2005-328.dec.omeract

Current Status of Outcome Measures in Vasculitis:Focus on Wegener’s Granulomatosis and MicroscopicPolyangiitis. Report from OMERACT 7 PETER A. MERKEL, PHILIP SEO, PETER ARIES, TUHINA NEOGI, ALEXANDRA VILLA-FORTE, MAARTEN BOERS, DAVID CUTHBERTSON, DAVID T. FELSON, BERNHARD HELLMICH, GARY S. HOFFMAN,DAVID R. JAYNE, CEES G.M. KALLENBERG, JEFFREY KRISCHER, ALFRED MAHR, ERIC L. MATTESON,ULRICH SPECKS, RAASHID LUQMANI, and JOHN H. STONE; for the Vasculitis Clinical Research Consortium ABSTRACT. The complexity of assessing disease activity, disease status, and damage in the vasculitides reflects
the multisystemic pathologic manifestations of these often chronic illnesses. Major progress hasbeen made in the past decade in the development of validated and widely accepted outcome meas-ures for use in clinical trials. Over time, these tools have been regularly revised, expanded, and sup-plemented with new measures of disease prognosis and damage. As a result clinical research in thisarea has become increasingly complex. This article critically reviews the current status of tools forassessing disease activity and damage in “ANCA-associated” vasculitides (Wegener’s granulomato-sis and microscopic polyangiitis), summarizes the current level of validation of each measure,addresses central problems and controversies to be considered during development of new vasculi-tis assessment tools, and proposes a series of research agendas for consideration by the vasculitisresearch community. (J Rheumatol 2005;32:2488–95) Key Indexing Terms:VASCULITIS OUTCOME MEASURESWEGENER’S GRANULOMATOSIS MICROSCOPIC POLYANGIITIS From the Boston University School of Medicine, Boston, MA; Johns Major progress has been made in the past decade in the Hopkins University, Baltimore, MD, USA; University Schleswig-Holstein, design and conduct of therapeutic clinical trials of vasculi- Lubeck, Germany; Cleveland Clinic, Cleveland, OH, USA; VU UniversityMedical Center, Amsterdam, The Netherlands; Moffitt Cancer Center, tis. Clinical research in vasculitis has evolved from single- Tampa, FL, USA; Addenbrookes Hospital, Cambridge, UK; University center, open-label case series to larger, randomized, multi- Hospital, Groningen, The Netherlands; Hôpital Cochin, Paris, France; center, controlled clinical trials. The formation of interna- Mayo Clinic College of Medicine, Rochester, MN, USA; and University ofEdinburgh, Edinburgh, UK. tional collaborative research groups has been a major factor P.A. Merkel, MD, MPH, Boston University School of Medicine; P. Seo, in the success of these trials. Validated outcome measures MD, Johns Hopkins University; P. Aries, MD, University Schleswig- for use in clinical trials have developed in parallel to this ini- Holstein; T. Neogi, MD, Boston University School of Medicine; A. Villa-Forte, MD, Cleveland Clinic; M. Boers, MD, PhD; D. Cuthbertson, MD, tiative. The initial set of outcome tools for measuring vas- VU University Medical Center; D.T. Felson, Boston University School of culitis disease activity and damage were widely accepted Medicine; B. Hellmich, MD, Johns Hopkins University; G.S. Hoffman, and utilized in trials. They have also been regularly revised, MD, Cleveland Clinic; D. Jayne, MD, Addenbrookes Hospital; J. Krischer, MD, Moffitt Cancer Center; A. Mahr, MD, Hôpital Cochin; expanded, and supplemented with new measures of disease E.L. Matteson, MD; U. Specks, MD, Mayo Clinic College of Medicine; prognosis. However, the introduction of these additional R. Luqmani, MD, Boston University School of Medicine; J.H. Stone, MD, outcome measures for vasculitis has made clinical vasculitis Johns Hopkins University; for the Vasculitis Clinical ResearchConsortium. Supported by The National Institutes of Health/National Institute of Multiple different outcome measures for vasculitis dis- Arthritis and Musculoskeletal and Skin Diseases and the National Center ease assessment are currently in use. While these measures for Research Resources/NIH. The Vasculitis Clinical Research Consortium share many similarities, they are sufficiently different as to is part of the NIH Rare Diseases Clinical Research Network(http://rarediseasesnetwork.org/vcrc). make comparison among trials and sharing of data problem- Drs. Merkel, Matteson, and Stone are supported by Mid-Career atic. Problems include whether a single disease activity and Development Awards in Clinical Investigation (NIH-NIAMS: K24 outcomes tool can be utilized for illnesses that are clinically AR02224, AR47578-01A1, and AR049185). distinct; there is also controversy about how to measure dis- Address reprint requests to Dr. P.A. Merkel, Vasculitis Center, E5, BostonUniversity School of Medicine, 715 Albany Street, Boston, MA 02118. ease activity and damage and define disease states and class- es. Moreover, with the increased size and greater sophistica- Personal non-commercial use only. The Journal of Rheumatology Copyright 2005. All rights reserved.
