- Email: [email protected]
Vasculitis assessment and Takayasu aorto-arteritis
Indian Journal of Rheumatology 2012 September Volume 7, Number 3; pp. 153e158
Perspective
Vasculitis assessment and Takayasu aorto-arteritis Paul Bacona,*, Rajappa Sivakumarb, Debashish Dandac, Ramnath Misrad
ABSTRACT Assessment of disease activity using clinical instruments like Birmingham Vasculitis Activity Score and Vasculitis Damage index has been extensively used both in trial and clinic setting. It has revolutionised outcome assessment for small size vasculitis as evidenced from studies carried out by the European vasculitis group. There is a need for clinical assessment tools for large vessel disease like Takayasu arteritis, which is seen more frequently in India. An attempt has been made by the Indian Rheumatology Association Vasculitis core group to validate instruments, like Disease Extent Index for Takayasu Arteritis (DEI.Tak), Indian Takayasu Activity Score (ITAS) and Takayasu Arteritis Damage Scores. Both DEI.Tak and ITAS have received interests from international investigators. Widespread usage of these instruments will pave the way to controlled clinical trials for TA. Copyright © 2012, Indian Rheumatology Association. All rights reserved. Keywords: DEI.Tak, Indian Takayasu Activity Score, Takayasu Arteritis Damage Score
MEASUREMENT IN RHEUMATIC DISEASE The clinical outcome in diffuse connective tissue diseases has improved enormously over the past half-century. This progress has come despite a paucity of breakthroughs in understanding basic disease mechanisms.1 Improvement in diseases like Systemic Lupus Erythematosus (SLE) has come despite the absence of new therapies, in contrast to Rheumatoid Arthritis (RA) where the concept that Tumour Necrosis Factor (TNF) is the key inflammatory cytokine driving synovial inflammation has led to striking advances in therapy. Better management has come from improved definition of the aims of treatment. Development of detailed clinical measurement has produced quantitation of disease severity and encouraged a focus on the specific problems in individual cases. This in turn has directed attention at controlling specific aspects of disease instead of futile efforts to “cure” multi-system disease with single regimes. For example renal involvement in SLE may require active immuno-suppression plus blood pressure control and support for renal failure. a
In systemic vasculitis, this approach has improved the immediate prognosis but turned acute life-threatening disease into chronic relapsing syndromes typical of persistent rheumatic diseases. Detailed assessments have also been the basis for data-sharing collaborations which have provided an evidence-base for choosing more effective regimes in the short-term with diminished long-term toxicity compared to the previous “standard National Institute of Health (NIH) regime”. The series of trials in Small Vessel Vasculitis (SSV) conducted by the European Vasculitis Consortium, EUVAS, illustrate the advantages of quantitating clinical measurement. We will first review what should be measured and what has been learnt from this in SSV before discussing adaption of this schema to aorto-arteritis.
CLINICAL ASSESSMENT IN SSV e LESSONS LEARNT Standardised assessment has provided the basis for national/international networks that have been able to
Professor Emeritus, Department of Rheumatology, Medical School (East Wing), Birmingham University, Vincent Drive, Birmingham, B15 3QG, UK, bConsultant Neurology, Chennai, cProfessor and Head of Rheumatology and Clinical Immunology, Christian Medical College, Vellore, dProfessor and Head, Department of Clinical Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India. * Corresponding author. email: [email protected] Received: 19.6.2012; Accepted: 4.7.2012; Available online: 10.7.2012 Copyright Ó 2012, Indian Rheumatology Association. All rights reserved. http://dx.doi.org/10.1016/j.injr.2012.07.001
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accumulate sufficient numbers of rare syndromes to set up major clinical trials in Small Vessel Vasculitis (SSV). These Randomised Controlled Trials (RCTs) have revolutionised the approach to therapy which now has a secure evidence-base for specified aspects of disease control. The result has been improved short-term survival rates and lower long-term toxicity. It is important to understand the basis for this so that the lessons learnt can be applied to TA. The essence of disease assessment is to quantitate disease severity. The extent of disease and whether this relates to current active inflammation or to established scars (fixed damage) are the factors that define severity from the physicians’ viewpoint e although we must remember that patients are more concerned about function and economic burden.2 It is important to resist the easy idea that “tests” (laboratory, imaging, etc) will provide the data needed when careful clinical study is what works best. Even disease-related auto-antibodies such as Anti Neutrophil Cytoplasmic Antibodies (ANCA) titres do not closely reflect clinical disease activity. Clinical assessment of chronic disease has many advantages since it is cheap and readily available. It is also directly related to the patient’s disease, unlike non-specific blood tests for inflammation. The acute phase response often fails to correlate well with other evidence of ongoing vasculitic inflammation and may reflect other factors such as infection. However to be of use for more than a single clinician, clinical assessment has to both be standardised and to provide a quantitative score for serial use. It can then be used to compare with new diagnostic tests that are developed as well as for quantifying response to therapy in formal trials or in routine clinical use. The most frequent methodologies used for vasculitis are the well-validated activity score Birmingham Vasculitis Assessment Score (BVAS)3 and the damage score, Vasculitis Damage Index, VDI.4 Assessment of disease activity is the first priority for clinicians treating new vasculitis. BVAS (Birmingham Vasculitis Activity Score) was developed to collect a comprehensive index of disease involvement across 10 organ-related systems. BVAS was used to study responses in both the EUVAS clinical trials and in standard practice by the French Vasculitis Collaboration. The quantitative measure of disease severity provided by a BVAS score at presentation offers a guide to long-term prognosis.5 High BVAS score patients have increased early mortality and a continued reduction in long-term survival. Cumulative development of scars from disease and therapy adds to this. Measurement of the Vasculitis Damage Index (VDI) shows that scars develop early and have a poor prognosis.6 Both the total VDI score and the number of organs involved contribute to fatality. Aggressive initial treatment is key to limiting inflammation rapidly and blocking scar
Bacon et al.
