Autoimmune diseases therapy

Lee SJ, Kavanaugh A. Adverse reactions to biologic agents focus on autoimmune disease therapies. J Allergy Clin Immunol 2005 116(4) 900-5. 

As discussed above, the vast majority of autoimmune diseases is associated with chronic inflammation. The therapy thus rests on two principles ... 

Immune defense mechanisms can become deleterious for an individual when they are not controlled properly. Then they can cause disease. In such situations therapy is aimed to dampen immune reactions. Important examples are sqttic shock, allergy, autoimmune diseases, and chronic inflammatory diseases such as rheumatoid arthritis. Also, the success of organ transplantation... 

Immunosuppressive agents are indicated for the therapy of systemic autoimmune diseases (e.g., systemic lupus... 

First trials with CD3 antibodies for therapy of autoimmune diseases (insulin-dependent diabetes mellitus psoriatic arthritis... 

Furlan, R., Butti, E., Pluchino, S., and Martino, G. 2004. Gene therapy for autoimmune diseases. Current Opinion in Molecular Therapeutics 6(5), 525-536. 

The overall effect of Li+ on the hematopoietic system is of stimulation of the immune system. Not surprisingly then, Li+ is reported to exacerbate the activity of a number of autoimmune diseases, such as psoriasis [212] and rheumatoid arthritis [213], and to result in the production of autoantibodies in some patients [214]. However, there is no evidence that Li+ s stimulation of the immune system leads to any reduction in the occurrence of viral or bacterial infections in patients on Li+ therapy. 

Penicillamine onset may be seen in 1 to 3 months, and most responses occur within 6 months. Early adverse effects include skin rash, metallic taste, hypogeusia, stomatitis, anorexia, nausea, vomiting, and dyspepsia. Glomerulonephritis may occur, which manifests as proteinuria and hematuria. Penicillamine is usually reserved for patients who are resistant to other therapies because of the rare but potentially serious induction of autoimmune diseases (e.g., Goodpasture s syndrome, myasthenia gravis). 

Initiation factors initiate kidney damage and can be modified by drug therapy. Initiation factors include diabetes mellitus, hypertension, autoimmune disease, polycystic kidney disease, and drug toxicity. 

Some xenobiotics may have divergent mechanisms of autoimmune responses. For example, hydralazine demonstrates adduct reactivity as well as inhibition of DNA methylation [68,73], while procainamide inhibits DNA methylation, forms immunogenic NPA, and disrupts clonal selection in the thymus [68, 72, 74], It is this complicated pattern of effects that makes assessment of autoimmune potential in the laboratory for new xenobiotics almost impossible. Animal models can sometimes be recreated to resemble human disease [74], and thus may be useful for therapy considerations, but are difficult to utilize for screening chemicals for hazard potential due to the diverse nature of autoimmunity mechanisms and physiological presentation. While evidence supports many different mechanisms for xenobiotic-induced autoimmune reactions, none have conclusively demonstrated the critical events necessary to lead to the development of autoimmune disease. Therefore, it is difficult to predict or identify xenobiotics that might possess the potential to elicit autoimmune disorders. 

Several pro-inflammatory cytokines, such as TNFa, IL-1, IL-6, are important in the initiation and maintenance of various autoimmune diseases, such as RA, CD, and psoriasis. Thus, targeted therapies, which have been developed to inhibit their activity, have resulted in clinical improvement of these patients. Currently, there are three TNFa inhibitors (etanercept, infliximab, and adalimumab) and one IL-1 receptor antagonist (anakinra) that have been approved for the treatment of at least one of these diseases. In addition, a number of other anti-cytokine therapies are in clinical development. The TNFa antagonists will be reviewed here. 

Steinman, L., Despite epitope spreading in the pathogenesis of autoimmune disease, highly restricted approaches to immune therapy may still succeed [with a hedge on this bet], J. Autoimmun., 14, 278, 2000. 

Steinman, L., Immune therapy for autoimmune diseases, Science, 305, 212, 2004. 

Wandl, U.B. et al., Lupus-like autoimmune disease induced by interferon therapy for myeloproliferative disorders, Clin. Immunol. Immunopathol., 65, 70, 1992. 

The finding that the administration of 6-mercaptopurine to rabbits following exposure to bovine serum albumin prevented antibody formation [374] formed the basis for a new area of chemotherapy for purine analogues and other antimetabolites and was soon followed by the use of these drugs for the therapy of autoimmune disease and the suppression of homograft rejection. This subject has been reviewed in depth [ 12, 375, 375a], has occasioned a symposium [376], and has received much recent publicity as a result of human heart transplants. 

Kazkaz H, Isenberg D. Anti B cell therapy (rituximab) in the treatment of autoimmune diseases. Curr Opin Pharmacol 2004 4 398 02. 

Unfortunately, a substantial proportion of patients with autoimmune inflammatory diseases have become refractory to NSAIDs, and/or oral or intravenous Disease Modifying Anti Rheumatic Drugs (DMARDs). However, oral combinations of DMARDs generate better outcomes compared to single drug therapy in autoimmune disease. Even autoimmune diseases can become refractory to oral DMARD combinations. 

With the advent of biological-DMARD combinations with Methotrexate (MTX) a new era of therapy in autoimmune disease is introduced. DMARD-refractory autoimmune diseases are treated with combinations of a biological with MTX with achievement of improvements of ACR 20 and ASAS 20 in the majority of patients. A small minority of around 20% obtains improvements of ACR 70 and ASAS 70. ACR responses are American College of Rheumatology response criteria and ASAS stands for Assessment in Ankylosing Spondylitis. ACR and ASAS 20, 50 or 70 scores are exactly defined improvements of respectively 20%, 50% or 70%. 

Autoimmune diseases may have an acute or a chronic insidious onset with a chronic progressive course with varying periods of severe or mild disease activity and spontaneous remissions in a minority of patients. Inherent to the initially chronic progression, reversible autoimmune inflammation and disability are susceptible to effective therapy when still no irreversible organ damage has occurred. Nowadays these reversible joint or organ changes in autoimmune arthritis and autoimmune nephritis can be normalized with novel treatment modalities. 

Based on the bio-molecular pathogenesis, novel therapeutic agents have been developed since 1998 for the treatment of DMARDs refractory autoimmune diseases. These biological-DMARDs include infliximab, etanercept, adalimumab, rituximab and abatacept. The biological-DMARDs anti TNF-a were first approved for therapy of refractory RA, followed by Crohn s disease, AS, and PsA. Scores of other biological DMARDs in Phase I, II, and III clinical trials in autoimmune diseases indicate that the number of these biological agents may ultimately become equal to the number of NSAIDs introduced over the last 50 years. 

Darmawan J, Rasker JJ, Nasution AR, Zhao DB, ChenS-L, Haq SA et al. WHO-ILAR COPCORD Stage II treatment of the autoimmune diseases with step-down bridge combination of five immunosuppressants (SBC-5-IMNs) in therapy of rheumatoid arthritis. Proceedings book of the 12th APLAR Congress of Rheumatology. Kuala Lumpur (Malaysia) 2006. 

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