DISEASE ASSESSMENT IN SYSTEMIC VASCULITIS R A Luqmani

Transcription

1 Review article J Indian Rheumatol Assoc 2003 : 11 : DISEASE ASSESSMENT IN SYSTEMIC VASCULITIS R A Luqmani Consultant Rheumatologist/Senior Lecturer in Rheumatology Rheumatology Department, Western General Hospital, Crewe Road, Edinburgh Abstract : The vasculitides represent a set of uncommon but chronic persistent relapsing disorders which were previously fatal without the advent of effective immunosuppressive therapy. In the absence of a cure for most forms of vasculitis, we need to use accurate tools to measure disease status in order to establish an appropriate therapeutic regimen in every case. Accurate serological markers of disease activity remain elusive. Therefore the clinician must use the quantitative and qualitative information available form careful clinical evaluation of these patients. Effective measurement of disease activity, disease damage and function are the current gold standards of evaluation of patient status. In this review, we review the evidence for the usefulness of serological markers of disease activity and discuss the role of the Birmingham Vasculitis Activity Score, the Vasculitis Damage Index and the Short Form 36 in the comprehensive evaluation of systemic vasculitis. Keywords: Vasculitis, Wegener s granulomatosis, ANCA, microscopic polyangiitis, chemotherapy Introduction: The systemic vasculitides are an important cause of mortality (if untreated) and morbidity (despite current best treatment), even though they are relatively uncommon, with around 100 to 150 new cases per million every year 1 with around 13 per million per year due to primary systemic vasculitis 2. The mechanism by which disease arises is through occlusion of blood vessels resulting in tissue or organ damage. The pattern of the vasculitides varies throughout the body and this results in patients suffering from single organ-system disease through to multi organ-system disease. The mechanisms by which blood vessel occlusion occurs are more complex and not fully understood 3,4. In many cases, the vessel wall becomes inflamed and thickened and then occluded. In other cases there may be occlusion of the blood flow as a result of immune complex Address for correspondence Dr. R A Luqmani Consultant Rheumatologist/Senior Lecturer in Rheumatology Rheumatology Department, Western General Hospital, Crewe Road, Edinburgh EH4 2XU Fax: Raashid.Luqmani@ed.ac.uk formation. It is likely that the endothelium plays an active role in the process and the precise mechanism by which vasculitis arises in any single disease entity may be difficult to determine 5,6. There has been significant progress in understanding the pathogenesis as a result of discovering autoantibodies against neutrophil cytoplasm (ANCA) 7 particularly in the vasculitides which affect small blood vessels. The introduction of immunosuppressants for management of vasculitis has resulted in significant changes in mortality but the morbidity of vasculitides remains very high with up to 20% of patients with renal vasculitis suffering chronic renal impairment, up to 50% of patients with systemic vasculitis experiencing flares of their disease, and possibly over 80% of patients with Wegener s granulomatosis suffering either a combination of flare or low grade grumbling disease activity 8 9. The result is that the management of the vasculitides remains unsatisfactory despite major advances in the prevention of mortality. Disease assessment becomes very important in the setting of chronic relapsing disease because current therapies as well as future therapies must be tested on the basis that they improve dis-

2 R A Luqmani ease control. In this review we discuss the role of clinical indices of disease assessment and their applicability to systemic vasculitis. Outcome from current therapy: The introduction of cyclophosphamide for small vessel vasculitis has transformed the outcome of diseases such as Wegener s granulomatosis and microscopic polyangiitis. Wegener s had a > 80% mortality with steroids alone 10 or nearer 100% mortality without treatment at 2-5 years follow-up. In 1958, Walton introduced steroid treatment for vasculitis and demonstrated 50% survival at one year but this was not sustained. In the 1970s cyclophosphamide and azathioprine were introduced in addition to steroid therapy and the results have been dramatic with azathioprine. Leib, Restivo and Paulus 11 showed that the addition of chemotherapy to steroids resulted in the most favourable outcome for patients with systemic vasculitis. This was not a randomised control trial but paved the way for more aggressive therapeutic approaches to systemic vasculitis. Cyclophosphamide has become the gold standard