Outcome Measures & Classification Criteria
Successes of clinical trials in vasculitis were greatly advanced by projects focused on development, validation and acceptance by the international research community of standardized outcome measures. The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group has helped advance much of this work (see Table 2), including in ANCA-associated vasculitis, large-vessel vasculitis and Behçet’s disease. OMERACT is an international collaboration of investigators, clinicians, biopharmaceutical industry professionals and patient partners involved in outcome measures in rheumatology.
Table 2: OMERACT Outcome Measures in Vasculitis Projects
| PROJECTS | CURRENT STATUS | References |
|---|---|---|
| ANCA-ASSOCIATED VASCULITIS | ||
| Core set of outcome measures for use in trials | • Core set of domain and instruments endorsed and in widespread use | Merkel PA et al. J Rheumatol 2011 |
| Disease-specific patient-reported outcomes | • The AAV-PRO instrument developed and validated • Now in use in clinical trials and other projects • Translations underway in many different languages | Robson JC et al. Ann Rheum Dis. 2018 |
| Treatment response criteria | • American College of Rheumatology-European League Against Rheumatism-supported project to develop data-driven response criteria in ANCA-associated vasculitis • Systematic literature review of outcome measures in randomized trials revealed substantial heterogeneity and non-inclusion of important outcome measures • Ongoing international physician and patient Delphi exercise to select items for inclusion in treatment response criteria • Planned process to lead to an expert panel finalizing response criteria, followed by developing of a weighting system | Monti S et al. Arthritis Rheumatol. 2019 Monti S et al. Semin Arthritis Rheum. 2020 |
| LARGE-VESSEL VASCULITIS | ||
| Core set of outcome measures for use in trials | • Systematic literature review completed • International Physician Delphi exercise and qualitative patient interviews identified domains of interest and outcome measures • Some common and some disease-specific measures for giant cell arteritis and Takayasu’s arteritis identified • Preliminary core set of domains for trial in large-vessel vasculitis published | Direnskeneli H. et al. J Rheumatol. 2011; Aydin SZ et al. Curr Opin Rheumatol. 2015; Sreih AG et al. J Rheumatol. 2017; Aydin SZ et al. J Rheumatol. 2019 |
| Patient preferences and patient-reported outcomes | • Qualitative research in multiple countries conducted with patients with giant cell arteritis or Takayasu’s arteritis led to understanding of themes central to any future patient-reported outcome instrument • Next steps: • Development of candidate questionnaire items for disease-specific patient-reported outcome instrument for giant cell arteritis and Takayasu’s arteritis | Robson J et al. Ann Rheum Dis. 2018 Tomasson G et al. Arthritis Rheumatol. 2016 Sreih AG et al. Clin Exp Rheumatol. 2018 |
| Development of definitions of disease states and response criteria for use in clinical trials | • Define disease states and definitions of flare for giant cell arteritis and Takayasu’s arteritis • Next steps: • International patient Delphi to complement completed physician Delphi • Expert meeting including patient partners for item reduction and drafting data elements for study • Prospective data collection: multicenter, international study to collect data using items generated in previous steps and define active disease, remission, low disease activity • Develop response criteria in giant cell arteritis for use in clinical trials and other research studies • Next steps: • International Steering Committee formed with full study plans for a systematic literature review, Delphi exercise, and prospective data collection to subsequently generate the response criteria | Aydin SZ et al. J Rheumatol. 2017 |
| BEHÇET’S DISEASE | ||
| Core set of outcome measures for use in trials | • Core set of domains of illness for inclusion in all clinical trials in Behçet’s disease developed and endorsed • Next steps: • Identification or development of validated outcome measurement tools for each domain in core set | Hatemi G et al. Semin Arthritis Rheum. 2021 |
Another landmark research project in vasculitis conducted in the past 10 years is the Diagnostic and Classification Criteria for Vasculitis (DCVAS) project (ClinicalTrials.gov identifier: NCT01066208), funded by the ACR, the European League Against Rheumatism (EULAR), the VF and other sources. DCVAS is a multinational, observational study designed to update classification criteria and develop diagnostic criteria in vasculitis. The largest vasculitis research project in the world, DCVAS involves comprehensive data collection on thousands of patients at more than 100 sites across 30 countries in Asia, Australia, Europe, North America and South America.
Classification criteria in vasculitis were originally developed 30 years ago, before the advent of ANCA testing and newer imaging modalities. It was important to develop new classification criteria for successful and accurate recruitment into clinical trials. Draft classification criteria for the three types of ANCA-associated vasculitis, Takayasu’s arteritis and GCA were presented at ACR and EULAR annual meetings in 2019, and the final versions are expected to be published soon.
The DCVAS group is also considering approaches to establishing diagnostic criteria. Additionally, the large DCVAS database has been used by investigators for the conduct of clinical and epidemiologic studies, and remains an important research resource.
Clinical Trials
Tremendous progress has been made in the field of clinical trials in vasculitis. Several investigator-initiated, industry-sponsored and combined investigator-industry hybrid trials are ongoing. Current approaches to the treatment of ANCA-associated vasculitis have significantly improved survival and other outcomes.
Current regimens are often associated with serious side effects, such as infections and other complications of high-dose and prolonged glucocorticoid use. Trials involving new glucocorticoid-sparing induction regimens using novel complement component 5a inhibitors (i.e., avacopan and IFX-1) have been conducted or are underway.
Several ongoing trials in North America, Europe and Japan are also testing low-dose and shorter duration of glucocorticoids for the maintenance of remission in ANCA-associated vasculitis (see Table 1). Following the success of trials of rituximab as a treatment for ANCA-associated vasculitis, additional trials tested this drug for new indications, such as relapsing ANCA-associated vasculitis, mild to moderate MPA and EGPA. Other drugs and treatments are also under investigation for GPA, EGPA and MPA.
Clinical trials in large-vessel vasculitis have been less frequently conducted than for ANCA-associated vasculitis, but are now seeing increasing success. There was no FDA-approved drug for GCA until 2017. The success of the GiACTA trial, which led to the approval of tocilizumab for GCA, generated further interest in this disease. Presently, several national and international clinical trials in GCA are testing different biologics and small molecule inhibitors. Two clinical trials are ongoing in Takayasu’s arteritis, an extremely rare type of vasculitis, in Turkey and China (see Table 1).
Exciting advancements have been made through trials in other vasculitides, such as Behçet’s disease and cutaneous vasculitis, some of which incorporate patient-reported physical health as the primary outcome measure (ClinicalTrials.gov identifier: NCT03482479).
Despite the substantial success of clinical trials in several vasculitides, there is still a relative lack of clinical trials and approved drugs in many types of vasculitis, such as PAN and urticarial vasculitis. The relative rarity and heterogeneity in clinical presentations are among the several challenges in studying these diseases. However, with the growth and sophistication of international collaborations and networks, these challenges are expected to be overcome.