The Journal of Rheumatology 2005; 32:12 tion of treatment trials, the inherent deficiencies of each Physical examination findings include periorbital edema, injected right conjunctiva, right lacrimal gland enlargement, There is consensus in the vasculitis research community right nasal cavity dry crusts, and fresh submucosal blood.
that uniform, improved, and universally accepted instru- Diagnostic studies reveal hematocrit 31%, white blood cell ments for use in future primary systemic vasculitides trials count 7570/ml, creatinine 1.8 mg/dl (increased from 1.4 the would be highly desirable. Several members of the vasculi- previous month), and erythrocyte sedimentation rate 40 tis research community with experience in the development mm/hour. Urine from the ileal conduit contains abundant and use of disease assessment tools formed a special inter- debris and is positive for protein (1+), hemoglobin (1+), and est group in anticipation of OMERACT 7, with the goal of red blood cell casts; the casts are a new finding. A chest reviewing assessment instruments for disease activity and computerized tomographic scan reveals areas of scarring damage in vasculitis and revising them, or developing new from prior injury but is unchanged from previous study.
consensus tools as needed. This project is sponsored by therecently formed Vasculitis Clinical Research Consortium • What are the best approaches to evaluating this patient’s A first step for the VCRC-OMERACT initiative was to • How to quantify his disease activity now? revisit existing tools in order to identify advantages and • What was his disease state one month ago? weaknesses of the respective instruments. The group’s ini- tial focus is on “ANCA-associated” vasculitides of Wegener’s granulomatosis (WG) and microscopic polyangi- • How to quantify his level of disease-related damage now? itis (MPA). During OMERACT 7 a research agenda and pri-orities for future work in this area were developed. The cur- Introduction to Vasculitis Disease Assessment Tools
rent state of disease assessment in vasculitis and the In patients with primary systemic vasculitides, assessment research agenda were presented by members of the group to of response to therapy in clinical trials needs to include 3 other OMERACT 7 participants, and important feedback distinct categories that can be influenced by an experimen- was received from experts experienced in disease assess- tal treatment independently from each other: disease activi- ment who are not involved in vasculitis research.
ty, disease damage, and function. Disease activity is defined This article critically reviews the current status of tools as any clinical manifestation of the specific disease, such as for assessment of disease activity and damage and the cur- glomerulonephritis, purpura, or fevers; disease activity rent level of validation of each measure. In addition, central needs to be distinguished from clinical comorbidities and problems and controversies are addressed that need to be treatment-related complications. In contrast, disease damage considered during the development of a new disease assess- represents scars that resulted from previously active vas- culitis, or from therapy. It is important, but often difficult, todifferentiate disease activity from damage in vasculitis Illustrative Case
because both can be present simultaneously, even in the A case summary from real clinical practice is presented to same organ system. Finally, changes in physical function highlight the current state of, and challenges faced by, clin- and health-related quality of life may be a result of disease activity, disease damage, or comorbidities.
A 53-year-old man with a 10 year history of WG returns Due to the diversity of clinical manifestations present in for evaluation. His disease manifestations have included patients with vasculitis, response to treatment cannot be episcleritis, rhinitis, sinusitis, lung nodules and infiltrates, judged by observation of a single clinical or laboratory glomerulonephritis, and an upper eyelid mass. He was treat- measure or by functional assessment of a limited number of ed for a total of 36 months with cyclophosphamide, and organs. With the goal of obtaining a single quantitative extensively with glucorticoids. Current medications include measure of disease activity or damage in patients with vas- prednisone (20 mg/day) and azathioprine (150 mg/day).
culitis, a number of compound indices have been developed Two years ago he was diagnosed with transitional-cell blad- by different investigators1-7, which will be briefly reviewed.
der carcinoma requiring cystectomy and an ileal conduit.
