Publications by authors named "Peter A Merkel"

287 Publications

Avacopan for the Treatment of ANCA-Associated Vasculitis. Reply.

N Engl J Med 2021 05;384(21):e81

ChemoCentryx, Mountain View, CA.

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http://dx.doi.org/10.1056/NEJMc2104672DOI Listing
May 2021

Clinical Manifestations and Long-Term Outcomes of Eosinophilic Granulomatosis With Polyangiitis in North America.

ACR Open Rheumatol 2021 Jun 25;3(6):404-412. Epub 2021 May 25.

Vasculitis Clinic, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Objective: To describe clinical manifestations and outcomes in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in North America.

Methods: Analysis of patients aged 18 years or older who fulfilled the 1990 American College of Rheumatology Classification Criteria for EGPA enrolled in the Vasculitis Clinical Research Consortium from 2003 to 2019. Main clinical characteristics, treatments, outcomes, and accumulated damage were studied.

Results: The cohort included 354 patients; 59% female; age at diagnosis of 50.0 (±14) years; 39% were antineutrophil cytoplasm antibody (ANCA) positive. Time from diagnosis to last follow-up was 7.0 (±6.2) years; 49.4% had one or more relapse. Patients positive for ANCA more commonly had neurological and kidney involvement when compared with patients negative for ANCA, who had more cardiac and lung manifestations. At last study visit, only 35 (12.6%) patients had been off all therapy for more than 2 years during their follow-up. The overall mortality rate was 4.0% and did not differ by ANCA status or cyclophosphamide use. Scores on the Vasculitis Damage Index (VDI) for 134 patients with two or more visits and more than 1 year of follow-up increased from 1.7 (±1.8) at enrollment (3.7 [±5.1] years after diagnosis) to 3.35 (±2.1) at last follow-up (7.5 [±5.8] years after diagnosis), mainly represented by chronic asthma (67.5%), peripheral neuropathy (49.6%), and chronic sinusitis (31.3%). Longer duration of glucocorticoid use and relapse were associated with higher VDI scores.

Conclusion: This analysis describes the many clinical manifestations and varied outcomes of EGPA and highlights the ongoing need to attain more sustained, long-term remission to limit the accrual of disease-related damage.
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http://dx.doi.org/10.1002/acr2.11263DOI Listing
June 2021

Temporal Artery Biopsy Revealing Marginal Zone Lymphoma in a Patient with Eosinophilic Granulomatosis with Polyangiitis.

Rheumatology (Oxford) 2021 May 17. Epub 2021 May 17.

Division of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

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http://dx.doi.org/10.1093/rheumatology/keab444DOI Listing
May 2021

Developing a core set of outcome measure domains to study Raynaud's phenomenon and digital ulcers in systemic sclerosis: Report from OMERACT 2020.

Semin Arthritis Rheum 2021 Jun 21;51(3):640-643. Epub 2021 Apr 21.

Division of Rheumatology, Department of Medicine, Division of Clinical Epidemiology, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, USA.

Raynaud's phenomenon (RP) and digital ulcers (DUs) are important disease manifestations of systemic sclerosis (SSc) that can lead to significant pain and disability. It is essential when studying these disease features to utilize outcome measures that fully evaluate the complexities of RP and DUs . The Outcome Measures in Rheumatology (OMERACT) Vascular Disease in SSc Working Group is applying the OMERACT filter 2.1 to identify a core set of disease domains that encompass the full burden of SSc-related RP and DUs. Progress to date and future research plans were presented during a Special Interest Group held in December 2020.
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http://dx.doi.org/10.1016/j.semarthrit.2021.04.005DOI Listing
June 2021

Identifying Clinical Risk Factors for Opioid Use Disorder using a Distributed Algorithm to Combine Real-World Data from a Large Clinical Data Research Network.

AMIA Annu Symp Proc 2020 25;2020:1220-1229. Epub 2021 Jan 25.

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.

Because they contain detailed individual-level data on various patient characteristics including their medical conditions and treatment histories, electronic health record (EHR) systems have been widely adopted as an efficient source for health research. Compared to data from a single health system, real-world data (RWD) from multiple clinical sites provide a larger and more generalizable population for accurate estimation, leading to better decision making for health care. However, due to concerns over protecting patient privacy, it is challenging to share individual patient-level data across sites in practice. To tackle this issue, many distributed algorithms have been developed to transfer summary-level statistics to derive accurate estimates. Nevertheless, many of these algorithms require multiple rounds of communication to exchange intermediate results across different sites. Among them, the One-shot Distributed Algorithm for Logistic regression (termed ODAL) was developed to reduce communication overhead while protecting patient privacy. In this paper, we applied the ODAL algorithm to RWD from a large clinical data research network-the OneFlorida Clinical Research Consortium and estimated the associations between risk factors and the diagnosis of opioid use disorder (OUD) among individuals who received at least one opioid prescription. The ODAL algorithm provided consistent findings of the associated risk factors and yielded better estimates than meta-analysis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075517PMC
June 2021

Social Distancing, Health Care Disruptions, Telemedicine Use, and Treatment Interruption During the COVID-19 Pandemic in Patients With or Without Autoimmune Rheumatic Disease.

ACR Open Rheumatol 2021 Jun 2;3(6):381-389. Epub 2021 May 2.

University of Alabama at Birmingham.

Background: We aimed to compare concerns, social distancing, health care disruptions, and telemedicine use in patients with autoimmune rheumatic disease (ARD) and non-ARD and to evaluate factors associated with immunomodulatory medication interruptions.

