Tumor necrosis factor (TNF) is a cytokine produced by macrophages and T cells. Its name is based on the original observations 25 years ago that TNF killed tumor cells in vitro. Further research has revealed that TNF has a broad spectrum of biologic activities; in particular, it is a key mediator of inflammation and is produced in response to infection and immunologic injury. There are a number of drugs currently available that inhibit the activity of TNF: etanercept, self-administered via a subcutaneous injection; adalimumab, administered via subcutaneous injection; thalidomide, an oral drug; and infliximab (Remicade), which is administered via an intravenous (IV) infusion in the physician's office, outpatient setting, or infusion center. This policy focuses on infliximab that is administered in the physician's office and is thus typically adjudicated under the medical benefit.

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

Infliximab, in combination with methotrexate, may be considered medically necessary for treatment of moderately to severely active rheumatoid arthritis.*

Infliximab may be considered medically necessary for reducing signs and symptoms and inducing and maintaining clinical remission in adult and pediatric patients with moderately to severely active Crohn's disease who have had an inadeqate response to conventional therapy.*

Infliximab may be considered medically necessary in adult patients with fistulizing Crohn's disease.*

Infliximab may be considered medically necessary for reducing signs and symptoms in patients with active ankylosing spondylitis.*

Infliximab may be considered medically necessary for patients with psoriatic arthritis.*

Infliximab may be considered medically necessary indicated for the treatment of adult patients with chronic severe plaque psoriasis who are candidates for systemic therapy and when other systemic theraies are medically less appropriate.*

Infliximab may be condisered medically necessary 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 respinse to conventional therapy.*

Other uses of infliximab are considered investigational, including, but not limited to, use in Kawasaki syndrome, sarcoidosis, uveitis, systemic necrotizing vasculitides, renal cell carcinoma, polymyalgia rheumatica, giant cell arteritis, endometriosis, sclerosing colangitis and cancer cachexia.

*Indicates FDA-approved indication.

Infliximab is typically administered initially in a 3-dose induction regimen generally every 3 weeks, followed by maintenance therapy every 8 weeks.

BlueCard/National Account Issues

This policy may be superseded by state or federal mandates requiring coverage for FDA-approved drugs.

Dermatologic Manifestations of Psoriasis

The infliximab multinational psoriatic arthritis controlled trial (IMPACT) was a randomized study of infliximab as a treatment of psoriatic arthritis. (1) A secondary outcome focused on improvements in dermatologic manifestations of psoriasis. A total of 104 patients with psoriatic arthritis participated in this randomized, placebo-controlled and blinded study. Of these, only 39 had significant psoriatic skin lesions, as evidenced by a psoriasis area and severity index (PASI) score of >= 2.5. (The maximum PASI score is 72. The score reflects lesional erythema, scaling, and thickness in 4 anatomic areas.) Patients received infliximab or placebo at 0, 2, 6, and 14 weeks. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab every 8 weeks through week 50, while patients randomized to infliximab continued to receive active treatment. Changes in the PASI score were analyzed for the 39 patients with skin lesions; 68% of infliximab patients achieved improvement of > = 75% in the PASI score at week 16 compared to none in the placebo group. However, interpretation of these results is limited. The sample size was only 39 patients. In addition, patients were recruited to this trial based on arthritic manifestations with previous failure of one or more disease-modifying anti-rheumatic drugs (DMARDs). In contrast, it is not known whether previous therapies had been successful in controlling dermatologic manifestations of psoriasis.