In general, each of these instruments requires a comprehen- One prior relapse was associated with lower extremity deep- sive assessment of disease status in all organs and summary vein thrombosis and pulmonary embolus. He has bilateral scores arrived at after the weighting of single items.
cataracts. When last seen, one month ago, he was well andreported only chronic non-bloody nasal crusting and dis- Challenges and Controversies in Vasculitis Disease
charge. He called for the present appointment because of a Assessment
3 week history of arthralgias, left eyelid and periorbital The vasculitis research community faces several important region pain and swelling, lacrimal gland enlargement, challenges and controversies regarding the currently avail- bloody nasal discharge, and maxillary region discomfort.
Personal non-commercial use only. The Journal of Rheumatology Copyright 2005. All rights reserved.
Merkel, et al: Outcome measures in vasculitis Multiplicity of instruments. The existence of different vas- ease-specific module could be added that incorporates items culitis disease assessment tools has led to problems compar- specific for a given entity (e.g., nasal crusting in a WG-spe- ing data across clinical trials and between cohorts. Further, cific module, or eosinophilic pneumonia in a Churg-Strauss while each features unique advantages for use in certain sit- syndrome-specific module). This approach may lend itself uations (e.g., clinical trial, longitudinal observational study, well to MPA and WG, where there are both many overlap- clinical practice), no tool is ideal for general use.
ping and differing features8-10. Future work of this study Disease-specific versus generic vasculitis instruments. group will focus on whether the concept of a disease-specif- While some manifestations of primary systemic vasculitis ic and modular approach is feasible and advantageous.
are common to many different vasculitides (e.g., polyneu- Nomenclature and classification of vasculitides and assess- ropathy, purpura), other features are more or less specific for ment instruments. The ongoing debates regarding diagnostic certain entities within the broad spectrum of vasculitic dis- criteria, disease classification, and disease subclassification eases (e.g., pulmonary nodules in WG, aortitis in large ves- in clinical vasculitis are paralleled in the field of outcome sel vasculitis). Few manifestations are seen in all of the dis- measure development in vasculitis11-13. In particular, use of the terms ANCA-associated vasculitis (AAV) and ANCA- The simplicity of using a single tool in all vasculitides is positive vasculitis (APV) to represent WG, microscopic appealing. Alternatively, given the differences in disease polyangiitis, and sometimes, but not always, Churg-Strauss spectrum, treatment, and prognosis across the vasculitides, syndrome, are not uniformly applied or accepted. Marked disease-specific instruments may provide greater precision similarities in disease presentation, prognosis, and treatment and focus for use in clinical trials.
between WG and MPA make it attractive to link these 2 dis- While the single tool offers the advantage of systemati- eases for purposes of outcome assessment (they are increas- cally capturing all possible manifestations of vasculitis ingly studied in combination in clinical trials); however, independent of the specific disease under study, some com- such linkage remains controversial. Similarly, the treatment ponent items may never be used in clinical trials investigat- of Churg-Strauss syndrome differs enough from treatment ing one vasculitis subtype only (e.g., WG); moreover, a less of WG or MPA to exclude it from this initial series of proj- common, but important feature of that disease may not be ects. This issue of merging assessments of WG, MPA, and listed. Although more uncommon items may be scored Churg Strauss syndrome, however, may be remedied by a under a free-text category “other,” they may not be recog- modular approach to disease activity index design as dis- nized by less experienced investigators if not separately list- ed and may not contribute to an active vasculitis score when Multiple uses of disease assessment tools: complexity versus they should. Conversely, listing all potential items of disease feasibility. As they evolve, disease assessment tools in vas- activity for all diseases would generate an impossibly long culitis increasingly serve to quantify disease activity and determine disease stratification, trial randomization, prog- The issue of disease-specific versus pan-vasculitis dis- nostication, and other uses. Their multiple uses, described in ease tools also arises when studying inflammatory arthritis.
