months (79% vs 19%; p=0.004). However, in Kaplan-Meier survival analysis, CDAI scores between the 2 arms were not significantly different at either 12 or 36 months. No adverse events were observed. Future multicenter trials in larger cohorts of patients and over a longer time period are needed to confirm these findings.(20)

A 2011 systematic review of 11 RCTs of infliximab and adalimumab for the treatment of CD found both agents improved outcomes in moderate to severe and fistulizing CD compared with placebo.(21) A multicenter open-label 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 MTX) or conventional management (induction with corticosteroids and sequentially adding antimetabolites [azathioprine or MTX] and
infliximab) with 2-year follow-up, found that early immunosuppression was more effective than conventional therapy for preventing disease progression.(22) At 26 weeks, 60% versus 36% of the early immunosuppression and conventional treatment groups, respectively, were in remission; remission rates were statistically different at 1 year (62% vs 42%, respectively) but not at 2 years. Corticosteroid, but not antimetabolite, use was lower, and 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, the randomized, double-blind SONIC trial was published.(23) In the SONIC trial, 508 adult patients with moderate to severe CD received either infliximab monotherapy, azathioprine monotherapy, or a combination of these 2 drugs. At week 26, corticosteroid-free clinical remission was achieved in 96 (57%) of 169 combination therapy patients, 75 (44%) of 169 infliximab monotherapy patients (p=0.02), and 51 (30%) of 170 azathioprine monotherapy patients (comparison with combination therapy, p<0.001; comparison with infliximab, p=0.006). At week 50, numerical trends were similar. Complete mucosal
healing at week 26 occurred in 47 (44%) of 107 combination therapy patients, 28 (30%) of 93 infliximab patients (p=0.06), and 18 (17%) of 109 azathioprine patients (comparison with combination therapy, p<0.001; comparison with infliximab, p=0.02). In post hoc subgroup analyses, researchers examined the
prognostic ability of alternative outcome measures, eg, 50% mucosal healing, CRP, and CDAI; none were shown to accurately predict complete mucosal healing.(24,25)

A 2008 systematic review examined 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.(26) 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 maintained clinical remission (risk ratio, 2.50; 95% CI, 1.64 to 3.80), clinical response (risk ratio, 2.19; 95% CI, 1.27 to 3.75), and fistula healing (risk ratio, 1.87; 95% CI, 1.15 to 3.04), and had corticosteroid-sparing effects (risk ratio, 3.13; 95% CI, 1.25 to 7.8) in patients with CD responsive to infliximab induction therapy. Two RCTs showed that adalimumab maintained clinical remission to week 54 (risk ratio, 3.28; 95% CI, 2.13 to 5.06), had higher rates of steroid-free remission at week 26 and week 56 versus placebo (6% placebo vs 29% adalimumab), and was superior to placebo for maintenance of steroid-free remission to week 54 (risk ratio, 4.24; 95% CI, 1.57 to 11.47). One RCT compared certolizumab pegol with placebo and found that certolizumab pegol was effective for maintenance of clinical remission (risk ratio, 1.68; 95% CI, 1.30 to 2.16) and clinical response (risk ratio, 1.74; 95% CI, 1.41 to 2.13) to week 26.

The authors concluded that infliximab 5 mg/kg or 10 mg/kg, given every 8 weeks, was effective for 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, was effective for maintenance of remission in patients who have responded to adalimumab induction therapy. Certolizumab pegol, 400 mg every 4 weeks was effective for 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 were insufficient to allow an adequate assessment of serious adverse events associated with long-term use.(26)

A 2008 review examined the evidence base of both established treatments (eg, enteral nutrition, corticosteroids, 5-aminosalicylates, immunosuppressive agents) and emerging treatments (eg, the anti-TNF-α agents, infliximab and adalimumab) used to induce and maintain remission in CD. The authors concluded that: Exclusive enteral nutrition is recommended as first-line treatment for induction of remission in pediatric CD. Corticosteroids also are 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 MTX. 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 severe 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 maintenance of remission include azathioprine, MTX, infliximab, and adalimumab. Evidence also suggested 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.(27)


A 2008 meta-analysis examined placebo-controlled trials to evaluate safety and efficacy of TNF antagonists for CD.(28) Primary end points were clinical remission for luminal CD and fistula closure at 2 or more 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 to 25; p<0.001). In 21 studies enrolling 5356 subjects, anti-TNF therapy did not increase the risk of death, malignancy, or serious infection. The authors concluded that infliximab, adalimumab, and certolizumab were effective in luminal CD. Efficacy of anti-TNF agents other than infliximab for fistulizing CD requires additional investigations. Longer follow-up and larger samples are required to better assess the safety profile of TNF antagonists in CD.

A 2008 review article explored conventional and emerging treatments for CD and UC. The authors discussed 5-aminosalycylic acid agents (mesalamine, olsalazine), a mainstay in the treatment of both CD and UC. Antibiotics may have a limited role in the treatment of colonic CD. Steroids were 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 UC, respectively, also are effective in mild-moderate disease. 6-mercaptopurine and its prodrug azathioprine are steroid-sparing immunomodulators, effective for maintenance of remission in both CD and UC; MTX may be used in both induction and maintenance of CD.(29)

In 2012, Kopylov et al published a systematic review with meta-analysis of infliximab treatment given preoperatively to patients with CD.(30) 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 a 2011 systematic review with meta-analysis, Ehteshami-Afshar et al also found an increase in postoperative infections in patients using infliximab for inflammatory bowel disease.(31) Pouch-related complications, sepsis, and thrombotic events also were more common in patients using infliximab. However, as reviewers noted, patients receiving infliximab usually have more severe disease and are 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 2007 REACH trial, 112 children, age 6 to 17 years, with severe CD (Pediatric Crohn's Disease Activity Index score >30) who responded inadequately to standard therapy were given infliximab intravenous therapy.(32) Patients who
responded to infliximab therapy at 10 weeks were randomized to 5 mg/kg every 8 or 12 weeks. After 10 weeks of treatment, 99 (88%) of 112 patients responded to infliximab, and 66 (59%) of 112 patients reached clinical remission. After 54 weeks of treatment, clinical remission was achieved in more patients
on an 8-week infliximab schedule compared with a 12-week schedule (29 [56%] of 52 vs 12 [24%] of 51, respectively). At 46 weeks, 60 patients continued infliximab treatment for 3 more years in the open-label extension trial.(33) 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, 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. Efficacy of anti-TNF agents, other than infliximab, in treating fistulizing CD requires additional investigation. Longer follow-up and larger patient samples are required to better assess the long-term safety profile of TNF antagonists in CD.

UCFDA’s 2005 approval of infliximab for the treatment of UC was based in part on results of the ACT 1 and ACT 2 RCTs.(34) These trials 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 end point of both trials was induction of clinical response; secondary end points included clinical remission. In both studies, the infliximab group had significant improvements in clinical response and clinical remission at all time points compared with placebo. Also, a significantly greater percentage of patients in the infliximab group were able to discontinue steroids during clinical remission. Based on results of these studies, FDA granted infliximab priority review.

In 2012, Reinisch et al reported on the long-term extension trial of 229 patients from the ACT-1 and ACT2 trials.(35) 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 patients (31%) due to adverse events, lack of efficacy, and other reasons.