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

Treatment of Ulcerative Colitis

The recent approval by the U.S. Food and Drug Administration (FDA) of infliximab for the treatment of ulcerative colitis was based in part on the results of ACT 1 and ACT 2 randomized studies. These studies enrolled patients with disease refractory to at least 1 standard therapy, including corticosteroids, immunosuppressants, or mesalamine. Patients received infliximab or placebo infusions at 0, 2, and 6 weeks and then every 8 weeks. The ACT 1 trial continued infusions until week 46, with final evaluation at week 54. (3) In contrast, the ACT 2 trial continued infusions until week 22, with final evaluation at week 30. (4) The primary endpoint of both trials was induction of clinical response, while secondary endpoints included clinical remission. Results of these trials have now been presented as abstracts at the 2005 Digestive Disease Week meeting. In both studies, the infliximab group had a significant improvement in both clinical response and clinical remission at all time points studied. Also, a significantly greater percentage of patients in the infliximab group were able to discontinue steroids while in clinical remission. Based on the results of these studies, the FDA designated infliximab for priority review.

2006 – 2007 Update

A literature search was conducted using MEDLINE through April 2007. None of the studies identified alter the conclusions in the policy statements above, which are unchanged. Studies, which should be viewed as preliminary, are being reported on use of infliximab for treatment of refractory Kawasaki syndrome. (5) In addition, a publication reported on positive results from intra-articular injections of infliximab in patients with ankylosing spondylitis. (6)

The FDA has approved infliximab for use in pediatric patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy and for use in patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate.

2008 Update

The policy was updated to include both on- and off-label uses of infliximab. The FDA-approved indications have not changed since the 2007 update. A MEDLINE search was conducted for the period April 2007 through June 2008 to update the policy. In addition to its labeled uses, infliximab is being studied in treatment-refractory inflammatory diseases. The discussion here will include only publications reporting the use of infliximab in 10 or more patients.

Early Crohn's Disease

A multicenter open-label randomized controlled trial from Europe of 133 patients with active Crohn's disease who had not been previously treated with corticosteroids, antimetabolites or biological agents who were assigned either early combined immunosuppression (infliximab + either azathioprine or methotrexate) or conventional management (induction with corticosteroids and sequentially adding antimetabolites [azathioprine or methortrexate] and infliximab) with 2-year follow-up found that early immunosuppression was more effective than conventional therapy for preventing disease progression. (7) At 26 weeks, 60% vs 36% of the early immunosuppression and conventional treatment groups were in remission (remission rates were statistically different at 1 year (62% and 42%), but not 2 years). Corticosteroid, but not antimetabolite, usage was lower, and the median time to relapse was longer in the early immunosuppression group (329 days vs 175 days). Safety profiles were similar, although the study was not powered to detect safety differences. A phase III randomized trial of 500 patients with early Crohn's disease is nearing completion. The results are expected to be reported in late 2008; and could alter the treatment approach for Crohn's disease.(8,9)

Sarcoidosis

An analysis from a previously published [KP1] randomized trial of 138 patients with pulmonary sarcoidosis was published. The observed treatment benefit in extrapulmonary sarcoidosis in patients receiving infliximab for 24 weeks was reported as an improvement in ePOST (extrapulmonary Physician Organ Severity Tool, a metric designed for the present study that summarizes the involvement of 17 organs). While a statistical improvement on group-mean scoer was noted at 24 weeks, this measure has not been clinically validated and its relationship to clinical outcomes is unknown. The accompanying editorial concluded that "a routine rolfe for infliximab has not been established by these data." (10,11) Use of infliximab for sarcoidosis is considered investigational.

Uveitis

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

Other Uses

A number of pacebo-controlled trials of infliximab were conducted for other indications such as polymyalgia rheumatica ('n=51), giant cell arteritis ('n=44), endometriosis ('n=21), sclerosing colangitis ('n=24), and pancreatic cancer cachexia ('n=89). (14-18) None of these trials showed a clinical benefit of infliximab in their stated outcomes. While small sample sizes may account for some lack of reported effect due to study power, 2 studies (giant cell arteritis, sclerosing colangitis) were terminated early due to lack of treatment effect at interim analysis. (15-17) Several observational studies reported negative results as well. A prospective cohort study of 19 patients given infliximab to prevent acute graft versus host disease did not do so compared to non-treated controls. (19)

