Publications by authors named "Dafna D Gladman"

512 Publications

Axial Psoriatic Arthritis.

Authors:
Dafna D Gladman

Curr Rheumatol Rep 2021 Apr 28;23(6):35. Epub 2021 Apr 28.

Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, Ontario, 1E-410B, Canada.

Purpose Of Review: To review current understanding of the prevalence, clinical features, outcome measures and recent therapeutic trials in axial psoriatic arthritis (axPsA).

Recent Findings: The prevalence of axPsA is estimated at 40-50%. However, the definition of axPsA remains unclear, therefore these estimates may be inaccurate. Ax PsA appears to be distinct from ankylosing spondylitis in demographic, clinical, genetic and therapeutic features. Because of the lack of widely accepted definition of axPsA it has been difficult to design therapeutic trials for this domain of PsA. Several studies have demonstrated the uniquness of axPsA. Few recent trials suggest that therapies that work for peripheral arthritis also work for axPsA.
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http://dx.doi.org/10.1007/s11926-021-00999-8DOI Listing
April 2021

Author Correction: Evolving concepts in systemic lupus erythematosus damage assessment.

Nat Rev Rheumatol 2021 Apr 27. Epub 2021 Apr 27.

Manchester University Hospitals NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UK.

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http://dx.doi.org/10.1038/s41584-021-00620-3DOI Listing
April 2021

The incidence and risk factors for venous thromboembolic events in patients with psoriasis and psoriatic arthritis.

Semin Arthritis Rheum 2021 Apr 18;51(3):547-552. Epub 2021 Apr 18.

Division of Rheumatology, Women's College Hospital, Toronto, ON, Canada; Department of Medicine, University of Toronto, Toronto, ON, Canada. Electronic address:

Objectives: The risk of arterial vascular events is increased in patients with psoriatic disease (PsD), however, limited information exists about the risk of venous thromboembolism (VTE) in these patients. We assessed the incidence and risk factors for VTE in patients with PsD.

Methods: A multicentre cohort study was conducted involving patients with PsD followed prospectively from 1994 to 2020. Information about VTE, including pulmonary embolism (PE) and deep venous thrombosis (DVT), was obtained from provincial hospitalization databases. The incidence rate and cumulative probability of developing VTE were computed. Cox proportional hazards models were used to assess the association between risk factors, including comorbidities and disease-related factors, and the first VTE.

Results: A total 2,433 patients with PsD were analysed with 26 incident VTE (7 DVT alone, 12 PE alone, and 7 both PE and DVT). The incidence rates of the first VTE, DVT, and PE were 12, 6.5, and 8.8 events per 10,000 patient-years, respectively. The cumulative proportion of individuals developing VTE was 4.6% by 80 years of age. Independent predictors for VTE included older age, diabetes mellitus, and corticosteroid usage (all p<0.05).

Conclusion: Older patients with PsD, those with diabetes, and those using corticosteroids are at a higher risk of developing VTE. Risk stratification of patients with these identified risk factors for VTE will allow for more individualized patient management and improved medication selection.
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http://dx.doi.org/10.1016/j.semarthrit.2021.04.008DOI Listing
April 2021

Evolving concepts in systemic lupus erythematosus damage assessment.

Nat Rev Rheumatol 2021 Apr 15. Epub 2021 Apr 15.

Manchester University Hospitals NHS Foundation Trust, NIHR Manchester Biomedical Research Centre, Manchester Academic Health Science Centre, Manchester, UK.

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http://dx.doi.org/10.1038/s41584-021-00611-4DOI Listing
April 2021

Test-retest reliability for HAQ-DI and SF-36 PF for the measurement of physical function in psoriatic arthritis.

J Rheumatol 2021 Apr 15. Epub 2021 Apr 15.

Singapore General Hospital, Duke-NUS Medical School, Singapore; Duke-NUS Medical School, Singapore; Royal National Hospital for Rheumatic Diseases, University of Bath, Bath, United Kingdom; Department of Rheumatology, Holbaek Hospital, Danmark; Section for Biostatistics and Evidence-Based Research, the Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen; Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; Concord Repatriation General Hospital, Sydney, Australia; The Copenhagen Center for Arthritis Research, Centre for Rheumatology and Spine Disorders, Rigshospitalet Glostrup, University of Copenhagen, Denmark; Centre for Prognosis Studies in Rheumatic Diseases, Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario Canada; Department of Clinical Immunology & Rheumatology, Christian Medical College, Vellore, India; Patient Research Partner, Adjunct Assistant Professor, Duke University School of Medicine, Durham, North Carolina, USA; Patient Research Partner, Hong Kong; Patient Research Partner, Employed by Aurinia Pharma US Inc., Prosper, Texas USA; Medicine and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; National Institute for Health Research Clinician Scientist, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; Research Unit of Rheumatology, Department of Clinical Research, University of Southern Denmark, Odense University Hospital, Denmark; Rheumatology Research, Swedish Medical Center and University of Washington School of Medicine, Seattle, Washington, USA; Division of Immunology/Rheumatology, Stanford University School of Medicine, Palo Alto, California, USA; Medicine, University of Toronto, Senior Scientist, Krembil Research Institute, Director, Psoriatic Arthritis Program, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada. Correspondence to: Ying-Ying Leung, MD; Department of Rheumatology and Immunology, Singapore General Hospital, The Academia, level 4, 20 College Road, Singapore 169856. E-mail:

Objective: Due to no existing data, we aimed to derive evidence to support test-retest reliability for the Health Assessment Questionnaire-Disability Index (HAQ-DI) and Medical Outcome Survey Short-Form-36 item physical functioning domain (SF-36 PF) in psoriatic arthritis (PsA).

Methods: We identified datasets that collected relevant data for test-retest reliability for HAQ-DI and SF-36 PF; and evaluated them using OMERACT Filter 2.1 methodology. We calculated intra-class correlation coefficients (ICC) as a measure of test-retest reliability. We then conducted a quality assessment and evaluated the adequacy of test-retest reliability performance.

Results: Two datasets were identified for HAQ-DI and one for SF-36 PF in PsA. The quality of the datasets was good. The ICCs for HAQ-DI were excellent in both datasets: 0.94 (95% CI: 0.88 to 0.97) and 0.94 (95% CI: 0.89 to 0.97). The ICC of SF-36 PF was good (0.89, 95% CI: 0.76 to 0.95). The performance of test-retest reliability for both instruments was judged to be adequate.

Conclusion: The new data derived support good and reasonable test-retest reliability for HAQ-DI and SF-36 PF in PsA.
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http://dx.doi.org/10.3899/jrheum.210175DOI Listing
April 2021

Axial Disease in Psoriatic arthritis: The presence and progression of unilateral grade 2 sacroiliitis in a psoriatic arthritis cohort.

Semin Arthritis Rheum 2021 Mar 20;51(2):464-468. Epub 2021 Mar 20.

Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, ON, Canada; Division of Rheumatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background/purpose: A universally accepted definition of axial psoriatic arthritis (axPsA) is lacking. We aimed to 1) assess the presence of axial involvement as defined by "at least unilateral grade 2 sacroiliitis (Uni2SI)" and 2) assess the radiographic progression of Uni2SI and identify risk factors for progression.

Methods: PsA patients participating in a prospective observational cohort were classified according to their highest sacroiliitis grade. The baseline features of patients with Uni2SI were compared to patients meeting the radiographic criteria of the modified New York Ankylosing Spondylitis (mNY AS) criteria. Risk factors were examined for progression from Uni2SI in a sub-group of patients with >1 follow-up radiographs. Logistic regression and a survival analysis were carried out and identified risk factors associated with radiographic mNY AS compared to Uni2SI.

Results: Axial disease defined as ≥Uni2SI was detected in 612/1354 patients (45%). mNY AS sacroiliitis was observed in 477 patients (35%). Radiographic progression of Uni2SI was assessed in 154 patients, 80 (52%) progressed to mNY AS criteria within 5.5 years. At baseline, progressors were diagnosed at a younger age (35.6 vs. 38.9, p = 0.05), had less degenerative disc disease (OR = 0.47, p = 0.02), worse peripheral radiographic damage (OR=1.02, p = 0.03) and worse psoriasis (OR = 1.09, p = 0.01) compared to non-progressors. Patients with an elevated erythrocyte sedimentation rate were more likely to progress (HR = 1.83, p = 0.02), while patients with longer disease duration were less likely to progress (HR = 0.95, p = 0.02).

