Objectives A novel longitudinal clustering technique was applied to comprehensive autoantibody data from a large, well-characterised, multinational inception systemic lupus erythematosus (SLE) cohort to determine profiles predictive of clinical outcomes.
Methods Demographic, clinical and serological data from 805 patients with SLE obtained within 15 months of diagnosis and at 3-year and 5-year follow-up were included. For each visit, sera were assessed for 29 antinuclear antibodies (ANA) immunofluorescence patterns and 20 autoantibodies. K-means clustering on principal component analysis-transformed longitudinal autoantibody profiles identified discrete phenotypic clusters. One-way analysis of variance compared cluster enrolment demographics and clinical outcomes at 10-year follow-up. Cox proportional hazards model estimated the HR for survival adjusting for age of disease onset.
Results Cluster 1 (n=137, high frequency of anti-Smith, anti-U1RNP, AC-5 (large nuclear speckled pattern) and high ANA titres) had the highest cumulative disease activity and immunosuppressants/biologics use at year 10. Cluster 2 (n=376, low anti-double stranded DNA (dsDNA) and ANA titres) had the lowest disease activity, frequency of lupus nephritis and immunosuppressants/biologics use. Cluster 3 (n=80, highest frequency of all five antiphospholipid antibodies) had the highest frequency of seizures and hypocomplementaemia. Cluster 4 (n=212) also had high disease activity and was characterised by multiple autoantibody reactivity including to antihistone, anti-dsDNA, antiribosomal P, anti-Sjögren syndrome antigen A or Ro60, anti-Sjögren syndrome antigen B or La, anti-Ro52/Tripartite Motif Protein 21, antiproliferating cell nuclear antigen and anticentromere B). Clusters 1 (adjusted HR 2.60 (95% CI 1.12 to 6.05), p=0.03) and 3 (adjusted HR 2.87 (95% CI 1.22 to 6.74), p=0.02) had lower survival compared with cluster 2.
Conclusion Four discrete SLE patient longitudinal autoantibody clusters were predictive of long-term disease activity, organ involvement, treatment requirements and mortality risk.
- systemic lupus erythematosus
Data availability statement
Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information.
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Handling editor Josef S Smolen
Contributors All authors were involved in the concept and design, data analysis and interpretation and editing for intellectual content. MYC, AEC, MJF and KHC were involved in manuscript drafting. MYC is responsible for the overall content as the guarantor.
Funding MYC is supported by the Lupus Foundation of America Gary S. Gilkeson Career Development Award and research gifts in kind from MitogenDx (Calgary, Canada). AEC holds The Arthritis Society Research Chair in Rheumatic Diseases at the University of Calgary. JH’s work was supported by the Canadian Institutes of Health Research (research grant MOP-88526). CG’s work was supported by Lupus UK, Sandwell and West Birmingham Hospitals NHS Trust and the NIHR/Wellcome Trust Clinical Research Facility in Birmingham. S-CB’s work was supported by Basic Science Research Programme through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2021R1A6A1A03038899). The Montreal General Hospital Lupus Clinic is partially supported by the Singer Family Fund for Lupus Research. AR and DAI are supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The Hopkins Lupus Cohort is supported by NIH Grants AR043727 and AR069572. PRF presently holds a tier 1 Canada Research Chair on Systemic Autoimmune Rheumatic Diseases at Université Laval, and part of this work was done while he was still holding a Distinguished Senior Investigator of The Arthritis Society. INB is an NIHR Senior Investigator and is funded by Arthritis Research UK, the National Institute for Health Research Manchester Biomedical Research Centre and the NIHR/Wellcome Trust Manchester Clinical Research Facility. MAD’s work was supported by the NIH grant RR00046. RR-G’s work was supported by the NIH (grants 1U54TR001353 formerly 8UL1TR000150 and UL-1RR-025741, K24-AR-02318 and P60AR064464 formerly P60-AR-48098). SM is supported by grants R01 AR046588 and K24 AR002213. GR-I is supported by the Department of Education, Universities and Research of the Basque Government. SJ is supported by the Danish Rheumatism Association (A1028) and the Novo Nordisk Foundation (A05990). KHC is supported by NIH K24 AR066109.
Disclaimer The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.
Competing interests MYC has received consulting fees from Janssen, AstraZeneca, Mallinckrodt Pharmaceuticals and MitogenDx. AEC has received consulting fees, speaking fees and/or honoraria from AstraZeneca, Bristol Myers Squibb and GlaxoSmithKline (<US$10 000 each) and research support from GlaxoSmithKline. MJF is Director of Mitogen Diagnostics (Calgary, Alberta, Canada) and a consultant to Werfen International (San Diego, California, USA; Barcelona, Spain), Aesku Group (Wendelsheim, Germany) and Alexion Canada (<US$10 000). CG has received consulting fees, speaking fees and/or honoraria from Eli Lilly, UCB, GlaxoSmithKline, Merck Serono and BMS (<US$10 000 each) and grants from UCB. Grants from UCB were not to CG but to Sandwell and West Birmingham Hospitals NHS Trust. DDG received consulting fees, speaking fees and/or honoraria from GlaxoSmithKline (<US$10 000). INB has received consulting fees, speaking fees and/or honoraria from Eli Lilly, UCB, Roche, Merck Serono, MedImmune (<US$10 000 each) and grants from UCB, Genzyme Sanofi and GlaxoSmithKline. EMG has paid consultation with investment analysts Guidepoint Global Gerson Lerman Group. KK has received grants from UCB, Human Genome Sciences/GlaxoSmithKline, Takeda, Ablynx, Bristol Myers Squibb, Pfizer and Kyowa Hakko Kirin, and has received consulting fees from Exagen Diagnostics, Genentech, Eli Lilly, Bristol Myers Squibb and Anthera (<US$10 000 each). KHC has consulted for or collaborated on research projects with Janssen, GlaxoSmithKline, Gilead, Exagen Diagnostics, Lilly, Merck, AstraZeneca, Amgen and Neutrolis (<US$10 000 each). The remainder of the authors have no disclosures.
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