development.7 BVAS scores can direct choice of therapy, for example reserving more severe immuno-suppression such a Cyclophosphamide (Cyc) for more extensive disease.8,9 However EUVAS trials have also shown that early switch from Cyc to milder longer-term maintenance therapy does not increase relapse but does diminish cumulative drug toxicity.10
DEVELOPMENT OF ASSESSMENTS FOR TAKAYASU AORTO-ARTERITIS BVAS and VDI were both designed and validated for use in AA.SV (ANCA-associated systemic vasculitis and similar syndromes with largely small vessel involvement). The pattern of symptoms scored in these diseases is largely produced by widespread small arterial lesions affecting multiple organs. However, in TA restricted large vessel involvement leads to a markedly different pattern of clinical disease. TA typically presents with narrowing or occlusion of one or two large vessels, such as subclavian claudication or hypertension in young adults related to renal artery involvement. Thus TA requires dedicated disease-specific tools but the situation here is at least a decade behind SSV, with no validated assessments and no evidence-base for therapy. The Physicians Global Assessment (PGA) is still often the basis for treatment decisions in TA. It is based on clinical features, acute phase reactants, and image abnormalities.11 The acute phase response is neither sensitive nor specific enough to be helpful11e13 as ESR/CRP are not necessarily elevated, even in acute vascular occlusions.14,15 Standard vascular imaging shows damage as well as “activity” and may not reverse with medical therapy. Validated outcome assessments specifically relevant to Large Vessel Disease (LVV) are needed and the OMERACT group has noted the particular challenge of developing these for TA.16 The high incidence of TA in India provided a strong stimulus for correcting this deficiency. As the disease is seen frequently in Indian Rheumatology Clinics, the Vasculitis Study Group of the IRA (IRAVAS) set out to devise and validate assessments for TA, with the intention of producing both an activity score and a damage score that together would document the extent and severity of disease.
Disease extent Initial discussions amongst interested experts showed no clear consensus on the key items needed for an activity index. Thus the first move was agreeing an inclusive organ-based list, modified from the BVAS, of the main clinical features expected in TA. The resultant Disease Extent Index (DEI.Tak) was validated by using it to analyse
Vasculitis assessment and Takayasu aorto-arteritis
the actual disease pattern recorded in 145 cases from 2 main Indian centres.17 The cardiovascular system was most frequently scored and 88 cases had overt CVS disease at the time of assessment. 72 had renal involvement, which like the items scored in CVS is again a direct result of major artery disease. 68 had systemic symptoms such as fever, headaches, arthralgias and myalgias e but weight loss was very uncommon, in contrast to its frequency in SSV. Other systems, such as skin, mucous membranes, eyes and ENT, were rarely scored in TA despite making a major contribution to SSV scores. Thus the DEI.Tak truly reflects the restricted large vessel involvement of TA. The details of this CVS involvement are important. Pulse loss (seen in nearly half the CVS cases) and pulse inequality were the most common, followed by bruits and then claudication. Pulse loss was most frequently noted in the brachialis (1/ 3rd of cases), followed by radial, femoral and foot pulses and least commonly the carotids. However bruits were most frequently noted in the carotids. Thus regular use of DEI.Tak gives a picture of the common clinical pattern of the disease and is a useful teaching aide informing trainees what to look for. The 2-centre Indian data was presented at international meetings17 and the DEI.Tak has since been used to characterise Turkish cases.18 This index has real value as a data-base in individual clinics and if widely applied would provide low-level evidence to compare the arbitrary drug regimes adopted at present. It should also have value as an epidemiologic tool to compare disease expression between countries worldwide. However it is not an activity index, as the Turkish group also concluded.