Methods: Patients in a multistate community rheumatology practice network completed surveys from April 2020 to May 2020. Adults with common ARD (rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus) or non-ARD (gout, osteoarthritis, osteoporosis) were evaluated. Concerns about coronavirus disease 2019 (COVID-19), social distancing, health care disruptions, and telemedicine use were compared in patients with ARD versus non-ARD, adjusting for demographics, rural residence, and zipcode-based measures of socioeconomic status and COVID-19 activity. Factors associated with medication interruptions were assessed in patients with ARD.

Results: Surveys were completed by 2319/36 193 (6.4%) patients with non-ARD and 6885/64 303 (10.7%) with ARD. Concerns about COVID-19 and social distancing behaviors were similar in both groups, although patients receiving a biologic or Janus kinase (JAK) inhibitor reported greater concerns and were more likely to avoid friends/family, stores, or leaving the house. Patients with ARD were less likely to avoid office visits (45.2% vs. 51.0%, odds ratio [OR] 0.79 [0.70-0.89]) with similar telemedicine use. Immunomodulatory medications were stopped in 9.7% of patients with ARD, usually (86.9%) without a physician recommendation. Compared with patients with an office visit, the likelihood of stopping medication was higher for patients with a telemedicine visit (OR 1.54 [1.19-1.99]) but highest for patients with no visits (OR 2.26 [1.79-2.86]).

Conclusion: Patients with ARD and non-ARD reported similar concerns about COVID-19 and similar social distancing behaviors. Missed office visits were strongly associated with interruptions in immunomodulatory medication.
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http://dx.doi.org/10.1002/acr2.11239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207682PMC
June 2021

Patient-Powered Research Networks of the Autoimmune Research Collaborative: Rationale, Capacity, and Future Directions.

Patient 2021 Apr 27. Epub 2021 Apr 27.

University of North Carolina, Chapel Hill, NC, USA.

Patient-Powered Research Networks (PPRNs) are US-based registry infrastructures co-created by advocacy groups, patient research partners, academic investigators, and other healthcare stakeholders. Patient-Powered Research Networks collect information directly from patients to conduct and disseminate the results of patient-centered/powered research that helps patients make more informed decisions about their healthcare. Patient-Powered Research Networks gather and utilize real-world data and patient-reported outcomes to conduct comparative effectiveness, safety, and other research, and leverage the Internet to accomplish this effectively and efficiently. Four PPRNs focused on autoimmune and immune-mediated conditions formed the Autoimmune Research Collaborative: ArthritisPower (rheumatoid arthritis, spondyloarthritis, and other rheumatic and musculoskeletal diseases), IBD Partners (inflammatory bowel disease), iConquerMS (multiple sclerosis), and the Vasculitis PPRN (vasculitis). The Autoimmune Research Collaborative aims to inform the healthcare decision making of patients, care partners, and other stakeholders, such as clinicians, regulators, and payers. Illustrated by practical applications from the Autoimmune Research Collaborative and its constituent PPRNs, this article discusses the shared capacities and challenges of the PPRN model, and the opportunities presented by collaborating across autoimmune conditions to design, conduct, and disseminate patient-centered outcomes research.
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http://dx.doi.org/10.1007/s40271-021-00515-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075709PMC
April 2021

Diagnostic delays in vasculitis and factors associated with time to diagnosis.

Orphanet J Rare Dis 2021 Apr 21;16(1):184. Epub 2021 Apr 21.

Division of Rheumatology, University of Pennsylvania, White Building, 5th Floor, 3400 Spruce Street, Philadelphia, PA, 19104, USA.

Background: Patients with vasculitis, a set of rare diseases, encounter delays in obtaining an accurate diagnosis which can lead to substantial morbidity and increased mortality. This study sought to describe the diagnostic journey of patients with vasculitis and identify factors associated with time to diagnosis.

Methods: Patients with vasculitis enrolled in an online registry completed a two-stage study: Stage 1: survey of open-ended questions about patients' diagnostic journeys and perceived factors associated with rapid or delayed diagnosis; Stage 2: survey with specific questions based on data from Stage 1 and additional investigator-identified factors.

Results: 375 patients with vasculitis participated in Stage 1; 456 patients participated in Stage 2. 85% of patients were seen by a healthcare provider within 3 months of the onset of symptoms. The median time to diagnosis of vasculitis was 7 months. 313/456 (73%) of patients were misdiagnosed initially. 40% of diagnoses were made in a hospital setting; 2% of diagnoses were made at a specialized vasculitis center. 60% of patients had at least 1 visit to an emergency room prior to diagnosis. Unemployment, time to travel to a medical center > 1 h, initial misdiagnosis, and delays in seeing a specialist were all associated with longer times to diagnosis. 373/456 (82%) of patients reported that a delayed diagnosis had negative consequences on their health.

Conclusion: Patients with vasculitis encounter substantial delays in achieving an accurate diagnosis and these delays are associated with negative health consequences. Both patient-related factors and healthcare-related factors are associated with diagnostic delays.
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http://dx.doi.org/10.1186/s13023-021-01794-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059170PMC
April 2021

Pulmonary Involvement in Primary Systemic Vasculitides.

Rheumatology (Oxford) 2021 Mar 31. Epub 2021 Mar 31.

Vasculitis Clinic, Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Objectives: This study describes the spectrum and initial impact of pulmonary manifestations in the primary systemic vasculitides.

Methods: Description and comparison of pulmonary manifestations in adults with Takayasu's arteritis (TAK), giant cell arteritis (GCA), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), polyarteritis nodosa (PAN), and IgA vasculitis (IgAV), using data collected within the Diagnostic and Classification Criteria in Vasculitis (DCVAS) study.

