NIH Public Access Author Manuscript Ann Rheum Dis. Author manuscript; available in PMC 2011 July 19.

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1 NIH Public Access Author Manuscript Published in final edited form as: Ann Rheum Dis January ; 68(1): doi: /ard Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis PA Merkel 1, DD Cuthbertson 2, B Hellmich 3, GS Hoffman 4, DRW Jayne 5, CGM Kallenberg 6, JP Krischer 2, R Luqmani 7, AD Mahr 8, EL Matteson 9, U Specks 9, and JH Stone 10 for the Vasculitis Clinical Research Consortium 1 Boston University School of Medicine, Boston, Massachussets, USA 2 University of South Florida, Tampa, Florida, USA 3 Kreiskrankenhaus Plochingen, Plochingen, Germany 4 Cleveland Clinic, Cleveland, Ohio, USA 5 Addenbrookes Hospital, Cambridge, UK 6 University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 7 University of Oxford, Oxford, UK 8 Hospital Cochin, Paris, France 9 Mayo Clinic, Rochester, Minnesota, USA 10 Massachusetts General Hospital, Boston, Massachussets, USA Abstract Aim Currently, several different instruments are used to measure disease activity and extent in clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading to division among investigative groups and difficulty comparing study results. An exercise comparing six different vasculitis instruments was performed. Methods A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in the literature of Wegener granulomatosis or microscopic polyangiitis using 6 disease assessment tools: the Birmingham Vasculitis Activity Score (BVAS), The BVAS for Wegener granulomatosis (BVAS/WG), BVAS 2003, a Physician Global Assessment (PGA), the Disease Extent Index (DEI) and the Five Factor Score (FFS). Five cases were rescored by all raters. Results Reliability of the measures was extremely high (intraclass correlations for the six measures all=0.98). Within each instrument, there were no significant differences or outliers among the scores from the 10 investigators. Test/retest reliability was high for each measure: range=0.77 to The scores of the five acute activity measures correlated extremely well with one another. Conclusions Currently available tools for measuring disease extent and activity in ANCAassociated vasculitis are highly correlated and reliable. These results provide investigators with confidence to compare different clinical trial data and helps form common ground as international research groups develop new, improved and universally accepted vasculitis disease assessment instruments. Wegener granulomatosis (WG) and microscopic polyangiitis (MPA) are forms of small medium vessel vasculitis that are commonly associated with positive tests for anti-neutrophil cytoplasmic autoantibodies (ANCA) and both diseases have overlapping clinical and pathological manifestations. 12 These diseases are complex, multisystem processes that usually threaten vital organs and are associated with substantial morbidity and increased mortality. 3 The similarities of these two diseases regarding clinical presentation and Correspondence to: P A Merkel, Vasculitis Center, E5, Boston University School of Medicine, 72 East Concord Street, Boston, Massachussets, 02118, USA; pmerkel@bu.edu. Competing interests: None declared.

2 Merkel et al. Page 2 METHODS Study overview Participants Cases Assessment tools treatment regimens has led to their being commonly studied together in clinical therapeutic trials and routinely being classified as ANCA-associated vasculitides (AAV), despite the lack of perfect accuracy of this label. Assessment of disease activity in AAV is a significant challenge. There are currently several different instruments used to measure disease activity and extent in clinical trials of AAV. 4 Some measures aim to quantify disease activity, others aim to predict long-term outcome and some aim to do both. Most of these measures are derived from the original Birmingham Vasculitis Activity Score (BVAS) 56 and attempt to catalogue organ system involvement in similar fashions. Although similar in many ways, the three BVAS tools differ in several important respects, including item selection, method of attribution, weighting and application, 4 making comparison of cohorts and data difficult, leading to divisions among investigative groups, and resulting in difficulty comparing study results We performed an exercise comparing six different instruments in terms of reliability, correlation of disease activity scores, ease of use, and other features. This study is part of an effort to develop a new international consensus and data-driven vasculitis disease assessment tools. Multiple investigators scored the same set of 20 case summaries in the literature using 6 different vasculitis disease assessment instruments; 5 cases were scored twice by each rater. Results were compared across instruments and among investigators. The study was conducted by the Vasculitis Clinical Research Consortium (VCRC). The study personnel include 10 experienced vasculitis investigators from 4 countries in the EU and the USA (5 countries total) and the group included specialists from internal medicine, rheumatology, nephrology and pulmonology. A total of 20 case summaries were written in a standardised fashion by 4 different investigators based on actual patients with WG or MPA evaluated in their respective internal medicine, rheumatology, nephrology and pulmonology clinics. Six different disease assessment tools were completed by each investigator for each case. The activity measures used were: The BVAS. 5 The weighted total score was used for analysis. The BVAS for Wegener granulomatosis (BVAS/WG). 6 The weighted total score was used for analysis. The BVAS The weighted total score was used for analysis. The Physician Global Assessment (PGA) that is included in BVAS/WG. 6 This PGA is a visual analogue scale (VAS). The Disease Extent Index (DEI). 11 The total score was used for analysis. The disease prognosis tool used was the Five Factor Score (FFS), 12 (modified to allow for scoring a patient whose disease is already established). The total FFS score was used for analysis.

