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Abstract
Objectives: Peptidylarginine deiminases (PADs) are a family of calcium-dependent enzymes catalysing the conversion of arginine residues to citrulline, which may constitute a risk factor in rheumatoid arthritis (RA) pathogenesis. We investigated PAD activation by serum (PADAct) in early RA, and the associations between PAD activation and disease characteristics, treatment response, and progression of radiographic damage.
Method: Sera from disease-modifying anti-rheumatic drug (DMARD)-naïve early RA patients (n = 225), classified according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria, and healthy controls (n = 63) were analysed for PAD4 activating capacity at 0, 3, 12, and 24 months using a high-performance liquid chromatography fluorometric method. Associations for PADAct were evaluated by Mann–Whitney U and chi-squared tests. Changes in PADAct levels were compared using the Wilcoxon signed-rank test.
Results: PADAct positivity occurred in 42% (n = 95) of the patients and was more prevalent in anti-citrullinated protein antibody (ACPA)-positive vs ACPA-negative patients (47% vs 20%, p = 0.002), but not in rheumatoid factor (RF)-positive vs RF-negative patients (44% vs 38%, p = 0.49). PADAct-positive were younger than PADAct-negative patients [mean ± sd 48.7 ± 13.5 vs 53.2 ± 13.7 years, p = 0.011]. Median [25th, 75th percentile] PADAct levels were higher in patients than in controls (8768 [7491, 11 393] vs 7046 [6347, 7906], p < 0.0001) and decreased after initiation of DMARD treatment, but were not associated with treatment response or progression of radiographic damage after 2 years of follow-up.
Conclusion: Serum capacity to activate PAD4 was associated with ACPA and RF positivity and earlier disease onset in early RA patients, and decreased after initiation of DMARD treatment, indicating that anti-PAD treatment could potentially be beneficial in RA.
Acknowledgements
We would like to thank Ellen Moholt and Camilla Fongen at Diakonhjemmet Hospital, Marianne Eidsheim and Kjerstin Jakobsen at the Broegelmann Research Laboratory, and the ARCTIC investigators: Hallvard Fremstad, Tor Magne Madland, Åse Stavland Lexberg, Hilde Haukeland, Erik Rødevand, Christian Høili, Hilde Stray, Anne Noraas, Inger Johanne Widding Hansen, and Gunnstein Bakland.
The study has received grants from the Norwegian Research Council, the Southern and Eastern Norway Regional Health Association, the Norwegian Rheumatism Association, the Western Norway Regional Health Authority, the Norwegian ExtraFoundation for Health and Rehabilitation, the National Science Center (2014/14/E/NZ6/00162 Sonata Bis, 2016/22/E/NZ5/00332 Sonata Bis, and 2016/23/B/NZ5/011469 OPUS, Poland), and unrestricted grant support from AbbVie, Pfizer, MSD, UCB, and Roche.
Disclosure statement
MKJ reports grants from the Norwegian ExtraFoundation for Health and Rehabilitation and the Western Norway Regional Health Authority. AA, TK, and PM were supported by the Broegelmann Foundation and by grants from the Polish National Science Center. The Faculty of Biochemistry, Biophysics and Biotechnology is a partner of the Polish Leading National Research Centre (KNOW) supported by the Ministry of Science and Higher Education. EAH has received investigator-initiated grants from AbbVie, Pfizer, MSD, UCB Pharma, and Roche.
Supporting Information
Additional Supporting Information may be found in the online version of this article.
Supplementary table S1: Baseline disease activity measures in PADAct-positive patients, comparing differences by ACPA status.
Supplementary table S2: Spearman correlations (p-values in parenthesis) between baseline PADAct levels and disease activity measures.
Supplementary table S3: Median baseline PADAct level by response/remission status for patients on methotrexate monotherapy.
Supplementary table S4: PADAct baseline status by response/remission status for patients on methotrexate monotherapy.
Supplementary table S5: PADAct baseline activity status and radiographic progression.
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