In 2013, Chang et al conducted a meta-analysis to evaluate outcomes of UC patients receiving infliximab or cyclosporine as rescue therapy in acute severe steroid-refractory exacerbations.(36) Six retrospective cohort studies (published through May 2012) describing 321 patients met inclusion criteria. Meta-analysis did not show significant differences between infliximab and cyclosporine in 3-month colectomy rate (OR=0.86; 95% CI, 0.31 to 2.41; p=0.775), 12-month colectomy rate (OR=0.60; 95% CI, 0.19 to 1.89; p=0.381), adverse drug reactions (OR=0.76; 95% CI, 0.34 to 1.70; p=0.508), or postoperative
complications (OR=1.66; 95% CI, 0.26 to 10.50; p=0.591). Limitations of this meta-analysis include lack of control groups, heterogeneous patient samples, and variation across studies in dosage and serum levels of cyclosporine and accrual periods (range, 1993-2011), the latter spanning a period of major advancement in laparoscopic surgical techniques and devices with probable major impacts on overall management and operative outcomes of these patients.(36)

In 2012, Yang et al 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.(37) Thirteen studies involving 2933 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 to 1.37; p=0.47), infectious (OR=1.10; 95% CI, 0.51 to 2.38; p=0.81), or noninfectious (OR=1.10; 95% CI, 0.76 to 1.59; p=0.61) postoperative complications. A significantly decreased risk of infectious complications was reported with infliximab use within 12 weeks before surgery (OR=0.43; 95% CI, 0.22 to 0.83; p=0.01). Publication bias was not observed. However, for the outcome of infectious complications, heterogeneity was significant.(37)

In a 2011 systematic review of treatments for pediatric UC, data from 6 studies on infliximab (total N=126) yielded a pooled short-term response of 75% (95% CI, 67% to 83%) with 1-year pooled response of 64% (95% CI, 56% to 72%).(38) FDA’s 2011 approval of infliximab for pediatric use was based on data from a phase 3, randomized, multicenter, open-label study of moderately to severely active UC in patients aged 6 to 17 years.(39) Patients were refractory or unable to tolerate standard therapy with 6-mercaptopurine, azathioprine, corticosteroids, or 5-aminosalicylate. In this study, 44 (73%) of 60 patients responded to infliximab at 8 weeks. Adverse events were similar to those observed in adult patients. In a 2010 prospective multicenter study, children with severe UC were treated with infliximab after failed intravenous corticosteroids.(40) Twenty-five (76%) of 33 patients responded to infliximab, which was considered to demonstrate efficacy.

Additional, reviews of TNF inhibitors for the treatment of UC were published in 2009,41 2010,42 and 2014.(43-46) The reviews found infliximab treatment appropriate for acute exacerbations of severely active UC when cyclosporine is not appropriate or contraindicated and confirmed that TNF inhibitors are
effective for the induction and maintenance of remission in UC.

Juvenile Idiopathic Arthritis

Two 2013 retrospective studies examined biologic treatments (etanercept, infliximab, adalimumab, anakinra) for juvenile idiopathic arthritis (JIA) in children(47) and adults.(48) Study authors observed that evidence-based guidance for use of biologic agents in JIA was lacking and prospective controlled studies
are needed.

In August 2011, the Agency for Healthcare Research and Quality (AHRQ) published a Comparative Effectiveness Review of DMARDs for children with JIA.(49) The review found that evidence on biologic DMARDs was limited, although symptom improvement had been reported. Heterogeneity of studies and
in outcome reporting, as well as varied categories of JIA, made meaningful comparisons of DMARDs difficult. Additionally, many questions remained regarding the safety of DMARDs in children, especially because of the associated malignancy risk, particularly for lymphoma, with the use of TNF-α blocking
agents.

Ruperto et al (2010) reported on an open-label extension trial of infliximab for JIA in 78 children.(50) However, this study was limited by the high number of patients who discontinued infliximab treatment (42 patients [58%]) 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. Thirteen percent of patients achieved inactive disease status.

In a 2011 report of a multicenter, 54-week, randomized, open-label trial of 60 patients with JIA by Tynjala, et al, patients taking infliximab plus MTX had better outcomes than those taking MTX alone or in combination with sulfasalazine and hydroxychloroquine.(51) In patients taking infliximab, 19 (100%) of 19
achieved ACR-Pedi 75 compared with 13 (65%) of 20 on combination treatment and 10 (50%) of 20 on MTX. Thirteen (68%) of patients taking infliximab achieved inactive disease status compared with 8 (40%) and 5 (25%) in the combination and MTX groups, respectively. Inactive disease also continued for a
longer duration in the infliximab group compared with the combination and MTX groups (mean, 26 weeks versus 13 weeks and 6 weeks, respectively). A 2010 evidence-based review noted that infliximab is frequently used to treat JIA in clinical practice, despite not having FDA approval for this indication.(52)

Plaque Psoriasis and Psoriatic Arthritis

In 2012, 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.(53) In total, 5 RCTs (n=1227) and 4 observational studies (n=1066)  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 1 outcome of interest. Five RCTs (2 good, 2 fair, 1 poor quality) and 2 fair-quality observational studies evaluated the comparative effectiveness of systemic biologic agents and systemic nonbiologic agents. Comparisons included adalimumab, etanercept, infliximab, and ustekinumab versus MTX, and etanercept versus acitretin. Comparative effectiveness of these therapies with regard to final health outcomes other than health-related quality of life (HRQOL) could not be determined due to a lack of evaluation in the included literature. In comparison with MTX, 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. Evidence for the comparative safety of systemic biologic agents and systemic nonbiologic agents or phototherapy was sparse. Overall, 5 RCTs (2 good, 2 fair, 1 poor quality) and 2 observational studies (both fair quality) directly compared biologics with nonbiologics and reported at least 1 adverse outcome of interest; there were no studies that directly compared infliximab with other biologics/agents in the evaluation of harms. Additional RCTs or large observational studies and registries that directly compare individual rugs/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 also may supplement the lack of direct comparative data.(53)

Systematic reviews published in 2012, 2013, and 2014 assessed the effectiveness and safety of TNF inhibitors for psoriasis and psoriatic arthritis.(54-59) These reviews reported no significant differences in effectiveness and overall adverse reactions between available anti-TNF agents in patients with psoriasis
or psoriatic arthritis.

In 2012, AHRQ issued an update of its 2007 report on drug therapy for adult psoriatic arthritis.(60) The review found that evidence on biologic DMARDs was limited, although symptom improvement had been reported. Reviewers noted that 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 that each of these 3 agents was effective in reducing skin disease and joint symptoms.(61) In Bayesian indirect comparison, infliximab was more effective in improving skin and joint outcomes compared with etanercept
and adalimumab. Another 2011 systematic review and meta-analysis of 20 studies examined the risk of infections and lymphoma from TNF-blocker therapy for psoriatic disease. Overall odds (OR) increase of infection risk was 1.18 (95% CI, 1.05 to 1.33). Odds increase of serious infection risk and of increased
malignancy risk were 0.70 (95% CI, 0.40 to 1.21) and 1.48 (95% CI, 0.71 to 3.09), respectively.

RCTs comparing the effectiveness of TNF-blocking agents for psoriatic arthritis are lacking. Migliore et al (2012) conducted a mixed treatment comparison analysis of etanercept, infliximab, and adalimumab and found that ACR 20 response occurred more commonly with etanercept compared with placebo.(62)
In a 2012 systematic review and meta-analysis, Reich et al compared biologics available in Europe for the treatment of moderate to severe psoriasis in adults.(63) Four RCTs of infliximab were included. 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 that infliximab and
ustekinumab were most effective over a 24-week treatment period followed by adalimumab and etanercept.(64) Effectiveness of infliximab, adalimumab, and etanercept decreased after 24 weeks. However, these analyses were limited by the use of indirect comparisons.

The 2005 Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) was a randomized, placebo-controlled, blinded trial of infliximab for the treatment of psoriatic arthritis.(65) A secondary outcome focused on improvements in dermatologic manifestations of psoriasis. Of 104 participants, only 39 (38%) had significant psoriatic skin lesions, as evidenced by a PASI score of 2.5 or greater. (Maximum PASI score is 72 [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, and patients randomized to infliximab continued to receive active treatment. Changes in PASI score were analyzed for the 39 patients with skin lesions; 68% of infliximab patients achieved improvement of 75% or more in PASI score at week 16
compared with none in the placebo group. However, interpretation of these results was limited by small sample size. Additionally, patients were recruited to this trial based on arthritic manifestations with previous failure of 1 or more DMARD; it is unknown whether previous therapies had been successful in controlling dermatologic manifestations of psoriasis.