greater detail below, highlight the struggle between keeping While rheumatoid arthritis, psoriatic arthritis, and juvenile an instrument simple yet comprehensive enough to provide rheumatoid arthritis share many features, these diseases detailed information on these complex diseases.
have different enough features and prognosis to justify sep-arate disease assessment tools, which have evolved for use Differing disease-state definitions. Investigators have used different definitions of active disease, remission, and flare to The above arguments led to a revision of the original describe patients in clinical trials of vasculitis. These differ- Birmingham Vasculitis Activity Score (BVAS)1, a “generic” ing disease-state definitions have led to problems in com- vasculitis disease assessment tool, and creation of a specific paring efficacy of different therapeutic regimens, in apply- instrument for WG (BVAS/WG) for use in clinical trials ing results to clinical practice, and in developing outcomes involving patients with WG only2. However, not all research groups have adopted this new approach, resulting in further Inadequacies of current instruments regarding scalability, weighting, comprehensiveness. The systems for weighting Given the well recognized advantages and disadvantages items and overall scaling for the current vasculitis outcome of the generic versus the specific approach, a modular dis- instruments were arrived at mostly through expert opinion ease activity index in vasculitis may constitute a promising rather than longitudinal data reflecting prognosis or result- compromise. In such a system, a “base” module would ant disability. The weighting systems are clearly problemat- include manifestations common within this disease spec- ic. Currently, the weights neither address the many grada- trum (e.g., arthritis, neuropathy, purpura); weighting and tions of specific disease manifestations, nor clearly reflect scoring of these “general” items would be the same regard- the degree of either biological or functional impact on less of disease under study. To this “base” module, a dis- patients. There is also a need for more patient input into the Personal non-commercial use only. The Journal of Rheumatology Copyright 2005. All rights reserved.
The Journal of Rheumatology 2005; 32:12 process. Further, there are potential discrepancies between a Table 1. Desirable properties of a vasculitis disease activity tool.
patient’s disease state and the corresponding score. For 1. Ability to quantify disease activity on a continuous scale example, a patient with multiple “minor” disease items in 2. Ability to quantify change in disease activity over both long and short WG may have a higher score, even with weighting, versus a patient with one major item such as alveolar hemorrhage; 3. Ability to determine disease states by distinguishing among: yet the latter patient is universally thought to be in a more severe disease state. These problems exist for measures of both disease activity and disease damage.
4. Ability to discriminate clinically relevant disease subsets with unique Acceptance by regulatory agencies and the pharmaceutical industry. It is essential that outcome tools for vasculitis be 5. Ability to provide prognostic information in regard to both morbidity and accepted by government drug-approval agencies and by the 6. Feasibility for use in clinical trials pharmaceutical industry. Feedback from the US Food and 7. Feasibility for use in clinical practice Drug Administration, the European Medicines Evaluation 8. Simple, one-page format for use with paper-based or computer-based Agency, other similar bodies, and industry partners will be an important part of developing the next generation of out-come tools in vasculitis.
the methods of item weighting and overall scoring. All 3 Philosophy of Disease Activity Assessment in Vasculitis
activity measures catalog disease manifestations grouped by Measures of disease activity, extent, and severity are neces- organ systems, require investigators to determine whether a sary now that markedly improved prognosis of systemic feature is due to active vasculitis in the past 28 days, and vasculitis means death is no longer the common endpoint.
assign weights to different items that were empirically Physicians need to measure disease activity and morbidity determined by expert opinion. The issue of differentiating in vasculitis patients in order to make therapeutic decisions, persistent, or “grumbling,” vasculitis activity from more catalog disease manifestations, provide prognostic informa- clear-cut active disease is part of all 3 activity measures, but tion, and compare different groups of patients. Measures of this item remains problematic and there is no consensus as disease activity are also important in assessing response to to how to resolve the issue. Further, the instruments vary in treatment over time. This is particularly true for diseases in the range of gradation of disease severity recorded.