Disease activity The subsequent development of ITAS (the Indian activity index for TA) was data-driven, taking the new disease items (occurring within the past 3 months) that were scored in DEI.Tak in the 2-centre series. It was validated using live patient assessments at a series of group work-shops in major centres. The clinical relevance of the draft format was tested by scoring the large series of patients from a major single clinic in Vellore. Analysis of data recorded in their series of 177 patients confirmed that 5 organ-based systems were rarely or never relevant in TA, so could be omitted from an activity index. Serial assessments allowed further selection of a set of items reflecting active disease, focussing on CVS items, with special emphasis on bruits, pulse loss, and claudication. All individual items scored in <5% were examined and the majority omitted. The resultant slimmeddown ITAS2010 (Indian Takayasu Activity Score) contains 43 items in 6 systems, is convenient for individual physicians to use in the clinic, and has been extensively validated by
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IRAVAS [Misra et al communicated]. The convergent validity of the ITAS was examined by comparing the new score to the BVAS index well-validated in small vessel disease. The scores showed a strong correlation when used by a single observer in the large clinic series, particularly in patients with recent onset and clinically active disease. In the group exercise, ITAS again showed a highly significant correlation with BVAS. The reproducibility in group usage scoring live patients was excellent, with inter-rater variability equivalent to BVAS. Both were clearly superior in this respect to Physician Global Opinion, (PGO), confirming that careful standardised assessment produces far more consistent agreement than doctors opinion. Weighting has been applied to 7 items related to the major vessel involvement that is clearly most relevant clinically. Importantly, serial assessments in the clinic showed that ITAS both reflects response to therapy and detects flares. It has been used in therapy trials both by the Vellore centre to assess patients on mycophenolate mofetil and by the Italian group to study the effect of IL-6 receptor blockade.19,20 In practice, the principle value may be to inform therapy decisions in individual cases. Consistent use to assess response to drugs should improve overall success rates in this condition where there is no established evidence-base for any therapies. ITAS is also a useful teaching aide for trainees unsure of the full spectrum of disease possible in this condition. A glossary has been produced to aid standardisation of usage across centres.
Damage/disease scars Damage is conceptually different from disease activity since it reflects scars that will not heal completely. It is clinically important to recognize that it needs to be scored separately as it will not respond to drugs that suppress immunemediated inflammation. Thus damage scores can only increase or stay static e they do not revert to zero as an activity index should with successful therapy. Accumulating damage adds to the disease burden experienced by patients and may contribute to poor prognosis. TADS (Takayasu Damage Score) has been derived from DEI.Tak to capture this aspect of TA. It contains 42 items in 7 systems, again with a strong focus on CVS items but also including drug-related problems. Disease-related damage resulting from arterial blockage is a common feature of TA that often requires vascular interventions. At onset, arterial blockage results from a combination of inflammation and scarring, so TADS only scores features present for at least three months. When used in another large cohort followed over 2 decades, TADS scores showed that the increase in damage/scars over time was related to disease duration and to features of poor outcome such as pulse
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loss.21 One third of cases underwent vascular interventions and over 90% of stents remained patent at 5 years. 18% of TA cases died over 2 decades and the TADS scores in fatal disease were higher than in non-fatal cases. These data show that recording a damage score can delineate features associated with clinically relevant outcomes, including pulse loss, long-term stent patency and mortality. The prognostic value of early increases in damage still needs to be fully tested. The four methodologies described provide a comprehensive clinical approach to documenting the diverse clinical disease that develops in aorto-arteritis. They represent major progress in quantitating disease severity which is particularly relevant given the absence of any diseasespecific biomarkers for TA and the poor correlation between activity and acute phase response well documented in TA. Imaging is the most commonly used investigational tool in TA, so it is relevant to consider the place of this beside clinical assessment. Its role in diagnosis is outside the scope of this review but a brief consideration of imaging in assessment of severity of disease activity and of damage is appropriate. Imaging is the basis of the anatomic classification of TA22 and that may correlate with the DEI.Tak score but this has not been tested yet.
Angiography The most widely used tool for diagnosis in TA is angiography (DSA), which remains the gold standard to delineate the site and extent of occlusive lesions. DSA images the vessel lumen and thus provides information on established or late lesions.23 It is essentially imaging scars, or the late results of vascular interventions, so looking for the correlation between angiograms and TADS scores would be sensible. Imaging will not tell you the age of the lesions but in a disease where events are not uncommonly sub-clinical, it may provide extra information.12 Thus the potential gain from incorporating a lesion score from imaging into the TADS needs to be explored.
MR imaging Significant alterations of blood flow can occur before the stenotic stage. Information on the state of the vessel wall is needed if inflammation is to be controlled before scarring occurs. Magnetic Resonance Imaging (MR) and Positron Emission (PET) scans can image the vessel wall and offer hope that questions about ongoing or grumbling activity can be resolved. The studies that have looked at this in TA have had largely positive messages but they remain research tools. There have been repeated reports of MR’s
Bacon et al.
ability to image vascular inflammation but serious studies have cast doubts on the reliability of the information provided. The major Cleveland clinic report on 77 studies in 24 patients showed that aortic wall oedema was demonstrated in 94% of lesions thought to be clinically active.24 This encouraging result has to be balanced against similar wall oedema found in three-quarters of equivocally active disease and half clinically inactive lesions. This is similar to the percentage of lesions with active histology found at vascular surgery e but the changes noted on MR showed little ability to predict subsequent sites of disease flare and showed no correlations with ESR or CRP.
