Tofacitinib has been just approved by U.S. FDA (November, 2012) for the treatment of moderate to severe rheumatoid arthritis refractory to first-line treatments, such as methotrexate. It has been marketed by Pfizer under the name Xeljanz. It is the first anti-rheumatic drug that acts by inhibiting intracellular enzymes (Janus kinase), a novel and promising mechanism of action. These enzymes, generically called tyrosin kinases, are pivotal for producing the inflammatory response. Clinical trials indicate that tofacitinib may be as efficacious as anti-TNFs in those patients who have failed methotrexate. Compared to Anti-TNFs, tofacitinib is oral and not more expensive but share with them the same toxicity profile. Suggested Readings: N Engl J Med 2012 Aug 9; 367 (6) :495-507. N Engl J Med 2012 Aug 9; 367 (6) :508-19.
Tocilizumab, marketed by Roche as Actemra, is a recombinant monoclonal antibody that blocks the receptor of interleukin 6 (IL-6) that, as TNF, is a pivotal mediator in the immune inflammatory response. Tocilizumab belongs to those biologics that block other molecules different from TNF such as abatacept, rituximab, anakinra or tofacitinib. It is an interesting alternative for those rheumatoid arthritis patients in which Anti-TNFs have failed. Clinical trials indicate that Tocilizumab may have similar or even higher efficacy than Anti-TNFs, but, its toxicity profile is not as well established as the formers. Dose is based on clinical response and varies between 4 and 8 mg/kg intravenously every month. Suggested Readings: Ann Rheum Dis. 2009 Oct, 68 (10):1580-4. Drugs. 2009, 69 (5):609-32.
Abatacept (CTLA4-Ig), marketed by Bristol-Myers Squibb as Orencia, is a molecule that reduces cellular immune response mediated by T lymphocytes. Abatacept has been approved for the treatment of patients with moderately to severely active RA who have had an inadequate response to one or more disease modifying antirheumatic drugs (DMARDs) or TNF inhibitors. Rheumatoid arthritis patients on abatacept with previous inadequate response to methotrexate or Anti-TNF a, significantly improve in physical function and reduction in disease activity and pain. Abatacept was initially available only for intravenous use but can also be administered subcutaneously every week preceded by iv loading dose. Treatment of RA patients with abatacept has not been associated with an increased frequency of malignancy but should not be used concurrently with TNF inhibitors or with the interleukin-1 receptor antagonist, anakinra. Live vaccines should not be given concurrently or within three months of stopping abatacept. Suggested readings: N Engl J Med.2003;349(20):1907; Ann Intern Med. 2006; 144(12): 865
RITUXIMAB (Mabthera, Rituxan)
Rituximab, marketed by Roche as Mabthera and as Rituxan by Genentech & Biotech, is an anti-CD20 chimeric monoclonal antibody that reduces humoral immune response by depleting B lymphocytes. B Lymphocytes are the immune cells that produce antibodies, therefore, B cell depletion implies decrease production of autoantibodies, the hallmark of autoimmune diseases. It is widely used in hematology to treat non-Hodgking’s lymphoma and chronic lymphocytic leukemia but it is also used in rheumatology to treat Lupus and rheumatoid arthritis. Rituximab, in combination with methotrexate, is indicated for the treatment of rheumatoid arthritis patients who have had an inadequate response to one or more TNF antagonist therapies. Rituximab requires intravenous administration on days 0 and 15 with retreatments every 6 months. Rituximab therapy can result in serious side effects some which can be life-threatening such as infusion reactions, severe mucocutaneous reactions or progressive multifocal leukoencephalopathy. Premedication may reduce the incidence and/or the severity of infusion reactions. It is not recommended for patients with severe active infections. Suggested readings: Arthritis Rheum. 2006; 54 (9):2793; Arthritis Rheum.2004; 50(8):2580
ANTI-TNFs (Etanercept, Ifliximab, Adalimumab, Certolizumab, Golimumab)
Anti-TNFs are biologic agents that block Tumor Necrosis Factor a, a key inflammatory mediator in the pathogenesis of rheumatoid arthritis (RA). They are often reserved for people who have not completely responded to classic DMARDs (methotrexate, leflunamide, salazopyrine or antimalarial) or for those who cannot tolerate DMARDs in doses large enough to control inflammation. A combination of an anti-TNF agent with methotrexate provides better clinical response than anti-TNF monotherapy or methotrexate alone. All of them have similar efficacy or safety profiles. Frequently, RA patients whose do not get a good response with one Anti-TNF are switched to a second before trying other agents. Unlike DMARDs, which can take six weeks or more to begin working, biologics tend to work more rapidly.
Etanercept (Pfizer, Enbrel): is a protein that avoids TNF-inflammatory response because it blocks TNF receptors. It is effective for the treatment of a number of inflammatory arthritis and other conditions, including RA, psoriatic arthritis, and ankylosing spondylitis. It is administered once or twice weekly via subcutaneous injection.
Infliximab (Merck Sharpe & Dome, Remicade): is a chimeric monoclonal directed against TNF. The term “chimeric” refers to the use of both murine and human components of the drug. Infliximab is administered via intravenous infusion approximately every six weeks once a steady state has been achieved. Infliximab is effective for the treatment of a number of forms of inflammatory arthritis, inflammatory bowel disease, and other conditions.
Adalimumab (Abbot, Humira): is also a monoclonal antibody directed against TNF. However, Adalimumab is associated with a lower risk of anti-drug antibody formation compared with infliximab, by virtue of its humanized construction. By contrast to infliximab, it is administered subcutaneously rather than intravenously. The recommended interval between administrations is every two weeks. Adalimumab has been approved for use in RA, psoriatic arthritis, ankylosing spondylitis, and Crohn’s disease
Certolizumab (UCB pharma, Cimzia): is a human anti-TNF-alpha antibody Fab’ fragment that is chemically linked to polyethylene glycol. By virtue of this chemical peculiarity, certolizumab avoids complement activation, antibody-dependent cellular cytotoxicity or apoptosis, therefore, it is supposed to have a lower risk of anti-drug antibody formation. It is administered every two weeks by subcutaneous injection, and dosing at four-week intervals can be considered for maintenance therapy. Certolizumab has been approved for use in Crohn’s disease and in rheumatoid arthritis.
Golimumab (Centocor Ortho Biotech Inc, Simponi): is a human monoclonal antibody specific for human TNF-alpha that neutralizes TNF-alpha activity. It is administered once monthly by subcutaneous injection. Golimumab has been approved for use in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.