which remission may not be immediately achieved and in Additionally, all the measures have an open-text category which relapses are common14. Recurrent exacerbations of “other,” where items can be added for scoring individual vasculitis often lead to increased morbidity due to both the patients. “Other” categories allow flexibility and accommo- disease and its treatment. Therefore, the ability to define, date unusual disease features (e.g., granulomatous breast quantify, and differentiate disease activity from irreversible mass), but also lead to inclusion of unstandardized items.
damage is crucial to guide treatment and minimize treatment All 3 tools include glossaries with item definitions; users are required to undergo training to learn the proper scoring Several indices have been developed to accurately meas- ure disease activity in systemic vasculitis, for application in The Disease Extent Index (DEI) provides information clinical trials and in clinical practice1-6. Some indices are regarding the number of organ systems with active vasculi- designed to be comprehensive and can be applied to many tis (i.e., disease extent)4,15. Thus, the DEI has been used in forms of vasculitis (e.g., Birmingham Vasculitis Activity clinical trials as an adjunct to the BVAS to provide informa- Score)1, while others are disease-specific (e.g., the BVAS tion not contained in the BVAS score, specifically whether a certain BVAS score is due to activity in one major (low DEI) Desirable properties of a vasculitis disease activity tool The Five Factor Score (FFS) was designed as a prognos- tic tool for vasculitis assessment and not for serial measures Summary of Vasculitis Disease Assessment Tools
of disease activity7. The instrument is simple to use and has The most commonly used indices in clinical practice and been validated in several studies. The included items are all research settings are outlined in Table 2; copies of the instru- disease activity tools and their prognostic information can, ments and instructions for use can be found at the VCRC therefore, be derived from the information obtained with the website (http://rarediseasesnetwork.org/vcrc). All these activity measures at any chosen “baseline.” tools share many features and serve to catalog manifesta-tions of systemic vasculitis. BVAS/WG and BVAS 2003 are Vasculitis Disease Activity Measures: VCRC-
variations on the same theme, each having evolved from the OMERACT Research Agenda
original BVAS, but differ mainly in disease specificity ver- No current vasculitis disease measure meets all the desirable sus generalizability, attention to persistent disease, and in properties outlined in Table 1. Our overall goal is to devel- Personal non-commercial use only. The Journal of Rheumatology Copyright 2005. All rights reserved.
Merkel, et al: Outcome measures in vasculitis Table 2. Vasculitis disease assessment tools.
1. Incorporates changesin light of BVAS andBVAS/WG 1. Similar approach toBVAS variants but lessdetailed2. May be more valuable as prognosticthan assessment tool 1. Only damage indexin use2. No casual attribution3. No scaling * Per OMERACT filter of truth, discrimination, feasibility23; NA: not applicable; BVAS: Birmingham Vasculitis Activity Scale; BVAS/WG: BVAS forWegener’s Granulomatosus; DEI: Disease Extent Index; FFS: Five Factor Score; VDI: Vasculitis Damage Index.
op a single, consensus-approved, disease activity measure Assessment of Illustrative Case: Disease Activity
specific for WG and MPA (ANCA-associated vasculitis) for Cataloging the above described patient’s disease activity use in clinical trials that includes all those properties. Our can be done by noting arthralgias, periorbital and objective is to improve upon the existing tools by extracting lacrimal gland swelling, rhinitis, sinusitis, and nephritis.
the most effective components or modifying existing tools Some of the current tools directly collect most of these to develop a more accurate vasculitis disease activity index.
items, but no tool captures all the items well. More chal- Although some expert opinion will drive the process, data- lenging is how to quantify his active disease burden to driven approaches will be used whenever possible. Sources allow assessment of treatment efficacy and prediction of of data appropriate for activity tool development include outcome. Further, assessment using each of the current various clinical trial and longitudinal cohort databases avail- instruments would identify subtle but distinct differences able to the investigators, and prospectively collected data from both virtual patient evaluation exercises and clinicalpractice information. Validation of the newly created con- Definitions of Disease Status and Disease Classification
sensus instrument(s) and direct comparisons to current tools in Vasculitis
will be performed at multiple international centers.
Establishing well founded definitions of disease status is a A better understanding of the underlying pathogenesis of cornerstone for accurately describing populations and out- these diseases may lead to a markedly different approach to comes for all types of clinical cohorts and therapeutic trials disease assessment. However, at present we are committed in vasculitis. Further, such definitions may serve as refer- to improving existing tools and winning widespread accept- ence points to validate disease activity tools. Treatment may ance of a single, data-derived, standard disease assessment lead to patients with vasculitis achieving a state of clinical remission that may sometimes last even for long periods Personal non-commercial use only. The Journal of Rheumatology Copyright 2005. All rights reserved.