of current therapy for small vessel vasculitis with significant organ involvement. However, it is clear that in some types of vasculitis this is not the required approach but therapy will be discussed in a later section in this review. The overall results of our current approach to systemic vasculitis suggest that the outcome of optimal therapy is still far from unsatisfactory. In large vessel vasculitis such as Giant cell arteritis there is still a 5 to 13% incidence of blindness 12,13 ischaemic lesions in Takayasu s cause significant damage, chronic upper airways disease is common in Wegener s granulomatosis and renal failure as a result of systemic vasculitis may account for up to 25% of patients on dialysis programmes 14,15 although <5% are formally recorded as due to vasculitis. Classification and diagnostic criteria for vasculitis: The vasculitides are separated according to different disease patterns and current classification criteria are largely based on pathology with the dominant vessel size involvement being used as the basis of classification as proposed by Zeek 16. This approach uses small vessel vasculitis, medium vessel vasculitis and large vessel vasculitis as the three main divisions. The Chapel Hill consensus conference in 1994 revised this approach 17 suggesting this classification should represent the smallest vessel size involved, i.e. that small vessel vasculitis may also involve medium and large vessel vasculitides. Similarly, medium vessel vasculitis may involve large vessel vasculitis but does not include small vessel vasculitis. The distinction is, therefore, being made on the basis of the minimum size vessel involvement. The classification has resulted in a reconfiguration of polyarteritis (or polyangiitis) so that microscopic polyangiitis is now considered to be a small vessel vasculitis and associated with significant mortality and morbidity without treatment and which normally involves the kidney. By contrast, polyarteritis nodosa does not involve small vessels and is at the level of small arterioles. This rarely involves the kidney and has a very different clinical and pathological picture. The classification criteria proposed by the American College of Rheumatology in the early 1990s are complex and have some advantages, although there are many disadvantages with overlap between different forms of vasculitis being the chief one 18 along with a failure to distinguish microscopic polyangiitis as a separate disease from polyarteritis nodosa 19. Neither system (Chapel Hill or ACR) is a set of diagnostic criteria and we still do not have diagnostic criteria for systemic vasculitis. This poses a problem to the practising clinician when faced with a case of uncertain disease process. In very typi- 36

3 Disease Assessment in Systemic Vasculitis cal cases for example in Wegener s granulomatosis where there is a clear history of upper airway chronic disease associated with pulmonary haemorrhage or pulmonary infiltrate and renal manifestation such as nephritis, hypertension and renal impairment, there is no difficulty in achieving a diagnosis. However, in less clear cut cases, there may be considerable confusion between vasculitis and other disease manifestations such as lupus, malignancy, infection and drug related toxicity. There is still a need to develop appropriate diagnostic criteria to assist in this differentiation. Role of serological markers in disease assessment The introduction of ANCA 7 has led to significant advances in understanding the pathogenesis of vasculitis 6 but also increased the confidence and awareness of clinicians in making a diagnosis of vasculitis. 20 However, ANCA is not present in all types of vasculitis and, indeed, is only present in a proportion of patients with small vessel vasculitis. The majority of patients with Wegener s granulomatosis would be expected to have ANCA as would patients with microscopic polyangiitis. 21 A significant proportion of Churg Strauss patients have ANCA, in some series reaching over 70% 22. However, for large vessel and medium vessel vasculitis ANCA is generally not present. ANCA is important as a diagnostic tool although it is of limited value when used without appropriate clinical indications 23. ANCA may have a dual role in not only achieving helpful diagnosis but also in monitoring disease activity. However, its role in this area is controversial There is evidence that in Wegener s granulomatosis it may be important to monitor the PR3 ANCA level in order to determine the likelihood of treatment response and subsequent reactivation of disease but it is known that in careful studies, despite apparent rises in ANCA titre, there may be no clinical consequence in up to a third of patients with