Conclusion: The radiographic mNY AS criteria appear to be suitable for defining axial PsA according to radiographs. MRI definitions are needed as well for the most appropriate definition of axial PsA.
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http://dx.doi.org/10.1016/j.semarthrit.2021.03.007DOI Listing
March 2021

Relationships between psoriatic arthritis composite measures of disease activity with patient-reported outcomes in phase 3 studies of tofacitinib.

Arthritis Res Ther 2021 03 26;23(1):94. Epub 2021 Mar 26.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, 2nd Floor Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK.

Background: In psoriatic arthritis (PsA), further understanding of the relationships between clinical measures and patient-reported outcomes (PROs) is needed. This post hoc analysis evaluated associations between minimal disease activity (MDA) as a continuous outcome (termed ScoreMDA) or Psoriatic Arthritis Disease Activity Score (PASDAS) with selected PROs not included in the composite measures.

Methods: Data from two phase 3 studies of tofacitinib in PsA (OPAL Broaden [NCT01877668; N = 422]; OPAL Beyond [NCT01882439; N = 394]) were included. MDA (binary outcome) was defined as meeting ≥5/7 criteria. For ScoreMDA, each criterion was assigned a value (1 = true; 0 = false; score range, 0-7; scores ≥5 indicated MDA). For PASDAS (score range, 0-10), higher scores indicated worse disease activity. PROs analyzed included Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Patient's Assessment of Arthritis Pain visual analog scale (Pain VAS), and EuroQoL-Five Dimensions-Three Level Health Questionnaire visual analog scale (EQ-5D-3L VAS) and utility index. Relationships were evaluated using repeated measures regression models.

Results: Similar, approximately linear relationships were confirmed between PASDAS or ScoreMDA and PROs in both studies. In OPAL Broaden and OPAL Beyond, a one-point difference in PASDAS was associated with clinically relevant differences in PROs, including EQ-5D-3L VAS (- 6.7 mm, - 6.9 mm), Pain VAS (9.9 mm, 10.7 mm), and FACIT-F (- 2.8, - 3.3). A one-point difference in ScoreMDA was associated with clinically relevant differences in PROs, including EQ-5D-3L VAS (5.0 mm, 5.5 mm) and FACIT-F (1.9, 2.7) in OPAL Broaden and OPAL Beyond, respectively.

Conclusions: Linear associations between PASDAS or ScoreMDA and PROs provide interpretable and quantifiable metrics between composite clinical measures and PROs, highlighting the importance of these measures in understanding the relevance of treat-to-target goals in PsA.

Trial Registration: ClinicalTrials.gov, NCT01877668 . Registered on June 12, 2013. ClinicalTrials.gov, NCT01882439 . Registered on June 18, 2013.
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http://dx.doi.org/10.1186/s13075-021-02474-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995583PMC
March 2021

Depression and Anxiety Reduce the Probability of Achieving a State of Sustained Minimal Disease Activity in Patients with Psoriatic Arthritis.

Arthritis Care Res (Hoboken) 2021 Mar 4. Epub 2021 Mar 4.

Psoriatic Disease Program, Centre for Prognosis Studies in the Rheumatic Diseases, Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Canada.

Objective: We aimed to determine whether the presence of depression or anxiety is associated with the achieving sustained minimal disease activity (MDA) in patients with psoriatic arthritis (PsA).

Methods: Adult patients satisfying CASPAR criteria prospectively followed from 2008 to 2017 were included. A standard protocol including physician assessment and patient-reported outcomes defined whether patients achieved sustained MDA, defined when MDA criteria were met for two or more consecutive visits. The presence of depression/anxiety was determined using three definitions: 1) a score of <=38 on the Mental Component Summary score of the SF-36 questionnaire; 2) a score of <=56 on the Mental Health sub-scale score; and 3) rheumatologist's report of a diagnosis or treatment for depression/anxiety. A discrete time-to-event analyses was conducted based on a proportional odds model to identify factors associated with achieving sustained MDA.

Results: 743 patients were included in the study. The number of patients identified as having depression/anxiety at baseline was: Definition 1- 331 (44.54%), 2- 364 (48.99%), and 3- 211 (28.4%). 337 patients (45.36%) failed to achieve sustained MDA. The presence of depression/anxiety was associated with reduced probability of achieving sustained MDA with OR=0.30, p <0.0001, OR=0.34, p <0.0001, and OR=0.47, p <0.0001 for Definitions 1, 2 and 3, respectively. Other variables associated with a reduced probability of achieving sustained MDA included the Charlson comorbidity index and fibromyalgia.

Conclusion: Symptoms of anxiety/depression reduce the probability of achieving sustained MDA in PsA. Comprehensive management of PsA should include measures for addressing these comorbidities.
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http://dx.doi.org/10.1002/acr.24593DOI Listing
March 2021

Medium versus high initial prednisone dose for remission induction in lupus nephritis: A propensity score matched analysis.

Arthritis Care Res (Hoboken) 2021 Mar 4. Epub 2021 Mar 4.

Centre for Prognosis Studies in Rheumatic Diseases, Toronto Lupus Clinic, University Health Network, Toronto, Ontario, Canada.

Background: The existing guidelines for lupus nephritis (LN) recommend initial prednisone doses of 0.3-1mg/kg/day. However, recent studies reported non-inferior outcomes with lower doses. The aim of this study was to compare the complete renal response rates in LN patients treated with prednisone ≤30mg/day or ≥40mg/day.

Patients-methods: Patients with new-onset LN and standard immunosuppressive treatment were followed for at least 12 months, divided into medium (≤30mg/day) and high prednisone groups (≥40mg/day) and matched (propensity score) based on the baseline differences. Complete renal response was defined as proteinuria <0.5g/day and no worsening in renal function. Glucocorticoid-related damage was also assessed.

Results: High prednisone patients (n=103, mean dose 48.6±12.3 mg/day) achieved better rates of complete response compared to the medium group (n=103, mean dose 24.2±4.6 mg/day) [61.8% vs. 38.2%, p=0.024] at 12 months. The difference in response rates was reproduced for several subgroups (concomitant immunosuppressive treatment, proliferative/non-proliferative LN). Complete remission rates were higher at two [67.8% vs. 39%, p=0.002] and three years [64.9% vs. 49.1%, p=0.025] after LN diagnosis. Cumulative glucocorticoid dose was comparable at two and three years. Glucocorticoid-related damage was accelerated in both groups for the same period.

Conclusion: Higher initial prednisone doses (median 45mg/day) achieved significantly better rates of complete renal response at 12 months in new-onset LN. Cumulative glucocorticoid dose and damage accrual was not different at 2 and 3 years after LN. Damage was more prominent in the late phases of LN in both groups, underlining the importance of rapid tapering and the need to implement alternative strategies.
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http://dx.doi.org/10.1002/acr.24592DOI Listing
March 2021

Instruments Measuring Physical Function for Psoriatic Arthritis Endorsed at GRAPPA 2020 Annual Meeting: Updates of the GRAPPA-OMERACT Working Group.

J Rheumatol 2021 Mar 1. Epub 2021 Mar 1.