PET scanning The use of PET to image early active disease was suggested by studies of problem PUO patients correctly labelled as aortitis.25 PET labelled the aortic wall as well three-quarters of major artery lesions detected on angiography, in contrast to MR studies which detected aortic wall changes but markedly fewer major artery lesions. Repeat imaging after clinically successful immuno-suppression found improvement in many e but not all e sites on PET scans but few on MR. Other centres have since noted “clear reduction” of pathologic uptake after therapy but not complete clearance, despite suppression of clinical signs, suggesting PET is detecting something different.26,12 An interesting feature in preclinical disease is the appearance of a thin streak of uptake apparently lining the entire aorta (plus some larger vessels). This is different to the focal lesions of stenosed vessels of established disease and its pathological significance is unclear. It may represent a precursor to typical focal TA lesions but does not correlate closely with clinical status.26 Studies on a wider spectrum of clinical disease reported positive PET scans in most of 12 clinically active cases e but also half clinically inactive cases. Finally some patients show areas of new activity despite overall improvement.27 Thus the initial reports that PET directly images the typical vessel wall inflammation seen in TA seem optimistic. PET detects labelled glucose uptake, an indicator of metabolic activity which is up-regulated in inflammation but also in other states such as cell activation and healing. The persistent uptake after therapy could be due to healing processes. The linear pattern of PUO cases might be attributable to endothelial activation occurring prior to (but possibly triggering) subsequent development of focal granulomatous lesions. Thus these important attempts to image vessel wall inflammation have intriguing positive messages but they remain research tools. They suggest the need for a more sophisticated concept of disease activity than the simple idea that TA is
Vasculitis assessment and Takayasu aorto-arteritis
either “active” or “inactive” and offers the hope that questions about ongoing grumbling activity can be resolved. These are the same goals pursued by IRAVAS in the clinical scoring of disease extent. It will be important in future to correlate vessel wall imaging with clinical scores of activity and damage as well as with sites of occlusion. Since neurological manifestations are seen in 20e25% of patients with TA, attempts have been made to assess carotid and intracranial vessel imaging by Doppler and transcranial Doppler ultrasound. We described increased IMT thickness in TA, irrespective of the type of disease and reversal with use of corticosteroids, atorvastatin and mycophenolate mofetil over a 2-year period.28 Further vascular interventions were performed after documenting significant carotid stenosis by carotid Doppler.29 Intracranial stenosis has been demonstrated using transcranial Doppler.
USES OF ASSESSMENTS IN TA The worldwide challenge in treating TA is to provide an evidence-base for therapies. Standardised assessment is an essential part of clinical trial development but it is not only needed in that area. It adds strength to epidemiological studies and clinical practice, where it enables the “treat to target” approach. All physicians seeing aorto-arteritis need to quantify the effects of current recommended procedures in their cases as well as contributing cases to studies of the effect of new therapies on disease activity and damage. The work of IRAVAS has established a sound basis for setting up prospective randomised controlled trials and the large collections of cases in major Indian centres make this an ideal place to conduct them. Effective trial work will require collaborations between rheumatologists and other specialities seeing TA. A first joint meeting between rheumatologists and cardiologists has already been held by the IRA to introduce the new disease assessments. A widespread integration with interested groups across the continent would greatly facilitate the first planned RCT for TA and all physicians seeing any cases of TA are cordially invited to join the trial work.
CONFLICTS OF INTEREST All authors have none to declare.
REFERENCES 1. Bacon P, Wollheim FA. Advances in CTDs. Rheumatology (Oxford). 2011;50(11):1933e1935.
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2. Flossmann O, Bacon P, de Groot K, et al. Development of comprehensive disease assessment in systemic vasculitis. Ann Rheum Dis. 2007;66(3):283e292. 3. Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham vasculitis activity score (BVAS) in system necrotizing vasculitis. QJM. 1994;87(11):671e678. 4. Exley AR, Bacon PA, Luqmani RA, et al. Development and initial validation of the vasculitis damage index for the standardized clinical assessment of damage in the systemic vasculitides. Arthritis Rheum. 1997;40(2):371e380. 5. Gayraud M, Guillevin L, le TP, et al. Long-term follow up of polyarteritis nodosa, microscopic polyangiitis, and ChurgeStrauss syndrome: analysis of four prospective trials including 278 patients. Arthritis Rheum. 2001;44(3): 666e675. 6. Exley AR, Carruthers DM, Luqmani RA, et al. Damage occurs early in systemic vasculitis and is an index of outcome. QJM. 1997;90(6):391e399. 7. Lapraik C, Watts R, Bacon P, et al. BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology (Oxford). 2007;46(10):1615e1616. 8. de Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52(8): 2561e3469. 9. Ribi C, Cohen P, Pagnoux C, et al. Treatment of ChurgeStrauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients. Arthritis Rheum. 2008;58(2):586e594. 10. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36e44. 11. Direskeneli H, Aydin SZ, Merkel PA. Assessment of disease activity and progression in Takayasu’s arteritis. Clin Exp Rheumatol. 2011;29(1 suppl 64):S86eS91. 12. Mason JC. Takayasu arteritis e advances in diagnosis and management. Nat Rev Rheumatol. 2010;6(7):406e415. 13. Hoffman GS, Ahmed AE. Surrogate markers of disease activity in patients with Takayasu arteritis. A preliminary report from The International Network for the Study of the Systemic Vasculitides (INSSYS). Int J Cardiol. 1998;66(suppl 1):S191eS194. 14. Numano F. Takayasu’s arteritis: clinical aspects. In: Hoffman GS, WCM, eds. Inflammatory Diseases of Blood Vessels. New York: Marcel Dekker; 2002:455e466. 15. Maksimowicz-McKinnon K, Clark TM, Hoffman GS. Limitations of therapy and a guarded prognosis in an american cohort of Takayasu arteritis patients. Arthritis Rheum. 2008;56(3):1000e1009. 16. Direskeneli H, Aydin SZ, Kermani TA, et al. Development of outcome measures for large-vessel vasculitis for use in clinical
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trials: opportunities, challenges, and research agenda. J Rheumatol. 2011;38(7):1471e1479. Sivakumar MR, Misra R, Bacon PA for the IRAVAS Group. Indian prospective of TA and development of disease extent index in Takayasu arteritis. Rheumatology (Oxford). 2005;44(suppl iii):6e7. Aydin SZ, Yilmaz N, Akar S, et al. Assessment of disease activity and progression in Takayasu’s arteritis with disease extent indexTakayasu. Rheumatology (Oxford). 2010;49(10):1889e1893. Goel R, Danda D, Mathew J, Edwin N. Mycophenolate mofetil in Takayasu’s arteritis. Clin Rheumatol. 2010 Mar;29(3): 329e332. Salvarani C, Magnani L, Catanoso M, et al. Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology (Oxford); 2011. Sivakumar MR. Outcome of vascular interventions in Takayasu arteritis using the Takayasu arteritis damage score. Arthritis Rheum. 2011;63(10):S588. Hata A, Noda M, Moriwaki R, Numano F. Angiographic findings of Takayasu arteritis: new classification. Int J Cardiol. 1996;54(suppl 1):S155eS163.