Gottlieb et al (2004) 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.(66) In contrast to the IMPACT study, which enrolled patients with a PASI score of 2.5 or greater, this study
was limited to patients with a PASI score of 12 or greater and with psoriatic plaques covering at least 10% of body surface. Primary end point 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 PASI score, compared with 6% in the placebo group (p<0.001 for both comparisons vs placebo). Although no study directly compared various agents, these positive results were considered similar to those associated with cyclosporine, better than those associated with etanercept, and better than topical agents. Results from this larger trial demonstrated efficacy of infliximab in patients with moderately severe psoriasis who met study criteria.

In 2010, Atteno et al reported on a randomized trial of 100 patients treated with infliximab, etanercept, or adalimumab for psoriatic arthritis.(67) All 3 agents were effective in controlling signs and symptoms of psoriatic arthritis at 12 months.

In 2012, Baranauskaite et al reported on the randomized, open-label RESPOND trial, which compared infliximab plus MTX with infliximab alone in 115 patients with psoriatic arthritis.(68) Infliximab plus MTX yielded greater improvements in outcomes and disease suppression than MTX alone. In intention-to-treat analysis at 16 weeks, 44 (86%) of 51 patients in the infliximab plus MTX group achieved an ACR 20 response versus 32 (67%) of 48 patients in the MTX only group (p=0.021). ACR 50 and ACR 70 responses also were significantly greater in the combination treatment group. Improvements in PASI scores were statistically significantly greater in the combination treatment group at each time point; mean reduction in PASI score by 16 weeks was 93.3% in the combination group and 67.4% in the MTX only group (p=0.003). Although adverse events were higher in the combination group, most adverse events
were considered to be mild to moderate. Barker et al (2011) reported on a randomized, open-label study of infliximab versus MTX in 868 MTX-naive patients with moderate-to-severe plaque psoriasis in the RESTORE1 trial.(69) At 16 weeks, significantly more patients achieved PASI 75 in the infliximab-treated
group (508/653 [78%]) than in the MTX group (90/215 [42%]; p<0·001).

Rheumatoid Arthritis

Many studies have demonstrated that TNF blockers, including infliximab, are more effective than placebo for the treatment of RA. In 2013, Callhoff et al published a meta-analysis to estimate the impact of biologic agents on physical function in patients with RA.(70) Thirty-five RCTs were included in the analysis, 10 with DMARD-naive patients and 25 with DMARD inadequate responders. Of 43 active treatment arms, 5 were with abatacept, 15 with adalimumab, 3 with certolizumab, 7 with etanercept, 4 with golimumab, 5 with infliximab, and 4 with rituximab. Overall, biologic DMARDs led to greater  improvements in physical function compared with nonbiologic DMARDs, with a standardized mean difference in Health Assessment Questionnaire of 0.44 (95% CI, 0.38 to 0.50). There were no significant differences between individual biologics in both patient groups. Meta-analyses published in 2014 supported the efficacy of TNF inhibitors for patients with RA, particularly as add-on therapy in the second-line setting.(71-73)

A 2014 double-blind RCT in 112 new-onset (3-12 months duration), DMARD-naive patients with RA compared the efficacy of MTX and infliximab with MTX and high-dose intravenous corticosteroid for remission induction.(74) At 50-week follow-up, there was no statistical between-group difference in mean
modified total Sharp score, proportion of patients with radiographic nonprogression, improvement in quality of life.

In April 2012, AHRQ published an update to its 2007 Comparative Effectiveness Review on RA drug therapy and found that comparative studies on biologic DMARDs were limited.(75) Although there were 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 1 head-to-head RCT by Schiff et al (2008) was identified for the AHRQ review.(76) In this trial, in which abatacept and infliximab were compared with placebo, disease activity decreased more with abatacept, but remission was not significant at 1 year, as measured by the
Disease Activity Score. The other 7 trials included in the AHRQ review 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 strength evidence was considered low, which limited interpretation of the MTC meta-analysis. Tolerability of biologic DMARDs was similar overall; however, cohort studies reported increased heart failure risk with biologic DMARDS, including infliximab.

In 2 systematic reviews and meta-analyses published in 2012 (Aaltonen et al and Gallego-Galisteo et al), no TNF blocker produced superior outcomes in the treatment of RA.(31,77) In Aaltonen et al, outcomes with TNF blockers were comparable with outcomes with MTX, but when used in combination, outcomes were superior to those reported with MTX or TNF blockers alone.(77)

In another 2012 systematic review, Schmitz et al compared TNF blockers for the treatment of RA using a Bayesian MTC.(78) Etanercept and certolizumab were estimated to be more efficacious than infliximab. Additionally, adalimumab, certolizumab, etanercept and golimumab resulted in better Health Assessment Questionnaire quality of life 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, suggested that etanercept and certolizumab may be more effective than abatacept, adalimumab, anakinra, golimumab, infliximab, rituximab, and tocilizumab for treatment of RA.(79)

A 2011 systematic review by Malottki et al included adalimumab, etanercept, infliximab, rituximab, and abatacept for treatment of RA after failed treatment with a TNF blocker.(80) Evidence indicated that rituximab and abatacept were more effective than supportive care. However, data on clinical effectiveness and comparisons of these TNF blockers was limited. Additionally, benefits of using an alternative TNF blocker after failed first TNF blocker are uncertain.

A 2009 review of 6 Cochrane reviews, including data from 4 studies on infliximab, compared the safety and efficacy of abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab for RA.(81) Based on indirect comparisons, all biologics were similarly efficacious for the primary outcome of ACR 50 score, except for 3 comparisons with anakinra.

A 2008 meta-analysis of 12 RCTs suggested a clear benefit of anti-TNF agents over placebo or MTX in the treatment of RA.(82) Patients with late disease appeared to have higher response, irrespective of 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.”83 The authors concluded that infliximab and etanercept
used concomitantly with MTX have moderate efficacy in the long-term treatment of active RA that is resistant to conventional therapy. Short-term (<12 months) safety profile was found acceptable; long-term safety remained a concern. Economic review showed that costs per QALY were high (>$100,000 per QALY), exceeding generally accepted thresholds for cost-effectiveness. Results suggest that infliximab plus MTX, and etanercept plus MTX were cost-effective only as second-line therapies after failure with traditional 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.(84,85) In 1 of these, incidence of adverse events was not statistically different.(85) However, Pavelka et al (2009) found that treatment efficacy did not improve and toxicity increased moderately after increasing infliximab dosage to 5 mg/kg.(86)

In 2012, van Vollenhoven et al reported on 2-year results of the randomized, open-label SweFot (Swedish Pharmacotherapy) trial, which compared conventional combination treatment for RA with infliximab therapy in 258 patients refractory to MTX.(87) Clinical treatment response was not significantly different
between groups at 18 and 24 months, and radiographic response was not significantly different between groups at 18 months. However, the infliximab treatment group had less radiologic disease progression at 24 months (mean [SD], 4.00 [10.0] vs 7.23 [12.7]; p=0.009). Karlsson et al (2013) examined quality-of-life outcomes at 21 months and found no statistical between-group difference.(88)

Sarcoidosis

Analysis from a previously published randomized trial of 138 patients with pulmonary sarcoidosis was published.(89,90) 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 relationship with clinical outcomes was unknown. An accompanying editorial concluded that “a routine role for infliximab has not been established by these data.” 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.(91) The authors noted the need for further studies. Maneiro et al (2012) conducted a systematic review of sarcoidosis treatment with TNF blockers.(92) The authors found insufficient evidence to support the use of TNF blockers for the treatment of sarcoidosis.

Scleroderma (Systemic Sclerosis)

A 2011 systematic review evaluated 3 observational studies on biologic agents for systemic sclerosis.(93) Infliximab and etanercept treatment resulted in improved inflammatory arthritis and disability scores on the Health Assessment Questionnaire Disability Index. Reviewers noted the need for larger, long-term
studies to understand the role of biologics for the treatment of scleroderma.