As part of the supplement series GRAPPA 2020, this report was reviewed internally and approved by the Guest Editors for integrity, accuracy, and consistency with scientific and ethical standards. The authors are members of the Outcome Measures in Rheumatology (OMERACT), an organization that develops and validates outcome measures in rheumatology randomized controlled trials and longitudinal observational studies and receives arms-length funding from 36 sponsors. YYL is funded by the Clinician Scientist award of the National Medical Research Council, Singapore (NMRC/CSA-INV/0022/2017). The views expressed are those of the author(s) and not necessarily those of the NMRC. AMO is funded by the Jerome L. Greene Foundation Scholar Award, the Staurulakis Family Discovery Award, the Rheumatology Research Foundation, and the National Institutes of Health (NIH) through the Rheumatic Diseases Resource-based Core Center (P30-AR053503, Cores A and D; and P30-AR070254, Cores A and B). All statements in this report, including its findings and conclusions, are solely those of the authors and do not necessarily represent the views of the NIH, the National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS), or the Rheumatology Research Foundation (RRF). AO is funded by the Rheumatology Research Foundation and NIH/NIAMS K23 AR063764 and R01 AR072363. RC (the Parker Institute) is supported by a core grant from the Oak Foundation (OCAY-18-774-OFIL). AJM is funded by the National Psoriasis Foundation Psoriatic Disease Research Fellowship. LCC is funded by a National Institute of Health Research (NIHR) Research Clinician Scientist award. The research was supported by the NIHR Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. Y.Y. Leung, MB ChB, MD, Associate Professor, Duke-NUS Medical School, and Department of Rheumatology and Immunology, Singapore General Hospital, Singapore; A.M. Orbai, MD, MHS, Assistant Professor of Medicine, Director, Psoriatic Arthritis Program, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; W. Tillett, BSc, MB ChB, PhD, MRCP, Consultant Rheumatologist, Senior Lecturer, Royal National Hospital for Rheumatic Diseases, University of Bath, Bath, UK; A. Ogdie, MD, MSCE, Associate Professor of Medicine and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; L. Eder, MD, PhD, Women's College Research Institute, Women's College Hospital, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; N. Goel, MD, Patient Research Partner, Consultant, Caduceus Biomedical Consulting, LLC, and Adjunct Assistant Professor, Duke University School of Medicine, Durham, North Carolina, USA; P. Hojgaard, MD, PhD, Department of Rheumatology, Holbaek Hospital, Holbaek, and the Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark; R. Holland, MBBS, Concord Repatriation General Hospital, Sydney, Australia; A.J. Mathew, MBBS, DNB, DM, Associate Professor in Rheumatology, Christian Medical College, Vellore, India and Clinical Research Fellow, Psoriatic Arthritis Program, University Health Network, University of Toronto, Toronto, Ontario, Canada; C.A. Lindsay, PharmD, Patient Research Partner, VP Professional and Advocacy Relations, Aurinia Pharma U.S., Inc., Rockville, Maryland, USA; A. Antony, MBBS, Monash University School of Clinical Sciences, Monash Medical Centre, Clayton, Melbourne, Australia; J. Chau, GRAPPA Patient Research Partner, Hong Kong; R. Christensen, BSc, MSc, PhD, Musculoskeletal Statistics Unit, The Parker Institute, Bispebjerg and Frederiksberg Hospital, University of Copenhagen, Copenhagen, and Professor of Biostatistics and Clinical Epidemiology, Research Unit of Rheumatology, Department of Clinical Research, University of Southern Denmark, Odense University Hospital, Odense, Denmark; L.C. Coates, MB ChB, PhD, Associate Professor, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; P.J. Mease, MD, Rheumatology Research, Swedish Medical Center/Providence St. Joseph Health, and University of Washington School of Medicine, Seattle, Washington, USA; V. Strand, MD, Division of Immunology/Rheumatology, Stanford University School of Medicine, Palo Alto, California, USA; O. FitzGerald, MD, FRCPI, FRCP(UK), Consultant Rheumatologist and Newman Clinical Research Professor, Conway Institute for Biomolecular Research, University College Dublin, Dublin, Ireland; M. de Wit, PhD, Patient Research Partner, Amsterdam, The Netherlands; K. Callis Duffin, MD, MS, Department of Dermatology, University of Utah, Salt Lake City, Utah, USA; D.D. Gladman, MD, FRCPC, Professor of Medicine, University of Toronto, Senior Scientist, Krembil Research Institute, and Director, Psoriatic Arthritis Program, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada. LE has been on advisory boards or received educational/research grants from Novartis, UCB, Eli Lily, Pfizer, and Janssen. There are no conflicts of interest from other co-authors. This paper does not require institutional review board approval. Address correspondence to Dr. Y.Y. Leung, Department of Rheumatology and Immunology, Singapore General Hospital, 20 College Road, The Academia, Singapore. 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The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis (PsA) Working Group provided updates at the 2020 GRAPPA annual meeting on its work toward developing a core outcome set for PsA. Working groups were set up for the 4 prioritized domains: enthesitis, fatigue, structural damage, and physical function. Two instruments for measurement of physical function were provisionally endorsed: (1) the Health Assessment Questionnaire-Disability Index and (2) the physical functioning domain in the Medical Outcomes Study 36-item Short Form survey.
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http://dx.doi.org/10.3899/jrheum.201679DOI Listing
March 2021

Updates on Axial Psoriatic Arthritis From the 2020 GRAPPA Annual Meeting.

J Rheumatol 2021 Mar 1. Epub 2021 Mar 1.

As part of the supplement series GRAPPA 2020, this report was reviewed internally and approved by the Guest Editors for integrity, accuracy, and consistency with scientific and ethical standards. 1D.D. Gladman, MD, FRCPC, Professor of Medicine, University of Toronto, Senior Scientist, Schoeder Arthritis Institute, Krembil Research Institute, University Health Network. Director, Psoriatic Arthritis Program, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada; 2P.S. Helliwell, MD, PhD, Professor of Clinical Rheumatology, Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Harehills Lane, Leeds, and NIHR Leeds Biomedical Research Centre, Leeds, UK; 3D. Poddubnyy, MD, MSc, Professor of Rheumatology, Charité, Universitätsmedizin Berlin, Berlin, Germany; 4P.J. Mease, MD, Rheumatology Research, Swedish Medical Center/Providence St. Joseph Health, and University of Washington School of Medicine, Seattle, Washington, USA. PJM declares research grants, consultation fees, and/or speaker honoraria from AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, SUN Pharma, and UCB. DDG, PSH, and DP do not declare any conflicts of interest. This paper did not require institutional review board approval. Address correspondence to Dr. D.D. Gladman, Toronto Western Hospital, 399 Bathurst St. 1E-410B, Toronto, ON M5T 2S8, Canada. Email:

This article summarizes sessions that dealt with axial psoriatic arthritis (axPsA) at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2020 virtual meeting. The summary includes the symposium, which comprised a plenary presentation by Dr. Dafna Gladman from Toronto, Canada, as well as a panel discussion with Dr. Philip Helliwell, Dr. Denis Poddubnyy, and Dr. Gladman, moderated by Dr. Philip Mease. In addition, the paper also summarizes Dr. Mease's "Meet the Expert" session, which focused on axPsA.
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http://dx.doi.org/10.3899/jrheum.201672DOI Listing
March 2021

Measurement properties of radiographic outcome measures in Psoriatic Arthritis: A systematic review from the GRAPPA-OMERACT initiative.

Semin Arthritis Rheum 2021 Feb 11;51(2):367-386. Epub 2021 Feb 11.

Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom.

Background: Structural damage is as an important outcome in the Psoriatic Arthritis (PsA) Core Domain Set and its assessment is recommended at least once in the development of a new drug.

Objectives: To conduct a systematic review (SR) to identify studies addressing the measurement properties of radiographic outcome instruments for structural damage in PsA and appraise the evidence through the Outcome Measures in Rheumatology (OMERACT) Filter 2.1 Framework Instrument Selection Algorithm (OFISA).

Methods: A SR was conducted using search strategies in EMBASE and MEDLINE to identify full-text English studies which aimed to develop or assess the measurement properties of radiographic outcome instruments in PsA. Determination of eligibility and data extraction was performed independently by two reviewers with input from a third to achieve consensus. Two reviewers assessed the methodology and results of eligible studies and synthesized the evidence using OMERACT methodology.

Results: Twelve articles evaluating radiographic instruments were included. The articles assessed nine peripheral (hands, wrists and/or feet) and six axial (spinal and/or sacroiliac joints) radiographic instruments. The peripheral radiographic instruments with some evidence for reliability, cross-sectional construct validity and longitudinal construct validity were the Ratingen and modified Sharp van der Heijde scores. No instruments had evidence for clinical trial discrimination or thresholds of meaning. There was limited evidence for the measurement properties of all identified axial instruments.

Conclusion: There are significant knowledge gaps in the responsiveness of peripheral radiographic instruments. Axial radiographic instruments require further validation, and the need to generate novel instruments and utilise other imaging modalities should be considered.
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http://dx.doi.org/10.1016/j.semarthrit.2021.01.008DOI Listing
February 2021

Prologue: 2020 Annual Meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).