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23. Kissin EY, Merkel PA. Diagnostic imaging in Takayasu arteritis. Curr Opin Rheumatol. 2004;16(1):31e37. 24. Tso E, Flamm SD, White RD, Schvartzman PR, Mascha E, Hoffman GS. Takayasu arteritis: utility and limitations of magnetic resonance imaging in diagnosis and treatment. Arthritis Rheum. 2002;46(6):1634e1642. 25. Meller J, Strutz F, Siefker U, et al. Early diagnosis and followup of aortitis with [(18)F]FDG PET and MRI. Eur J Nucl Med Mol Imaging. 2003;30(5):730e736. 26. Pipitone N, Versari A, Salvarani C. Role of imaging studies in the diagnosis and follow-up of large-vessel vasculitis: an update. Rheumatology (Oxford). 2008;47(4):403e408. 27. Gupta R, Kavimandan A, Kumar R. Does PET-CT predict disease activity in Takayasu’s arteritis? Scand J Rheumatol. 2008;37(3):237e239. 28. Sivakumar S, Arjundas D, Sivakumar MR. Use of transcranial Doppler for the detection of severe carotid stenosis. Neurology. 2010;74(suppl 2):A228. 29. Sivakumar S, Sivakumar MR. Intimal medial thickness in Takayasu arteritis and change with treatment. Rheumatology. 2010;49(suppl 1):i123ei134.
Perspective
Vasculitis assessment and Takayasu aorto-arteritis Paul Bacona,*, Rajappa Sivakumarb, Debashish Dandac, Ramnath Misrad
ABSTRACT Assessment of disease activity using clinical instruments like Birmingham Vasculitis Activity Score and Vasculitis Damage index has been extensively used both in trial and clinic setting. It has revolutionised outcome assessment for small size vasculitis as evidenced from studies carried out by the European vasculitis group. There is a need for clinical assessment tools for large vessel disease like Takayasu arteritis, which is seen more frequently in India. An attempt has been made by the Indian Rheumatology Association Vasculitis core group to validate instruments, like Disease Extent Index for Takayasu Arteritis (DEI.Tak), Indian Takayasu Activity Score (ITAS) and Takayasu Arteritis Damage Scores. Both DEI.Tak and ITAS have received interests from international investigators. Widespread usage of these instruments will pave the way to controlled clinical trials for TA. Copyright © 2012, Indian Rheumatology Association. All rights reserved. Keywords: DEI.Tak, Indian Takayasu Activity Score, Takayasu Arteritis Damage Score
MEASUREMENT IN RHEUMATIC DISEASE The clinical outcome in diffuse connective tissue diseases has improved enormously over the past half-century. This progress has come despite a paucity of breakthroughs in understanding basic disease mechanisms.1 Improvement in diseases like Systemic Lupus Erythematosus (SLE) has come despite the absence of new therapies, in contrast to Rheumatoid Arthritis (RA) where the concept that Tumour Necrosis Factor (TNF) is the key inflammatory cytokine driving synovial inflammation has led to striking advances in therapy. Better management has come from improved definition of the aims of treatment. Development of detailed clinical measurement has produced quantitation of disease severity and encouraged a focus on the specific problems in individual cases. This in turn has directed attention at controlling specific aspects of disease instead of futile efforts to “cure” multi-system disease with single regimes. For example renal involvement in SLE may require active immuno-suppression plus blood pressure control and support for renal failure. a
In systemic vasculitis, this approach has improved the immediate prognosis but turned acute life-threatening disease into chronic relapsing syndromes typical of persistent rheumatic diseases. Detailed assessments have also been the basis for data-sharing collaborations which have provided an evidence-base for choosing more effective regimes in the short-term with diminished long-term toxicity compared to the previous “standard National Institute of Health (NIH) regime”. The series of trials in Small Vessel Vasculitis (SSV) conducted by the European Vasculitis Consortium, EUVAS, illustrate the advantages of quantitating clinical measurement. We will first review what should be measured and what has been learnt from this in SSV before discussing adaption of this schema to aorto-arteritis.