vasculitis As a rule, however, ANCA may serve as an important prognostic marker defining a sub-group of patients who are likely to have more severe disease 27. Persistent presence of ANCA does associate with greater likelihood of failure to respond to primary therapy and also increases the likelihood of subsequent relapse. However, the use of ANCA as a marker for disease activity to directly determine therapy changes is extremely flawed and hazardous and could not be recommended at present 26. There is a significant danger of over-treating patients on the basis of ANCA titres rising (up to a third of cases) and the corollary is also true in that ANCA may remain normal or static in patients who have fluctuating clinical disease activity 26. Other markers of disease activity have been suggested such as CRP but unfortunately this fluctuates in response to infection as well as disease flares and particularly in Wegener s granulomatosis 28. These two clinical states may be difficult to distinguish in the upper airways where it may be difficult to separate active vasculitis with crusting and bleeding from a coincident infection resulting in the same clinical manifestation. In some patients possibly both may be present because it is known that active upper airways infection may promote a flare of disease activity. Other serological markers that have been proposed includes von Willebrand factor which is predominantly released by platelets and endothelial cells in response to injury or activation. However, von Willebrand factor levels do not correlate well with disease activity measures. Other surrogate markers such as soluble adhesion molecule levels have been proposed, but their role is uncertain 29. Some studies have suggested relationship with disease activity. Overall the surrogate outcome measures are simple to apply but difficult to interpret and whether they assist in determining current disease status or fu- 37

4 R A Luqmani ture prognosis is still subject to further study and one could not conclude that their role is clear cut at this stage 30. Development of clinical indices of disease assessment The clinical features of systemic vasculitis are relatively straightforward to assess and it would seem logical to evaluate patients on a clinical basis given the failure of surrogate markers to indicate clear cut disease activity. We have spent some time developing quantitative indices of clinical activity on the basis that patients undergo disease activity which leads to chronic damage from scars and in turn impacts on their lifestyle or function. It is vital that these three separate areas of disease activity, disease damage and effect on function are clearly delineated from a therapeutic point of view because we don t want to address each of the three problems with the same solution 31. For example, it would be inappropriate to offer increased immunosuppression for managing disease damage or effects on function. By contract, it would be entirely appropriate to respond with more immunosuppression for clearcut evidence of clinical disease activity. We will review the developments in these three areas in more detail. 1. Disease activity: Given the spectrum of clinical problems in systemic vasculitis the range of abnormalities that occur can involve all systems of the body and it is therefore important to evaluate all systems in patients with vasculitis. There is a danger of neglecting some organ systems and this may result in loss of function of organs in the initial phase of disease. Where a diagnostic delay in evaluating patients with suspected vasculitis has led to significant loss of renal function during the course of their time in hospital 32. Therefore, the earlier we can make a comprehensive assessment of disease status in all organs the sooner we can start to potentially manage these patients. Clinical assessment of disease activity would evaluate common features of the disease as well as allowing for uncommon features. Disease activity measures have been proposed since 1988 with the first measure, the five factor score 33. Disease activity was determined in five separate areas (the presence of proteinuria, renal impairment, cardiac involvement, GI involvement and LNS upper motor-neurone involvement). The five factor score has been an important measure of disease activity and has also given prognostic information for patients with vasculitis 34. It is simple to complete but may lack some precision in disease evaluation. However it could form the basis of which therapy would be most appropriate to use for patients with systemic vasculitis 34. Disease specific activity tools such as the Groningen index for Wegener s granulomatosis have the advantage of being more comprehensive