Antibody therapies rheumatoid arthritis

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. 

Taylor PC (2003) Antibody therapy for rheumatoid arthritis. Current Opin Pharmacol 3 323-328... 

Keystone, E. C., Kavanaugh, A. E., Sharp, J. T., et al. (2004) Radiographic, cUnical, and functional outcomes of treatment with adaUmumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy a randomized, placebo-controUed, 52-week trial. Arthritis and Rheumatism. 50, 1400-1411. 

A variety of medical conditions are now believed to be caused or exacerbated by overproduction of certain cytokines in the body. A variety of pro-inflammatory cytokines, including IL-6 and IL-8 as well as TNF, have been implicated in the pathogenesis of both septic shock and rheumatoid arthritis. Inhibiting the biological activity of such cytokines may provide effective therapies for such conditions. This may be achieved by administration of monoclonal antibodies raised against the target cytokine, or administration of soluble forms of its receptor which will compete with cell surface receptors for cytokine binding. 

The effectiveness of immunosuppressive drugs in autoimmune disorders varies widely. Nonetheless, with immunosuppressive therapy, remissions can be obtained in many instances of autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, type 1 diabetes, Hashimoto s thyroiditis, and temporal arteritis. Improvement is also often seen in patients with systemic lupus erythematosus, acute glomerulonephritis, acquired factor VIII inhibitors (antibodies), rheumatoid arthritis, inflammatory myopathy, scleroderma, and certain other autoimmune states. 

Glass D, Nuki G, Daly JR. Development of antibodies during long-term therapy with corticotrophin in rheumatoid arthritis. II. Zinc tetracosactrin (Depot Synacthen). Ann Rheum Dis 1971 30(6) 593-6. 

Elliott, M. J., Maini, R. N., Feldmann, M., Long-Fox, A., Charles, P., Bijl, H., and Woody, J. N. (1994). Repeated therapy with monoclonal antibody to tumour necrosis factor a (cA2) in patients with rheumatoid arthritis. Lancet 344, 1125-1127. 

Tesser, J. R. P., Wiesenhutter, C., Levy, R., Schiff, M., Lipani, J., Solinger, A., Mac Donald, B., Elliott, M., and Sing, K (1997). Tratment of rheumatoid arthritis with a primatized anti-CD4 monoclonal antibody, SB-210396 (DEC-CE9.1) Results of an open label extension study in patients responding to induction therapy. Arthritis Rheum. 40 (Suppl 9), S224. 

The first therapeutic antibody approved (Orthoclone OKT-3 or Muromonab CD3, 1986) was indicated not for cancer treatment, but for controlling acute rejection of transplanted organs (kidney, heart, and liver). Nowadays, other clinical indications such as asthma, rheumatoid arthritis, psoriasis, and Crohn s disease are treated with mAbs (see Chapter 17) (Antibody Engineering and Manufacture, 2005 Monoclonal Antibodies and Therapies, 2004 Hot Drugs, 2004 Walsh, 2004). 

Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006 295 2275-85. 

Minocycline-induced lupus usually occurs some months, or even years, after the start of therapy, and it usually resolves when the drug is withdrawn. The diagnosis can easily be overlooked, especially in patients with rheumatoid arthritis (37). It would always be wise to foUow the recommendation that a patient s antinuclear antibody be checked before starting minocycline and when drug-induced lupus is suspected. 

Rankin ECC, Isenberg DA. Monoclonal antibody therapy in rheumatoid arthritis. An update on recent progress. Clin Immunother 1996 6 143-53. 

Selective inhibition of inflammatory cytokines is also an attractive approach. In animal models, antibodies to TNFa prevent lung fibrosis when given prior to injury from silica, bleomycin or antigen-induced extrinsic allergic alveolitis (Piguet etal., 1989, 1990 Denis et al., 1991). This approach may be an option in humans since TNFa antibodies have been used successfully as a therapy in patients with rheumatoid arthritis (Elliot etal., 1993). 

Because antibodies bind to antigens, their function is often to augment intrinsic clearance mechanisms as well as potentially exerting definitive therapeutic effects. It is not surprising, therefore, that the therapeutic targets for antibody therapy are extremely broad, ranging from antitumor therapy to specific immunological diseases, for example rheumatoid arthritis. 

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