Sjögren Syndrome

A 2010 systematic review found anti-TNF agents have not demonstrated effectiveness in the treatment of Sjögren syndrome.(94) Two placebo-controlled trials of infliximab and etanercept and 2 trials of fewer than 30 patients were included in the review. In placebo-controlled trials, anti-TNF agents 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 2014, Simonini et al published 2 systematic reviews with meta-analyses of anti-TNF agents for treatment of autoimmune chronic uveitis in refractory pediatric (≤16 years old) patients. In both studies, primary outcome was the change in intraocular inflammation using standardized criteria that have been
validated in adults but not in children.(95) One study included only patients previously untreated with biological agents.(96) Literature was searched through September 2012; 23 studies (1 RCT of etanercept and 22 retrospective studies; total N=229) were included. Most patients (63%) received infliximab; 24%
received etanercept; and 13% received adalimumab. Meta-analysis of observational studies showed high response rates with infliximab (72% [95% CI, 64 to 79]) and adalimumab (87% [95% CI, 75-98]; chisquare vs infliximab, p=0.08) but not with etanercept (33% [95% CI, 19 to 47]; chi-square vs either group,
p<0.001). The other study examined changing anti-TNF after failure of a first anti-TNF course.(97) Literature was searched through April 2013; 10 observational studies were included (total N=40). Ninety-eight percent of patients had JIA, the leading cause of autoimmune chronic uveitis in children. Most children
(58%) were switched from infliximab to adalimumab; 27% were switched from etanercept to adalimumab; and 15% were switched from etanercept to infliximab. Thirty patients (75% [95% CI, 51 to 100]) responded to treatment, 6 (100%) of 6 children on infliximab and 24 (32%) of 34 children on adalimumab.
Adverse events occurred in 6 (23%) of 26 children for whom events were reported; 5 who were taking adalimumab reported local pain or discomfort, and 1 who was taking infliximab reported transient bronchospastic cough. Adverse event severity was not reported. Although results suggested that switching between anti-TNF drugs may be appropriate in some patients when response to a first anti-TNF drug is insufficient, RCTs are recommended.

In 2013, Cordero-Coma et al published a systematic review of anti-TNF agents for managing uveitis.(98) A total of 54 studies (published through October 2011) were included. Evidence for infliximab comprised 4 open trials, 1 cross-sectional study, 12 prospective studies, and 33 retrospective studies and/or case
series (total N=517). Reviewers rated the level of evidence for infliximab for treatment of noninfectious immune-mediated uveitis as level 2b (findings based on extrapolation from individual cohort study, or lowquality RCTs). 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.(98)

Small studies (N=10-19 treated with infliximab) of both multiple etiology uveitis and Behçet uveitis have been published. Studies were uncontrolled and ranged in follow-up duration from 12 to 44 months. Outcomes of interest were visual acuity, inflammation, and episodes of recurrent severe uveitis. For 2
prospective open-label trials, 3 (30%) of 10 patients were free of recurrence at 24 months, and 7 (58%) of 12 patients were free of recurrence at 36 months.(99-101) These small studies are promising, yet, without control groups, they do not provide sufficient evidence 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-blocking agents in 10 or more patients.

Hidradenitis Suppurativa

Two 2013 systematic reviews evaluated anti-TNF agents in hidradenitis suppurativa; based on data from observational studies, moderate to good response rates were observed in over 80% of patients treated with infliximab.(102,103) However, evidence quality was low overall and differed among the agents, making direct comparisons difficult. Two 2012 systematic reviews also suggested a role for infliximab in the treatment of hidradenitis suppurativa.(104,105)

Behçet Disease

An evidence-based review suggested that there may be a role for biologic drugs for the treatment of Behçet disease.(106) However, there is a need for RCTs and further study.

Vasculitides

Preliminary studies have investigated infliximab for treatment of Wegener granulomatosis(107) and other vasculitides. A 2007 placebo-controlled trial of 44 patients with giant cell arteritis was terminated early due to lack of treatment effect for clinical outcomes at interim analysis.(108) In subsequent analysis, serum inflammatory biomarkers and markers of vascular remodeling on temporal artery biopsy also did not differ between groups.(109)

Silva-Fernandez et al (2013) conducted a systematic review of biological therapies for systemic vasculitides.(110) Literature was searched through April 2013; of 80 included studies, 29 primarily uncontrolled, observational studies assessed TNF inhibitors (infliximab, etanercept, adalimumab, golimumab). Evidence was contradictory for infliximab efficacy in antineutrophil cytoplasmic antibodyassociated vasculitides (granulomatosis with polyangiitis and microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis) and in large vessel vasculitides (giant cell arteritis and Takayasu arteritis).
A case series of refractory systemic necrotizing vasculitides (eg, Wegener granulomatosis, microscopic polyangiitis, RA-associated vasculitis) with more than 35 months of follow-up reported that 11 (73%) of 15 patients entered remission and 5 (33%) of 15 patients achieved sustained remission (>6 months) with
infliximab.(111) However, 10 patients (67%) relapsed after a median of 13 months.

Kawasaki Disease

Preliminary studies have investigated infliximab for treatment of refractory Kawasaki disease.(112,113) 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.(114) Patients were randomized 1:1 to a single dose of
infliximab or placebo administered before intravenous 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, Fisher’s exact test, p=0.81). Observed reductions at 2 weeks in
fever duration, serum inflammatory markers, and left anterior descending coronary artery dimension did not persist to week 5. An accompanying editorial observed that larger studies with longer follow-up are required to establish efficacy and safety of infliximab for Kawasaki disease.

Renal Cell Carcinoma

One report of 2 phase 2 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.(115)

Pain Syndromes

Infliximab and other TNF inhibitors have been investigated for the treatment of various pain syndromes. Two systematic reviews of low back pain with radiculopathy (sciatica) found insufficient evidence to conclude that TNF inhibitors were safe and effective for treatment of these conditions.(116,117) A placebo-controlled RCT of 13 patients with complex regional pain syndrome found statistically significant reductions in quality of life in patients who received infliximab.(118) Preliminary studies have investigated infliximab for treatment of sacroiliitis119 and endometriosis-associated pelvic pain.)(120,121)

Mixed Indications

Preliminary studies have investigated infliximab for treatment of pemphigus vulgaris,(122) severe alcoholic hepatitis,(123) systemic lupus erythematosus,(124) and diabetic macular edema.(125)

A number of placebo-controlled trials of infliximab were conducted for other indications such as polymyalgia rheumatica (n=51), giant cell arteritis (n=44), sclerosing colangitis (n=24), pancreatic cancer cachexia (n=89), non-small-cell lung cancer‒related weight loss (n=61), depression, and graft-versushost disease.(126-132) None of these trials showed a clinical benefit of infliximab in their stated outcomes. Although small sample sizes may account for some lack of reported effect due to reduced power, a study of sclerosing cholangitis was terminated early due to lack of treatment effect at interim analysis.(128) Other studies also reported negative results. Infliximab was not effective for the treatment of age-related macular degeneration in an open-label, randomized, single-center phase 1/2 pilot study.(133) 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).(134) In this study, improvements were greater with methylprednisolone.

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

Ongoing and Unpublished Clinical Trials

An online search of ClinicalTrials.gov identified 54 active studies of infliximab. These included 28 studies in inflammatory bowel disease, 20 studies in RA and spondyloarthropathies, 4 studies in psoriasis, 1 study in Behçet arthritis, and 1 study in steroid-refractory, acute graft-versus-host disease. Additionally,
early-phase studies are investigating conditions not reviewed in this policy (see Table 2).




Table 2. Active Studies of Infliximab for Novel Indications

NCT Number

Title

Phase

Enrollmenta

Completion Dateb

Stevens-Johnson syndrome

CT01256489

Infliximab to Improve  Retention of the Boston Keratoprosthesis in Patients After Stevens Johnson Syndrome/ Toxic Epidermal Necrolysis (SJS/TENS)

1/2

4

Jul 2015

NCT02126020

Topical Infliximab in Autoimmune Eyes With Keratoprosthesis

1/2

4

Mar 2017

Reperfusion Injury

NCT01886443

Combined Drug Approach to Prevent Ischemiareperfusion Injury During Transplantation of Livers (CAPITL)

1

10

Dec 2013


a Expected
b Estimated

Summary of Evidence

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

Head-to-head comparative trials that have evaluated the relative efficacy of TNF-blocking agents in the treatment of various conditions are limited. However, the literature, which includes several systematic reviews, considers TNF-blocking agents, primarily infliximab, adalimumab, and etanercept, to have similar
efficacy in RA, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis. For maintenance of CD 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 than the IV administration of infliximab.