The Journal of Rheumatology 2005; 32:12 after cessation of therapy. Nevertheless, disease relapse is defined in terms of glucocorticoid and other treatments.
common and can range from mild, perhaps necessitating Further, difficult issues need to be addressed regarding the only a small increase or additional dose of glucocorticoids, concept of persistent disease. Finally, time elements for the to a severe flare involving vital organs and causing life- disease states need to be clearly defined.
threatening complications, requiring institutions of or esca- These definitions will be derived both by consensus lation of high-dose glucocorticoids and cytotoxic therapy.
opinion and by reference to available datasets from US and Thus, any definition of disease state (a categorical measure European clinical trials. The utility and validity of disease of disease activity) and disease class (a categorical rating of states will be determined through analysis of clinical trial disease that takes prognosis and response to treatment into data and performance of validation exercises with multiple consideration) must, at time of assessment, take into consid- international investigators in actual practice.
eration: level of disease activity, current treatment, past dis- Similar approaches will be used in drafting consensus ease manifestations, and transitions from one disease state to definitions and validating final versions of disease classifi- another. Finally, these definitions should both correlate with cations for WG and MPA. Further, any resulting consensus clinical practice and be useful for clinical trial outcome definitions of disease states and strata for WG and MPA assessment and subject stratification.
must be fully compatible with the new disease activity and Significant differences in defining disease status for damage assessment tools being developed.
patients with WG and MPA exist among investigators, lead-ing to problems when comparing study results. For example, Assessment of Illustrative Case: Disease State and
the definition of “remission” in a recent European trial Classification
allowed for use of low-dose glucocorticoids, while the defi- What was this patient’s disease state one month ago? nition in a recent US trial reserved the term mostly for Could he be considered in remission although still taking patients completely off glucocorticoids16,17. Multiple defini- tions exist for complete or partial remission and persistent, What is his current disease state? High disease or low active, limited, or severe disease states18-20, yet these terms do not cover all disease states patients present during a trial.
What will it take to deem him in remission? Further, the definitions are not all precise and were not What effect do chronic nasal and sinus problems have on arrived at by data-driven processes.
Classification (stratification) of patients by disease sever- What is his disease class? Limited or severe? Do we ity has important implications for prognosis and therapeutic determine classification based on past or current mani- decision-making. Thus, it is critical to use such definitions when describing patient populations and designing clinicaltrials. Disease classification in WG and MPA is hampered Assessment of Damage in Vasculitis: Introduction
by multiple systems of nomenclature, each derived by Clinical trials frequently focus on the concept of disease expert opinion and not more comprehensive data validation.
activity. However, for some patients, especially after the ini- Early definitions of limited WG do not correlate with later tial flare has been treated, the most troublesome issue may ones. The EUVAS group defines 5 disease strata in vasculi- be disease damage. Although the concept of damage seems tis: localized, early systemic, generalized, severe renal, and intuitive, it must be strictly defined to ensure reproducibili- refractory19, while the WGET (US) group defined 2 states: ty among clinicians and between studies. It is essential to dif- ferentiate damage from active disease, although this can bedifficult. Additionally, attribution of damage to vasculitis, Vasculitis Disease States and Classes: VCRC-OMER-
treatment, or other medical problems can also be challenging.
ACT Research Agenda
The Vasculitis Damage Index (VDI) was introduced in As outlined above, there is currently no consensus on how 1997 as a generic measure of vasculitis damage and is the disease status should be defined for vasculitis, or which only tool for damage assessment used on a regular basis5.
terms should be used, particularly for WG and MPA. The The VDI comprises 64 items of damage, grouped into 11 VCRC-OMERACT group had extensive discussions about organ-based systems. Damage is defined in the VDI as irre- disease status and classification and have agreed to a com- versible pathology lasting longer than 3 months, a time peri- prehensive research agenda that seeks to generate interna- od chosen to help ensure that reversible problems were not tional consensus and to achieve data-driven improvements Application of the VDI has yielded several important les- We propose to first derive operational definitions of 3 sons: (1) Accumulation of damage appears to be bimodal, disease states: high disease activity, low disease activity, and with an earlier phase due to the vasculitis itself, and a later remission. The 3 states may be qualified by the 2 conditions phase likely due to therapy21; (2) early damage is predictive “on treatment” or “off treatment,” which must be clearly of mortality21; (3) fatal vasculitis is characterized by higher Personal non-commercial use only. The Journal of Rheumatology Copyright 2005. All rights reserved.