J Rheumatol 2021 Feb 15. Epub 2021 Feb 15.

As part of the supplement series GRAPPA 2020, this report was reviewed internally and approved by the Guest Editors for integrity, accuracy, and consistency with scientific and ethical standards. The source of support to enable these meetings was provided in 2020 by AbbVie, Amgen, Eli Lilly & Co., Janssen, Novartis, Pfizer, UCB, Bristol Myers Squibb, Gilead, Boehringer-Ingelheim, and SunPharma. In addition, our Innovation Partner in 2020 was Nordic Bioscience. K. Callis Duffin, MD, MS, Department of Dermatology, University of Utah, Salt Lake City, Utah, USA; A.B. Gottlieb, MD, PhD, Clinical Professor of Dermatology, Department of Dermatology, Icahn School of Medicine at Mount Sinai, and Co-chair, GRAPPA Publication Committee, New York, New York, USA; D. O'Sullivan, BE, GRAPPA Patient Research Partner, Our Lady's Hospice & Care Services, Rheumatic & Musculoskeletal Disease Unit, Dublin, Ireland; D.D. Gladman, MD, FRCPC, Professor of Medicine, University of Toronto, Senior Scientist, Krembil Research Institute, Director, Psoriatic Arthritis Program, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada; L.V. McFarland, MS, PhD, Consultant, Public Health Reserves Corps, Seattle, Washington, USA. KCD reports the following conflicts of interest: grants/investigator for Amgen, AbbVie, Celgene, Eli Lilly, Janssen, Bristol Myers Squibb, Stiefel, Novartis, Pfizer, Sienna, UCB, Regeneron, Boehringer-Ingelheim; speaker's bureau for Novartis (nonpromotional only); consultant/advisory board for Amgen, AbbVie, Celgene, Eli Lilly, Janssen, Bristol Myers Squibb, Stiefel, Novartis, Pfizer, Sienna, UCB, Ortho Dermatologic, Boehringer-Ingelheim. There are no conflicts of interest for all other coauthors. Address correspondence to Dr. K. Callis Duffin, University of Utah, 4A330 Dermatology, SOM, 30 North 1900 East, Salt Lake City, UT 84132, USA. Email:

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held its annual meeting in 2020 in an online format due to travel restrictions during the coronavirus disease 2019 (COVID‑19; caused by SARS-CoV-2) pandemic. The virtual meeting was attended by 351 rheumatologists, dermatologists, representatives of biopharmaceutical companies, and patient research partners. Similar to previous years, GRAPPA's annual meeting focused on the 3 overlapping missions of education, research, and clinical care of psoriatic disease. Trainee sessions this year included the annual trainee symposium and a grant-writing workshop. Plenary sessions included updates on COVID-19 and psoriatic disease from multispecialty and patient perspectives, and updates on pustular psoriasis and associated musculoskeletal manifestations. Progress on research and updates were presented for the following groups: Collaborative Research Network, Outcome Measures in Rheumatology (OMERACT) Psoriatic Arthritis Working Group, International Dermatology Outcome Measures, Composite Measures, Education Committee, and Treatment Guidelines. New this year were 3 concurrent workshops on ultrasound assessment of joints and entheses, magnetic resonance imaging of psoriatic arthritis, and pustular psoriasis efficacy endpoints; 6 "Meet the Expert" sessions; and facilitated "poster tours." In our prologue, we introduce the papers that summarize this meeting.
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http://dx.doi.org/10.3899/jrheum.201666DOI Listing
February 2021

Incidence of and Risk Factors for Heart Failure in Patients with Psoriatic Disease - A Cohort Study.

Arthritis Care Res (Hoboken) 2021 Feb 11. Epub 2021 Feb 11.

Division of Rheumatology, Women's College Hospital, Toronto, ON, Canada.

Objectives: To assess the incidence and risk factors for heart failure (HF) in patients with psoriatic disease (PsD) and describe their electrocardiographic and echocardiographic findings.

Methods: A cohort analysis was conducted involving patients with PsD followed prospectively from 1978 to 2018. Participants were assessed according to a standard protocol every 6 to 12-months. The primary outcome was the time to first event of HF, further classified into ischemic and non-ischemic HF (secondary outcomes). The association between cardiovascular risk factors, measures of disease activity and HF events was assessed using Cox proportional hazards regression. Electrocardiographic and echocardiographic findings associated with HF events were described.

Results: A total of 1994 patients with PsD were analyzed with 64 incident HF events (38 ischemic, 26 non-ischemic). The incidence rate of first HF event was 2.85 per 1000 patient years. In all events, most common electrocardiographic findings were atrial fibrillation (22%) and bundle branch blocks (29%). Echocardiogram revealed 37% reduced ejection fraction and 63% preserved ejection fraction. In multivariable analysis, independent risk factors for all HF events were ischemic heart disease, adjusted mean (AM)-tender joint count, AM-swollen joint count, AM-erythrocyte sedimentation rate, AM-C-reactive protein, and physical function (by health assessment questionnaire) (all p<0.05). Minimal disease activity state was protective for all HF (p<0.05).

Conclusions: Increased risk of HF is associated with a combination of known cardiovascular risk factors and measures of disease activity, particularly in non-ischemic HF. The effect of inflammation on HF may be partially independent of atherosclerotic disease.
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http://dx.doi.org/10.1002/acr.24578DOI Listing
February 2021

European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria item performance.

Ann Rheum Dis 2021 Feb 10. Epub 2021 Feb 10.

Department of Medicine, Division of Rheumatology, University of California at San Francisco and the VA Medical Center, San Francisco, California, USA.

Background/objectives: The European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) 2019 classification criteria for systemic lupus erythematosus system showed high specificity, while attaining also high sensitivity. We hereby analysed the performance of the individual criteria items and their contribution to the overall performance of the criteria.

Methods: We combined the EULAR/ACR derivation and validation cohorts for a total of 1197 systemic lupus erythematosus (SLE) and n=1074 non-SLE patients with a variety of conditions mimicking SLE, such as other autoimmune diseases, and calculated the sensitivity and specificity for antinuclear antibodies (ANA) and the 23 specific criteria items. We also tested performance omitting the EULAR/ACR criteria attribution rule, which defines that items are only counted if not more likely explained by a cause other than SLE.

Results: Positive ANA, the new entry criterion, was 99.5% sensitive, but only 19.4% specific, against a non-SLE population that included other inflammatory rheumatic, infectious, malignant and metabolic diseases. The specific criteria items were highly variable in sensitivity (from 0.42% for delirium and 1.84% for psychosis to 75.6% for antibodies to double-stranded DNA), but their specificity was uniformly high, with low C3 or C4 (83.0%) and leucopenia <4.000/mm³ (83.8%) at the lowest end. Unexplained fever was 95.3% specific in this cohort. Applying the attribution rule improved specificity, particularly for joint involvement.

Conclusions: Changing the position of the highly sensitive, non-specific ANA to an entry criterion and the attribution rule resulted in a specificity of >80% for all items, explaining the higher overall specificity of the criteria set.
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http://dx.doi.org/10.1136/annrheumdis-2020-219373DOI Listing
February 2021

Lower vitamin D is associated with metabolic syndrome and insulin resistance in systemic lupus: data from an international inception cohort.

Rheumatology (Oxford) 2021 Feb 8. Epub 2021 Feb 8.

Department of Rheumatology, Kantonsspital Schaffhausen, Schaffhausen, Schaffhausen, CH.

Objectives: Vitamin D (25(OH)D) deficiency and metabolic syndrome (MetS) may both contribute to increased cardiovascular risk in systemic lupus erythematosus (SLE). We aimed to examine the association of demographic factors, SLE phenotype, therapy and vitamin D levels with MetS and insulin resistance.

Methods: The Systemic Lupus International Collaborating Clinics (SLICC) enrolled patients recently diagnosed with SLE (<15 months) from 33 centres across 11 countries from 2000. Clinical, laboratory and therapeutic data were collected. Vitamin D level was defined according to tertiles based on distribution across this cohort, which were set at T1 (10-36 nmol/l), T2 (37-60 nmol/l) and T3 (61-174 nmol/l). MetS was defined according to the 2009 consensus statement from the International Diabetes Federation. Insulin resistance was determined using the HOMA-IR model. Linear and logistic regressions were used to assess the association of variables with vitamin D levels.