Given the lack of comparative trials and randomized controlled trials for agents across conditions, evidence does not definitively demonstrate that clinical outcomes are equivalent for 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, because available evidence is preliminary or not supportive of the use of infliximab for these conditions.

Practice Guidelines and Position Statements
American Academy of Dermatology

In May 2008, the American Academy of Dermatology released guidelines for the management of psoriasis and psoriatic arthritis.(135) These guidelines addressed the treatment of both adult and childhood psoriasis and psoriatic arthritis including biologics. As of August 2014, updates of the sections on biologic
drugs are in progress.

American College of Rheumatology

In 2012, the American College of Rheumatology (ACR) issued an evidence-based, consensus update to their 2008 recommendations for the use of DMARDs and biologic agents in the treatment of RA.(136) In patients with early RA (disease duration, <6 months), anti-TNF biologics with or without methotrexate are recommended for patients who have high disease activity with poor prognostic features (functional limitation, extra-articular disease, positive rheumatoid factor [RF], positive anti-cyclic citrullinated peptide [CCP] antibodies, bony erosions by radiograph). (Level of evidence, A-B [data derived from multiple
RCTs, a single randomized trial, or nonrandomized studies]) Infliximab is the only exception and is recommended for use in combination with methotrexate but not as monotherapy. For patients with established RA (disease duration, ≥6 months), biologic agents, including anti-TNF drugs, are recommended if disease activity is moderate or high after 3 months of methotrexate therapy alone or in combination with other conventional DMARDs. (Level of evidence, A-C data derived from multiple RCTs, a single randomized trial, nonrandomized studies, consensus opinion, case studies, or standards of care)

ACR’s 2011 Model Biologics Policy indicated that infliximab may be used off-label for the following indications: undifferentiated polyarthritis, undifferentiated spondyloarthropathy, sarcoidosis, myositis, Behçet disease, uveitis, adult-onset Still disease, reactive arthritis, JIA, and autoinflammatory diseases.(137)
ACR also recommends dose escalation of infliximab to 10 mg/kg in patients with RA or CD that does not completely respond to induction dosage.

American Uveitis Society

In 2014, the American Uveitis Society published evidence-based consensus recommendations for the use of anti-TNF agents in patients with ocular inflammatory disorders.(138) Literature was searched through April 2013, and approximately 400 publications were reviewed. The panel made the following
recommendations:

  • Infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of vision-threatening ocular manifestations of Behçet’s disease (strong recommendation based on good [infliximab] or moderate [adalimumab] quality evidence).
  • Infliximab and adalimumab can be considered as second-line immunomodulatory agents for the treatment of vision-threatening uveitis associated with JIA (strong recommendation based on good [infliximab] or moderate [adalimumab] quality evidence).
  • Infliximab and potentially adalimumab can be considered as potential second-line immunomodulatory agents for the treatment of vision-threatening ocular inflammatory conditions (eg, posterior uveitis, panuveitis, severe uveitis associated with seronegative spondyloarthropathy [strong recommendation based on moderate-to-good quality evidence], and scleritis) in patients who require immunomodulation and have failed or are not candidates for antimetabolite or calcineurin inhibitor therapy (for all other indications: discretionary recommendation based on moderate-to-good quality evidence).
  • Infliximab and adalimumab can be considered in these patients in preference to etanercept, which seems to be associated with lower rates of treatment success strong recommendation; evidence quality not reported).

European League Against Rheumatism

In 2013, the European League Against Rheumatism updated its evidence-based consensus recommendations for the management of RA with conventional and biological DMARDs.(139) Biological DMARDs are recommended as second-line, add-on treatment for patients with poor prognostic factors
(positive RF, positive anti-CCP antibodies, very high disease activity, early joint damage) (grade of recommendation D [based on expert opinion without explicit critical appraisal]), and for patients responding inadequately to conventional DMARDs (grade of recommendation A [based on individual RCT with narrow confidence interval]). Biological DMARDs, including TNF inhibitors and others, were considered to have similar efficacy and safety. If a first biological DMARD fails, patients should be treated with another biological DMARD; if a first TNF inhibitor fails, patients may receive another TNF inhibitor or
a biological agent with another mode of action (eg, abatacept, tocilizumab, or, under certain circumstances [history of lymphoma or demyelinating disease], rituximab) (grade of recommendation A [based on systematic review of RCTs with homogeneity]).

National Psoriasis Foundation

A 2010 task force of the National Psoriasis Foundation developed consensus treatment recommendations for erythrodermic or exfoliative psoriasis.(140) 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.

American Gastroenterological Association Institute

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.(141) These recommendations are intended for adult
patients and are based on the interpretation and assimilation of scientifically valid research. The objective was to review evidence based on prospective, randomized placebo-controlled trials; however, when this was not possible, expert consensus was used. The recommendation for infliximab is for the treatment of patients with inflammatory and fistulizing CD that failed to respond to other therapies.

World Congress of Gastroenterology

In 2011, the World Congress of Gastroenterology issued the London Position Statement on biologics for inflammatory bowel disease.(142) Infliximab is considered appropriate for the treatment of CD 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.

U.S. Preventive Services Task Force Recommendations
Use of infliximab is not a preventive service.

Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.

References:

