Stem cell therapy: resetting autoimmunity or postponing the inevitable?

Abstract

Autoimmune diseases (ADs) comprise a heterogeneous group of conditions characterized by the presence of autoantibodies and/or T- or B-lymphocyte reactivity against autoantigens. In many conditions the precise relationship between autoimmune responses and clinical features remains to be defined, but the prevailing notion is that failure of central or peripheral immune tolerance leading to autoimmunity precedes clinically overt autoimmune disease which in the case of rheumatic autoimmune conditions is characterized by systemic inflammation, vasculopathy and signs and symptoms of musculoskeletal involvement. Except for rheumatoid arthritis (RA), rheumatic autoimmune diseases are rare, affecting less than 1% of the population. Nevertheless, they account for a high share of public health expenditure, due to their chronic debilitating nature [Gabriel and Michaud, 2009]. It is not therefore surprising that new therapeutic avenues are constantly being explored. While biologicals have resulted in major breakthroughs in the treatment of RA and juvenile idiopathic arthritis (JIA), connective tissue diseases such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) still pose major challenges to clinicians seeking effective treatment options. Biologicals which interfere with the immune response such as rituximab (anti-CD20 mAb) and abatacept (CTLA4-Ig) have not been proven more effective than placebo in controlled clinical trials, which contrasts with the positive collective rituximab experience from large case series. Belimumab (anti-BAFF mAb) is the first new drug to be licensed for use in SLE for several decades, but its efficacy is modest, and its place in the treatment paradigm of lupus remains to be established. Imatinib was hailed as a promising drug for the treatment of systemic sclerosis based on its mechanism of action and on studies in animal models of scleroderma, but it is unlikely that its clinical development in systemic sclerosis will be pursued following disappointing results from pilot studies. Conventional immunosuppressive drugs including glucocorticoids, cyclophosphamide, azathioprine, methotrexate and mycophenolate mofetil therefore still remain the cornerstone in the treatment of connective tissue diseases. However, long-term drug-free remissions are rare and adverse drug reactions and clinical sequelae of long-term use contribute to compliance problems.