Methotrexate with infliximab

Maintenance of remission of Crohn s disease may be achieved with oral or topical aminosalicylate derivatives, immunosuppressants (such as azathioprine, 6-mercaptopurine, and methotrexate), or infliximab. 

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. 

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. 

Adverse effects Long-term use of infliximab is associated with development of anti-infliximab antibodies unless the drug is used in combination with methotrexate. Infusion reactions such as fever, chill, pruritus, or urticaria have occurred. Infections leading to pneumonia, cellulitis, and other conditions have also been reported. Whether treatment with infliximab predisposes to lymphoma, a condition that occurs with immunosuppressive or immune-altering drugs, remains to be established. 

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. 

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). 

The drug may increase risk of infection as noted above. An acnte infnsion reaction with symptoms including fever, chills, pmritns, and rash may occur within 1 to 2 hours after giving the dmg. Antoanti-bodies and lupus-like syndrome also have been reported. In chnical trials, the combination of methotrexate plus infliximab halted progression of joint damage in patients and was superior to methotrexate monotherapy. " ... 

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. 

A progressive multifocal leukoencephalo-pathy, confirmed by an MRI scan and biopsy, has been reported in a 72-year-old man with erosive rheumatoid arthritis, in whom subacute neurologic and psychiatric symptoms developed after 3 years of treatment with infliximab, prednisone, and methotrexate [46 ]. 

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. 

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. 

Infliximab (Remicade) is a chimeric monoclonal antibody directed against TNF-a. Recently, its indications have been expanded to include psoriatic arthritis and treatment of adults with chronic severe plaque psoriasis. An advantage over other systemic psoriasis treatments is that infliximab does not adversely affect blood counts, hepatic enzyme levels, or kidney function. The recommended dose is 5 mg/kg as an IV infusion at weeks 0, 2, and 6, then every 8 weeks thereafter. For psoriatic arthritis, it may be used with or without methotrexate. Adverse effects include headaches, fever, chills, fatigue, diarrhea, pharyngitis, upper respiratory and urinary tract infec-... 

In the majority of patients, active Crohn s disease is treated with sulfasalazine, mesalamine derivatives, or steroids, although azathioprine, mercap-topurine, methotrexate, infliximab, and metronidazole are frequently used. 

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 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. 

Etanercept is a dimeric fusion protein composed of human IgGj constant regions (CH2, CH3, and hinge, but not CH ) fused to the TNF receptor. Etanercept binds to both TNF- and TNF-3 and appears to have effects similar to that of infliximab, ie, inhibition of TNF-K-mediated inflammation, but its half-life is shorter due to its physical form (fusion protein) and the route of injection (subcutaneously, twice weekly). Etanercept is approved for adult rheumatoid arthritis, polyarticular-course juvenile rheumatoid arthritis, and psoriatic arthritis. It may be used in combination with methotrexate. 

Infliximab is administered in combination with methotrexate for rheumatoid arthritis. A dose of 3 mg/kg is administered via intravenous infusion and is repeated after 2 and 6 weeks followed by the maintenance dose every 8 weeks. The recommended dose for Crohn s disease is 5 mg/kg. The side effects associated with the administration of infliximab include acute infusion reactions (fever, chills, chest pain, hypotension and rare anaphylaxis), increased risk of infection, production... 

Infliximab Remicade Slow intravenous infusion 3 mg/ kg body weight. Additional doses at 2 and 6 weeks after first infusion, then every 8 weeks thereafter. Should be administered in combination with methotrexate. 

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. 

---