Results: Data from 1952 patients with primary vasculitides were included: 170 TAK, 657 GCA, 555 GPA, 223 MPA, 146 EGPA, 153 IgAV, and 48 PAN. Pulmonary manifestations were observed in patients with TAK (21.8%), GCA (15.8%), GPA (64.5%), MPA (65.9%), EGPA (89.0%), PAN (27.1%) and IgAV (5.9%). Dyspnea occurred in patients with TAK (14.7%), GCA (7.8%), GPA (41.8%), MPA (43.5%), EGPA (65.8%), PAN (18.8%) and IgAV (2.6%). Cough was reported in TAK (7.6%), GCA (9.3%), GPA (34.8%), MPA (37.7%), EGPA (55.5%), PAN (16.7%) and IgAV (3.3%). Hemoptysis occurred mainly in patients with ANCA-associated vasculitis (AAV). Fibrosis on imaging at diagnosis was documented in GPA (1.9%), MPA (24.9%), and EGPA (6.3%). Only patients with AAV (GPA 2.7%, MPA 2.7% and EGPA 3.4%) required mechanical ventilation. At 6 months, the presence of at least one pulmonary item in the Vasculitis Damage Index (VDI) was observed in TAK (4.1%), GCA (3.3%), GPA (15.4%), MPA (28.7%), EGPA (52.7%), PAN (6.2%), and IgAV (1.3%).

Conclusions: Pulmonary manifestations can occur in all primary systemic vasculitides, but are more frequent and more often associated with permanent damage in AAV.
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http://dx.doi.org/10.1093/rheumatology/keab325DOI Listing
March 2021

Effects of the COVID-19 Pandemic on Patients Living With Vasculitis.

ACR Open Rheumatol 2021 Jan 8;3(1):17-24. Epub 2020 Dec 8.

University of Pennsylvania, Philadelphia.

Objective: This study aimed to analyze the concerns and health-related behaviors in patients with vasculitis during the early phase of the coronavirus disease 2019 (COVID-19) pandemic in North America.

Methods: Patients with vasculitis in North America were invited to complete an online survey through the Vasculitis Patient-Powered Research Network in collaboration with the Vasculitis Foundation and the Relapsing Polychondritis Foundation. Questions focused on concerns and behaviors related to doctors' visits, tests, medication, and telehealth use. Factors affecting their concern and health-related behaviors were determined.

Results: Data from 662 patients were included: 90% of patients were White, 78% were women, 83% expressed moderate or high levels of concern about COVID-19, and 87% reported that their vasculitis moderately or extremely affected their level of concern. Older age, female sex, lung disease, and immunosuppression were associated with greater concern. Doctors' visits, laboratory tests, and other tests were avoided by 66%, 46%, and 40% of patients, respectively. Younger age, urban location, higher income, higher concern levels, and prednisone use (>10 mg/day) were associated with greater likelihood of avoiding visits or tests. Ten percent of patients on immunosuppressive therapy stopped their medication. Twenty-nine percent patients on rituximab avoided an infusion. Forty-four percent of patients had telehealth visits; more visits were reported for younger patients, for patients on glucocorticoids, and in Canada versus the United States.

Conclusion: During the COVID-19 pandemic, patients with vasculitis have high levels of concern and exhibit potentially harmful health-related behaviors. Health care use varies across different demographic groups and geographic regions. Specific strategies are warranted to facilitate engagement of these patients with the health care system during the pandemic.
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http://dx.doi.org/10.1002/acr2.11204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811691PMC
January 2021

Dynamic Changes in the Nasal Microbiome Associated with Disease Activity in Patients with Granulomatosis with Polyangiitis.

Arthritis Rheumatol 2021 Mar 7. Epub 2021 Mar 7.

Division of Rheumatology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: Little is known about temporal changes in nasal bacteria in granulomatosis with polyangiitis (GPA). We examined longitudinal changes in the nasal microbiome in association with relapse in GPA patients.

Methods: Bacterial 16S gene sequencing was performed on nasal swabs of 19 patients with GPA followed longitudinally for a total of 78 visits, including 9 patients who developed a relapse and 10 patients who remained in remission. Relative abundance of bacteria and ratios between bacteria were examined. Generalized estimating equation models evaluated the association between bacterial composition and 1) disease activity and 2) PR3-ANCA level, adjusting for medications.

Results: Corynebacterium and Staphylococcus were the most abundant bacterial genera across all nasal samples. Patients with quiescent disease maintained a stable ratio of Corynebacterium to Staphylococcus across visits. In contrast, in patients who experienced a relapse, a significantly lower ratio occurred at the visit prior to relapse, followed by a higher ratio at time of relapse (adjusted P < 0.01). Species-level analysis identified an association between higher abundance of nasal Corynebacterium tuberculostearicum and relapse (adjusted P = 0.04) and higher PR3-ANCA levels (adjusted P = 0.02).

Conclusion: In GPA, significant changes occur in the nasal microbiome over time and are associated with disease activity. The occurrence of these changes months prior to onset of relapse supports a pathogenic role of nasal bacteria in GPA. Our results uphold existing hypotheses implicating Staphylococcus as an instigator of disease and have generated a novel finding involving Corynebacterium as a potential mediator of disease in GPA.
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http://dx.doi.org/10.1002/art.41723DOI Listing
March 2021

Multifocal neutrophilic meningoencephalitis: a novel disorder responsive to anakinra.

J Neurol 2021 Feb 26. Epub 2021 Feb 26.

Division of Neuropathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.