Other publications suggested potentially useful indications. One is a case series of refractory systemic necrotizing vasculitides, where, over 35 months of follow-up, 11/15 patients entered remission and 5/15 patients achieved sustained remission ('>6 months). However, 10 patients relapsed after a median of 13 months. (20) One report of 2 phase II trials of infliximab as a treatment for refractory renal cell carcinoma ('n=18 treated with 10 mg/kg, n=-19 treated with 5mg/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. (21)

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

References:

1. Antoni CE, Kavanaugh A, Kirkham B et al. Sustained benefits of infliximab for dermatologic and articular manifestations of psoriatic arthritisresults from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 2005; 52(4):1227-36.
2. 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 2004; 51(4):534-42.
3. Rutgeerts P, Feagan BG, Olson A et al. A randomized placebo controlled trial of infliximab therapy for active ulcerative colitis: Act 1 trial. Gastroenterology 2005; 128(4 suppl 2):A-105 (abstract).
4. Sandborn WJ, Rachmilewitz DR, Hanauer SB et al. Infliximab induction and maintenance therapy for ulcerative colitis: the Act 2 trial. Gastroenterology 2005; 128(4 suppl 2):A-104 (abstract).
5. Burns JC, Mason WH, Hauger SB et al. Infliximab treatment for refractory Kawasaki syndrome. J Pediatr 2005; 146(5):662-7.
6. Schatteman L, Gyselbrecht L, De Clercq L et al. Treatment of refractory inflammatory monoarthritis in ankylosing spondylitis by intraarticular injection of infliximab. J Rheumatol 2006; 33(1):82-5.
7. S'Haens G, Baerrt F, van Assche G et al. Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease; an open randomized trial. Lancet 2008; 371(9613):660-7
8. SONIC Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease. NCT00094458, Accessible at www.clinicaltrials.gov (Last accessed 06/24/08)
9. Sandborn WJ. Initial combination therapy in early Crohn's disease, Lancet 2008: 371(9613):635-6.
10. Judson MA, Baughman RP, Costabel U et al. Efficacy of infliximab in extrapulmonary sarcoidosis: results from a randomized trial. Eur Respir J 2008; 31(6):1189-96
11. Wells AU, Infliximab in extrapulmonary sarcoidosis: tantalizing but inconclusive. Eur Respir J 2008; 31(6):1148-9
12. 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. 2008 May 22 [Epub ahead of print]
13. 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) 2007; 46(7):1161-4
14. Salvarani C, Macchioni P, Manzini C et al. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of plymyalgia rheumatica: a randomized trial. Ann Intern Med 2007; 146(9):631-9
15. Hoffman GS, Cld MC, Rendt-Zagar KE et al. Infliximab for maintainance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med 2007; 146(9):621-30
16. Koninchx PR, Craessaerts M, Timmerman D et al. Anti-TNF-(alpha) treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial. Hum Report 2008 Jun 12 [Epub ahead of print]
17. Hommes DW, Erkelens W, Ponsioen C et al, A double-blind, placebo-controlled, randomized study of infliximab in primary sclerosing cholangitis, J Clin Gastroeneteral 2008; 42(5):522-6
18. Wiedenmann B, Malfertheiner P, Friess H et al, A multicenter, phase II study of infliximab plus gemcitabine in pancreatic cancer cachexia. J Support Oncol 2008; 6(1):18-25
19. Hamandani M, Hofmeister CC, Jansak B et al. Addition of infliximab to standard acute graft-versus-host disease prophylaxis following allogeneic peripheral blood cell transplantation. Biol Blood Marrow Transplant 2008; 14(7):783-9
20. Josselin L, Mahr A, Cohen P et al. Infliximab efficacy and safety against refractory systemic necrotizing vasculitides: long-term follow-up of 15 patients. Ann Rheum Dis 2008 Apr 29 [Epub ahead of print]
21. 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 2007; 25(29):4542-9

Ankylosing Spondylitis, Infliximab Therapy
Infliximab, Off-Label Uses
Psoriatic Arthritis, Infliximab Therapy
Remicade, Off-Label Uses
Spondyloarthropathy, Infliximab Therapy