Results: Of the 1847 patients, 1163 (63%) had vitamin D measured and 398 (34.2%) subjects were in the lowest 25(OH)D tertile. MetS was present in 286 of 860 (33%) patients whose status could be determined. Patients with lower 25(OH)D were more likely to have MetS and higher HOMA-IR. The MetS components, hypertension, hypertriglyceridemia and decreased HDL were all significantly associated with lower 25(OH)D. Increased average glucocorticoid exposure was associated with higher insulin resistance.

Conclusions: MetS and insulin resistance are associated with lower vitamin D in patients with SLE. Further studies could determine whether vitamin D repletion confers better control of these cardiovascular risk factors and improve long-term outcomes in SLE.
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http://dx.doi.org/10.1093/rheumatology/keab090DOI Listing
February 2021

Systematic literature review of non-topical treatments for early, untreated (systemic therapy naïve) psoriatic disease: a GRAPPA initiative.

Rheumatol Adv Pract 2020 11;4(2):rkaa032. Epub 2020 Jul 11.

NIHR Leeds Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds.

Background: Psoriatic disease (PsD) is a complex systemic disorder with cutaneous and musculoskeletal manifestations. Current evidence on pharmacological interventions, effective across the spectrum of clinical manifestations of early, systemic treatment-naïve PsD, is limited. This review aims to appraise such evidence.

Methods: This systematic review examined seven patient-intervention-comparator-outcome research questions to address the efficacy of the interventions on the following: across the spectrum of clinical manifestations PsD activity; peripheral arthritis; dactylitis; spondylitis; enthesitis; skin; and nails. Early PsD was defined as a disease duration of ≤2 years, except for studies investigating outcomes restricted to the skin. Eligible references were clinical trials or well-designed prospective studies/series reporting on adult humans, untreated, with cutaneous and/or musculoskeletal features of PsD.

Results: Nine references (out of 160 319, publication range 1946-2019) fulfilled the eligibility criteria. No study adopted comprehensive (that is, simultaneous assessment of different PsD manifestations) composite indices as primary outcome measures. Individual studies reported that apremilast and biologics successfully improved outcomes (disease activity index for PsA, minimal disease activity, PsA DAS, psoriasis area and severity index, PsA response criteria) when efficacy analyses were restricted to single manifestations of untreated PsD. Only qualitative synthesis of evidence was possible, owing to the following factors: data heterogeneity (disease classification criteria, outcome measures); unavailable data subsets (focused on early, untreated PsD) at the single study level; and insufficient data on the exposure of participants to previous treatment.

Conclusion: Effective interventions, albeit limited in scope, were found for early, treatment-naïve PsD. No study provided evidence about the management of co-occurring cutaneous and musculoskeletal manifestations in early, treatment-naïve PsD. This review highlights an unmet need in research on early PsD.
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http://dx.doi.org/10.1093/rap/rkaa032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850142PMC
July 2020

New EULAR/ACR 2019 SLE Classification Criteria: defining ominosity in SLE.

Ann Rheum Dis 2021 Jan 15. Epub 2021 Jan 15.

Division of Rheumatology, Department of Medicine, Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

Objective: To determine the ominosity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) Systemic Lupus Erythematosus Classification Criteria by determining its predictive role for disease severity in the first 5 years following diagnosis.

Methods: 867 patients with systemic lupus erythematosus (SLE) from the Toronto Lupus Clinic were included (all first 12 months after SLE diagnosis). The EULAR/ACR criteria score was calculated based on baseline information. To determine disease severity in the first 5 years after diagnosis, adjusted mean SLE Disease Activity Index 2000 (AMS), flares, remission and immunosuppressive treatment were used as outcomes. The Systemic Lupus International Collaborating Clinics (SLICC) registry comprised the validation cohort.

Results: Based on receiver operating characteristic analysis, a EULAR/ACR score of 20 was used as a threshold to compare outcomes between groups. In the first 5 years of disease course, patients with a score of ≥20 had higher AMS scores (p<0.001) and were more likely to ever experience a flare (p<0.001). These patients had lower probabilities of achieving remission and higher requirements for immunosuppressives. Results were confirmed in the SLICC validation cohort. Patients with a score of ≥20 had higher AMS during the first 5 years of disease (5.4 vs 3.1% and ≥20 vs <20 respectively, p≤0.001). The score correlated with AMS (r=0.43, p≤0.001) in the same time frame.

Conclusion: A EULAR/ACR score of ≥20 is an indicator of ominosity in SLE. Patients with a score of ≥20 were characterised by a more active disease course throughout the first 5 years. These criteria provide prognostic information regarding disease severity in the first 5 years following diagnosis.
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http://dx.doi.org/10.1136/annrheumdis-2020-218670DOI Listing
January 2021

The baseline interferon signature predicts disease severity over the subsequent 5 years in systemic lupus erythematosus.

Arthritis Res Ther 2021 01 16;23(1):29. Epub 2021 Jan 16.

Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Canada.

Objectives: Type I interferons (IFNs) play an important role in the pathophysiology of systemic lupus erythematosus (SLE). While cross-sectional data suggest an association between IFN-induced gene expression and SLE disease activity, interest in this as a biomarker of flare has been tempered by a lack of fluctuation with disease activity in the majority of patients. This led us to question whether IFN-induced gene expression might instead be a biomarker of overall disease severity, with patients with high levels spending more time in an active disease state.

Methods: Levels of five interferon-responsive genes were measured in the whole peripheral blood at baseline visit for 137 SLE patients subsequently followed for 5 years. Log transformed values were summed to yield a composite IFN5 score, and the correlation with various disease outcomes examined. Receiver operator characteristic analyses were performed for outcomes of interest. Kaplan-Meier curves were generated to compare the proportion of flare-free patients with high and low IFN5 scores over time.

Results: The baseline IFN5 score was positively correlated with the adjusted mean SLE disease activity index-2000, number of flares, adjusted mean prednisone dose, and number of new immunosuppressive medications over the subsequent 5 years. Optimal cut-offs for the IFN5 score were determined using Youden's index and predicted more severe outcomes with 57-67% accuracy. A high baseline IFN5 level was associated with a significantly increased risk of subsequent flare.

Conclusions: Measurement of the type I IFN signature is a useful tool for predicting the subsequent disease activity course.
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http://dx.doi.org/10.1186/s13075-021-02414-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811214PMC
January 2021

Malignancy in psoriatic disease: Results from prospective longitudinal cohorts.

Semin Arthritis Rheum 2021 Feb 24;51(1):144-149. Epub 2020 Dec 24.

Center for Prognostic Studies in the Rheumatic Diseases, Krembil Research Institute, University Health Network, Toronto, ON Canada; Department of Medicine, University of Toronto, Toronto, ON Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada. Electronic address:

Objectives: To estimate the prevalence and incidence of malignancy and its types in psoriatic arthritis (PsA) and psoriasis without arthritis (PsC) patients, in comparison to the general population, and to identify the predictive factors for developing cancer in psoriatic disease (PsD).

Methods: PsA patients followed prospectively since 1978 and PsC patients followed since 2006 at 6-to-12 month intervals according to a standard protocol were included. Malignancies were recorded prospectively and linkages with Cancer Care Ontario and the Death Registry were carried out to confirm the presence and type of malignancy up to December 2016. Standardized incidence ratios (SIR) were calculated for overall cancers and by age and sex. Cox regression analysis was conducted to identify risk factors associated with the development of malignancy after the diagnosis of PsD.

Results: 2051 patients (PsD) were included of whom 228 (11%) developed cancer. 168 patients developed cancer after first clinic visit and are included in this report. Overall SIR for malignancy was 0.83 (0.68, 1.00), SIR for females was 1.06 (0.80, 1.37), and for males was 0.67 (0.50, 0.88). The most common malignancies were skin, breast, and hematological. Skin cancer was the only specific cancer that had a higher incidence than the general population with SIR = 3.37 (1.84, 5.66). There was insufficient evidence to suggest an increased risk of malignancy associated with biologics use.

