JAMA -- Therapeutic Interventions for Systemic Vasculitis, November 8, 2010, Hoffman 0 (2010): jama.2010.1676v1

Therapeutic Interventions for Systemic Vasculitis
Gary S. Hoffman, MD, MS


JAMA. Published online November 8, 2010. doi:10.1001/jama.2010.1676

Less than 20 years ago, the literature on vasculitis was primarily descriptive; reports were mostly from single centers and treatment outcomes were compared with historical controls. Few institutions had programs dedicated to treating patients with various forms of vasculitis, clinician-investigators who had bona fide expertise with these disorders were uncommon, the diseases were (and are) rare, and funding to support vasculitis research was limited.

Nonetheless, 50 years of earlier descriptive reports had revealed that certain forms of vasculitis were uniformly fatal without therapy. Consequently, studies with untreated controls were considered unethical. Despite these shortcomings, important information emerged from the pre-1990 era. For instance, several studies demonstrated that without treatment, diseases such as Wegener granulomatosis (WG)1 and microscopic polyangiitis (MPA)2 were often fatal within weeks to months. These sobering outcomes were especially common among patients who presented with pulmonary-renal syndromes, gastrointestinal ischemia, or central nervous system involvement. In addition, while glucocorticosteroid discovery and clinical application was a major breakthrough for many illnesses, it was not effective for the most severe types of systemic vasculitis. Many patients with critical organ involvement still died within months.

In 1983, Fauci et al3 reported that adding cyclophosphamide to glucocorticosteroid therapy was often lifesaving, even among the most seriously ill patients. The trade-off for lifesaving therapy often was acute and chronic adverse effects, many of which were reversible, although others were permanent and some were fatal.4 Other studies suggested that some forms of severe vasculitis were not as ominous as initially thought. Recognition of more subtle and indolent disease presentations raised questions about the utility of less toxic immunosuppressive protocols. Subsequently, uncontrolled, open-label, single-treatment group studies demonstrated that not all patients required cyclophosphamide. Some could be treated with safer drugs such as methotrexate.5 However, most forms of vasculitis, whether mild or severe, were not cured by these interventions and relapses were common following tapering and discontinuation of therapy.

More recently, the emergence of effective therapies as well as new insights into mechanism of action of pharmaceuticals and disease pathogenesis have generated increasing interest in vasculitis. The numbers of investigators and centers dedicated to the care of patients with vasculitis increased in the United States and in Europe. Interest developed in performing controlled clinical trials that compared alternatives with cyclophosphamide for mild disease, and short-term cyclophosphamide (3-6 months), followed by other less toxic therapies for more severe disease once substantial improvement had occurred. Planning and orchestrating these ambitious undertakings in rare diseases is difficult. Multicenter consortia such as the International Network for the Study of Systemic Vasculitides, the French Vasculitis Study Group, the European Vasculitis Study Group (EUVAS), the Italian Vasculitis Study Group, and the Vasculitis Clinical Research Consortium were created to meet these challenges. Funding for rigorous trials emerged and the field started to attract trainees to expand the network of vasculitis professionals in rheumatology, nephrology, pulmonary-critical care, clinical immunology, pathology, and basic science.

FULL-TEXT JAMA:
JAMA -- Therapeutic Interventions for Systemic Vasculitis, November 8, 2010, Hoffman 0 (2010): jama.2010.1676v1