CLINICAL ASSESSMENT IN SSV e LESSONS LEARNT Standardised assessment has provided the basis for national/international networks that have been able to
Professor Emeritus, Department of Rheumatology, Medical School (East Wing), Birmingham University, Vincent Drive, Birmingham, B15 3QG, UK, bConsultant Neurology, Chennai, cProfessor and Head of Rheumatology and Clinical Immunology, Christian Medical College, Vellore, dProfessor and Head, Department of Clinical Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, India. * Corresponding author. email: [email protected] Received: 19.6.2012; Accepted: 4.7.2012; Available online: 10.7.2012 Copyright Ó 2012, Indian Rheumatology Association. All rights reserved. http://dx.doi.org/10.1016/j.injr.2012.07.001
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accumulate sufficient numbers of rare syndromes to set up major clinical trials in Small Vessel Vasculitis (SSV). These Randomised Controlled Trials (RCTs) have revolutionised the approach to therapy which now has a secure evidence-base for specified aspects of disease control. The result has been improved short-term survival rates and lower long-term toxicity. It is important to understand the basis for this so that the lessons learnt can be applied to TA. The essence of disease assessment is to quantitate disease severity. The extent of disease and whether this relates to current active inflammation or to established scars (fixed damage) are the factors that define severity from the physicians’ viewpoint e although we must remember that patients are more concerned about function and economic burden.2 It is important to resist the easy idea that “tests” (laboratory, imaging, etc) will provide the data needed when careful clinical study is what works best. Even disease-related auto-antibodies such as Anti Neutrophil Cytoplasmic Antibodies (ANCA) titres do not closely reflect clinical disease activity. Clinical assessment of chronic disease has many advantages since it is cheap and readily available. It is also directly related to the patient’s disease, unlike non-specific blood tests for inflammation. The acute phase response often fails to correlate well with other evidence of ongoing vasculitic inflammation and may reflect other factors such as infection. However to be of use for more than a single clinician, clinical assessment has to both be standardised and to provide a quantitative score for serial use. It can then be used to compare with new diagnostic tests that are developed as well as for quantifying response to therapy in formal trials or in routine clinical use. The most frequent methodologies used for vasculitis are the well-validated activity score Birmingham Vasculitis Assessment Score (BVAS)3 and the damage score, Vasculitis Damage Index, VDI.4 Assessment of disease activity is the first priority for clinicians treating new vasculitis. BVAS (Birmingham Vasculitis Activity Score) was developed to collect a comprehensive index of disease involvement across 10 organ-related systems. BVAS was used to study responses in both the EUVAS clinical trials and in standard practice by the French Vasculitis Collaboration. The quantitative measure of disease severity provided by a BVAS score at presentation offers a guide to long-term prognosis.5 High BVAS score patients have increased early mortality and a continued reduction in long-term survival. Cumulative development of scars from disease and therapy adds to this. Measurement of the Vasculitis Damage Index (VDI) shows that scars develop early and have a poor prognosis.6 Both the total VDI score and the number of organs involved contribute to fatality. Aggressive initial treatment is key to limiting inflammation rapidly and blocking scar
Bacon et al.
development.7 BVAS scores can direct choice of therapy, for example reserving more severe immuno-suppression such a Cyclophosphamide (Cyc) for more extensive disease.8,9 However EUVAS trials have also shown that early switch from Cyc to milder longer-term maintenance therapy does not increase relapse but does diminish cumulative drug toxicity.10
DEVELOPMENT OF ASSESSMENTS FOR TAKAYASU AORTO-ARTERITIS BVAS and VDI were both designed and validated for use in AA.SV (ANCA-associated systemic vasculitis and similar syndromes with largely small vessel involvement). The pattern of symptoms scored in these diseases is largely produced by widespread small arterial lesions affecting multiple organs. However, in TA restricted large vessel involvement leads to a markedly different pattern of clinical disease. TA typically presents with narrowing or occlusion of one or two large vessels, such as subclavian claudication or hypertension in young adults related to renal artery involvement. Thus TA requires dedicated disease-specific tools but the situation here is at least a decade behind SSV, with no validated assessments and no evidence-base for therapy. The Physicians Global Assessment (PGA) is still often the basis for treatment decisions in TA. It is based on clinical features, acute phase reactants, and image abnormalities.11 The acute phase response is neither sensitive nor specific enough to be helpful11e13 as ESR/CRP are not necessarily elevated, even in acute vascular occlusions.14,15 Standard vascular imaging shows damage as well as “activity” and may not reverse with medical therapy. Validated outcome assessments specifically relevant to Large Vessel Disease (LVV) are needed and the OMERACT group has noted the particular challenge of developing these for TA.16 The high incidence of TA in India provided a strong stimulus for correcting this deficiency. As the disease is seen frequently in Indian Rheumatology Clinics, the Vasculitis Study Group of the IRA (IRAVAS) set out to devise and validate assessments for TA, with the intention of producing both an activity score and a damage score that together would document the extent and severity of disease.