and detailed but rely heavily on the use of pathology to determine disease status which may be useful for diagnosis but difficult to apply for serial follow-up 35. The group in Baltimore have introduced a vasculitis activity index (VAI) which is a rating scale of disease in several organ systems but it is not widely used and may be subject to significant observer bias 36. The Disease Extent Index (DEI) 37 is based on renal organ systems and activity and damage and is more specific for Wegener s granulomatosis but does provide some useful prognostic information and may be of value in long-term outcome studies of vasculitis. The most widely used index is the Birmingham vasculitis activity score (BVAS) 28, which is based on an intention to treat premise. The items that are commonly involved in systemic vasculitis are listed in organ systems and deny assessment of the patient, the doctor must assume the responsibility for making a decision as 38

5 Disease Assessment in Systemic Vasculitis to whether or not any abnormalities demand a change in therapy. It is essential to score BVAS on this basis. Therefore, the assumption is made that the doctor evaluating the patient will make a clinical decision as to whether or not the abnormality represents vasculitis (as distinct from infection or other cause) and furthermore that the abnormality is active at the present time and therefore merits intervention. This is important because many of the items in the BVAS index might well be present but may not be due to vasculitis or equally they could be inactive. For example, the presence of haematuria and proteinuria may be an indication of active vasculitis but clearly infection may need to be excluded first. Similarly, the presence of long-standing changes such as a hemi-paresis, which may or may not have been due to previous vasculitis, should only be assessed as positive if the item represents a recent change, usually within the last month. Therefore, a patient who has had established cerebrovascular disease and who just happens to develop vasculitis does not in all likelihood have active vasculitis of the CNS causing his or her stroke and therefore the BVAS item stroke should not be scored as positive in this circumstance. However, if the patient has established diagnosis of Wegener s granulomatosis and then presents with a new stroke that the clinician decides is due to active vasculitis then, of course, you must be scored it. This might seem an obvious approach but in fact this is the root of many areas of controversy and confusion in the use of BVAS. BVAS has been widely applied in European vasculitis studies 38,39 and is regarded as the standard assessment tool for disease activity in many studies. It serves not only as an item list of disease activity but the items can be translated into a numerical score representing a quantitative measure of disease activity. The score is calculated by measuring the contribution of this to each organ system. Calculating the score is based on the assumption that each organ system contributes a maximum number of points towards the score and the maximum value is less than the total maximum score if all items in that system are ticked. The organ systems are given a weighting according to their importance in clinical terms so that the renal system is given a higher weighting than the skin. Within each system certain items are regarded as more important than others and they are ranked in order. The weighting is multiplied by their ranking to give the score for the individual item. The weights and ranks have been determined by consensus agreement between expert clinicians. The system has been tested and validated in many patients with systemic vasculitis 28,40,41. Applying BVAS as an assessment tool provides a quantitative measure of disease definitions such as relapse and remission or partial remission or partial relapse. It also acts as a prognostic tool and has been demonstrated to be an effective marker of outcome in a number of studies of systemic vasculitis 34, 28. The item checklist in BVAS is a simple one page assessment. Current and future studies of systemic vasculitis therapy from the European Vasculitis Study Group (EUVAS) and the International Network for the Study of Systemic Vasculitis (INSSYS) use BVAS as the basic assessment tool. We would advocate its use on a day to day basis for managing individual patients as well as being an effective research tool for clinical studies. We modified BVAS for use specifically in Wegener s granulomatosis and in 2001 we published a new version of BVAS specifically for Wegener s granulomatosis 42. This has been applied in a new study of Etanercept versus placebo in the adjunctive management of Wegener s granulomatosis 43. BVAS Wegener s is also a simple effective tool to use on a practical day-to-day basis with patients with Wegener s 39

