Rheumatoid arthritis, treatment infliximab

Harriman G, Harper LK, Schaible TF. Summary of clinical trials in rheumatoid arthritis using infliximab, an anti-TNFalpha treatment. Ann Rheum Dis 1999 58(Suppl l) I61-64. 

Anticytokine antibodies Infliximab Chimeric (mouse/human) monoclonal antibody against TNEa. Effective in the treatment of severe forms of rheumatoid arthritis where it can halt disease progression, or inflammatory bowel disease (EBD). 

Tumor necrosis factor-a (TNF-a) is a critical mediator of inflammation in autoimmune diseases like Crohn s disease and rheumatoid arthritis. Infliximab binds TNF-a and prevents its binding to the TNF receptor for treatment of these diseases. 

Kobelt, G., L. Jonsson, A. Young, and K. Eberhardt. 2003. The Cost-Effectiveness of Infliximab (Remicade) in the Treatment of Rheumatoid Arthritis in Sweden and the United Kingdom Based on the ATTRACT Study. Rheumatology 42 326-335. 

Etanercept is a recombinant human soluble tumor necrosis factor-alpha (TNFo ) receptor fusion protein that binds to TNFo and decreases its role in disorders involving excess inflammation. It is approved for subcutaneous use in the treatment of patients with moderate to severe active rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing arthritis and plaque psoriasis. To the adverse reactions mentioned for infliximab, rare reports of congestive heart failure should be added. 

Infliximab is a monoclonal antibody against TNF-a (see Chapter 26, Section III.d.1). It has been approved for the treatment of psoriasis, Crohn s disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. Similar immunosuppressants are etanercept, and adali-mumab. 

Two recently introduced biological therapies were designed to interfere with the inflammatory cascade initiate by TNF-a. Etanercept (Enbrel) is indicated for the treatment of moderate to severe rheumatoid arthritis in individuals over age 4. Infliximab in conjunction with methotrexate (Remicade) is approved for use by adults in the treatment of rheumatoid arthritis. It is also indicated for therapy of Crohn s disease. Over the short term, the efficacy of these drugs in the treatment of rheumatoid arthritis appears to be superior to that of methotrexate alone however, their ability to prevent bone erosion for longer than 24 months must be further studied. The cost of both drugs is significantly higher than that of the other DMARDs. 

Infliximab treatment of rheumatoid arthritis and Crohn s disease. Ann. Phar-macother. 37 1256-1265. 

NICE (National Institute for Health and Clinical Excellence) (2007) Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. Available at http //www.nice.org.uk/nicemedia/pdf/TA130guidance.pdf [Accessed 2 July 2008]. 

A comprehensive review discusses the therapeutic management of RA (Turesson and Matteson, 2004). Epidemiological studies link extra-articular rheumatoid arthritis manifestations with premature mortality and support aggressive anti rheumatoid therapies for those patients. Cyclophosphamide is favored in patients with systemic rheumatoid vasculitis and methotrexate in those cases with other manifestations of extra-articular rheumatoid arthritis (Turesson and Matteson, 2004). Cyclophosphamide and TNFa inhibitors such as infliximab have some positive success in treatment resistant vasculitis associated with RA (Unger et al., 2003). However, TNFa inhibitors have also been associated with the opposite effect, an induction of extra articular rheumatoid arthritis so their use should be used only in specific cases when close monitoring is in place. 

Treatment with infliximab can be associated with the formation of human antichimeric antibodies. Such antibodies were rarely detected in patients with rheumatoid arthritis who were also taking methotrexate, and low titers were detected in about 13% of patients with Crohn s disease. Their clinical relevance is unclear, although their presence has sometimes been associated with an increased risk of infusion reactions, the occurrence of serum sickness-like reactions after delayed re-treatment, and a shorter duration of response. 

