Cytokines play a central part in the human immune response and therefore rheumatoid arthritis. Out of wide range of cytokines TNF-ct (tissue necrosing factor-alfa) appears to be at the heart of the inflammatory process in the joints of rheumatoid arthritis patients.
Anti TNF Drugs: TNF-ct is produced by macrophages and activated T cells. It stimulates the release of other inflammatory cytokines, including interleukins-IL-a,-6, and -8, and proteases such as collagenase and neutral metalloprotienases.
These TNF-a cytokines require activation of specific membrane bound TNF-receptors for their effect. So anti-TNF-ct drugs have been developed to treat rheumatoid arthritis.
1. Infliximab: It is a chimeric (25% mouse and 75% human) monoclonal antibody. It binds with high affinity and specificity to human TNF-cx. The drug is given as i.v. infusion in doses of 3 or 10 mg/kg at 0, 2 and 6 weeks and thereafter at interval of 4 or 8 weeks. The median duration of response after a single infusion is 6 to 8 weeks. It has been given in severe cases of rheumatoid arthritis along with methotrexate. This combination significantly slows down radiographic damage compared with methotrexate alone.
Common adverse effects are upper respiratory tract infection, headache, nausea, sinusitis, rash and cough. Infliximab leads to the formation of human antichimeric antibodies (HACA). However, concurrent therapy with methotrexate greatly decreases the prevalence of HACA. Rarely it causes mild reversible drug induced lupus like illness.
2. Ftanercept: It is a recombination fusion protein. It binds with two TNF-cc molecules. It is usually administered as 25 mg s.c. twice weekly. It is used to treat:
- Serious rheumatoid arthritis
- Psoriatic arthritis
- Juvenile chronic arthritis
It is equally effective as that of methotrexate. Radiographic progression is slowed more by the methotrexate – evanescent combination. Adverse effects at injection site are mild erythema, local pain, swelling and itching.
3. Leflunomide: It is a new immunosuppressive prodrug. It undergoes rapid conversion to its active metabolite (A77— 1726) predominately in the intestinal mucosa and plasma. Its metabolite acts by inhibiting dihydroorotate dehydrogenase (DHODH) enzyme. Finally, it inhibits autoimmune T cells proliferation and production of autoantibodies by B cells. It also increases the mRNA level of IL-b receptor, decreases TL-8 receptor type A mRNA concentrations and blocks TNF dependent nuclear factor-kappa B activation.
Leflunomide is given orally. It is rapidly arid completely absorbed from the intestinal tract. It has been found effective in patients with early rheumatoid arthritis. Patients who do not respond to methotrexate alone benefit from combination therapy with leflunomide and methotrexate. Common side effects are diarrhea and elevation of liver enzymes.