Optimisation of vasculitis disease assessments in clinical trials, clinical care and long-term databases.

The systemic vasculitides are a group of rare, chronic, relapsing, but often progressive inflammatory conditions. They are associated with a significant burden of morbidity both due to scarring from the disease itself and as a consequence of treatment with glucocorticoids and other potent immunosuppressive agents. Careful assessment of disease activity is critical to guide appropriate use of these potentially toxic therapies. It is also important to differentiate features of active disease from those attributable to damage, which will not respond to immunosuppression. As these are chronic complex conditions, the impact on a patient's functional ability and quality of life are also important considerations. Given the lack of a reliable biomarker for assessment of disease activity or damage in systemic vasculitis, clinical tools developed and validated for use initially in clinically trials are key outcome measures in the evaluation of these patients. While the conduct of randomised clinical trials in vasculitis has been significantly enhanced by the development and use of validated outcome measures, regular use of validated disease activity and damage measurements as part of routine care offers a structured approach, which can serve as the basis of justifying treatment decisions. The authors review the concepts of clinical assessment tools used in the evaluation of patients with systemic vasculitis in the setting of clinical practice, clinical trials and long term databases with particular emphasis on disease activity, damage, prognosis and function.

Clinical and biological assessment in systemic necrotizing vasculitides.

The systemic vasculitides are multi-system disorders with significant mortality and morbidity and frequent relapses. Treatment is usually effective but fraught with potentially serious effects. Disease Assessment is important to ensure that patients receive the appropriate treatment. Disease Assessment should comprise measurement of disease activity, chronic irreversible damage and impairment of function. Serological markers can be helpful in assessing disease activity but lack sufficient sensitivity and specificity to be used on their own. Radiological techniques such as Magnetic Resonance Imaging, Ultrasound and Positron Emission Tomography show promise in the large vessel vasculitides but require validation in large studies. Clinical Assessment tools are the current gold standard for the assessment of disease activity, damage and function.

Diagnosis and assessment of systemic vasculitis.

The diagnosis of systemic vasculitis requires clinical evidence with appropriate symptoms and physical signs, supported by histological or radiological confirmation. Earlier recognition of these diseases has been facilitated by a greater awareness of their incidence, and also by the more widespread introduction of the anti-neutrophil cytoplasmic antibody (ANCA) test. Early diagnosis provides a greater potential for effective intervention in the course of disease and this may limit subsequent damage. However, an early diagnosis poses the more difficult challenge in the classification of the vasculitides, since traditional classification systems have depended on the presence of well-established manifestations of the disease. The accurate assessment of disease activity and damage in vasculitis has become necessary as a result of significant improvements in survival with the use of chemotherapy. The disease course however is frequently characterised by relapse as well as the scars of irreversible organ damage from disease and drug toxicity. Clinical methods of assessment are simple to apply, reliable and often more effective than any current laboratory test in evaluating the effects of therapy and determining changes in therapy. The increasing use of surrogate clinical measures of disease should provide a greater opportunity to establish the effectiveness of existing and novel therapies in the management of these complex diseases.

Optimisation of cyclophosphamide therapy in systemic vasculitis.

There 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.

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.

Development and initial validation of the Vasculitis Damage Index for the standardized clinical assessment of damage in the systemic vasculitides.

OBJECTIVE: To develop and validate the Vasculitis Damage Index (VDI) for the standardized clinical assessment of damage in the systemic vasculitides. METHODS: Using a nominal group consensus approach, the Birmingham Vasculitis Group generated guiding principles for assessment of damage in all systemic vasculitides. Damage was defined as irreversible change resulting from scars. Consensus principles were developed into the VDI, including guidelines for use, a list of items of damage, and a glossary. RESULTS: For 100 surviving patients with systemic vasculitis, the median VDI score at last observation was 3 (range 0-8). Within the Wegener's granulomatosis subgroup, the median VDI score for 12 non-survivors was higher than for 47 survivors (non-survivors median score 7, interquartile range 5-8 versus survivors median score 4, interquartile range 2-5; P = 0.003). VDI scores for 100 patients with systemic vasculitis increased from initial presentation to last observation by a median score of 3 (range 1-4; P < 0.001). The VDI assesses more items and is more sensitive to change than other indices of damage (P < 0.001). Using the VDI, trained observers can produce moderately consistent damage scores. CONCLUSION: The VDI is a sensitive, reproducible, comprehensive, and credible clinical tool for quantifying damage. The data presented herein should enable further validation and testing of the VDI in specific vasculitic syndromes, and should facilitate the comparison of different therapies.