We report a 57-year-old man with recurrent meningoencephalitis resulting in bouts of altered consciousness, encephalopathy, tremors, focal seizures, and paraparesis. The neurological manifestations were accompanied by fever and leukocytosis in the absence of other systemic manifestations. MRI abnormalities of the brain, brainstem, spinal cord and meninges and CSF pleocytosis and elevated protein were observed. Exhaustive studies failed to reveal an etiology. Brain biopsy revealed nodules of neutrophils and macrophages, but no vasculitis. The lesions were not vasocentric as would be expected with neuro-Behcet's disease and neuro-Sweet's disease. The disorder was responsive to high-dose corticosteroid therapy and, ultimately, to anakinra, an IL-1α and IL-1β receptor antagonist.
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http://dx.doi.org/10.1007/s00415-021-10431-xDOI Listing
February 2021

Avacopan for the Treatment of ANCA-Associated Vasculitis.

N Engl J Med 2021 02;384(7):599-609

From Addenbrooke's Hospital, Cambridge, United Kingdom (D.R.W.J.); the University of Pennsylvania, Philadelphia (P.A.M.); and ChemoCentryx, Mountain View, CA (T.J.S., P.B.).

Background: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

Methods: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority.

Results: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone.

Conclusions: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).
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http://dx.doi.org/10.1056/NEJMoa2023386DOI Listing
February 2021

Response to: 'Correspondence on 'Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis'' by Parikh .

Ann Rheum Dis 2021 Feb 4. Epub 2021 Feb 4.

Department of Nephrology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

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http://dx.doi.org/10.1136/annrheumdis-2020-219329DOI Listing
February 2021

Venous thromboembolism in ANCA-associated vasculitis. A population-based cohort study.

Rheumatology (Oxford) 2021 Jan 28. Epub 2021 Jan 28.

Lund University, Department of Clinical Sciences Lund, Section of Rheumatology, Skåne University Hospital, Lund, Sweden.

Objective: To determine incidence rate and predictors of venous thromboembolism (VTE) in a population-based cohort with ANCA-associated vasculitis (AAV).

Design: The study comprised 325 patients diagnosed with AAV from 1997-2016. All cases of VTE from prior to vasculitis diagnosis to the end of the study period were identified. The Birmingham Vasculitis Activity Score (BVAS) was used to assess disease activity at diagnosis. Venous thromboembolisms occurring in a period beginning three months prior to AAV diagnosis were considered to be AAV-related. The standardized incidence ratio (SIR) and 95% confidence intervals (CI) of VTE were calculated using the incidence rate in the general population.

Results: Fifty-nine patients (18%) suffered 69 VTE events. Of these, 48 (81%) suffered AAV-related VTE [deep vein thrombosis (DVT, n = 23), pulmonary embolism (PE, n = 18), and other (n = 9)]. The incidence rate of AAV-related VTE was 2.4/100 person-years (95% CI 1.7-3.0) during 2039 person-years of follow-up. The incidence during the first three months post-AAV diagnosis was 20.4/100 person-years (95% CI 11.5-29.4), decreasing to 8.9 (95% CI 0.2-17.6) and 1.5 (95% CI 0.0-3.5) in months 4-6 and months 7-12 post-AAV diagnosis, respectively. The SIR was 34.2 (95% CI 20.2-48.1) for DVT and 10.4 (95% CI 5.6-15.1) for PE. In multivariate Cox-regression analyses, only age and BVAS were predictive of VTE.

Conclusions: The incidence rate and SIR of AAV-related VTE is high, and higher early in the course of the disease. Vasculitis activity and age are positively associated with VTE.
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http://dx.doi.org/10.1093/rheumatology/keab057DOI Listing
January 2021

Reply.

Arthritis Rheumatol 2021 Jun 30;73(6):1089. Epub 2021 Mar 30.

University of Pennsylvania, Philadelphia, PA.

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http://dx.doi.org/10.1002/art.41661DOI Listing
June 2021

Clinicopathologic Associations in a Large International Cohort of Patients with Giant Cell Arteritis.

Arthritis Care Res (Hoboken) 2020 Dec 18. Epub 2020 Dec 18.

Systemic Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, MD, USA.

Objective: In addition to aiding in diagnosis, histopathologic findings from temporal artery biopsy (TAB) specimens in giant cell arteritis (GCA) may be valuable for their associations with clinical features of the disease. This study compared histopathologic findings on TAB with biopsy interpretation and demographic, clinical, and imaging features at time of diagnosis.

Methods: Patients with a clinical diagnosis of GCA who had a TAB were selected from an international, multicenter observational cohort of vasculitis. Associations between demographic, clinical, radiographic, and histopathologic features were identified using bivariate testing and multivariate regression modeling.

Results: Out of 705 patients with GCA who underwent TAB, 69% had histopathological evidence of definite vasculitis. Specific histopathological findings included the presence of giant cells (51%), fragmentation of the internal elastic lamina (41%), intimal thickening (33%), and predominantly mononuclear leukocyte infiltration (32%). Histopathologic interpretation of definite vasculitis was independently associated with giant cells (odds ratios (OR) 151.8, 95% confidence interval (CI): 60.2-551.6), predominantly mononuclear leukocyte infiltration (OR 11.8, CI 5.9-24.9), and fragmentation of the internal elastic lamina (OR 3.7, CI 1.9-7.4). A halo sign on temporal artery ultrasound and luminal damage of large arteries on angiography were significantly associated with presence of giant cells (OR 2.6, CI 1.1-6.5 and OR 2.4, CI 1.1-5.2, respectively). Specific histopathologic findings were associated with older age but no associations were identified with vision loss or other clinical features.