  1. U.S. Food and Drug Administration (FDA). Remicade (infliximab) lyophilized concentrate for injection, for intravenous use, prescribing information, November 2013. http://www.remicade.com/. Accessed August 11, 2014.
  2. 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
  3. Michaud TL, Rho YH, Shamliyan T, et al. The Comparative Safety of TNF Inhibitors in Rheumatoid Arthritis - A Meta-Analysis Update of 44 Randomized Controlled Trials. Am J Med. Jun 17 2014. PMID 24950486
  4. 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 5 2012;308(9):898-908. PMID 22948700
  5. 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. 2012;7(11):e48991. PMID 23155441
  6. 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
  7. Askling J, Fahrbach K, Nordstrom B, et al. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: metaanalysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf. Feb 2011;20(2):119-130. PMID 21254282
  8. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011(2):CD008794. PMID 21328309
  9. Machado MA, Barbosa MM, Almeida AM, et al. Treatment of ankylosing spondylitis with TNF blockers: a metaanalysis. Rheumatol Int. Sep 2013;33(9):2199-2213. PMID 23686218
  10. Ren L, Li J, Luo R, et al. Efficacy of Antitumor Necrosis Factor(alpha) Agents on Patients With Ankylosing Spondylitis. Am J Med Sci. May 24 2013. PMID 23715113
  11. Shu T, Chen GH, Rong L, et al. Indirect comparison of anti-TNF-alpha agents for active ankylosing spondylitis: mixed treatment comparison of randomized controlled trials. Clin Exp Rheumatol. Jul 31 2013. PMID 23899710
  12. Callhoff J, Sieper J, Weiss A, et al. Efficacy of TNFalpha blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann Rheum Dis. Apr 9 2014. PMID 24718959
  13. Migliore A, Broccoli S, Bizzi E, et al. Indirect comparison of the effects of anti-TNF biological agents in patients with ankylosing spondylitis by means of a mixed treatment comparison performed on efficacy data from published randomised, controlled trials. J Med Econ. 2012;15(3):473-480. PMID 22335398
  14. McLeod C, Bagust A, Boland A, et al. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: a systematic review and economic evaluation. Health Technol Assess. Aug 2007;11(28):1-158, iii-iv. PMID 17651658
  15. Schatteman L, Gyselbrecht L, De Clercq L, et al. Treatment of refractory inflammatory monoarthritis in ankylosing spondylitis by intraarticular injection of infliximab. J Rheumatol. Jan 2006;33(1):82-85. PMID 16292792
  16. Costa J, Magro F, Caldeira D, et al. Infliximab Reduces Hospitalizations and Surgery Interventions in Patients With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Inflamm Bowel Dis. Sep 2013;19(10):2098-2110. PMID 23860567
  17. Lichtenstein GR, Rutgeerts P, Sandborn WJ, et al. A pooled analysis of infections, malignancy, and mortality in infliximab- and immunomodulator-treated adult patients with inflammatory bowel disease. Am J Gastroenterol. Jul 2012;107(7):1051-1063. PMID 22613901
  18. Rosenfeld G, Qian H, Bressler B. The risks of post-operative complications following pre-operative infliximab therapy for Crohn's disease in patients undergoing abdominal surgery: A systematic review and meta-analysis. J Crohns Colitis. Mar 2 2013. PMID 23466411
  19. Stidham RW, Lee TC, Higgins PD, et al. Systematic review with network meta-analysis: the efficacy of anti-TNF agents for the treatment of Crohn's disease. Aliment Pharmacol Ther. Jun 2014;39(12):1349-1362. PMID 24749763
  20. Yoshida K, Fukunaga K, Ikeuchi H, et al. Scheduled infliximab monotherapy to prevent recurrence of Crohn's disease following ileocolic or ileal resection: a 3-year prospective randomized open trial. Inflamm Bowel Dis. Sep 2012;18(9):1617-1623. PMID 22081474
  21. Dretzke J, Edlin R, Round J, et al. A systematic review and economic evaluation of the use of tumour necrosis factor-alpha (TNF-alpha) inhibitors, adalimumab and infliximab, for Crohn's disease. Health Technol Assess. Feb 2011;15(6):1-244. PMID 21291629
  22. D'Haens G, Baert F, van Assche G, et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial. Lancet. Feb 23 2008;371(9613):660-667. PMID 18295023
  23. Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. Apr 15 2010;362(15):1383-1395. PMID 20393175
  24. Ferrante M, Colombel JF, Sandborn WJ, et al. Validation of endoscopic activity scores in patients with Crohn's disease based on a post hoc analysis of data from SONIC. Gastroenterology. Nov 2013;145(5):978-986 e975. PMID 23954314
  25. Peyrin-Biroulet L, Reinisch W, Colombel JF, et al. Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial. Gut. Jan 2014;63(1):88-95. PMID 23974954 
  26. ehm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2008(1):CD006893. PMID 18254120 
  27. kobeng AK. Crohn's disease: current treatment options. Arch Dis Child. Sep 2008;93(9):787-792. PMID 18456695
  28. Peyrin-Biroulet L, Deltenre P, de Suray N, et al. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol. Jun 2008;6(6):644-653. PMID 18550004
  29. Kozuch PL, Hanauer SB. Treatment of inflammatory bowel disease: a review of medical therapy. World J Gastroenterol. Jan 21 2008;14(3):354-377. PMID 18200659
  30. Kopylov U, Ben-Horin S, Zmora O, et al. Anti-tumor necrosis factor and postoperative complications in Crohn's disease: systematic review and meta-analysis. Inflamm Bowel Dis. Mar 29 2012. PMID 22467533
  31. Gallego-Galisteo M, Villa-Rubio A, Alegre-del Rey E, et al. Indirect comparison of biological treatments in refractory rheumatoid arthritis. J Clin Pharm Ther. Jun 2012;37(3):301-307. PMID 21831256
  32. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn's disease in children. Gastroenterology. Mar 2007;132(3):863-873; quiz 1165-1166. PMID 17324398
  33. Hyams J, Walters TD, Crandall W, et al. Safety and efficacy of maintenance infliximab therapy for moderate-tosevere Crohn's disease in children: REACH open-label extension. Curr Med Res Opin. Mar 2011;27(3):651-662. PMID 21241207
  34. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. Dec 8 2005;353(23):2462-2476. PMID 16339095
  35. Reinisch W, Sandborn WJ, Rutgeerts P, et al. Long-term infliximab maintenance therapy for ulcerative colitis: the ACT-1 and -2 extension studies. Inflamm Bowel Dis. Feb 2012;18(2):201-211. PMID 21484965
  36. Chang KH, Burke JP, Coffey JC. Infliximab versus cyclosporine as rescue therapy in acute severe steroidrefractory ulcerative colitis: a systematic review and meta-analysis. Int J Colorectal Dis. Mar 2013;28(3):287-293. PMID 23114475
  37. Yang Z, Wu Q, Wang F, et al. Meta-analysis: effect of preoperative infliximab use on early postoperative complications in patients with ulcerative colitis undergoing abdominal surgery. Aliment Pharmacol Ther. Nov 2012;36(10):922-928. PMID 23002804
  38. Turner D, Griffiths AM. Acute severe ulcerative colitis in children: a systematic review. Inflamm Bowel Dis. Jan 2011;17(1):440-449. PMID 20645317
  39. United States Food and Drug Administration. GI Advisory Committee Meeting. 2011; http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM263459.pdf. Accessed August 11, 2014.
  40. Turner D, Mack D, Leleiko N, et al. Severe pediatric ulcerative colitis: a prospective multicenter study of outcomes and predictors of response. Gastroenterology. Jun 2010;138(7):2282-2291. PMID 20193683
  41. Hyde C, Bryan S, Juarez-Garcia A, et al. Infliximab for the treatment of ulcerative colitis. Health Technol Assess. Oct 2009;13 Suppl 3:7-11. PMID 19846023
  42. Bryan S, Andronis L, Hyde C, et al. Infliximab for the treatment of acute exacerbations of ulcerative colitis. Health Technol Assess. May 2010;14 Suppl 1:9-15. PMID 20507798
  43. Lv R, Qiao W, Wu Z, et al. Tumor necrosis factor alpha blocking agents as treatment for ulcerative colitis intolerant or refractory to conventional medical therapy: a meta-analysis. PLoS One. 2014;9(1):e86692. PMID 24475168
  44. Danese S, Fiorino G, Peyrin-Biroulet L, et al. Biological agents for moderately to severely active ulcerative colitis: a systematic review and network meta-analysis. Ann Intern Med. May 20 2014;160(10):704-711. PMID 24842416
  45. Thorlund K, Druyts E, Mills EJ, et al. Adalimumab versus infliximab for the treatment of moderate to severe ulcerative colitis in adult patients naive to anti-TNF therapy: an indirect treatment comparison meta-analysis. J Crohns Colitis. Jul 1 2014;8(7):571-581. PMID 24491514
