Methotrexate infliximab therapy with

Infliximab is given as an intravenous infusion at doses of 3-10 mg/kg, although the usual dose is 3-5 mg/kg every 8 weeks. There is a relationship between serum concentration and effect, although individual clearances vary markedly. The terminal half-life is 9-12 days without accumulation after repeated dosing at the recommended interval of 8 weeks. After intermittent therapy, infliximab elicits human antichimeric antibodies in up to 62% of patients. Concurrent therapy with methotrexate markedly decreases the prevalence of human antichimeric antibodies. 

When added to methotrexate background therapy, cyclosporine, chloroquine, hydroxychloroquine, leflunomide, infliximab, adalimumab, rituximab, and etanercept have all shown improved efficacy. In contrast, azathioprine, auranofin, or sulfasalazine plus methotrexate results in no additional therapeutic benefit. Other combinations have occasionally been used, including the combination of intramuscular gold with hydroxychloroquine. 

Antibodies to the antibody (ATA) may develop with all three agents. These antibodies may attenuate or eliminate the clinical response and increase the likelihood of developing acute or delayed infusion or injection reactions. Antibody formation is much more likely in patients given episodic anti-TNF therapy than regular scheduled injections. In patients on chronic maintenance therapy, the prevalence of ATA with infliximab is 10%, certolizumab 8%, and adalimumab 3%. Antibody development also is less likely in patients who receive concomitant therapy with immunomodulators (ie, 6-MP or methotrexate). However, there are increasing concerns that concomitant treatment with anti-TNF agents and immunomodulators may increase the risk of lymphoma. 

Patients with rheumatoid arthritis have elevated levels of TNF-a in their joints, whereas patients with Crohn s disease have elevated levels of TNF-a in their stools. In one trial, infliximab plus methotrexate improved the signs and symptoms of rheumatoid arthritis more than methotrexate alone. Patients with active Crohn s disease who had not responded to other immunosuppressive therapies also improved when treated with infliximab, including those with Crohn s-related fistulae. Infliximab is approved in the United States for treating the symptoms of rheumatoid arthritis, and is used in combination with methotrexate in patients who do not respond to methotrexate alone. It also is approved for treatment of symptoms of moderate to severe Crohn s disease in patients who have failed to respond to conventional therapy, and in treatment to reduce the number of draining fistulae in Crohn s disease patients. About 1 of 6 patients receiving infliximab experiences an infusion reaction characterized by fever, urticaria, hypotension, and dyspnea within 1 to 2 hours after antibody administration. Serious infections also have occurred in infliximab-treated patients, most frequently in the upper respiratory and urinary tracts. The development of antinuclear antibodies, and rarely a lupus-like syndrome, have been reported after treatment with infliximab. 

Taki H, Kawagishi Y, Shinoda K, Hounoki H, Ogawa R, Sugiyama E, Tobe K. Interstitial pneumonitis associated with infliximab therapy without methotrexate treatment. Rheumatol Int 2009 30(2) 275-6. 

Patients with CD are at high risk for disease relapse after induction of remission. Within 2 years, up to 80% of patients suffer a relapse therefore, most patients should be evaluated for indefinite maintenance therapy. Maintenance of remission of CD may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

Systemic therapies are seldom used for mild to moderate psoriasis, and are generally reserved for patients with moderate to severe psoriasis.17 29 Oral agents include sulfasalazine, acitretin, methotrexate, cyclosporine, mycophenolate mofetil, azathioprine, tacrolimus, and hydroxyurea. Parenteral agents include the biologic response modifiers alefacept, efalizumab, etanercept, infliximab, and many others, currently at various stages of research or approval for psoriasis. 

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 leads to symptomatic improvement in two thirds and disease remission in one third of patients with moderately severe or fistulizing Crohn s disease, including patients who have been dependent on glucocorticoids or who have not responded to 6-mercaptopurine or methotrexate. The median time to clinical response is 2 weeks. Infliximab induction therapy is generally given in a dosage of 5 mg/kg at 0, 2, and 6 weeks. Patients who respond may be treated with repeat infusions every 6-12 weeks to maintain remission with or without other therapies. 

Treatment with available anti-TN F-a inhibitors can be associated with the development of antibodies to the administered biologies [10]. The incidence is reported to be higher in patients receiving infliximab (13 to 60%), the chimeric monoclonal antibody containing a murine variable region, compared with the incidences reported for the fusion protein etanercept (<5 %) or the fully human antibody, adalimumab (-12% as monotherapy). The observed incidence of antibody formation is reduced by concomitant immunosuppressive therapies, such as methotrexate. Lower efficacy and higher incidences of infusion-related reactions have been reported in antibody-positive patients receiving infliximab [80]. 

Infliximab (in FLICKS ih mab) is a chimeric IgGic monoclonal antibody composed of human and murine regions. The antibody binds specifically to human TNF-a, thereby neutralizing that cytokine. Infliximab has been approved for Crohn s disease for both fistulizing and non-fistula disease. [Note Increased levels of TNF-a are found in fecal samples of patients with Crohn s disease.] It is not approved for maintenance therapy beyond six weeks. Approval for the treatment of rheumatic arthritis in combination with methotrexate is anticipated in the near future. 

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. 

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). 

Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group [comment]. N Engl J Med 2000 343 1594-1602. 

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