Reactivation of latent tuberculosis is a major concern with infliximab (SEDA-26, 402), and accounts for about one-third of infections in these patients. According to data from the manufacturers, 130 cases of active tuberculosis were notified up to October 2001. Many of the cases were disseminated or extrapulmonary tuberculosis, and several patients died. Several case reports have provided detailed information in at least seven other patients, including three who developed miliary tuberculosis and one who developed Mycobacterium tuberculosis enteritis (44-48). A detailed analysis of 70 cases of tuberculosis reported to the FDA has been published (49). Two-thirds of the cases were noted after three or fewer infusions and 57% of the patients had extrapulmonary disease. There were 64 cases from countries with a low incidence of tuberculosis. From these reports and the number of patients treated with infliximab, the estimated rate of tuberculosis in patients with rheumatoid arthritis treated with infliximab was four times higher than the background rate. Patients with evidence of active infection should not receive infliximab until the infection is under control all should be screened for tuberculosis before starting infliximab (50). From these and other data it has been estimated that the risk of tuberculosis in the first year of infliximab treatment is 0.035 in US citizens and 0.2% in non-US citizens. Further investigations, such as a chest X-ray and a Mantoux test, and prophylactic treatment with isoniazid, will show whether the incidence can be reduced in patients taking anti-TNF treatment (51). 

Charles PJ, Smeenk RJ, De Jong J, Feldmaim M, Maini RN. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha findings in open-label and randomized placebo-controlled trials. Arthritis Rheum 2000 43(11) 2383-90. 

Mikuls TR, Moreland LW. Benefit-risk assessment of infliximab in the treatment of rheumatoid arthritis. Drug Saf 2003 26(l) 23-32. 

Favalli EG, Sinigaglia L, Varenna M, Arnold C. Drug-induced lupus following treatment with infliximab in rheumatoid arthritis. Lupus 2002 ll(ll) 753-5. 

Leflunomide has anti-inflammatory, immunosuppressive, and virustatic effects. Its efficacy has been demonstrated in patients with rheumatoid arthritis and psoriatic arthritis and other conditions in randomized, double-blind, placebo-controlled trials and other studies (8-32), and it was approved for treatment of adult rheumatoid arthritis in August 1998 (Table 1) (33). In three large phase III trials (US301, n = 482 MN301, n = 358 MN302, n = 999), leflunomide was as effective and well tolerated as methotrexate and sulfasalazine and superior to placebo (34). These data were confirmed by a meta-analysis (35,36). Leflunomide is therefore indicated for patients with rheumatoid arthritis who have failed first-line disease modifying anti-rheumatic drug therapy on the basis of efficacy, safety, and costs (36). It is effective as monotherapy and in combination with methotrexate or infliximab (6). 

Despite a good overall safety profile, anti-TNF antibodies can induce a number of adverse effects, including autoimmunity and infections. A trial in the treatment of Crohn s disease noted infusion reactions, transient increased of anti-dsDNA antibodies, and serum sickness-like delayed hypersensitivity with retreatment. Induction of human-antichimeric-antibodies was suggested as the cause of some of the infusion reactions [90]. A prospective study in 35 patients with Crohn s disease showed induction of ANA and anti-dsDNA autoantibodies in 53% and 35% of infliximab-treated patients [91]. A single patient showed clinical features consistent with drug-induced lupus, including the presence of ANA and anti-dsDNA autoantibodies, which quickly resolved after discontinuation of infliximab. Reports on renal adverse effects of anti-TNF antibodies are very rare. Saint Marcoux described the occurrence of crescentic GN in as few as 2 patients out of a cohort of 39 patients, treated with an anti-TNF antibody for rheumatoid arthritis [92]. A case report by Chin et al. [93] described the case of a 29-year-old Australia-born Vietnamese who presented with nephrotic syndrome. A renal biopsy showed membranous nephropathy. Symptoms attenuated after discontinuation of infliximab therapy. 

Antibody development radics can be learned by reviewing the product labeling for some agents mentioned. Antitumor necrosis factor alpha (infliximab Enbrel Amgen, Inc., Wyeth, Inc.) has revolutionized the treatment of rheumatoid arthritis, even if its labeling, in small font, occupies both sides of a small poster. 

Blumenauer B, Judd M, Wells G, et al. Infliximab for the treatment of rheumatoid arthritis. Cochrane Database Syst Rev 2002 3 CD003785. 

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