Conclusions: In this long-term prospective follow-up of patients with PsA and PsC the overall malignancy risk was not found to be higher than the general population, while skin cancer increased.
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http://dx.doi.org/10.1016/j.semarthrit.2020.12.008DOI Listing
February 2021

Prevalence and factors associated with osteoporosis and bone mineral density testing in psoriatic arthritis.

Arthritis Care Res (Hoboken) 2020 Dec 16. Epub 2020 Dec 16.

Department of Medicine Temerty Faculty of Medicine, University of Toronto, Ontario, Canada, Toronto.

Objectives: To determine bone mineral density (BMD) in psoriatic arthritis (PsA) patients, factors associated with undergoing BMD testing, and the effect of PsA clinical activity on BMD.

Methods: Patients attending the University of Toronto PsA Clinic with a BMD from cohort inception to January 2019 were included. Descriptive statistics summarized lumbar spine, femoral neck and total hip T-scores. Cox proportional hazard regression identified predictors for BMD testing. Logistic regression analysis determined odds of having normal (T-score ≥ -1.0) versus osteoporotic range BMD (T-score ≤ -2.5). A multi-state model determined factors associated with BMD state changes over time.

Results: Of the 1479 patients, 214 had BMDs. Mean T-scores at the lumbar spine, femoral neck and total hip were -0.30±0.32, -1.10±1.04 and -0.45±0.42 respectively. Osteopenia and osteoporosis occurred in 45.27% and 12.94% of patients. Increasing age, menopause, elevated acute phase reactants, biologic, methotrexate and systemic glucocorticoid use were associated with a higher chance of undergoing BMD testing. Increased BMI and biologic use were associated with a lower chance of having osteoporotic range BMD. In multi-state analysis, polyarthritis may portend lower BMDs over time, although this did not achieve statistical significance due to low patient numbers.

Conclusions: The prevalence of osteopenia and osteoporosis in the PsA cohort were similar to the general population. Clinicians are using osteoporosis risk factors and PsA disease severity markers to select patients for BMD testing. Polyarticular disease may portend worse BMDs. Biologic use and increased BMI appear to have a protective effect.
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http://dx.doi.org/10.1002/acr.24538DOI Listing
December 2020

Rho-GTPase pathways may differentiate treatment response to TNF-alpha and IL-17A inhibitors in psoriatic arthritis.

Sci Rep 2020 12 10;10(1):21703. Epub 2020 Dec 10.

Faculty of Medicine, Craig L Dobbin Genetics Research Centre, Memorial University, Suite 3M500, 300 Prince Philip Drive, St. John's, NL, A1B3V6, Canada.

Biological therapies have dramatically improved the therapeutic landscape of psoriatic arthritis (PsA); however, 40-50% of patients are primary non-responders with response rates declining significantly with each successive biological therapy. Therefore, there is a pressing need to develop a coherent strategy for effective initial and subsequent selection of biologic agents. We interrogated 40 PsA patients initiating either tumour necrosis factor inhibitors (TNFi) or interleukin-17A inhibitors (17Ai) for active PsA. Patients achieving low disease activity according to the Disease Activity Index for PsA (DAPSA) at 3 months were classified as responders. Baseline and 3-month CD4 transcript profiling were performed, and novel signaling pathways were identified using a multi-omics profiling and integrative computational analysis approach. Using transcriptomic data at initiation of therapy, we identified over 100 differentially expressed genes (DEGs) that differentiated IL-17Ai response from non-response and TNFi response from non-response. Integration of cell-type-specific DEGs with protein-protein interactions and further comprehensive pathway enrichment analysis revealed several pathways. Rho GTPase signaling pathway exhibited a strong signal specific to IL-17Ai response and the genes, RAC1 and ROCKs, are supported by results from prior research. Our detailed network and pathway analyses have identified the rewiring of Rho GTPase pathways as potential markers of response to IL17Ai but not TNFi. These results need further verification.
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http://dx.doi.org/10.1038/s41598-020-78866-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728744PMC
December 2020

Factors Associated With Rapid Progression to Endstage Kidney Disease in Lupus Nephritis.

J Rheumatol 2021 02 1;48(2):228-231. Epub 2020 Sep 1.

K. Tselios, MD, PhD, D.D. Gladman, MD, FRCPC, C. Taheri, BHSc, J. Su, MB, MSc, M.B. Urowitz, MD, FRCPC, University of Toronto Lupus Clinic, Centre of Prognosis Studies in the Rheumatic Diseases, University Health Network, Toronto, Ontario, Canada.

Objective: Lupus nephritis (LN) may lead to endstage kidney disease (ESKD) in 22% of patients over a period of 15 years, with the risk being particularly higher in diffuse proliferative forms. The rate of kidney function decline varies. However, a catastrophic course leading to ESKD within a few years from onset is uncommon. The aim of the present study was to assess the factors associated with rapid progression to ESKD in patients with LN.

Methods: Patients from the Toronto Lupus Clinic with biopsy-proven LN at presentation and estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m, who developed ESKD within 3 years were retrieved. Pathology reports were reviewed with particular emphasis on distinct histopathologic features. Demographic, clinical, laboratory, and therapeutic variables were also analyzed.

Results: Ten patients (1.8% of the total LN population) developed ESKD within 3 years of diagnosis. Their mean age was 34.2 ± 7.3 years, mean time to ESKD 19.2 ± 12.4 months, initial eGFR 90.2 ± 24.9 mL/min/1.73 m, proteinuria 2.7 ± 1.04 g/24 h. The median rate of kidney function decline was > 43 mL/min/1.73 m/year. One patient had LN class III, 5 had LN class IV, 2 had membranous LN (class V), and another 2 had mixed IV/V. Moreover, 2 patients had extensive thrombotic microangiopathy, 1 collapsing glomerulonephritis, and 1 concomitant antiglomerular basement membrane (anti-GBM) nephropathy. Four patients showed no unusual kidney pathology; all of them had severe noncompliance (discontinued all medications to follow alternative treatment).

Conclusion: Catastrophic progression to ESKD is uncommon in LN. The major associated factors are poor compliance and distinct histopathologic features such as thrombotic microangiopathy, collapsing glomerulopathy, and concomitant anti-GBM nephropathy.
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http://dx.doi.org/10.3899/jrheum.200161DOI Listing
February 2021

Prediction of hospitalizations in systemic lupus erythematosus using the Systemic Lupus International Collaborating Clinics Frailty Index (SLICC-FI).

Arthritis Care Res (Hoboken) 2020 Nov 5. Epub 2020 Nov 5.

Emory University School of Medicine, Division of Rheumatology, Atlanta, Georgia, USA.

Objective: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) predicts mortality and damage accrual in SLE, but its association with hospitalizations has not been described. We estimated the association of baseline SLICC-FI values with future hospitalizations in the SLICC inception cohort.

Methods: Baseline SLICC-FI scores were calculated. The number and duration of inpatient hospitalizations during follow-up were recorded. Negative binomial regression was used to estimate the association between baseline SLICC-FI values and the rate of hospitalizations per patient-year of follow-up. Linear regression was used to estimate the association of baseline SLICC-FI scores with the proportion of follow-up time spent in hospital. Multivariable models were adjusted for relevant baseline characteristics.

Results: The 1549 SLE patients eligible for this analysis were mostly female (88.7%) with mean (SD) age 35.7 (13.3) years and median (IQR) disease duration 1.2 (0.9-1.5) years at baseline. Mean (SD) baseline SLICC-FI was 0.17 (0.08). During mean (SD) follow-up of 7.2 (3.7) years, 614 patients (39.6%) experienced 1570 hospitalizations. Higher baseline SLICC-FI values (per 0.05 increment) were associated with more frequent hospitalizations during follow-up (Incidence Rate Ratio 1.21; 95%CI 1.13-1.30), adjusting for baseline age, sex, corticosteroid use, immunosuppressive use, ethnicity/location, SLE disease activity index 2000 (SLEDAI-2K), SLICC/ACR damage index (SDI), and disease duration. Among patients with ≥1 hospitalization, higher baseline SLICC-FI values predicted a greater proportion of follow-up time spent hospitalized (Relative Rate 1.09; 95%CI 1.02-1.16).