  46. Stidham RW, Lee TC, Higgins PD, et al. Systematic review with network meta-analysis: the efficacy of antitumour necrosis factor-alpha agents for the treatment of ulcerative colitis. Aliment Pharmacol Ther. Apr 2014;39(7):660-671. PMID 24506179
  47. Tambralli A, Beukelman T, Weiser P, et al. High doses of infliximab in the management of juvenile idiopathic arthritis. J Rheumatol. Oct 2013;40(10):1749-1755. PMID 23950184
  48. McErlane F, Foster HE, Davies R, et al. Biologic treatment response among adults with juvenile idiopathic arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (Oxford). Oct 2013;52(10):1905-1913. PMID 23873820
  49. Kemper AR Coeytaux R, Sanders GD, et al. Disease-Modifying Antirheumatic Drugs (DMARDs) in Children with Juvenile Idiopathic Arthritis. Comparative Effectiveness Review No. 28. AHRQ Publication No. 11-EHC039-EF.Rockville, MD: Agency for Healthcare Research and Quality. August 2011.
    www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed August 11, 2014.
  50. 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
  51. 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
  52. 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
  53. Lee S CC, Limone B, Kaur R, et al. Biologic and Nonbiologic Systemic Agents and Phototherapy for Treatment of Chronic Plaque Psoriasis. Comparative Effectiveness Review No. 85. (Prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center under Contract No. 290-2007-10067-I.) AHRQ Publication No. 12(13)-EHC144-EF. Rockville, MD: Agency for Healthcare Research and Quality. November 2012. PMID
  54. Thorlund K, Druyts E, Avina-Zubieta JA, et al. Anti-tumor necrosis factor (TNF) drugs for the treatment of psoriatic arthritis: an indirect comparison meta-analysis. Biologics. 2012;6:417-427. PMID 23271892 
  55. Fenix-Caballero S, Alegre-del Rey EJ, Castano-Lara R, et al. Direct and indirect comparison of the efficacy and safety of adalimumab, etanercept, infliximab and golimumab in psoriatic arthritis. J Clin Pharm Ther. Aug 2013;38(4):286-293. PMID 23590560
  56. Lemos LL, de Oliveira Costa J, Almeida AM, et al. Treatment of psoriatic arthritis with anti-TNF agents: a systematic review and meta-analysis of efficacy, effectiveness and safety. Rheumatol Int. Apr 13 2014. PMID 24728068
  57. Gupta AK, Daigle D, Lyons DC. Network Meta-analysis of Treatments for Chronic Plaque Psoriasis in Canada. J Cutan Med Surg. 2014;18(0):1-8. PMID 24762338
  58. Sandoval LF, Pierce A, Feldman SR. Systemic therapies for psoriasis: an evidence-based update. Am J Clin Dermatol. Jul 2014;15(3):165-180. PMID 24496885
  59. Schmitt J, Rosumeck S, Thomaschewski G, et al. Efficacy and safety of systemic treatments for moderate-tosevere psoriasis: meta-analysis of randomized controlled trials. Br J Dermatol. Feb 2014;170(2):274-303. PMID 24131260
  60. Donahue KE Jonas D, Hansen RA, et al. Drug Therapy for Psoriatic Arthritis in Adults: Update of a 2007 Report. Comparative Effectiveness Review No. 54. Agency for Healthcare Research and Quality. AHRQ Publication No. 12-EHC024-EF. April 2012; www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed August 11, 2014.
  61. Rodgers M, Epstein D, Bojke L, et al. Etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis: a systematic review and economic evaluation. Health Technol Assess. Feb 2011;15(10):i-xxi, 1-329. PMID 21333232
  62. Migliore A, Bizzi E, Broccoli S, et al. Indirect comparison of etanercept, infliximab, and adalimumab for psoriatic arthritis: mixed treatment comparison using placebo as common comparator. Clin Rheumatol. Jan 2012;31(1):133-137. PMID 21701796
  63. Reich K, Burden AD, Eaton JN, et al. Efficacy of biologics in the treatment of moderate to severe psoriasis: a network meta-analysis of randomized controlled trials. Br J Dermatol. Jan 2012;166(1):179-188. PMID 21910698
  64. Lucka TC, Pathirana D, Sammain A, et al. Efficacy of systemic therapies for moderate-to-severe psoriasis: a systematic review and meta-analysis of long-term treatment. J Eur Acad Dermatol Venereol. Mar 9 2012. PMID 22404617
  65. Antoni CE, Kavanaugh A, Kirkham B, et al. Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum. Apr 2005;52(4):1227-1236. PMID 15818699
  66. Gottlieb AB, Evans R, Li S, et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. Oct 2004;51(4):534-542. PMID 15389187
  67. Atteno M, Peluso R, Costa L, et al. Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous diseasemodifying antirheumatic drugs. Clin Rheumatol. Apr 2010;29(4):399-403. PMID 20066450
  68. Baranauskaite A, Raffayova H, Kungurov NV, et al. Infliximab plus methotrexate is superior to methotrexate alone in the treatment of psoriatic arthritis in methotrexate-naive patients: the RESPOND study. Ann Rheum Dis. Apr 2012;71(4):541-548. PMID 21994233
  69. Barker J, Hoffmann M, Wozel G, et al. Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1). Br J Dermatol. Nov 2011;165(5):1109-1117. PMID 21910713
  70. Callhoff J, Weiss A, Zink A, et al. Impact of biologic therapy on functional status in patients with rheumatoid arthritis--a meta-analysis. Rheumatology (Oxford). Aug 14 2013. PMID 23946435
  71. Jansen JP, Buckley F, Dejonckheere F, et al. Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs--a systematic review and network meta-analysis. Health Qual Life Outcomes. 2014;12:102. PMID 24988902
  72. Barra L, Ha A, Sun L, et al. Efficacy of biologic agents in improving the Health Assessment Questionnaire (HAQ) score in established and early rheumatoid arthritis: a meta-analysis with indirect comparisons. Clin Exp Rheumatol. May-Jun 2014;32(3):333-341. PMID 24480452
  73. Nam JL, Ramiro S, Gaujoux-Viala C, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. Mar 2014;73(3):516-528. PMID 24399231
  74. Nam JL, Villeneuve E, Hensor EM, et al. Remission induction comparing infliximab and high-dose intravenous steroid, followed by treat-to-target: a double-blind, randomised, controlled trial in new-onset, treatment-naive, rheumatoid arthritis (the IDEA study). Ann Rheum Dis. Jan 2014;73(1):75-85. PMID 23912798
  75. Donahue KE JD, Hansen RA, et al. Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Comparative Effectiveness Review No. 55. Rockville, MD: Agency for Healthcare Research and Quality. April 2012;www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed August 11, 2014.
  76. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. Aug 2008;67(8):1096-1103. PMID 18055472
  77. Aaltonen KJ, Virkki LM, Malmivaara A, et al. Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One. 2012;7(1):e30275. PMID 22272322
  78. Schmitz S, Adams R, Walsh CD, et al. A mixed treatment comparison of the efficacy of anti-TNF agents in rheumatoid arthritis for methotrexate non-responders demonstrates differences between treatments: a Bayesian approach. Ann Rheum Dis. Feb 2012;71(2):225-230. PMID 21960560
  79. Turkstra E, Ng SK, Scuffham PA. A mixed treatment comparison of the short-term efficacy of biologic disease modifying anti-rheumatic drugs in established rheumatoid arthritis. Curr Med Res Opin. Oct 2011;27(10):1885-1897. PMID 21848493
  80. Malottki K, Barton P, Tsourapas A, et al. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a tumour necrosis factor inhibitor: a systematic review and economic evaluation. Health Technol Assess. Mar 2011;15(14):1-278. PMID 21439251
  81. Singh JA, Christensen R, Wells GA, et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database Syst Rev. 2009(4):CD007848. PMID 19821440
  82. Lin J, Ziring D, Desai S, et al. TNFalpha blockade in human diseases: an overview of efficacy and safety. Clin Immunol. Jan 2008;126(1):13-30. PMID 17916445
  83. Canadian Agency for Drugs and Technologies in Health; HTA Technology Report. Infliximab and etanercept in rheumatoid arthritis: systematic review of long-term effectiveness, safety, and cost-effectiveness. Issue 85.March 2007; http://cadth.ca/media/pdf/318A_Anti-TNF_tr_e.pdf. Accessed August 11, 2014.
  84. Takeuchi T, Miyasaka N, Tatsuki Y, et al. Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis. Ann Rheum Dis. Jul 2011;70(7):1208-1215. PMID 21478189
  85. Takeuchi T, Miyasaka N, Inoue K, et al. Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Mod Rheumatol. 2009;19(5):478-487. PMID 19626391
  86. Pavelka K, Jarosova K, Suchy D, et al. Increasing the infliximab dose in rheumatoid arthritis patients: a randomised, double blind study failed to confirm its efficacy. Ann Rheum Dis. Aug 2009;68(8):1285-1289. PMID 19351624
  87. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. May 5 2012;379(9827):1712-1720. PMID 22464340