Disease extent Initial discussions amongst interested experts showed no clear consensus on the key items needed for an activity index. Thus the first move was agreeing an inclusive organ-based list, modified from the BVAS, of the main clinical features expected in TA. The resultant Disease Extent Index (DEI.Tak) was validated by using it to analyse
Vasculitis assessment and Takayasu aorto-arteritis
the actual disease pattern recorded in 145 cases from 2 main Indian centres.17 The cardiovascular system was most frequently scored and 88 cases had overt CVS disease at the time of assessment. 72 had renal involvement, which like the items scored in CVS is again a direct result of major artery disease. 68 had systemic symptoms such as fever, headaches, arthralgias and myalgias e but weight loss was very uncommon, in contrast to its frequency in SSV. Other systems, such as skin, mucous membranes, eyes and ENT, were rarely scored in TA despite making a major contribution to SSV scores. Thus the DEI.Tak truly reflects the restricted large vessel involvement of TA. The details of this CVS involvement are important. Pulse loss (seen in nearly half the CVS cases) and pulse inequality were the most common, followed by bruits and then claudication. Pulse loss was most frequently noted in the brachialis (1/ 3rd of cases), followed by radial, femoral and foot pulses and least commonly the carotids. However bruits were most frequently noted in the carotids. Thus regular use of DEI.Tak gives a picture of the common clinical pattern of the disease and is a useful teaching aide informing trainees what to look for. The 2-centre Indian data was presented at international meetings17 and the DEI.Tak has since been used to characterise Turkish cases.18 This index has real value as a data-base in individual clinics and if widely applied would provide low-level evidence to compare the arbitrary drug regimes adopted at present. It should also have value as an epidemiologic tool to compare disease expression between countries worldwide. However it is not an activity index, as the Turkish group also concluded.
Disease activity The subsequent development of ITAS (the Indian activity index for TA) was data-driven, taking the new disease items (occurring within the past 3 months) that were scored in DEI.Tak in the 2-centre series. It was validated using live patient assessments at a series of group work-shops in major centres. The clinical relevance of the draft format was tested by scoring the large series of patients from a major single clinic in Vellore. Analysis of data recorded in their series of 177 patients confirmed that 5 organ-based systems were rarely or never relevant in TA, so could be omitted from an activity index. Serial assessments allowed further selection of a set of items reflecting active disease, focussing on CVS items, with special emphasis on bruits, pulse loss, and claudication. All individual items scored in <5% were examined and the majority omitted. The resultant slimmeddown ITAS2010 (Indian Takayasu Activity Score) contains 43 items in 6 systems, is convenient for individual physicians to use in the clinic, and has been extensively validated by
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IRAVAS [Misra et al communicated]. The convergent validity of the ITAS was examined by comparing the new score to the BVAS index well-validated in small vessel disease. The scores showed a strong correlation when used by a single observer in the large clinic series, particularly in patients with recent onset and clinically active disease. In the group exercise, ITAS again showed a highly significant correlation with BVAS. The reproducibility in group usage scoring live patients was excellent, with inter-rater variability equivalent to BVAS. Both were clearly superior in this respect to Physician Global Opinion, (PGO), confirming that careful standardised assessment produces far more consistent agreement than doctors opinion. Weighting has been applied to 7 items related to the major vessel involvement that is clearly most relevant clinically. Importantly, serial assessments in the clinic showed that ITAS both reflects response to therapy and detects flares. It has been used in therapy trials both by the Vellore centre to assess patients on mycophenolate mofetil and by the Italian group to study the effect of IL-6 receptor blockade.19,20 In practice, the principle value may be to inform therapy decisions in individual cases. Consistent use to assess response to drugs should improve overall success rates in this condition where there is no established evidence-base for any therapies. ITAS is also a useful teaching aide for trainees unsure of the full spectrum of disease possible in this condition. A glossary has been produced to aid standardisation of usage across centres.
Damage/disease scars Damage is conceptually different from disease activity since it reflects scars that will not heal completely. It is clinically important to recognize that it needs to be scored separately as it will not respond to drugs that suppress immunemediated inflammation. Thus damage scores can only increase or stay static e they do not revert to zero as an activity index should with successful therapy. Accumulating damage adds to the disease burden experienced by patients and may contribute to poor prognosis. TADS (Takayasu Damage Score) has been derived from DEI.Tak to capture this aspect of TA. It contains 42 items in 7 systems, again with a strong focus on CVS items but also including drug-related problems. Disease-related damage resulting from arterial blockage is a common feature of TA that often requires vascular interventions. At onset, arterial blockage results from a combination of inflammation and scarring, so TADS only scores features present for at least three months. When used in another large cohort followed over 2 decades, TADS scores showed that the increase in damage/scars over time was related to disease duration and to features of poor outcome such as pulse
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loss.21 One third of cases underwent vascular interventions and over 90% of stents remained patent at 5 years. 18% of TA cases died over 2 decades and the TADS scores in fatal disease were higher than in non-fatal cases. These data show that recording a damage score can delineate features associated with clinically relevant outcomes, including pulse loss, long-term stent patency and mortality. The prognostic value of early increases in damage still needs to be fully tested. The four methodologies described provide a comprehensive clinical approach to documenting the diverse clinical disease that develops in aorto-arteritis. They represent major progress in quantitating disease severity which is particularly relevant given the absence of any diseasespecific biomarkers for TA and the poor correlation between activity and acute phase response well documented in TA. Imaging is the most commonly used investigational tool in TA, so it is relevant to consider the place of this beside clinical assessment. Its role in diagnosis is outside the scope of this review but a brief consideration of imaging in assessment of severity of disease activity and of damage is appropriate. Imaging is the basis of the anatomic classification of TA22 and that may correlate with the DEI.Tak score but this has not been tested yet.