Conclusion: The SLICC-FI predicts future hospitalizations among incident SLE patients, further supporting the SLICC-FI as a valid health measure in SLE.
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http://dx.doi.org/10.1002/acr.24504DOI Listing
November 2020

Response to placebo in non-renal, non-neuropsychiatric systemic lupus erythematosus: a systematic review and pooled analysis.

Rheumatology (Oxford) 2021 01;60(1):73-80

Centre for Prognosis Studies in Rheumatic Diseases, Toronto Lupus Clinic, University Health Network, Toronto, Canada.

Objectives: Most randomized controlled trials (RCTs) in SLE have failed to reach their respective end points, with the rates of response to placebo (plus standard-of-care treatment) being unexpectedly high. The aim of this systematic review was to quantify the response to placebo in non-renal, non-neuropsychiatric lupus.

Methods: The PubMed database was searched (from 2000 to December 2019) for phase II/III RCTs assessing the efficacy and safety of biologics in non-renal, non-neuropsychiatric SLE. Data on the efficacy and safety of the placebo-treated patients were collected in a pre-established data retrieval form. Descriptive statistics were used.

Results: A total of 24 RCTs (n = 11128 in total) were included. Placebo-treated patients (n = 3899) were mostly females (93.5%), Caucasians (60.2%), of mean age 39.7 years, and having a mean disease duration of 7.4 years. Their mean initial SLEDAI 2000 was 10.4, whereas 60.5% had positive anti-dsDNA antibodies, 41.9% low C3 and 35.6% low C4 at randomization. Standard-of-care treatment included glucocorticosteroids in 85.9%, antimalarials in 72.8% and immunosuppressives in 48.5%. The response to placebo was 36.2% for the primary end point (as defined in each study), 39.8% for the SLE Responder Index-4 (SRI-4), 29.2% for SRI-5, 28.4% for SRI-6 and 30.9% for BILAG-based Combined Lupus Assessment response. Regarding safety, there were serious adverse events in 16.3% of patients, serious infections in 5.5% and malignancies in 0.3%, and death occurred in 0.56% of patients.

Conclusion: More than one-third of the placebo-treated patients achieved their respective primary end points in RCTs with biologics in non-renal, non-neuropsychiatric SLE. The response rate was higher for certain end points, such as the SRI-4, while it decreased with more stringent end points.
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http://dx.doi.org/10.1093/rheumatology/keaa655DOI Listing
January 2021

Trends in mortality and cause-specific mortality among patients with psoriasis and psoriatic arthritis in Ontario, Canada.

J Am Acad Dermatol 2021 May 21;84(5):1302-1309. Epub 2020 Oct 21.

Women's College Hospital, Toronto, Canada; University of Toronto, Toronto, Canada. Electronic address:

Background: There is limited information about mortality rates among patients with psoriasis and psoriatic arthritis (PsA) in North America and their change over the past 2 decades.

Objective: To compare all-cause and cause-specific mortality rates in patients with psoriasis to the general population in Ontario, Canada, from 1996 to 2016.

Methods: We conducted a population-based, retrospective cohort study of adult residents using administrative health data. All-cause and cause-specific standardized mortality rates, standardized mortality ratios, and excess mortality rates were calculated.

Results: 176,858 (2,524 deaths) patients with psoriasis and 15,430 (221 deaths) patients with PsA were identified in 2016. Patients with psoriasis and PsA had standardized excess mortality rates of 1.44 and 2.43 per 1000 population, respectively. Standardized mortality rates decreased by approximately 30% over the study period in both disease groups but remained significantly elevated compared to the general population. The leading causes of death in psoriasis and PsA patients were cancer, circulatory disease, and respiratory conditions.

Limitations: We were unable to classify patients according to disease severity.

Conclusions: Despite improvements in psoriasis treatment, the relative excess mortality, which may be related to risk factors for psoriatic disease, remained unchanged, with an average of approximately 1 to 2 extra deaths per 1,000 patients in 2016.
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http://dx.doi.org/10.1016/j.jaad.2020.10.031DOI Listing
May 2021

Relationship Between Genetic Risk and Age of Diagnosis in Systemic Lupus Erythematosus.

J Rheumatol 2020 Oct 15. Epub 2020 Oct 15.

This work was funded by a grant from the Alliance for Lupus Research (number 417516) to EDS. JBH was supported by grants from the National Institutes of Health: AI024717 (R01), AI130830 (U01), and AI148276 (R01). D. Dominguez, MSc, Division of Rheumatology, Hospital for Sick Children, Hospital for Sick Children, Research Institute, University of Toronto, Toronto, Ontario, Canada; S. Kamphuis, MD, PhD, Division of Rheumatology Department of Pediatrics, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, the Netherlands; J. Beyene, PhD, Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton; J. Wither, MD, PhD, Division of Genetics and Development, Krembil Research Institute, Arthritis Centre of Excellence, Division of Rheumatology, Toronto Western Hospital, University Health Network, Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada; J.B. Harley, MD, PhD, Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, and Department of Pediatrics, University of Cincinnati, and US Department of Veterans Affairs Medical Center, Cincinnati, Ohio; I. Blanco, MD, C. Vila-Inda, MD, Albert Einstein College of Medicine, Division of Rheumatology, Bronx, New York; H. Brunner, MD, MSc, Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; M. Klein-Gitleman, MD, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois; D. McCurdy, MD, Division of Pediaitric Rheumatology, University of California Los Angeles, Los Angeles, California; D.M. Wahezi, MD, Children's Hospital at Montefiore, Division of Pediatric Rheumatology, Albert Einstein College of Medicine, the Bronx, New York; T. Lehman, MD, Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, New York, USA; M. Jelusic, MD, Department of Pediatric Rheumatology, University of Zagreb School of Medicine, Zagreb, Croatia; C.A. Peschken, MD, MSc, Departments of Medicine and Community Health Sciences, University of Manitoba, Winnipeg, Manitoba; J.E. Pope, MD, MPH, Professor of Medicine, Department of Medicine, University of Western Ontario, London, Ontario; D.D. Gladman, MD, Department of Medicine, University of Toronto, Toronto, Ontario; J.G. Hanly, MD, Division of Rheumatology, Department of Medicine and Department of Pathology, Queen Elizabeth II Health Sciences Center and Dalhousie University, Halifax, Nova Scotia; A.E. Clarke, MD, Cumming School of Medicine, University of Calgary, Calgary, Alberta; S. Bernatsky, MD, PhD, Department of Medicine, McGill University, Montreal, Quebec; C. Pineau, MD, Department of Medicine, McGill University Hospital, Montreal, Quebec; C.D. Smith, MD, Department of Medicine, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario; S. Barr, MD, Division of Rheumatology, Department of Medicine, University of Calgary, Calgary, Alberta; G. Boire, MD, Division of Rheumatology, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec, E. Rich, MD, Division of Rheumatology, Centre Hospitalier de l'Université de Montreal, Department of Medicine, University of Montreal School of Medicine, Montreal, Quebec; E.D. Silverman, MD, FRCPC, Professor Emeritus of Pediatrics, Division of Rheumatology, Department of Pediatrics, SickKids Hospital, SickKids Hospital Research Institute, University of Toronto, Toronto, Ontario, Canada. There are no competing interests for the principal investigator or any coinvestigators. There was no financial or other commercial support for any of the work associated with this manuscript in any way. Address correspondence to Dr. E.D. Silverman, Division of Rheumatology, Hospital for Sick Children, 555 University Ave., Toronto, ON M5N 1R2, Canada. Email: Full Release Article. For details see Reprints and Permissions at jrheum.org. Accepted for publication October 1, 2020.

Objective: Specific risk alleles for childhood-onset systemic lupus erythematosus SLE (cSLE) vs adult-onset SLE (aSLE) patients have not been identified. The aims of this study were to determine if there is an association (1) between non-HLA-related genetic risk score (GRS) and age of SLE diagnosis, and (2) between HLA-related GRS and age of SLE diagnosis.