3 Merkel et al. Page 3 Data collection Data analysis RESULTS For each instrument all investigators reviewed a manual of operations and an item glossary. Each investigator completed a training exercise that included scoring three cases with all six instruments and reviewed annotated scoring explanations. Copies of all material are available on the VCRC website ( Each investigator scored all 20 cases with all instruments. The case order was randomised for each investigator. Order of instruments scored was the same for all investigators. Each investigator rescored five of the cases using all instruments 1 2 weeks after the initial exercise without reference to prior scoring. Inter-rater and intrarater reliabilities were measured using intraclass correlations (ICC) fixed between observer pairs. General linear models were used to test for differences between reviewers. Correlations were measured using Pearson method. All analyses were based on a two-sided significance level of 0.5. Data analysis was conducted using the SAS system(cary, North Carolina, USA). Reliability of vasculitis disease assessment instruments Inter-rater reliability of the measures was extremely high for all six measures (ICC=0.98; table 1). Within each instrument, there were no significant differences or outliers among the scores from the 10 investigators. Intrarater (test/retest) reliability was also high for each of the measures, with ICCs ranging from (table 1). Correlations among vasculitis disease assessment instruments Table 2 and fig 1 list and depict the correlations among the various disease assessment instruments. The scores of the five acute activity measures (BVAS, BVAS/WG, PGA, BVAS 2003, DEI) were highly correlated with one another. As expected, the correlations between FFS (prognostic score) and other measures were poor. Operational characteristics of the disease activity measures DISCUSSION Following the data collection phase of the exercise, investigators held scheduled freeform discussions regarding the various instruments studied. All investigators agreed that each of the tools were easy to learn and use. Assessing disease activity in vasculitis involves several major challenges including recognising that vasculitis: (a) affects multiple organ systems; (b) produces manifestations ranging from fulminant and acute disease to chronic, smouldering problems; and (c) results in tissue damage leading to chronic signs and symptoms of disease similar to, but not caused by, active disease. Furthermore, the lack of reliable biomarkers means clinician assessments remain the mainstay of activity measurement. The introduction of validated measures of disease burden in vasculitis has been instrumental in conducting clinical trials of promising new therapies, particularly for WG and MPA. 710 However, the existence of multiple instruments to measure disease activity in clinical trials of WG and MPA is divisive for the

4 Merkel et al. Page 4 vasculitis research community, is a source of confusion for the wider medical community, and complicates the comparison of results from trials using different disease measures. 4 Acknowledgments This study, comparing six different vasculitis disease assessment instruments, demonstrates that the currently available tools for measuring disease extent and activity in AAV are highly reliable and correlated. These results, therefore, give investigators more confidence that some comparisons across trials are possible. This study also demonstrates that differences among the BVAS versions may not be as great as previously perceived. Although the BVAS/WG was designed to be more disease specific, 6 it correlated highly with BVAS and BVAS 2003, at least in the one-time measures of disease activity included in this exercise. This study has several notable strengths. The investigators were highly experienced in caring for patients with vasculitis as well as participating in clinical research in these diseases. Additionally, the investigator group included representatives from multiple medical specialties and several countries. While investigators were each familiar with at least one of the instruments under study, no investigator had used all of the tools and this enhanced the study of reliability of new measures. The 20 cases used in this study were chosen to represent a wide spectrum of clinical manifestations and disease activity states. This study has some limitations to consider. First, the exercise used paper-based cases; however, the logistics and expense of having 10 investigators question and examine the same 20 patients as well as review chart material are formidable. Second, 20 cases may not represent the full spectrum of these diseases and can not include all of the manifestations an investigator might see within the context of a clinical trial. The main aim of this study, however, was to compare the instruments against one another and not to revalidate their utility in WG and MPA. The results of this study apply only to AAV and to investigators trained in the use of these instruments. The study did not attempt to rank the utility of these different measures. The results do support the idea that these measures, despite the stated goals associated with their creation, are perhaps less different than anticipated. The strong correlations between different activity measures also illustrates that even if the use of a particular instrument is not intuitive, the careful training of investigators in the use of the instrument prior to its application may result in excellent reliability. The data and insight gained from this exercise provides clinical investigators studying vasculitis with confidence to easily compare different clinical trial data in WG/MPA. This study also helps form common ground as international research groups go forward with developing new, improved and universally accepted vasculitis disease assessment instruments. Funding: Grants were received from the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (UO1 AR51874) and the National Center for Research Resources/NIH: U54 RR The Vasculitis Clinical Research Consortium is part of the NIH Rare Diseases Clinical Research Network ( PAM, ELM and JHS were supported by Mid-Career Development Awards in Clinical Investigation (NIH-NIAMS: K24 AR02224, AR and AR049185). None of the funding sources for this study had any role in any aspect of conducting this research, drafting the manuscript, or the decision to publish the data.