Conclusion: Histopathologic findings in GCA are strongly associated with the clinical diagnosis of GCA but have a limited role in identifying patterns of disease.
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http://dx.doi.org/10.1002/acr.24540DOI Listing
December 2020

Identification of susceptibility loci for Takayasu arteritis through a large multi-ancestral genome-wide association study.

Am J Hum Genet 2021 01 11;108(1):84-99. Epub 2020 Dec 11.

Department of Internal Medicine, Division of Rheumatology, Ankara Numune Training and Research Hospital, Ankara 06100, Turkey; Department of Internal Medicine, Division of Rheumatology, Ankara University, Faculty of Medicine, Ankara 06100, Turkey.

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 × 10) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets.
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http://dx.doi.org/10.1016/j.ajhg.2020.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820633PMC
January 2021

The OMERACT Core Set of Domains for Outcome Measures in Behçet Syndrome.

Arthritis Care Res (Hoboken) 2020 Nov 17. Epub 2020 Nov 17.

Division of Rheumatology and Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: There is an unmet need for reliable, validated, and widely-accepted outcome measures for randomized clinical trials in Behçet syndrome (BS). The Outcome Measures in Rheumatology Clinical Trials (OMERACT) BS Working Group, a large, multi-disciplinary group of experts in BS and patients with BS, worked to develop a Core Set of data-driven outcome measures for use in all clinical trials of BS.

Methods: The Core Domain Set was developed through a comprehensive, iterative, multi-stage project which included a systematic review, a focus group meeting and qualitative patient interviews, a survey among experts in BS, a Delphi exercise involving both patients and physician-experts in BS, and utilization of the data, insight, and feedback generated by these processes to develop a final Core Domain Set.

Results: All steps were completed and domains were delineated across the organ systems involved in this disease. Since trials in BS often focus on specific manifestations and not the disease in its entirety, the final proposed Core Set includes 5 domains mandatory for study in all trials in BS (disease activity, new organ involvement, quality of life, adverse events, and death) with additional sub-domains mandatory for study of specific organ-systems. The final Core Set was endorsed at the 2018 OMERACT meeting.

Conclusion: The Core Set of Domains in BS provides the foundation through which the international research community, including clinical investigators, patients, biopharmaceutical industry, and government regulatory bodies can harmonize the study of this complex disease, compare findings across studies, and advance development of effective therapies.
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http://dx.doi.org/10.1002/acr.24511DOI Listing
November 2020

Efficacy of leflunomide in the treatment of vasculitis.

Clin Exp Rheumatol 2021 Mar-Apr;39 Suppl 129(2):114-118. Epub 2020 Nov 10.

Vasculitis Clinic, Division of Rheumatology, Mount Sinai Hospital, University of Toronto, ON, Canada.

Objectives: Only a few small case series, case reports, and one small clinical trial suggested some benefit of leflunomide (LEF) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and other vasculitides. We analysed the clinical efficacy and tolerability of LEF in a large cohort of patients with various vasculitides.

Methods: This was a retrospective analysis of patients who received LEF for treatment of their vasculitis enrolled in the Vasculitis Clinical Research Consortium (VCRC) Longitudinal Study and in 3 additional centres from the Canadian vasculitis research network (CanVasc).

Results: Data for 93 patients were analysed: 45 had granulomatosis with polyangiitis (GPA), 8 microscopic polyangiitis (MPA), 12 eosinophilic granulomatosis with polyangiitis (EGPA), 14 giant-cell arteritis (GCA), 9 Takayasu's arteritis (TAK), and 5 polyarteritis nodosa (PAN). The main reason for initiation of LEF was active disease (89%). LEF was efficacious for remission induction or maintenance at 6 months for 62 (67%) patients (64% with GCA, 89% with TAK, 80% with PAN, 69% with GPA, 75% with MPA, 33% with EGPA); 20% discontinued LEF before achieving remission because of persistent disease activity. Overall, 22 adverse events (gastrointestinal symptoms being the most common) led to drug discontinuation in 18 (19%) patients, of which 12 stopped LEF before month 6, before showing any benefit in 8/12 of these patients.

Conclusions: Leflunomide can be an effective therapeutic option for various vasculitides, especially for non-severe refractory or relapsing ANCA-associated vasculitis or large-vessel vasculitis. No new safety signals for LEF were identified in this population.
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May 2021

Concerns, Healthcare Use, and Treatment Interruptions in Patients With Common Autoimmune Rheumatic Diseases During the COVID-19 Pandemic.

J Rheumatol 2020 Nov 15. Epub 2020 Nov 15.