Merkel, et al: Outcome measures in vasculitis total VDI scores affecting a greater number of systems than the context of a multicenter clinical trial as well as interna- tional practice sites. The new tool incorporates some of the A modified version of the VDI, incorporating slightly concepts in the VDI, but will also address each of the chal- different time periods and dropping a few items, was used in lenges raised above. Validation of any new instrument will a recent multicenter trial17, thus adding to the variation in include comparison with the VDI and use of longitudinal data.
vasculitis disease assessment in the literature.
Assessment of Illustrative Case: Disease Damage
Challenges and Controversies in Vasculitis Damage
This patient has suffered considerable damage as a result Assessment
of his WG and the treatments he has received. Which of The purpose of a damage index for vasculitis is 3-fold: (1) to his many problems should be considered damage? What serve as an outcome for clinical trials; (2) to record the natu- relative weights should be given to his upper airway ral history of treated disease; and (3) to better define the dif- problems versus his ileal conduit versus his cataracts? ference between activity and damage. Any reexamination of What if his cataracts are corrected by surgery? Is it use- the measurement of damage in vasculitis must address how ful to differentiate the damage from WG (e.g., sinus) we may better accomplish these goals. Further, the definition from that from treatment (e.g., bladder carcinoma)? of damage used by the VDI5, while ostensibly straightfor-ward, makes several assumptions, each of which affects the tool’s utility and several of which are controversial.
The complexity of assessing disease activity, disease status, Irreversibility. Items of damage in the VDI are, by defini- and damage in the vasculitides reflects the multisystemic tion, irreversible; yet some features of disease, such as pathologic manifestations of these often chronic illnesses, peripheral neuropathy, reverse although it may take months and many groups of investigators have been confronted with this challenge. The VCRC-OMERACT group is optimisticthat by combining our collective expertise, resources, data, Time element. Three months is the period of time an item and experience, we will help advance the science of disease must be present to be considered damage; this was some- assessment in vasculitis and create widely accepted and uti- what arbitrary and should be reassessed in a data-driven lized outcome measures for clinical investigation into these Attribution. The VDI does not require any assessment ofdamage etiology. The VCRC-OMERACT group wishes to REFERENCES
investigate the usefulness and feasibility of attributing dam- 1. Luqmani RA, Bacon PA, Moots RJ, et al. Birmingham Vasculitis age to vasculitis, treatment, or other medical comorbidities.
Activity Score (BVAS) in systemic necrotizing vasculitis. Q J Med Weighting and grading. Each item of damage in the VDI is 2. Stone JH, Hoffman GS, Merkel PA, et al. A disease-specific activity given equal weight (one point), yet that clearly does not index for Wegener’s granulomatosis: modification of the reflect the relative severity of damage incurred. For example, Birmingham Vasculitis Activity Score. International Network for oxygen-dependent pulmonary disease or blindness must be the Study of the Systemic Vasculitides (INSSYS). Arthritis Rheum weighed differently than a healed pulmonary nodule or par- tial quadrant visual loss. Finer gradations of damage may 3. Whiting-O’Keefe QE, Stone JH, Hellmann DB. Validity of a vasculitis activity index for systemic necrotizing vasculitis. Arthritis also be needed to, for example, differentiate mild renal insuf- ficiency from endstage renal disease necessitating dialysis.