6 R A Luqmani granulomatosis. It is possible that future modifications to BVAS may incorporate changes suggested in BVAS for Wegener s and an attempt will be made to unify and standardise BVAS for generic use in all types of vasculitis. BVAS remains the most effective tool for use and it is important to concentrate on efforts to maintain its validity, revised by extensive usage. 2. Damage: Damage represents non-healing scars or a permanent effect as a result of developing vasculitis. The definition is very different from that of disease activity and should encompass not only the damage attributable to having had vasculitis but also the therapy of vasculitis and other inter-current events that have occurred since the timing of a diagnosis of vasculitis has been achieved. The implication, therefore, is that there is no attribution of the damage except in terms of when it has occurred. Therefore damage items may encompass the wider aspects of the impact of disease on the individual. The systemic necrotising vasculitis damage index 44 was introduced as an attempt to evaluate damage in polyarteritis nodosa but is specific to that disease. The vasculitis damage index 45 is the most comprehensive damage index available in vasculitis and is the most widely used. It consists of nine organ systems and a general section for other damage to include damage directly attributable to drug therapy. Damage items overlap to a small degree with disease activity items and this is a reflection of disease process. For example, in the ENT section nasal crusting may represent new disease but equally chronic nasal crusting and chronic nasal discharge may be a manifestation of scarring in the nasal passages. However, in other sections of the damage index the items are completely different from the BVAS. The emphasis is on the scars that are commonly seen in patients with systemic vasculitis and vary from organ system to organ system. In some areas such as the skin the presence of a leg ulcer for a persistent length of time would be scored as a damage item. The timing is important and three months is regarded as the minimum length of time before making an arbitrary decision that an item is due to damage. This is based on clinical practice because in most patients, disease is brought under control within three months but thereafter most persistent problems are due to damage rather than ongoing disease activity. This clearly is not always the case but in order to establish some coherence to the damage index it is necessary to introduce arbitrary divisions which may seem artificial at first but work in the majority of cases. The damage index (VDI) can be further sub-divided into critical damage, treatment-related damage and systems damage. These subsets are calculated from the total score and reflect different aspects of damage. Our original data suggest that the damage index is a very useful indicator of disease outcome; it accumulates rapidly early on in the disease course and may be predictive of future mortality 46, 47. The damage index could, therefore, serve as a surrogate marker for good or poor prognosis and future studies may look at role of achieving a target damage index of a value that is less likely to lead to eventual mortality. The VDI is being widely used in clinical trials of systemic vasculitis undertaken by the EUVAS group and the INSSYS group. The distinction between disease activity and damage is also important from a practical day-to-day basis because if the clinician seeing the patient can make the distinction between disease activity and damage then they may use this information as a more rational basis for managing the patient. There is some element of evaluation of damage by the disease extent index which includes activity as well as damage and this may provide overlapping information to 40

7 Disease Assessment in Systemic Vasculitis the VDI. An important feature of the damage index is that it is irreversible and therefore cannot improve. The damage index is a marker of how much disease damage has been sustained during the course of time since the patient has developed vasculitis. Some damage items represent single events such as a myocardial infarction or a stroke. Other damage items represent persistent chronic change such as a leg ulcer or a period of significant alopecia. Whilst we recognise that in many cases these clinical problems do appear to resolve, sometimes fully, the fact remains that the patient has suffered a period of persistent scarring and that it is unlikely that the body has fully recovered from the event. Most damage is accumulated early on in disease course 46. Therefore, the principle is an important one that damage never gets better. This is in contrast with disease activity, which fluctuates much more readily, especially in response to therapy. 