5 Merkel et al. Page 5 REFERENCES 1. Hoffman, GS.; Gross, WL. Wegener s granulomatosis: clinical aspects. In: Hoffman, GS.; Weyand, CM., editors. Inflammatory diseases of blood vessels. New York: Marcel Dekker; p Bacon, PA.; Adu, D. Microscopic polyangiitis: clinical aspects. In: Hoffman, GS.; Weyand, CM., editors. Inflammatory diseases of blood vessels. New York: Marcel Dekker; p Seo P, Min N, Holbrook JT, Hoffman GS, Merkel PA, Spiera R, et al. Damage from Wegener s granulomatosis and its treatment: prospective data from the Wegener s Granulomatosis Etanercept Trial (WGET). Arthritis Rheum. 2005; 52: [PubMed: ] 4. Merkel PA, Seo P, Aries P, Neogi T, Villa-Forte A, Boers M, et al. Current status of outcome measures in vasculitis: focus on Wegener s granulomatosis and microscopic polyangiitis. Report from OMERACT 7. J Rheumatol. 2005; 32: [PubMed: ] 5. Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, et al. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994; 87: [PubMed: ] 6. Stone JH, Hoffman GS, Merkel PA, Min YI, 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: [PubMed: ] 7. Jayne D, Rasmussen N, Andrassy K, Bacon P, Cohen Tervaert JW, Dadoniene J, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003; 349: [PubMed: ] 8. Guillevin L, Cohen P, Mahr A, Arene JP, Mouthon L, Puechal X, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis with poor prognosis factors: a prospective trial comparing glucocorticoids and six or twelve cyclophosphamide pulses in sixty-five patients. Arthritis Rheum. 2003; 49: [PubMed: ] 9. Guillevin L, Cordier JF, Lhote F, Cohen P, Jarrousse B, Royer I, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener s granulomatosis. Arthritis Rheum. 1997; 40: [PubMed: ] 10. WGET Research Group. Etanercept plus standard therapy for Wegener s granulomatosis. N Engl J Med. 2005; 352: [PubMed: ] 11. 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: [PubMed: ] 12. Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortholary O, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore). 1996; 75: [PubMed: ]

6 Merkel et al. Page 6 Figure 1. Correlations among the various disease assessment instruments.

7 Merkel et al. Page 7 Table 1 Inter-rater and intrarater intraclass correlations among vasculitis disease assessment indices Disease assessment tool Inter-rater ICC (95% CI) p Value for differences among reviewers Intrarater ICC (95% CI) BVAS 0.98 (0.97 to 0.99) (0.87 to 0.99) BVAS/WG 0.98 (0.96 to 0.99) (0.34 to 0.97) BVAS/ (0.97 to 0.99) (0.43 to 0.98) PGA 0.98 (0.96 to 0.99) (0.38 to 0.97) FFS 0.98 (0.96 to 0.99) (0.39 to 0.97) DEI 0.98 (0.97 to 0.99) (0.59 to 0.98) p Value for differences within reviewers BVAS, Birmingham Vasculitis Activity Score; BVAS/WG, BVAS for Wegener Granulomatosis; DEI, Disease Extent Index; FFS, Five Factor Score; ICC, intraclass correlation; PGA, Physician Global Assessment.

8 Merkel et al. Page 8 Table 2 Pearson correlation coefficients among vasculitis disease assessment indices DEI FFS BVAS/2003 PGA BVAS/WG BVAS r=0.80 r=0.56 r=0.95 r=0.87 r=0.86 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 BVAS/WG r=0.85 r=0.39 r=0.88 r=0.80 p<0.001 p<0.001 p<0.001 p<0.001 PGA r=0.74 r=0.49 r=0.84 p<0.001 p<0.001 p<0.001 BVAS/2003 r=0.85 r=0.49 p<0.001 p<0.001 FFS r=0.33 p<0.001 BVAS, Birmingham Vasculitis Activity Score; BVAS/WG, BVAS for Wegener Granulomatosis; DEI, Disease Extent Index; FFS, Five Factor Score; PGA, Physician Global Assessment.