Methods: Genomic DNA was obtained from 2001 multiethnic patients and genotyped using the Immunochip. Following quality control, genetic risk counting (GRCS), weighted (GRWS), standardized counting (GRSCS), and standardized weighted (GRSWS) scores were calculated based on independent single-nucleotide polymorphisms from validated SLE loci. Scores were analyzed in a regression model and adjusted by sex and ancestral population.

Results: The analyzed cohort consisted of 1540 patients: 1351 females and 189 males (675 cSLE and 865 aSLE). There were significant negative associations between all non-HLA GRS and age of SLE diagnosis: = 0.011 and r = 0.175 for GRWS; = 0.008 and r = 0.178 for GRSCS; = 0.002 and r = 0.176 for GRSWS (higher GRS correlated with lower age of diagnosis.) All HLA GRS showed significant positive associations with age of diagnosis: = 0.049 and r = 0.176 for GRCS; = 0.022 and r = 0.176 for GRWS; = 0.022 and r = 0.176 for GRSCS; = 0.011 and r = 0.177 for GRSWS (higher GRS correlated with higher age of diagnosis).

Conclusion: Our data suggest that there is a linear relationship between genetic risk and age of SLE diagnosis and that HLA and non-HLA GRS are associated with age of diagnosis in opposite directions.
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http://dx.doi.org/10.3899/jrheum.200002DOI Listing
October 2020

Network Meta-Analysis of Tofacitinib, Biologic Disease-Modifying Antirheumatic Drugs, and Apremilast for the Treatment of Psoriatic Arthritis.

Curr Ther Res Clin Exp 2020 12;93:100601. Epub 2020 Aug 12.

Pfizer Inc, Groton, Connecticut.

Background: Tofacitinib and other new treatments approved for use in psoriatic arthritis have only recently been included in psoriatic arthritis treatment guidelines, and studies evaluating the relative efficacy of available therapies are important to inform treatment decisions by healthcare professionals.

Objective: To perform a network meta-analysis to evaluate the efficacy and safety profiles of tofacitinib, biologic disease-modifying antirheumatic drugs (bDMARDs), and apremilast in patients with psoriatic arthritis naïve to tumor necrosis factor inhibitor therapy (TNFi-naïve) or with an inadequate response (TNFi-IR).

Methods: A systematic literature review used searches of MEDLINE, Embase, and The Cochrane Library on October 9, 2017. Randomized controlled trials including adult patients with psoriatic arthritis receiving treatment administered as monotherapy or with conventional synthetic DMARDs were selected. Efficacy outcomes included American College of Rheumatology 20 response, change from baseline in Health Assessment Questionnaire-Disability Index, ≥75% improvement in Psoriasis Area and Severity Index, and change from baseline in Dactylitis Severity Score and Leeds Enthesitis Index. Treatment effects were evaluated during placebo-controlled phases, using a binomial logit model for binary outcomes and a normal identify link model for other outcomes. Discontinuations due to adverse events and serious infection events were assessed as safety outcomes.

Results: The network meta-analysis included 24 published randomized controlled trials, of which 13 enrolled TNFi-naïve patients only, 3 enrolled TNFi-IR patients only, and 8 enrolled both TNFi-naïve and TNFi-IR patients. Placebo-controlled treatment durations ranged from 12 to 24 weeks. Indirect comparisons showed tofacitinib 5 and 10 mg BID to have similar efficacy compared with most bDMARDs and apremilast in improving joint symptoms (based on American College of Rheumatology 20 response), and with some bDMARDs in improving skin symptoms (based on Psoriasis Area and Severity Index) (tofacitinib 10 mg BID only in TNFi-IR) in patients with psoriatic arthritis who were TNFi-naïve or TNFi-IR. Results also showed that, compared with placebo, the improvement in physical functioning (based on Health Assessment Questionnaire-Disability Index) with tofacitinib 5 and 10 mg BID was similar to that observed with most bDMARDs and apremilast in TNFi-naïve patients, and similar to that observed with all bDMARDs with available data in the TNFi-IR population. Improvements in Dactylitis Severity Score and Leeds Enthesitis Index scores were comparable between treatments. Tofacitinib 5 and 10 mg BID were median-ranked 8 and 15, respectively, for discontinuation due to any adverse events, and 5 and 16, respectively, for a serious infection event out of a total of 20 treatments in the network (lower numbers are more favorable).

Conclusions: Tofacitinib provides an additional treatment option for patients with psoriatic arthritis, both in patients naïve to TNFi and in those with TNFi-IR. ( 2020; 81:XXX-XXX).
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http://dx.doi.org/10.1016/j.curtheres.2020.100601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494680PMC
August 2020

Clinical trial discrimination of physical function instruments for psoriatic arthritis: A systematic review.

Semin Arthritis Rheum 2020 10 18;50(5):1158-1181. Epub 2020 Jun 18.

Rheumatology Research, Swedish Medical Center and University of Washington School of Medicine, Seattle, WA, USA.

Objectives: Physical function (PF) is a core domain to be measured in randomized controlled trials (RCTs) of psoriatic arthritis (PsA), yet the discriminative performance of patient reported outcome measures (PROMs) for PF in RCTs has not been evaluated systematically. In this systematic review, we aimed to evaluate the clinical trial discrimination of PF-PROMs in PsA RCTs.

Methods: We searched PubMed and Scopus databases in English to identify all original RCTs on biological and targeted synthetic disease modifying anti-rheumatic drugs (DMARDs) conducted in PsA. We assessed quality in each article using the OMERACT good method checklist. Effect sizes (ES) for the PF-PROMs were calculated and appraised using a priori hypotheses. Evidence supporting clinical trial discrimination for each PF-PROM was summarized to derive recommendations.

Results: 35 articles from 31 RCTs were included. Four PF-PROMs had data for evaluation: HAQ-Disability Index (DI), HAQ-Spondyloarthritis (S), and Short Form 36-item Health Survey Physical Component Summary (SF-36 PCS) and Physical Functioning domain (SF-36 PF). As anticipated, higher ES values were observed for intervention groups than the control groups. Across all studies, for HAQ-DI, the median ES were -0.73 and -0.24 for intervention and control groups, respectively. Whereas for SF-36 PCS, the median ES were 0.77 and 0.23. For intervention and control groups, respectively.

Conclusion: Clinical trial discrimination was supported for HAQ-DI and SF-36 PCS in PsA with low risk of bias; and for SF-36 PF and HAQ-S with some caution. More studies are required for HAQ-S.
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http://dx.doi.org/10.1016/j.semarthrit.2020.05.022DOI Listing
October 2020

Performance of composite measures used in a trial of etanercept and methotrexate as monotherapy or in combination in psoriatic arthritis.

Rheumatology (Oxford) 2021 Mar;60(3):1137-1147

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

Objectives: To examine which composite measures are most sensitive to change when measuring psoriatic arthritis (PsA) disease activity, analyses compared the responsiveness of composite measures used in a 48-week randomized, controlled trial of MTX and etanercept in patients with PsA.

Methods: The trial randomised 851 patients to receive weekly: MTX (20 mg/week), etanercept (50 mg/week) or MTX plus etanercept. Dichotomous composite measures examined included ACR 20/50/70 responses, minimal disease activity (MDA) and very low disease activity (VLDA). Continuous composite measures examined included Disease Activity Score (28 joints) using CRP (DAS28-CRP), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Disease Activity for Psoriatic Arthritis (DAPSA) and Psoriatic Arthritis Disease Activity Score (PASDAS).

Results: At week 24, etanercept-treated groups were significantly more effective than MTX monotherapy to achieve ACR 20 (primary end point) and MDA (key secondary end point). When examining score changes from baseline at week 24 across the five continuous composite measures, PASDAS demonstrated relatively greater changes in the etanercept-treated groups compared with MTX monotherapy and had the largest effect size and standardized response. Joint count changes drove overall score changes at week 24 from baseline in all the continuous composite measures except for PASDAS, which was driven by the Physician and Patient Global Assessments.

Conclusion: PASDAS was the most sensitive continuous composite measure examined with results that mirrored the protocol-defined primary and key secondary outcomes. Composite measures with multiple domains, such as PASDAS, may better quantify change in PsA disease burden.

Trail Registration: https://ClinicalTrials.gov, number NCT02376790.
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http://dx.doi.org/10.1093/rheumatology/keaa271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937022PMC
March 2021