3. Function: There are no specific functional indices for systemic vasculitis. Instead we use the short form 36 as our functional index 48. This is a widely validated assessment score of health status which is applied in many types of disease, not specific for vasculitis. It can be summarised as mental health functioning and physical functioning into two separate numeric scores. Early evidence of the use of a functional index in systemic vasculitis suggests that patients who have resolved their disease as a result of chemotherapy, and who may or may not have damage sustained, may still have significantly abnormal physical functioning which persists for, on average, a year after complete resolution of the systemic vasculitis 49,50.Again this highlights the importance of evaluating patients carefully because if patients are scoring very significantly abnormal on their functional index but have no evidence of current disease activity this should be not unexpected and should help the clinician form a management plan for therapy for that individual. Therefore a highly abnormal SF36 with a normal or low BVAS would be an indication not to use aggressive chemotherapy. Functional indices are important for patients because they are a measure of how the patients cope with their illness and clearly as a long term outcome measure they are going to play a vital role in evaluating the effectiveness long-term of any intervention. Use of disease assessment for clinical trials of vasculitis: From the discussion above it is apparent that the quantitative information provided by these simple clinical tools of disease assessment is extremely valuable in designing and implementing clinical trials in systemic vasculitis and, as discussed earlier 38 the EUVAS study group and the INSSYS study group have implemented BVAS and VDI for their trials 43. The widespread use of these tools is an important step forward in providing a common framework by which to measure the effectiveness of current or new therapies. However, this common framework does need to be validated across different centres applying these tools and just as with any clinical or laboratory test it is important that the tool is subject to rigorous validation procedures between centres involved in such studies 40. We have, therefore, spent some effort developing an extensive training programme in disease assessment using paper cases which train observers to make the correct evaluation of patients with systemic vasculitis. We would strongly encourage all clinicians interested in this area to undertake the training programme of paper cases prior to entering patients into clinical studies of systemic vasculitis and, indeed, prior to evaluating their own patients with systemic vasculitis. The training 41

8 R A Luqmani is an extensive package of paper cases with a full explanation of the BVAS/VDI and provides a glossary of terms as well as the BVAS and VDI forms. Training cases can be evaluated either on a self evaluation basis or through our website. We strongly recommend that disease assessment training is followed by a maintenance programme of a further ten paper cases per annum in order to keep up the skills required of disease evaluation. Current and future role of disease assessment: The disease assessments can serve a number of purposes, including the following: 1. Teaching tools. The comprehensive list of abnormalities which have been designed by consensus by expert clinicians in managing vasculitis serves as an important training tool for less experienced clinicians who are involved in the management of patients with systemic vasculitis. The training package also provides strong support for this group of individuals and we are currently looking at ways of evaluating the effectiveness of training in less experienced clinicians. 2. On a practical day-to-day basis disease assessment may be of value in helping to understand the specific disease status of complex patients with multi-system disease and we would strongly advocate the role of BVAS and VDI in such patients. 3. As a basis for clinical trials in systemic vasculitis it is essential to have a comprehensive clinical tool or set of tools which will allow quantitative as well as qualitative evaluation of patient outcome, given the significant increase in overall survival in systemic vasculitis. This means that the measurement of morbidity which is afforded by the use of BVAS and VDI and SF36 makes these very effective tools for clinical trials. 