Immunotherapy offer good efficacies, as well as numerous side effects to autoimmune diseases patients. Side effects are different for different treatments.
As a clinical approach, antigen-specific therapy is still in its infancy and there are serious concerns about introducing a disease-relevant antigen into an individual who is already sensitized to that antigen. Two highly publicized clinical trials in patients with multiple sclerosis, which used altered peptide ligands (APLs) that mimic myelin epitopes, were halted owing to hypersensitivity responses and disease exacerbation.
Probably the best known and most widely used immunotherapy for rheumatoid arthritis is blockade of the pro-inflammatory cytokine tumour-necrosis factor (TNF) with TNF-specific antibodies or soluble TNF receptors. TNF blockade is now also used for psoriasis, Spondyloarthropathy and Crohn's disease. It was initially reported that TNF blockade in cultures of synovial tissue from inflamed joints reduced the production of many pro-inflammatory mediators, including IL-1, IL-6, GM-CSF and IL-8. This effect of TNF blockade on inflammation is central for its efficacy, but also underpins its severe side effects, as these pro-inflammatory cytokines are important for an effective host immune response against microorganisms. Although TNF blockade has been a successful treatment for many patients, it can cause lethal reactivation of latent infections, most commonly tuberculosis. It can also increase the probability of developing lymphoma, especially when administered in conjunction with immunosuppressive treatments, such as methotrexate or corticosteroids. Paradoxically, despite decreasing arthritis, TNF blockade for prolonged periods can increase the onset of multiple sclerosis and possibly lupus and other autoimmune disorders, an outcome that may be related to the role of TNF in promoting the apoptosis of effector T cells.
Another highly effective (and highly publicized) biological agent is the monoclonal antibody that is specific for the T-cell adhesion molecule VLA4 (very late antigen 4; also known as α4β1-integrin), natalizumab (Tysabri, Biogen Idec, Inc. and Elan Corporation PLC). Blockade of VLA4 prevents the entry of these T cells into the tissue in which they mediate immunopathology. However, inhibition of lymphocyte trafficking to the brain also prevents the normal physiological process of immune surveillance. A Phase III clinical trial in patients with multiple sclerosis that was showing every sign of success was halted owing to the emergence of progressive multifocal leukoencephalopathy (PML) in some patients who were concurrently being treated with IFNβ. This was caused by the reactivation of latent JC virus (a polyomavirus that is carried by 80% of the population) in the brains of these patients. PML has previously been associated only with severe immunodeficiency states, including AIDS and chemotherapy. Because the number of affected cases was low compared with the clear benefit of the therapy, the drug is now back on the market, albeit with restrictions on its use. Nevertheless, two new cases of PML were reported in July 2008, one of them in a patient not taking other multiple sclerosis drugs (see Medpage Today and Securities and Exchange Commission file). So, for both TNF- and VLA4-specific antibody therapies, their potent ability to block harmful immune responses goes hand in hand with their potential to cause severe complications.
Although we may never be able to eliminate the side effects for autoimmune diseases immunotherapy completely, as our knowledge and experience progress, the balance of safety and efficacy will undoubtedly improve.
Caspi RR. Immunotherapy of autoimmunity and cancer: the penalty for success. Nature reviews Immunology.