  88. Karlsson JA, Neovius M, Nilsson JA, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality-of-life results of the randomised, controlled, SWEFOT trial. Ann Rheum Dis. Dec 2013;72(12):1927-1933. PMID 23196701
  89. 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 
  90. Wells AU. Infliximab in extrapulmonary sarcoidosis: tantalising but inconclusive. Eur Respir J. Jun 2008;31(6):1148-1149. PMID 18515552
  91. 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
  92. 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
  93. Phumethum V, Jamal S, Johnson SR. Biologic therapy for systemic sclerosis: a systematic review. J Rheumatol. Feb 2011;38(2):289-296. PMID 21041277
  94. 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
  95. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. Sep 2005;140(3):509-516. PMID 16196117
  96. Simonini G, Druce K, Cimaz R, et al. Current evidence of anti-tumor necrosis factor alpha treatment efficacy in childhood chronic uveitis: A systematic review and meta-analysis approach of individual drugs. Arthritis Care Res (Hoboken). Jul 2014;66(7):1073-1084. PMID 24740981
  97. Simonini G, Katie D, Cimaz R, et al. Does switching anti-TNFalpha biologic agents represent an effective option in childhood chronic uveitis: The evidence from a systematic review and meta-analysis approach. Semin Arthritis Rheum. Aug 2014;44(1):39-46. PMID 24709278
  98. Cordero-Coma M, Yilmaz T, Onal S. Systematic review of anti-tumor necrosis factor-alpha therapy for treatment of immune-mediated uveitis. Ocul Immunol Inflamm. 2013;21(1):19-27. PMID 23323577
  99. Al-Rayes H, Al-Swailem R, Al-Balawi M, et al. Safety and efficacy of infliximab therapy in active behcet's uveitis: an open-label trial. Rheumatol Int. Nov 2008;29(1):53-57. PMID 18496694
  100. Niccoli L, Nannini C, Benucci M, et al. Long-term efficacy of infliximab in refractory posterior uveitis of Behcet's disease: a 24-month follow-up study. Rheumatology (Oxford). Jul 2007;46(7):1161-1164. PMID 17478466
  101. Al Rashidi S, Al Fawaz A, Kangave D, et al. Long-term clinical outcomes in patients with refractory uveitis associated with Behcet disease treated with infliximab. Ocul Immunol Inflamm. Dec 2013;21(6):468-474. PMID 23734940
  102. Blok JL, van Hattem S, Jonkman MF, et al. Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review. Br J Dermatol. Feb 2013;168(2):243-252. PMID 23106519 
  103. van Rappard DC, Limpens J, Mekkes JR. The off-label treatment of severe hidradenitis suppurativa with TNFalpha inhibitors: a systematic review. J Dermatolog Treat. Oct 2013;24(5):392-404. PMID 22397574 
  104. Alhusayen R, Shear NH. Pharmacologic interventions for hidradenitis suppurativa: what does the evidence say? Am J Clin Dermatol. Oct 1 2012;13(5):283-291. PMID 22676319
  105. Rambhatla PV, Lim HW, Hamzavi I. A systematic review of treatments for hidradenitis suppurativa. Arch Dermatol. Apr 2012;148(4):439-446. PMID 22184715
  106. Arida A, Fragiadaki K, Giavri E, et al. Anti-TNF agents for Behcet's disease: analysis of published data on 369patients. Semin Arthritis Rheum. Aug 2011;41(1):61-70. PMID 21168186
  107. 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
  108. 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
  109. 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
  110. 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
  111. Josselin L, Mahr A, Cohen P, et al. Infliximab efficacy and safety against refractory systemic necrotising vasculitides: long-term follow-up of 15 patients. Ann Rheum Dis. Sep 2008;67(9):1343-1346. PMID 18445626
  112. 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
  113. Burns JC, Mason WH, Hauger SB, et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr. May 2005;146(5):662-667. PMID 15870671
  114. 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
  115. Harrison ML, Obermueller E, Maisey NR, et al. Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose. J Clin Oncol. Oct 10 2007;25(29):4542-4549. PMID 17925549
  116. 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
  117. 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 
  118. 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. May 22 2013. PMID 23692303
  119. 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
  120. Koninckx PR, Craessaerts M, Timmerman D, et al. Anti-TNF-alpha treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial. Hum Reprod. Sep 2008;23(9):2017-2023. PMID 18556683 
  121. Lv D, Song H, Shi G. Anti-TNF-alpha treatment for pelvic pain associated with endometriosis. Cochrane Database Syst Rev. 2010(3):CD008088. PMID 20238362
  122. Hall RP, Fairley J, Woodley D, et al. A multi-centered randomized trial of the treatment of pemphigus vulgaris patients with infliximab and prednisone compared to prednisone alone. Br J Dermatol. Aug 13 2014. PMID 25123295
  123. Sharma P, Kumar A, Sharma BC, et al. Infliximab monotherapy for severe alcoholic hepatitis and predictors of survival: an open label trial. J Hepatol. Mar 2009;50(3):584-591. PMID 19155081
  124. Uppal SS, Hayat SJ, Raghupathy R. Efficacy and safety of infliximab in active SLE: a pilot study. Lupus. Jul 2009;18(8):690-697. PMID 19502264
  125. Sfikakis PP, Grigoropoulos V, Emfietzoglou I, et al. Infliximab for diabetic macular edema refractory to laser photocoagulation: a randomized, double-blind, placebo-controlled, crossover, 32-week study. Diabetes Care. Jul 2010;33(7):1523-1528. PMID 20413522
  126. 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
  127. Hernandez-Rodriguez J, Cid MC, Lopez-Soto A, et al. Treatment of polymyalgia rheumatica: a systematic review. Arch Intern Med. Nov 9 2009;169(20):1839-1850. PMID 19901135
  128. 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
  129. Jatoi A, Ritter HL, Dueck A, et al. A placebo-controlled, double-blind trial of infliximab for cancer-associated weight loss in elderly and/or poor performance non-small cell lung cancer patients (N01C9). Lung Cancer. May 2010;68(2):234-239. PMID 19665818
  130. Couriel DR, Saliba R, de Lima M, et al. A phase III study of infliximab and corticosteroids for the initial treatment of acute graft-versus-host disease. Biol Blood Marrow Transplant. Dec 2009;15(12):1555-1562. PMID 19896079
  131. Maas DW, Westendorp RG, Willems JM, et al. TNF-alpha antagonist infliximab in the treatment of depression in older adults: results of a prematurely ended, randomized, placebo-controlled trial. J Clin Psychopharmacol. Jun 2010;30(3):343-345. PMID 20473080
  132. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. Jan 2013;70(1):31-41. PMID 22945416
  133. Nussenblatt RB, Byrnes G, Sen HN, et al. A randomized pilot study of systemic immunosuppression in the treatment of age-related macular degeneration with choroidal neovascularization. Retina. Nov-Dec 2010;30(10):1579-1587. PMID 20847709
  134. 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
  135. 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
  136. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). May 2012;64(5):625-639. PMID 22473917
  137. American College of Rheumatology. Model Biologics Policy 2011; https://www.google.com/url?url=https://www.rheumatology.org/Practice/Office/Insurance/Model_Biologics_Policies/&rct=j&frm=1&q=&esrc=s&sa=U&ei=TyLpU52bMYqWyATS4oDwDw&ved=0CB8QFjAC&usg=AFQjCNG8FzljevCalrXwbOfWKNxOOTc4pQ. Accessed August 11, 2014.
  138. Levy-Clarke G, Jabs DA, Read RW, et al. Expert panel recommendations for the use of anti-tumor necrosis actor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. Mar 2014;121(3):785-796 783. PMID 24359625
  139. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. Mar 2014;73(3):492-509. PMID 24161836
  140. 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
  141. Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. Mar 2006;130(3):935-939. PMID 16530531
  142. D'Haens GR, Panaccione R, Higgins PD, et al. The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organization: when to start, when to stop, which drug to choose, and how to predict response? Am J Gastroenterol. Feb 2011;106(2):199-212; quiz 213. PMID 21045814



     

 

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.
10/09/14 Replace policy Policy updated with literature review through August 28, 2014; references 2-3, 11-12, 19, 24-25, 43-48, 56-59, 71-74, 88, 96-97, 101, 110, 114, 116-117, 122, and 138-139 added; references 1, 39, 49, 60, 75, 83, and 137 updated. Policy statements unchanged.