4. de Groot K, Gross WL, Herlyn K, Reinhold-Keller E. Development Patient-derived assessment. It may be necessary to take into and validation of a disease extent index for Wegener’s granulomatosis. Clin Nephrol 2001;55:31-8.
greater consideration patients’ self-assessment of the conse- 5. Exley AR, Bacon PA, Luqmani RA, et al. Development and initial quence of damage, either by incorporating patient self- validation of the Vasculitis Damage Index for the standardized assessments and/or including patients in the drafting of new clinical assessment of damage in the systemic vasculitides. Arthritis 6. Kallenberg CG, Tervaert JW, Stegeman CA. Criteria for disease Generic versus disease specificity. The VDI aims to meas- activity in Wegener’s granulomatosis: a requirement for ure damage in all forms of vasculitis. However, regarding longitudinal clinical studies. APMIS Suppl 1990;19:37-9.
disease activity, there are advantages to developing specific 7. Guillevin L, Lhote F, Gayraud M, et al. Prognostic factors in tools for assessing damage in the individual vasculitides.
polyarteritis nodosa and Churg-Strauss syndrome. A prospectivestudy in 342 patients. Medicine Baltimore 1996;75:17-28.
8. Savage CO. Microscopic polyarteritis: definition and relation to Vasculitis Damage Assessment: VCRC-OMERACT
Wegener’s granulomatosis. APMIS Suppl 1989;6:8-9.
Research Agenda
9. Nachman PH, Hogan SL, Jennette JC, Falk RJ. Treatment response The VCRC-OMERACT group is pursuing the development and relapse in antineutrophil cytoplasmic autoantibody-associated of a new damage assessment tool specific for WG and MPA.
microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol1996;7:33-9.
This process will include comprehensive data collection in 10. Hoffman GS, Specks U. Antineutrophil cytoplasmic antibodies.
Personal non-commercial use only. The Journal of Rheumatology Copyright 2005. All rights reserved.
The Journal of Rheumatology 2005; 32:12 17. WGET Research Group. Design of the Wegener’s granulomatosis 11. Hunder GG, Arend WP, Bloch DA, et al. The American College of etanercept trial (WGET). Control Clin Trials 2002;23:450-68.
Rheumatology 1990 criteria for the classification of vasculitis.
18. Carrington CB, Liebow A. Limited forms of angiitis and Introduction. Arthritis Rheum 1990;33:1065-7.
granulomatosis of Wegener’s type. Am J Med 1966;41:497-527.
12. Fries JF, Hunder GG, Bloch DA, et al. The American College of 19. Jayne D. Update on the European Vasculitis Study Group trials.
Rheumatology 1990 criteria for the classification of vasculitis.
20. WGET Research Group. Limited versus severe Wegener’s 13. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic granulomatosis: baseline data on patients in the Wegener’s vasculitis, proposal of an international conference. Arthritis Rheum granulomatosis etanercept trial. Arthritis Rheum 2003;48:2299-309.
21. Exley AR, Carruthers DM, Luqmani RA, et al. Damage occurs 14. Langford CA, Talar-Williams C, Barron KS, Sneller MC. Use of a early in systemic vasculitis and is an index of outcome. Q J Med cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener’s granulomatosis: extended follow-up 22. Exley AR, Bacon PA, Luqmani RA, Kitas GD, Carruthers DM, and rate of relapse. Am J Med 2003;114:463-9.
Moots R. Examination of disease severity in systemic vasculitis 15. de Groot K, Schmidt DK, Arlt AC, Gross WL, Reinhold-Keller E.
from the novel perspective of damage using the vasculitis damage Standardized neurologic evaluations of 128 patients with Wegener index. Br J Rheumatol 1998;37:57-63.
granulomatosis. Arch Neurol 2001;58:1215-21.
23. Boers M, Brooks P, Strand CV, Tugwell P. The OMERACT filter 16. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of for Outcome Measures in Rheumatology. J Rheumatol maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349:36-44.
Articles presented at OMERACT 7 Conference Special Interest Groups
• Measurement of Erosion Size/JSN• Magnetic Resonance Imaging Workshops
• Psycoeducational Self-Management Interventions • Patient Perspectives in Outcome Measurement • Reconciling Subject Differences in RCT • Outcome Measures in Psoriatic Arthritis • Outcome Measures in Fibromyalgia Syndrome Part 1 appeared in the October issue and Part 2 in the November issue of The Journal. Personal non-commercial use only. The Journal of Rheumatology Copyright 2005. All rights reserved.
Merkel, et al: Outcome measures in vasculitis

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