Angiography The most widely used tool for diagnosis in TA is angiography (DSA), which remains the gold standard to delineate the site and extent of occlusive lesions. DSA images the vessel lumen and thus provides information on established or late lesions.23 It is essentially imaging scars, or the late results of vascular interventions, so looking for the correlation between angiograms and TADS scores would be sensible. Imaging will not tell you the age of the lesions but in a disease where events are not uncommonly sub-clinical, it may provide extra information.12 Thus the potential gain from incorporating a lesion score from imaging into the TADS needs to be explored.
MR imaging Significant alterations of blood flow can occur before the stenotic stage. Information on the state of the vessel wall is needed if inflammation is to be controlled before scarring occurs. Magnetic Resonance Imaging (MR) and Positron Emission (PET) scans can image the vessel wall and offer hope that questions about ongoing or grumbling activity can be resolved. The studies that have looked at this in TA have had largely positive messages but they remain research tools. There have been repeated reports of MR’s
Bacon et al.
ability to image vascular inflammation but serious studies have cast doubts on the reliability of the information provided. The major Cleveland clinic report on 77 studies in 24 patients showed that aortic wall oedema was demonstrated in 94% of lesions thought to be clinically active.24 This encouraging result has to be balanced against similar wall oedema found in three-quarters of equivocally active disease and half clinically inactive lesions. This is similar to the percentage of lesions with active histology found at vascular surgery e but the changes noted on MR showed little ability to predict subsequent sites of disease flare and showed no correlations with ESR or CRP.
PET scanning The use of PET to image early active disease was suggested by studies of problem PUO patients correctly labelled as aortitis.25 PET labelled the aortic wall as well three-quarters of major artery lesions detected on angiography, in contrast to MR studies which detected aortic wall changes but markedly fewer major artery lesions. Repeat imaging after clinically successful immuno-suppression found improvement in many e but not all e sites on PET scans but few on MR. Other centres have since noted “clear reduction” of pathologic uptake after therapy but not complete clearance, despite suppression of clinical signs, suggesting PET is detecting something different.26,12 An interesting feature in preclinical disease is the appearance of a thin streak of uptake apparently lining the entire aorta (plus some larger vessels). This is different to the focal lesions of stenosed vessels of established disease and its pathological significance is unclear. It may represent a precursor to typical focal TA lesions but does not correlate closely with clinical status.26 Studies on a wider spectrum of clinical disease reported positive PET scans in most of 12 clinically active cases e but also half clinically inactive cases. Finally some patients show areas of new activity despite overall improvement.27 Thus the initial reports that PET directly images the typical vessel wall inflammation seen in TA seem optimistic. PET detects labelled glucose uptake, an indicator of metabolic activity which is up-regulated in inflammation but also in other states such as cell activation and healing. The persistent uptake after therapy could be due to healing processes. The linear pattern of PUO cases might be attributable to endothelial activation occurring prior to (but possibly triggering) subsequent development of focal granulomatous lesions. Thus these important attempts to image vessel wall inflammation have intriguing positive messages but they remain research tools. They suggest the need for a more sophisticated concept of disease activity than the simple idea that TA is
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either “active” or “inactive” and offers the hope that questions about ongoing grumbling activity can be resolved. These are the same goals pursued by IRAVAS in the clinical scoring of disease extent. It will be important in future to correlate vessel wall imaging with clinical scores of activity and damage as well as with sites of occlusion. Since neurological manifestations are seen in 20e25% of patients with TA, attempts have been made to assess carotid and intracranial vessel imaging by Doppler and transcranial Doppler ultrasound. We described increased IMT thickness in TA, irrespective of the type of disease and reversal with use of corticosteroids, atorvastatin and mycophenolate mofetil over a 2-year period.28 Further vascular interventions were performed after documenting significant carotid stenosis by carotid Doppler.29 Intracranial stenosis has been demonstrated using transcranial Doppler.
USES OF ASSESSMENTS IN TA The worldwide challenge in treating TA is to provide an evidence-base for therapies. Standardised assessment is an essential part of clinical trial development but it is not only needed in that area. It adds strength to epidemiological studies and clinical practice, where it enables the “treat to target” approach. All physicians seeing aorto-arteritis need to quantify the effects of current recommended procedures in their cases as well as contributing cases to studies of the effect of new therapies on disease activity and damage. The work of IRAVAS has established a sound basis for setting up prospective randomised controlled trials and the large collections of cases in major Indian centres make this an ideal place to conduct them. Effective trial work will require collaborations between rheumatologists and other specialities seeing TA. A first joint meeting between rheumatologists and cardiologists has already been held by the IRA to introduce the new disease assessments. A widespread integration with interested groups across the continent would greatly facilitate the first planned RCT for TA and all physicians seeing any cases of TA are cordially invited to join the trial work.
CONFLICTS OF INTEREST All authors have none to declare.
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