4. The future use of disease assessment tools as surrogate outcome measures is to be explored. For example, the aim of a clinical trial may be towards presenting a level of damage as measured by VDI. 5. Clinical assessment tools may provide effective guidance on most appropriate initial therapy. 6. Long term observational studies of survival in vasculitis indicate that disease course is often punctuated by episodes of relapse in up to 50% of cases but there is chronic ongoing damage in the majority and disease assessment tools provide an opportunity to measure this more effectively in order to determine the natural history of patients with vasculitis who are now expected to survive beyond the initial disease episode. 7. The development of more objective serological surrogate markers of disease activity or damage in vasculitis remains an active pursuit and our clinical tools serve as an important benchmark against which to test new laboratory tools. Conclusions: Clinical evaluation of patients with systemic vasculitis remains the cornerstone of clinical management and judgement of these patients. The disease assessment of systemic vasculitis has been facilitated significantly by the introduction of comprehensive quantitative tools such as the BVAS, VDI and SF36 and we strongly recommend their use in all patients with vasculitis. References: 1. Luqmani RA, Robinson H. Introduction to, and classification of, the systemic vasculitides. Best Pract Res Clin Rheumatol 2001;15: Gonzalez-Gay MA, Garcia-Porrua C, Guerrero J, Rodriguez- Ledo P, Llorca J. The epidemiology of the primary systemic vasculitides in northwest Spain: implications of the Chapel Hill Consensus Conference definitions. Arthritis Rheum 2003;46: Kallenberg CG, Rarok A, Stegeman CA, Limburg PC. New insights into the pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis. Autoimmun Rev 2002;1:

9 Disease Assessment in Systemic Vasculitis 4. Luqmani RA, McInnes I (2001). Mechanisms of Vasculitis: Chapter 7, pg Core Health Services Inc ISBN Muller Kobold AC, van der Geld YM, Limburg PC, Tervaert JW, Kallenberg CG. Pathophysiology of ANCA-associated glomerulonephritis. Nephrol Dial Transplant 1999; 14: Savage CO The evolving pathogenesis of systemic vasculitis. Clin Med 2002; 2: van der Woude FJ, Rasmussen N, Lobatto S, Wiik A, Permin H, van Es LA, et al Autoantibodies against neutrophils and monocytes: tool for diagnosis and marker of disease activity in Wegener s granulomatosis. Lancet ;(8426): Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116: Gordon M, Luqmani RA, Adu D, Greaves I, Richards N, Michael J, et al. Relapses in patients with a systemic vasculitis. Quart J Med 1993; 86: Walton EW. Giant-cell granuloma of the respiratory tract (Wegener s granulomatosis). Br Med J 1958;34: Leib ES, Restivo C, Paulus HE. Immunosuppressive and corticosteroid therapy of polyarteritis nodosa. Am J Med 1979; 67: Liozon E, Herrmann F, Ly K. Robert P-Y, Loustaud V, Soria P, Vidal E. Risk factors for visual loss in giant cell (temporal) arteritis: A prospective study of 174 patients. American 2001;111: Kobayashi S, Yano T, Matsumoto Y, Numano F, Nakajima N, Yasuda K, et al. Clinical and epidemiologic analysis of giant cell (temporal) arteritis from a nationwide survey in 1998 in Japan: the first government-supported nationwide survey. Arthritis Rheum 2003;49: Nissenson AR, Port FK. Outcome of end-stage renal disease in patients with rare causes of renal failure. III. Systemic/vascular disorders. Quart J Med 1990;74: Kaplan-Pavlovcic S. Cerk K, Kveder R, Lindic J, Vizjak A. Clinical prognostic factors of renal outcome in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis in elderly patients. Nephrology Dialysis Transplantation 2003;18(Suppl. 5):v5-v Zeek PM.Periarteritis nodosa and other forms of necrotizing angiitis. N Engl J Med 1953;248: Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994;37: Hunder GG, Arend WP, Bloch DA, Calabrese LH, Fauci AS, Fries JF, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Introduction. Arthritis Rheum 1990;33: Lightfoot RW Jr, Michel BA, Bloch DA, Hunder GG, Zvaifler NJ, McShane DJ, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa Arthritis Rheum 1990;33: Andrews M, Edmunds M, Campbell A, Walls J, Feehally J. Systemic vasculitis in the 1980s is there an increasing incidence of Wegener s granulomatosis and microscopic polyarteritis? J R Coll Physicians Lond 1990;24: Kallenberg CG. Laboratory findings in the vasculitides. Baillieres Clin Rheumatol 1997;11: Keogh KA, Specks U. Churg-Strauss syndrome. clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med 2003;115: McLaren JS, Stimson RH, McRorie ER, Coia JE, Luqmani RA. The diagnostic value of ANCA testing in a routine clinical setting. Quart J