MDG is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health (K23 AR073931-01). "The Arthritis and Rheumatic Disease COVID-19 Project" has received sponsorship support specifically from the Patient-Centered Outcomes Institute (PCORI), Eli Lilly and Company, and Janssen Pharmaceutical. M.D. George, MD, MSCE, Assistant Professor, S. Banerjee, MD, Assistant Professor, J.F. Baker, MD, MSCE, Assistant Professor, P.A. Merkel, MD, MPH, Professor, University of Pennsylvania, Philadelphia, Pennsylvania; S. Venkatachalam, PhD, MPH, K. Gavigan, MPH, D. Curtis, BA, W.B. Nowell, PhD, MSW, Global Healthy Living Foundation, Upper Nyack, New York; M.I. Danila, MD, MSc, MSPH, Associate Professor, J.R. Curtis, MD, MS, MPH, Professor, University of Alabama at Birmingham, Birmingham, Alabama, USA. J.R. Curtis and W.B. Nowell contributed equally to this work. MDG has received research support from Bristol-Myers Squibb for unrelated work. JB has received consulting fees from Bristol-Myers Squibb and Gilead. PM has received consulting fees from AbbVie, AstraZeneca, Biogen, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, CSL Behring, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Insmed, Jannsen, Kiniksa, Magenta, Pfizer, Sparrow, and Talaris; research support from AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, Celgene, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/ Sanofi, GlaxoSmithKline, and InflaRx; and royalties from UpToDate. MID has received consulting fees from Amgen, Novartis, and Sanofi Regeneron, and research support from Genentech, Pfizer, Boehringer, and Horizon for unrelated work. JR has received consulting fees from AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, and UCB, and research support from AbbVie, Amgen, Bristol-Myers Squibb, Corrona, Janssen, Lilly, Myriad, Pfizer, Regeneron, Roche, and UCB. DC, KG, WBN, and SV have no personal conflicts of interest to disclose and are employees of the Global Healthy Living Foundation (GHLF). GHLF receives grants, sponsorships and contracts from pharmaceutical manufacturers and private foundations. A full list of GHLF funders is publicly available at www.ghlf.org/our-partners. Address correspondence to Dr. M.D. George, Division of Rheumatology, 5 White Building, 3400 Spruce St., Philadelphia, PA 19104, USA. Email: Accepted for publication November 4, 2020.

Objective: To assess concerns and healthcare-related behaviors of patients with autoimmune rheumatic diseases during the coronavirus disease 2019 (COVID-19) pandemic.

Methods: Adults from the United States with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and systemic lupus erythematosus (SLE) from the ArthritisPower Patient-Powered Research Network and CreakyJoints patient community completed surveys. Concerns and behaviors were compared among patients with different autoimmune conditions, disease-modifying antirheumatic drug (DMARD) use, and geographic measures of urban status, income, education, and COVID-19 activity.

Results: Among 1517 participants (925 RA, 299 PsA, 185 AS, 108 SLE), mean age was 55.1 years, 88.3% were female, and 89.5% were White. COVID-19 concerns were similar across the country and were higher in biologic users ( < 0.001). Avoidance of doctor's office visits (56.6%) or laboratory testing (42.3%) and use of telehealth (29.5%) were more common in urban areas. Among participants receiving a DMARD without COVID-19 or other respiratory illness, 14.9% stopped a DMARD, with 78.7% of DMARD interruptions not recommended by a physician. DMARD stopping was more common in participants with lower socioeconomic status (SES) and in participants who avoided an office visit (OR 1.46, 95% CI 1.04-2.04) or reported lack of telehealth availability OR 2.26 (95% CI 1.25-4.08).

Conclusion: In the early months of the COVID-19 pandemic, patients with RA, PsA, AS, and SLE frequently avoided office visits and laboratory testing. DMARD interruptions commonly occurred without the advice of a physician and were associated with SES, office visits, and telehealth availability, highlighting the need for adequate healthcare access and attention to vulnerable populations during the pandemic.
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http://dx.doi.org/10.3899/jrheum.201017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121899PMC
November 2020

Clinical course of 602 patients with Takayasu's arteritis: comparison between Childhood-onset versus adult onset disease.

Rheumatology (Oxford) 2021 05;60(5):2246-2255

Systemic Autoimmunity Branch/NIAMS, National Institutes of Health, Bethesda, MD, USA.

Objectives: To describe the clinical profile of Asian Indian patients with Takayasu's arteritis (TAK) and to compare clinical features and outcome of childhood-onset Takayasu's arteritis (cTAK) with adult-onset TAK (aTAK).

Methods: Data related to clinical features and response to treatment of patients with cTAK (age of onset <16 years) and aTAK from a large observational cohort in our tertiary care teaching hospital were noted and compared.

Results: Altogether, 602 patients (cTAK = 119; aTAK = 483) were studied. Patients with cTAK had a blunted female: male ratio; but fever, elevated acute phase reactants, involvement of abdominal aorta or its branches, hypertension, abdominal pain, elevated serum creatinine and cardiomyopathy were more common in cTAK as compared with aTAK. Patients with aTAK were more likely to have aortic-arch disease and claudication than cTAK. During follow-up, complete remission was more common in cTAK (87% vs 66%; P < 0.01), but subsequent relapses were equally common (30% vs 27%; P = 0.63). Independent associations of disease duration at presentation with disease extent [Disease Extent Index in TAK (DEI.Tak)] and damage [TAK Damage Score (TADS)] were observed (P ≤ 0.01). Moreover, 54% of patients with symptom duration of >5 years at presentation still continued to have elevated CRP suggesting continued and active inflammation warranting escalation or inititation of immunosuppression.

Conclusion: Patients with cTAK are more likely to have arterial disease below the diaphragm, systemic inflammation and achieve remission. Disease of the aortic arch is more common in patients with aTAK. Longer duration of symptoms prior to initiation of immunosuppression, thereby leading to extensive disease and damage, reflects ongoing disease activity as the rule rather than exception in untreated TAK.
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http://dx.doi.org/10.1093/rheumatology/keaa569DOI Listing
May 2021

Use and reporting of outcome measures in randomized trials for anti-neutrophil cytoplasmic antibody-associated vasculitis: a systematic literature review.

Semin Arthritis Rheum 2020 12 29;50(6):1314-1325. Epub 2020 Sep 29.

Faculty of Medicine, University of Iceland, Reykjavik, Iceland, Department of rheumatology, University Hospital, Iceland. Centre for Rheumatology Research, University Hospital, Iceland.

Background: A comprehensive review of outcome measures used in randomized controlled trials (RCTs) of ANCA-associated vasculitis (AAV) could advance trial conductance for this disease.

Methods: A systematic literature review of outcome measures (as specified in methods section as primary and/or secondary outcomes) in RCTs of AAV was conducted. Medline, Cochrane CENTRAL, and ClinicalTrials.gov were searched from inception until April 30, 2019 for RCTs enrolling patients with granulomatosis with polyangiitis and/or microscopic polyangiitis. Outcome measures were organized according to domains (e.g. disease activity) and instruments [e.g. Birmingham Vasculitis Activity Score (BVAS)].

Results: Out of 1101 identified records, 68 RCTs were eligible. Disease activity was an outcome domain collected in 67 (98%) of the RCTs. The BVAS was the most widely used instrument for disease assessment but definitions for remissions and relapse varied for the purpose of primary endpoint definitions. Damage, most often assessed by the Vasculitis Damage Index, was an outcome in 30 (44%) of the RCTs. Mortality was specified as an outcome in 26 (38%) studies. The following outcome domains were assessed: patient-reported outcomes (PROs) in 28 (41%), drug exposure/safety in 58 (85%), and biomarkers [acute phase reactants, ANCA levels] in 24 (35%). Timing for outcome assessment differed substantially, with 3, 6, or 12 months being the most frequent time points.

Conclusion: Outcome measures used in trials in AAV commonly included vasculitis-specific tools for disease assessment, but with heterogeneity in endpoint-definitions and timing of assessments. Other core outcomes in AAV, including PROs, and damage measures, are often omitted in AAV trials.
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http://dx.doi.org/10.1016/j.semarthrit.2020.09.010DOI Listing
December 2020

Adjunctive Treatment With Avacopan, an Oral C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

ACR Open Rheumatol 2020 Nov 31;2(11):662-671. Epub 2020 Oct 31.

ChemoCentryx, Inc., Mountain View, California, United States.

Objective: This study aimed to evaluate the safety of avacopan, an orally administered C5a receptor inhibitor, for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in addition to standard-of-care (SOC) treatment with glucocorticoids with cyclophosphamide or rituximab.

Methods: In this randomized 12-week study, twice daily avacopan (10 mg or 30 mg) plus SOC was assessed versus SOC only in patients with newly diagnosed/relapsing ANCA-associated vasculitis. Efficacy measurements included 50% or greater reduction in Birmingham Vasculitis Activity Score (BVAS) at day 85, rapid reduction (day 29) of BVAS to a score of 0 that was sustained through day 85, change in Vasculitis Damage Index (VDI), renal response (improvement in estimated glomerular filtration rate [eGFR], hematuria, and albuminuria), and health-related quality of life (HRQoL).

Results: Forty-two patients were randomized (n = 13 SOC, n = 13 avacopan 10 mg, and n = 16 avacopan 30 mg). Serious adverse events occurred in 15% and 17% of patients receiving SOC only and patients receiving avacopan with SOC, respectively. In the intent-to-treat population, BVAS response was high across arms (11 of 13 SOC, 11 of 12 avacopan 10 mg, and 12 of 15 avacopan 30 mg); increases in mean VDI were greater with SOC only than with avacopan plus SOC (0.3 versus 0.1). Avacopan 30 mg was numerically superior to placebo and avacopan 10 mg in early remission (15%, 8%, and 20% for SOC only, avacopan 10 mg, and avacopan 30 mg, respectively), improved eGFR (+2.0 ml/min/1.73m , +1.3 ml/min/1.73m , and +6.2 ml/min/1.73m , respectively), renal response (17%, 40%, and 63%, respectively), and measures of HRQoL.

Conclusion: Avacopan in addition to SOC for ANCA-associated vasculitis was well tolerated, and at the higher study dose, it appeared to improve time to remission (ClinicalTrials.gov identifier NCT02222155).
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http://dx.doi.org/10.1002/acr2.11185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672305PMC
November 2020

Sequence-Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2.

Arthritis Rheumatol 2021 03 3;73(3):512-519. Epub 2021 Feb 3.

University of Pennsylvania, Philadelphia.

Objective: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease-causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA).

Methods: Patients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA-2 enzyme activity was assessed in selected serum samples.

Results: Nine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA-2 enzyme activity. ADA-2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA-2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2.

Conclusion: A subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA-2 testing should strongly be considered in patients with hepatitis B virus-negative idiopathic PAN.
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http://dx.doi.org/10.1002/art.41549DOI Listing
March 2021

Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3 in ANCA-Associated Vasculitis.

Front Immunol 2020 3;11:2053. Epub 2020 Sep 3.

Mayo Clinic and Mayo Foundation for Research and Education, Rochester, MN, United States.

The utility of ANCA testing as an indicator of disease activity in ANCA-associated vasculitis (AAV) remains controversial. This study aimed to determine the association of ANCA testing by various methods and subsequent remission and examine the utility of a widely used automated addressable laser-bead immunoassay (ALBIA) to predict disease relapses. Data from the Rituximab vs. Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. ANCA testing was performed by direct ELISA, capture ELISA, and ALBIA. Cox proportional hazards regression models were used to evaluate the association of PR3-ANCA level and subsequent remission or relapse. The ALBIA results are routinely reported as >8 when the value is high. For this study, samples were further titrated. A decrease and increase in PR3-ANCA were defined as a halving or doubling in value, respectively. A decrease in ANCA by ALBIA at 2 months was associated with shorter time to sustained remission (HR 4.52, = 0.035). A decrease in ANCA by direct ELISA at 4 months was associated with decreased time to sustained remission (HR 1.77, = 0.050). There were no other associations between ANCA decreases or negativity and time to remission. An increase in PR3-ANCA by ALBIA was found in 78 of 93 subjects (84%). Eleven (14%) had a PR3-ANCA value which required titration for detection of an increase. An increase of ANCA by ALBIA was associated with severe relapse across various subgroups. A decrease in ANCA by ALBIA at 2 months and by direct ELISA at 4 months may be predictive of subsequent remission. These results should be confirmed in a separate cohort with similarly protocolized sample and clinical data collection. A routinely used automated ALBIA for PR3-ANCA measurement is comparable to direct ELISA in predicting relapse in PR3-AAV. Without titration, 14% of the increases detected by ALBIA would have been missed. Titration is recommended when this assay is used for disease monitoring. The association of an increase in PR3-ANCA with the risk of subsequent relapse remains complex and is affected by disease phenotype and remission induction agent.
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http://dx.doi.org/10.3389/fimmu.2020.02053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495134PMC
May 2021

Performance of laser-derived imaging for assessing digital perfusion in clinical trials of systemic sclerosis-related digital vasculopathy: A systematic literature review.

Semin Arthritis Rheum 2020 10 6;50(5):1114-1130. Epub 2020 Jul 6.

University of Pennsylvania, Philadelphia, PA, USA.

Background: Raynaud's phenomenon (RP) and digital ulcers (DU) are important features of digital vasculopathy in systemic sclerosis (SSc). Laser Doppler flowmetry (LDF), Laser Doppler Imaging (LDI) and Laser Speckle Contrast Imaging (LSCI) can non-invasively quantify digital perfusion and may be useful outcome measures for SSc-RP and/or SSc-DU clinical trials. We undertook a systematic literature review to evaluate the performance of laser-derived imaging as outcome measures in clinical trials of SSc-related digital vasculopathy.

Methods: Standardized searches (EMBASE and MEDLINE) identified trials that incorporated laser-derived imaging of digital vasculopathy in adult subjects with SSc. Data was extracted (by >2 reviewers) on study design, laser endpoints, and reported outcomes. Study quality was assessed using validated instruments (PROSPERO 2019:CRD42019142409).

Results: Of 126 identified articles, full data extraction was undertaken from 29 studies. Fifteen randomized and 14 non-randomized trials (total of 689 SSc patients with mean 23.8/study) have evaluated a broad range of oral, intravenous and topical interventions for SSc-RP (n = 11), digital perfusion alone (n = 15) and SSc-DU (n = 3). The studies were published between 1987 and 2019 (17/29 since 2010) and incorporated LDF (11/29), LDI (15/29) and LSCI (4/29, including one with LDF); with LSCI and LDI more commonly incorporated in recent trials. Most studies (16/29, 55%) reported improvement in digital perfusion following intervention, often concordant with patient- and clinician-derived outcomes.

Conclusions: Establishing laser-derived methods as a surrogate for SSc-related digital vasculopathy will greatly support drug development. Full-field perfusion of the digits (with/without provocation testing) is a promising clinical trial outcome measure for trials of SSc-related digital vasculopathy.
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http://dx.doi.org/10.1016/j.semarthrit.2020.06.018DOI Listing
October 2020

ANCA-associated vasculitis.

Nat Rev Dis Primers 2020 08 27;6(1):71. Epub 2020 Aug 27.

Department of Pathology, Medical University Vienna, Vienna, Austria.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA or ANCA, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients.
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http://dx.doi.org/10.1038/s41572-020-0204-yDOI Listing
August 2020

Fc receptor-like 5 and anti-CD20 treatment response in granulomatosis with polyangiitis and microscopic polyangiitis.

JCI Insight 2020 09 17;5(18). Epub 2020 Sep 17.

Hoffmann - La Roche, Basel, Switzerland.

BACKGROUNDBaseline expression of FCRL5, a marker of naive and memory B cells, was shown to predict response to rituximab (RTX) in rheumatoid arthritis. This study investigated baseline expression of FCRL5 as a potential biomarker of clinical response to RTX in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).METHODSA previously validated quantitative PCR-based (qPCR-based) platform was used to assess FCRL5 expression in patients with GPA/MPA (RAVE trial, NCT00104299).RESULTSBaseline FCRL5 expression was significantly higher in patients achieving complete remission (CR) at 6, 12, and 18 months, independent of other clinical and serological variables, among those randomized to RTX but not cyclophosphamide-azathioprine (CYC/AZA). Patients with baseline FCRL5 expression ≥ 0.01 expression units (termed FCRL5hi) exhibited significantly higher CR rates at 6, 12, and 18 months as compared with FCRL5lo subjects (84% versus 57% [P = 0.016], 68% versus 40% [P = 0.02], and 68% versus 29% [P = 0.0009], respectively).CONCLUSIONOur data taken together suggest that FCRL5 is a biomarker of B cell lineage associated with increased achievement and maintenance of complete remission among patients treated with RTX and warrant further investigation in a prospective manner.FUNDINGThe analysis for this study was funded by Genentech Inc.
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http://dx.doi.org/10.1172/jci.insight.136180DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526555PMC
September 2020

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis.

Ann Rheum Dis 2020 09 24;79(9):1243-1249. Epub 2020 Jun 24.

University of Pittsburg, Pittsburg, Pennsylvania, USA.

Objectives: Evaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.

Methods: Patients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.

Results: 188 patients were studied: 95/188 (51%) men, median age 59 years (range 19-89), prior disease duration 5.0 years (range 0.4-34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections.

Conclusions: This large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.
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http://dx.doi.org/10.1136/annrheumdis-2019-216863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456549PMC
September 2020