R Luqmani

Development of comprehensive disease assessment in systemic vasculitis

The systemic vasculitides are multisystem disorders with considerable mortality and morbidity and frequent relapses. In the absence of reliable serological markers, accurate clinical tools are required to assess disease activity and damage for treatment decisions, and for the performance of clinical trials. This article reviews and summarises the development and use of disease assessment tools for determining activity and damage in systemic vasculitis and reports ongoing initiatives for further development of disease assessment tools. A literature search was conducted using PubMed and reference lists for vasculitis, assessment, clinical trials, outcome and prognosis. The findings indicate that comprehensive disease assessment in vasculitis requires documentation of disease activity, chronic irreversible damage and impairment of function.

Disease assessment and management of the vasculitides.

The improvement in survival with chemotherapy has resulted in a change of the natural history of the systemic vasculitic syndromes. The vasculitides are now viewed as chronic disease rather than fatal conditions. Their course is frequently characterized by relapse as well as the scars of irreversible organ damage from disease and drug toxicity. Assessment tools are available which can serve as outcome measures in clinical trials as well as a guide to better management of individual patients. Improvements in therapy in future are dependent on a better understanding of the pathogenesis of these conditions and the ability to assess disease accurately.

Optimisation of cyclophosphamide therapy in systemic vasculitis.

SummaryThere is no doubt that the prognosis for systemic vasculitides has been considerably improved by the use of immunosuppressive agents, chiefly cyclophosphamide. Increasingly, we are becoming aware of the enormous burden of chronic ‘grumbling’ disease, the high incidence of relapse and the longer term effects of toxic therapy in these patients. The general approach is more intense therapy (with intermittent high dose ‘pulses’ or lower dose continuous cyclophosphamide) in the initial phase of therapy to induce remission, followed by a less toxic therapy in the maintenance phase (either longer intervals between pulses or a switch to a less toxic drug, such as azathioprine).The pathogenetic mechanisms in vasculitis, which are becoming more precisely defined, are diverse, but cyclophosphamide remains the drug of choice. A number of different cyclophosphamide regimens are in use, which reflects the current dilemma of trying to balance effectiveness with toxicity in diseases where the quality of long term survival remains unsatisfactory.Evidence from controlled trials does not support major differences in immediate outcome between different regimens of cyclophosphamide. Future studies need to address the use of agents designed to interfere precisely with the underlying pathogenetic mechanisms. Alternative approaches should also be considered, for example the use of sublethal doses of cyclophosphamide, with autologous bone marrow rescue, which may achieve long lasting remission or even cure.

Assessment of systemic vasculitis.

The systemic vasculitides are an uncommon group of autoimmune diseases capable of causing multi organ failure and death. Current immunosuppressive strategies have substantially improved the outcome, but the natural history of treated disease is unstable, typically characterised by frequent relapses, drug toxicity and an increasing burden of damage. Early diagnosis, accurate staging and regular evaluation of disease status are important in the management of the vasculitides. Clinical evaluation tools have been developed and provide a comprehensive assessment of patients. Serological markers, especially anti-neutrophil cytoplasm antibody (ANCA), pathology and imaging investigations are a useful addition, but are more valuable in diagnosis rather than monitoring of disease activity. Advances in magnetic resonance imaging in large vessel vasculitis have improved our ability to characterise disease and may lead to earlier diagnosis and better control in future. Development of new biomarkers is required in vasculitis, and this is likely to advance our understanding as well as the management of these complex conditions.

Update on the use of biologics in primary systemic vasculitides

The introduction of biologic therapies, which selectively target components of the immune system, has revolutionized the treatment of rheumatoid arthritis. Anti-TNF-α therapy (infliximab, etanercept and adalimumab) and B-cell-depleting agents, such as rituximab, are the most widely used agents. Increased experience of the use of biologic drugs in other immune-mediated inflammatory diseases has led to the application of biologic therapies in the treatment of primary systemic vasculitis. Conversely, the success of biological agents has improved understanding of the immunopathogenesis of vascular inflammation. The need for biologic agents arises from the failure of the current standard of care to maintain remission while limiting drug toxicity. Evidence for the efficacy of biologic agents does not match that of conventional immunosuppressants yet, but it is building rapidly. This paper reviews the current evidence for the standard of care of patients with vasculitis and the role of biologic therapy in primary systemic vasculitis. In this review, we examine the rationale for using biologics based on the pathophysiology of primary systemic vasculitis. The risks and benefits of the use of biologics are discussed, together with future directions and predictions of these emerging therapies.