Med 2001;94: Kerr GS, Fleisher TA, Hallahan CW, Leavitt RY, Fauci AS, Hoffman GS. Limited prognostic value of changes in antineutrophil cytoplasmic antibody titer in patients with Wegener s granulomatosis. Arthritis Rheum 1993;36: Tervaert JW, Huitema MG, Hene RJ, Sluiter WJ, The TH, van der Hem GK, et al. Prevention of relapses in Wegener s granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet 1990;336: Boomsma MM, Stegeman CA, van der Leij MJ, Oost W, Hermans J, Kallenberg CG et al. Prediction of relapses in Wegener s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 2000;43: De Oliviera J, Gaskin G, Dash A, Rees AJ, Pusey CD. Relationship between disease activity and anti-neutrophil cytoplasmic antibody concentration in long-term management of systemic vasculitis. Am J Kidney Dis 1995;25: Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, Savage C, Adu D. Birmingham vasculitis activity score (BVAS) in systemic necrotizing vasculitis. Quart J Med 1994; 87: Janssen B, Luqmani RA, Gordon C, Hemingway IH, Bacon PA, Gearing AJH, et al. Correlation of blood levels of soluble vascular cell adhesion molecule-1 with disease activity in systemic lupus erythematosus and vasculitis Br J Rheumato 1994;33: Hoffman GS, Ahmed AE. Surrogate markers of disease activity in patients with Takayasu arteritis. A preliminary 43

10 R A Luqmani report from The International Network for the Study of the Systemic Vasculitides (INSSYS). Int J Cardiol 1998;66(Suppl 1):S191-4; discussion S Luqmani RA. Assessing disease activity in the systemic vasculitides. Current Opinion Rheumatol 2002; 14: Adu D, Howie AJ, Scott DG, Bacon PA, McGonigle RJ, Micheal J. Polyarteritis and the kidney. Quart J Med.1987;62: Guillevin L, Le Thi Huong D, Godeau P, Jais P, Wechsler B. Clinical findings and prognosis of polyarteritis nodosa and Churg-Strauss angiitis: a study in 165 patients. Br J Rheumatol 1988;27: Gayraud M, Guillevin L, le Toumelin P, Cohen P, Lhote F, Casassus P et al. French Vasculitis Study Group. Longterm followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum 2001;44: Kallenberg CG, Tervaert JW, Stegeman CA. Criteria for disease activity in Wegener s granulomatosis: a requirement for longitudinal clinical studies. APMIS Suppl 1990;19: Whiting-O Keefe QE, Stone JH, Hellmann DB. Validity of a vasculitis activity index for systemic necrotizing vasculitis. Arthritis Rheum 1999;42: de Groot K, Gross WL, Herlyn K, Reinhold-Keller E. Development and validation of a disease extent index for Wegener s granulomatosis. Clin Nephrol 2001;55: Rasmussen N, Jayne DRW, Abramowicz D, Andrassy K, Bacon PA, Cohen Tervaert JW, et al. European therapeutic trials in ANCA associated systemic vasculitis: disease scoring, consensus regimens and proposed clinical trials. Clin Exp Immunol 1995;101(Suppl 1): Luqmani RA. Evaluation of vasculitis disease activity in Europe. Europ of 200;12: Luqmani RA, Exley AR, Kitas GD, Bacon PA. Disease assessment and management of the vasculitides. Baillieres Clinical Rheumatology 1997;11: Adu D, Pall A, Luqmani RA, Richards N, Howie AJ, Michael J, et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of vasculitis. Quart J Med 1997;90: Stone JH, Hoffman GS, Merkel PA, Min Y-I., Uhlfelder ML, Hellmann DB, et al. A Disease-Specific Activity Index for Wegener s Granulomatosis: Modification of the Birmingham Vasculitis Activity Score. Arthritis Rheum 2001;44: WGET Research Group. Design of the Wegener s Granulomatosis Etanercept Trial (WGET). Control Clin Trials 2002;23: Abu-Shakra M, Smythe H, Lewtas J, Badley E, Weber D, Keystone E. Outcome of polyarteritis nodosa and Churg- Strauss syndrome. An analysis of twenty-five patients. Arthritis Rheum 1994;37: Exley AR, Bacon PA, Luqmani RA, Kitas GD, Gordon C, Savage COS. Development and Initial Validation of the Vasculitis Damage Index (VDI) for the Standardised Clinical Assessment of Damage in the Systemic Vasculitides. Arthritis Rheum.1997;40: Exley A, Carruthers DM, Luqmani RA, Kitas GD, Gordon C, Janssen BA. Damage occurs early in systemic vasculitis and is an index of outcome. Quart J Med 1997;90: Exley AR, Bacon PA, Luqmani RA, Kitas GD, Carruthers DM, Moots R. Examination of disease severity in systemic vasculitis from the novel perspective of damage using the vasculitis damage index (VDI). J Rheumatol 1998;37: Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30: Carruthers D, Bacon P. Activity, damage and outcome in systemic vasculitis. Best Pract Res Clin Rheumatol 2001;15: Reinhold-Keller E, Herlyn K, Wagner-Bastmeyer R, Gutfleisch J, Peter HH, Raspe HH. Effect of Wegener s granulomatosis on work disability, need for medical care, and quality of life in patients younger than 40 years at diagnosis. Arthritis Rheum 2002;47: