Publications by authors named "Philip Seo"

128 Publications

Serum Biomarkers of Disease Activity in Longitudinal Assessment of Patients with ANCA-Associated Vasculitis.

ACR Open Rheumatol 2021 Nov 18. Epub 2021 Nov 18.

University of Pennsylvania, Philadelphia.

Objective: Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares.

Methods: Twenty-two proteins were measured in 347 serum samples from 74 patients with AAV enrolled in a clinical trial. Samples were collected at Month 6 after remission induction, then every 3 months until Month 18, or at the time of flare. Associations of protein concentrations with concurrent disease activity and with future flare were analyzed using mixed-effects models, Cox proportional hazards models, and conditional logistic regression.

Results: Forty-two patients had flares during the 12-month follow-up period, and 32 remained in remission. Twenty-two patients had severe flares. Six experimental markers (CXCL13, IL-6, IL-8, IL-15, IL-18BP, and matrix metalloproteinase-3 [MMP-3]) and ESR were associated with disease activity using all three methods (P < 0.05, with P < 0.01 in at least one method). A rise in IL-8, IL-15, or IL-18BP was associated temporally with flare. Combining C-reactive protein (CRP), IL-18BP, neutrophil gelatinase-associated lipocalin (NGAL), and sIL-2Rα improved association with active AAV. CXCL13 and MMP-3 were increased during treatment with prednisone, independent of disease activity. Marker concentrations during remission were not predictive of future flare.

Conclusion: Serum biomarkers of inflammation and tissue damage and repair have been previously shown to be strongly associated with severe active AAV were less strongly associated with active AAV in a longitudinal study that included mild flares and varying treatment. Markers rising contemporaneously with flare or with an improved association in combination merit further study.
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http://dx.doi.org/10.1002/acr2.11366DOI Listing
November 2021

Hypothyroidism in Vasculitis.

Rheumatology (Oxford) 2021 Nov 3. Epub 2021 Nov 3.

Division of Rheumatology and Division of Clinical Epidemiology, University of Pennsylvania, Philadelphia, PA, USA.

Objective: To study the prevalence, risk and clinical associations of hypothyroidism among several forms of vasculitis.

Methods: Patients with giant cell arteritis (GCA), Takayasu arteritis (TAK), polyarteritis nodosa (PAN), and the three forms of ANCA-associated vasculitis (AAV, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) enrolled in a prospective, multicentre, longitudinal study were included.

Results: The study included data on 2,085 patients, 63% female, 90% White, mean age 54.6 (±17.2) years. Diagnoses were: GCA (20%), TAK (11%), PAN (5%), GPA (42%), MPA (8%), and EGPA (14%). Hypothyroidism was present in 217 patients (10%), 83% female, mean (±SD) age 59.8 (14.5) years.Age- and sex- adjusted, risk of hypothyroidism was: GCA (OR 0.61, 95% CI 0.41, 0.90), TAK (OR 0.57 95% CI 0.31, 1.03), PAN (OR 0.59 95% CI 0.25, 1.38), GPA (OR 1.51 95% CI 1.12, 2.05), MPA (OR 1.81, 95% CI 1.18, 2.80) and EGPA (OR 0.82, 95% CI 0.52, 1.30). Among patients with AAV, age- and sex- adjusted risk of hypothyroidism was higher with positive myeloperoxidase (MPO-ANCA) (OR 1.89, 95% CI 1.39, 2.76). The clinical manifestations of vasculitis were similar in patients with and without hypothyroidism except transient ischemic attacks which were more frequently observed in patients with GCA and hypothyroidism (12% vs 2%, p 0.001).

Conclusions: Differences in the risk of hypothyroidism among vasculitides may be due to genetic susceptibilities or immune responses. This study confirms an association of hypothyroidism with MPO-ANCA.
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http://dx.doi.org/10.1093/rheumatology/keab817DOI Listing
November 2021

Circulating autoreactive proteinase 3+ B cells and tolerance checkpoints in ANCA-associated vasculitis.

JCI Insight 2021 Nov 22;6(22). Epub 2021 Nov 22.

Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA.

BACKGROUNDLittle is known about the autoreactive B cells in antineutrophil cytoplasmic antibody-associated (ANCA-associated) vasculitis (AAV). We aimed to investigate tolerance checkpoints of circulating antigen-specific proteinase 3-reactive (PR3+) B cells.METHODSMulticolor flow cytometry in combination with bioinformatics and functional in vitro studies were performed on baseline samples of PBMCs from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-AAV and myeloperoxidase-AAV (MPO-AAV) and 27 healthy controls (HCs). Clinical data and outcomes from the trial were correlated with PR3+ B cells (total and subsets).RESULTSThe frequency of PR3+ B cells among circulating B cells was higher in participants with PR3-AAV (4.77% median [IQR, 3.98%-6.01%]) than in participants with MPO-AAV (3.16% median [IQR, 2.51%-5.22%]) and participants with AAV compared with HCs (1.67% median [IQR, 1.27%-2.16%], P < 0.001 for all comparisons), implying a defective central tolerance checkpoint in patients with AAV. Only PBMCs from participants with PR3-AAV contained PR3+ B cells capable of secreting PR3-ANCA IgG in vitro, proving they were functionally distinct from those of participants with MPO-AAV and HCs. Unsupervised clustering identified subtle subsets of atypical autoreactive PR3+ memory B cells accumulating through the maturation process in patients with PR3-AAV. PR3+ B cells were enriched in the memory B cell compartment of participants with PR3-AAV and were associated with higher serum CXCL13 levels, suggesting an increased germinal center activity. PR3+ B cells correlated with systemic inflammation (C-reactive protein and erythrocyte sedimentation rate, P < 0.05) and complete remission (P < 0.001).CONCLUSIONThis study suggests the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients with PR3-AAV, elucidating the selection process of autoreactive B cells.Trial registrationClinicalTrials.gov NCT00104299.FundingThe Vasculitis Foundation, the National Institute of Allergy and Infectious Diseases of the NIH, and the Mayo Foundation for Education and Research.
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http://dx.doi.org/10.1172/jci.insight.150999DOI Listing
November 2021

Reply to "Rituximab versus cyclophosphamide for remission induction in active, severe ANCA-associated vasculitis".

Arthritis Rheumatol 2021 Oct 3. Epub 2021 Oct 3.

Department of Rheumatic and Immunologic Diseases, Cleveland Clinic, Cleveland.

We appreciate the insights and concerns shared by Dr. Jain et al. regarding the use of rituximab (RTX) and cyclophosphamide (CYC) for the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), as outlined in the American College of Rheumatology/Vasculitis Foundation (ACR/VF) guideline for the treatment of ANCA-associated vasculitis (AAV) [1]. These concerns are timely given the ongoing COVID-19 pandemic.
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http://dx.doi.org/10.1002/art.41991DOI Listing
October 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Rheumatol 2021 08 8;73(8):1366-1383. Epub 2021 Jul 8.

Cleveland Clinic, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

Methods: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations.

Conclusion: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.
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http://dx.doi.org/10.1002/art.41773DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Polyarteritis Nodosa.

Arthritis Care Res (Hoboken) 2021 08 8;73(8):1061-1070. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of systemic polyarteritis nodosa (PAN).

Methods: Twenty-one clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for systemic, non-hepatitis B-related PAN. Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 16 recommendations and 1 ungraded position statement for PAN. Most recommendations were graded as conditional due to the paucity of evidence. These recommendations support early treatment of severe PAN with cyclophosphamide and glucocorticoids, limiting toxicity through minimizing long-term exposure to both treatments, and the use of imaging and tissue biopsy for disease diagnosis. These recommendations endorse minimizing risk to the patient by using established therapy at disease onset and identify new areas where adjunctive therapy may be warranted.

Conclusion: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and imaging for patients with PAN.
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http://dx.doi.org/10.1002/acr.24633DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis.

Arthritis Rheumatol 2021 08 8;73(8):1349-1365. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis.

Methods: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions.

Conclusion: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.
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http://dx.doi.org/10.1002/art.41774DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Polyarteritis Nodosa.

Arthritis Rheumatol 2021 08 8;73(8):1384-1393. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of systemic polyarteritis nodosa (PAN).

Methods: Twenty-one clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for systemic, non-hepatitis B-related PAN. Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 16 recommendations and 1 ungraded position statement for PAN. Most recommendations were graded as conditional due to the paucity of evidence. These recommendations support early treatment of severe PAN with cyclophosphamide and glucocorticoids, limiting toxicity through minimizing long-term exposure to both treatments, and the use of imaging and tissue biopsy for disease diagnosis. These recommendations endorse minimizing risk to the patient by using established therapy at disease onset and identify new areas where adjunctive therapy may be warranted.

Conclusion: These recommendations provide guidance regarding diagnostic strategies, use of pharmacologic agents, and imaging for patients with PAN.
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http://dx.doi.org/10.1002/art.41776DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Arthritis Care Res (Hoboken) 2021 08 8;73(8):1088-1105. Epub 2021 Jul 8.

Cleveland Clinic, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).

Methods: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations.

Conclusion: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases.
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http://dx.doi.org/10.1002/acr.24634DOI Listing
August 2021

2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis.

Arthritis Care Res (Hoboken) 2021 08 8;73(8):1071-1087. Epub 2021 Jul 8.

Cleveland Clinic Foundation, Cleveland, Ohio.

Objective: To provide evidence-based recommendations and expert guidance for the management of giant cell arteritis (GCA) and Takayasu arteritis (TAK) as exemplars of large vessel vasculitis.

Methods: Clinical questions regarding diagnostic testing, treatment, and management were developed in the population, intervention, comparator, and outcome (PICO) format for GCA and TAK (27 for GCA, 27 for TAK). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to rate the quality of the evidence. Recommendations were developed by the Voting Panel, comprising adult and pediatric rheumatologists and patients. Each recommendation required ≥70% consensus among the Voting Panel.

Results: We present 22 recommendations and 2 ungraded position statements for GCA, and 20 recommendations and 1 ungraded position statement for TAK. These recommendations and statements address clinical questions relating to the use of diagnostic testing, including imaging, treatments, and surgical interventions in GCA and TAK. Recommendations for GCA include support for the use of glucocorticoid-sparing immunosuppressive agents and the use of imaging to identify large vessel involvement. Recommendations for TAK include the use of nonglucocorticoid immunosuppressive agents with glucocorticoids as initial therapy. There were only 2 strong recommendations; the remaining recommendations were conditional due to the low quality of evidence available for most PICO questions.

Conclusion: These recommendations provide guidance regarding the evaluation and management of patients with GCA and TAK, including diagnostic strategies, use of pharmacologic agents, and surgical interventions.
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http://dx.doi.org/10.1002/acr.24632DOI Listing
August 2021

Serum and urinary metabolites discriminate disease activity in ANCA associated glomerulonephritis in a pilot study.

J Nephrol 2021 Jun 28. Epub 2021 Jun 28.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Renal biopsy is currently the gold standard for diagnosing active renal vasculitis. In this pilot study, metabolomics analysis was used to investigate the differences in metabolic profiles between paired patients' serum and urine samples collected during both the active and the remission phase of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). Ten patients with AAV renal disease were included. Mean age was 61 years, with 6 patients each being male and Caucasian. Mean Birmingham Vasculitis Activity Score (BVAS) and mean glomerular filtration rate (GFR) were 17 and 28, respectively. We found that while the citric acid cycle intermediates citrate, iso-citrate and oxaloacetate had lower intensities in the active phase samples as compared to the remission phase samples. The intensities of other metabolites of carbohydrate metabolism, amino acid metabolism, and nucleotide synthesis were significantly higher in the active phase samples, indicating the upregulation of these pathways for the production of energy and other biomolecules such as proteins and nucleic acids during the active phase of AAV. This pilot study suggests that serum and urinary metabolomic profiling may be useful to monitor disease activity in renal AAV.
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http://dx.doi.org/10.1007/s40620-021-01095-xDOI Listing
June 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207688PMC
June 2021

Factors Affecting Dilation Interval in Patients With Granulomatosis With Polyangiitis-Associated Subglottic and Glottic Stenosis.

Otolaryngol Head Neck Surg 2021 Apr 13:1945998211004264. Epub 2021 Apr 13.

Department of Otolaryngology-Head and Neck Surgery, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Objective: Subglottic stenosis (SGS) is a known complication of granulomatosis with polyangiitis (GPA). We investigated the impact of medical and surgical interventions on the surgical dilation interval and characterized patients with glottic involvement.

Study Design: A retrospective chart review of patients with GPA-associated SGS was performed from 2010 to 2019.

Setting: Tertiary academic medical center.

Methods: The impact of medical and surgical interventions on dilation interval was assessed. The prevalence of glottic involvement was assessed, and clinical characteristics and outcomes were compared with patients without glottic involvement.

Results: A total of 39 patients with GPA-associated SGS were analyzed. Dilation intervals in patients receiving leflunomide (n = 4; median, 484 days; 95% CI, 405-1099) were greater than in those not receiving leflunomide (median, 155 days; 95% CI, 48-305; = .033). The surgical technique used did not affect dilation interval. Patients with glottic involvement (n = 13) had a greater incidence of dysphonia (13/13 vs 15/26 [58%], = .007) and a shorter dilation interval with involvement (median, 91 days; interquartile range, 70-277) versus without involvement (median, 377 days; interquartile range, 175-1148; hazard ratio, 3.38; 95% CI, 2.26-5.05; < .001). Of 13 patients, 8 (62%) did not have glottic involvement on first presentation.

Conclusion: Although GPA is classically thought to affect the subglottis, it also involves the glottis in a subset of patients. These patients have greater complaints of dysphonia and require more frequent surgery. Systemic therapy may increase dilation intervals. In this preliminary study, patients taking leflunomide demonstrated an improvement, highlighting the need for further study of immunosuppression regimens in the treatment of GPA-associated SGS.
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http://dx.doi.org/10.1177/01945998211004264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511351PMC
April 2021

Reply.

Arthritis Rheumatol 2021 07 31;73(7):1342-1343. Epub 2021 May 31.

Children's Hospital of Philadelphia and University of Pennsylvania, Perelman School of Medicine.

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http://dx.doi.org/10.1002/art.41689DOI Listing
July 2021

Telemedicine in Adult Rheumatology: In Practice and In Training.

Arthritis Care Res (Hoboken) 2021 Feb 8. Epub 2021 Feb 8.

Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Bulfinch 165, Boston, MA, 02114, USA.

Telemedicine has been defined as "the use of medical information that is exchanged from one site to another through electronic communication to improve a patient's health" (1). There are several interactions to consider within telemedicine, including clinician-to-clinician, clinician-to-patient, and patient-to-mobile health technology, each of which can provide synchronous or asynchronous care. Traditionally, rheumatologists used telemedicine to provide care for patients with limited access to subspecialists, a care gap accentuated by the geographic maldistribution of rheumatologists in the United States.
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http://dx.doi.org/10.1002/acr.24569DOI Listing
February 2021

Antineutrophil Cytoplasmic Antibody.

Kidney Int Rep 2021 Mar 29;6(3):806-809. Epub 2020 Dec 29.

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1016/j.ekir.2020.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837286PMC
March 2021

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

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2.

Arthritis Rheumatol 2021 Apr 15;73(4):e13-e29. Epub 2021 Feb 15.

Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine.

Objective: To provide guidance on the management of Multisystem Inflammatory Syndrome in Children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Recommendations are also provided for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection.

Methods: The Task Force was composed of 9 pediatric rheumatologists and 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved anonymous voting and webinar discussion. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate). Consensus was rated as low, moderate, or high based on dispersion of the votes. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, which were prespecified before voting.

Results: The first version of the guidance was approved in June 2020, and consisted of 40 final guidance statements accompanied by a flow diagram depicting the diagnostic pathway for MIS-C. The document was revised in November 2020, and a new flow diagram with recommendations for initial immunomodulatory treatment of MIS-C was added.

Conclusion: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. This guidance document reflects currently available evidence coupled with expert opinion, and will be revised as further evidence becomes available.
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http://dx.doi.org/10.1002/art.41616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8559788PMC
April 2021

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

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

Rheumatology Fellowship Recruitment in 2020: Benefits, Challenges, and Adaptations.

Arthritis Care Res (Hoboken) 2021 04;73(4):459-461

Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1002/acr.24445DOI Listing
April 2021

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

American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 1.

Arthritis Rheumatol 2020 11 3;72(11):1791-1805. Epub 2020 Oct 3.

Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine.

Objective: To provide guidance on the management of multisystem inflammatory syndrome in children (MIS-C), a condition characterized by fever, inflammation, and multiorgan dysfunction that manifests late in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and to provide recommendations for children with hyperinflammation during coronavirus disease 2019 (COVID-19), the acute, infectious phase of SARS-CoV-2 infection.

Methods: A multidisciplinary task force was convened by the American College of Rheumatology (ACR) to provide guidance on the management of MIS-C associated with SARS-CoV-2 and hyperinflammation in COVID-19. The task force was composed of 9 pediatric rheumatologists, 2 adult rheumatologists, 2 pediatric cardiologists, 2 pediatric infectious disease specialists, and 1 pediatric critical care physician. Preliminary statements addressing clinical questions related to MIS-C and hyperinflammation in COVID-19 were developed based on evidence reports. Consensus was built through a modified Delphi process that involved 2 rounds of anonymous voting and 2 webinars. A 9-point scale was used to determine the appropriateness of each statement (median scores of 1-3 for inappropriate, 4-6 for uncertain, and 7-9 for appropriate), and consensus was rated as low, moderate, or high based on dispersion of the votes along the numeric scale. Approved guidance statements were those that were classified as appropriate with moderate or high levels of consensus, as prespecified prior to voting.

Results: The ACR task force approved a total of 128 guidance statements addressing the management of MIS-C and hyperinflammation in pediatric COVID-19. These statements were refined into 40 final clinical guidance statements, accompanied by a flow diagram depicting the diagnostic pathway for MIS-C.

Conclusion: Our understanding of SARS-CoV-2-related syndromes in the pediatric population continues to evolve. The guidance provided in this "living document" reflects currently available evidence, coupled with expert opinion, and will be revised as further evidence becomes available.
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http://dx.doi.org/10.1002/art.41454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405113PMC
November 2020

Patterns of clinical presentation in Takayasu's arteritis.

Semin Arthritis Rheum 2020 08 19;50(4):576-581. Epub 2020 May 19.

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

Objective: Takayasu's arteritis (TAK) is a clinically heterogenous disease. Patterns of clinical presentation in TAK at diagnosis have not been well described, and a "triphasic pattern" of constitutional symptoms evolving into vascular inflammation and fibrosis has been reported but never systematically evaluated.

Methods: Patients with TAK were prospectively recruited from the National Institutes of Health (NIH) and the Vasculitis Clinical Research Consortium (VCRC). Based on clinical presentation at diagnosis, patients were divided into five categories: (1) constitutional symptoms alone, (2) carotidynia, (3) other vascular-associated symptoms, (4) major ischemic event, or (5) asymptomatic. Associated clinical characteristics were evaluated in each category. Preceding symptoms were also assessed to determine the presence of a triphasic disease pattern.

Results: A total of 275 patients with TAK were included (VCRC=208; NIH=67). Similar heterogeneity of clinical presentation was identified in each cohort: constitutional symptoms (8%), carotidynia (13-15%), other vascular symptoms (43-47%), major ischemic event (28-30%), and asymptomatic (2-6%). An increased relative proportion of males was seen in patients who presented with constitutional symptoms or were asymptomatic at diagnosis (p<0.01). Patients who presented with constitutional symptoms and major ischemic events were youngest at diagnosis. Patients in the asymptomatic group were oldest at diagnosis and often were not treated (p<0.01). Relapse was most frequent in patients who presented with carotidynia (p<0.01). A minority of patients (19%) who presented with a major ischemic event reported a triphasic pattern of disease.

Conclusion: There are diverse clinical presentations at diagnosis in TAK. Patients do not necessarily progress sequentially through phases of disease.
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http://dx.doi.org/10.1016/j.semarthrit.2020.04.012DOI Listing
August 2020

Subcutaneous Immunoglobulin for Antibody Deficiency in Antineutrophil Cytoplasmic Antibody (ANCA)-associated Vasculitis.

Cureus 2019 Dec 12;11(12):e6367. Epub 2019 Dec 12.

Medicine, Johns Hopkins Hospital, Johns Hopkins University School of Medicine, Baltimore, USA.

Objectives Intravenous immunoglobulin G (IVIG) is used to treat antineutrophil cytoplasmic antibody (ANCA) patients with recurrent infections as a result of hypogammaglobulinemia (HG) induced by treatment regimens. We sought to characterize clinical features, treatment, and outcomes for patients treated with the novel subcutaneous IgG (SCIG) for the aforementioned purpose.  Methods We conducted a retrospective study of 136 patients in our ANCA database to identify patients with recurrent infections and HG subsequently treated with SCIG. Patient demographics, serologies, treatment, and immunological parameters were assessed.  Results Of 136 patients, four were treated with SCIG. All were Caucasian, proteinase-3 (PR3)-positive, and the majority (n = 3) were females. All patients had pulmonary involvement, and regimens of cyclophosphamide (CYC) and/or rituximab (RTX) were employed for induction and remission. Three patients each experienced recurrent bouts of respiratory tract infections and shingles. Ig levels (G, M, and A) were reduced in all patients, except for one patient who had normal IgA levels. CD19/20 cells were depleted and CD3/4/8/NK cells were preserved in all patients. Three patients had no discernible antibody response to the pneumococcal vaccine (specific pneumococcal serotypes measured pre- and post-vaccine). The mean duration elapsed between the first rituximab administration and commencement of SCIG was 7.2 years. The IgG level normalized and none of the patients had a recurrence of infection since the initiation of SCIG.  Conclusion This data, albeit preliminary, is the first series that demonstrates SCIG can be a reliable alternative to IVIG in ANCA patients with recurrent infections secondary to HG. Early identification of this subset of patients is likely to mitigate infectious risks, associated morbidity, and hospitalization.
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http://dx.doi.org/10.7759/cureus.6367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957027PMC
December 2019

Derivation of an angiographically based classification system in Takayasu's arteritis: an observational study from India and North America.

Rheumatology (Oxford) 2020 05;59(5):1118-1127

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

Objectives: To develop and replicate, using data-driven methods, a novel classification system in Takayasu's arteritis based on distribution of arterial lesions.

Methods: Patients were included from four international cohorts at major academic centres: India (Christian Medical College Vellore); North America (National Institutes of Health, Vasculitis Clinical Research Consortium and Cleveland Clinic Foundation). All patients underwent whole-body angiography of the aorta and branch vessels, with categorization of arterial damage (stenosis, occlusion or aneurysm) in 13 territories. K-means cluster analysis was performed to identify subgroups of patients based on pattern of angiographic involvement. Cluster groups were identified in the Indian cohort and independently replicated in the North American cohorts.

Results: A total of 806 patients with Takayasu's arteritis from India (n = 581) and North America (n = 225) were included. Three distinct clusters defined by arterial damage were identified in the Indian cohort and replicated in each of the North American cohorts. Patients in cluster one had significantly more disease in the abdominal aorta, renal and mesenteric arteries (P < 0.01). Patients in cluster two had significantly more bilateral disease in the carotid and subclavian arteries (P < 0.01). Compared with clusters one and two, patients in cluster three had asymmetric disease with fewer involved territories (P < 0.01). Demographics, clinical symptoms and clinical outcomes differed by cluster.

Conclusion: This large study in Takayasu's arteritis identified and replicated three novel subsets of patients based on patterns of arterial damage. Angiographic-based disease classification requires validation by demonstrating potential aetiological or prognostic implications.
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http://dx.doi.org/10.1093/rheumatology/kez421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850097PMC
May 2020
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