Rheumatoid factor isotype and Ro epitope distribution in primary Sjögren syndrome and rheumatoid arthritis with keratoconjunctivitis sicca
Primary Sjögren syndrome (pS) is associated with autoantibodies such as rheumatoid factor (RF) and anti-nuclear antibodies such as anti-Ro (SS-A) and/or La (SS-B). Recent developments within autoimmune diagnostics allow quantitation of RF subclasses and anti-Ro epitopes. Will this refinement by autoimmune diagnostics help predicting development of extraglandular manifestations (EGM) in pS patients? A cohort of pS and rheumatoid arthritis (RA) patients with keratoconjunctivitis sicca (n = 35 and 16, resp) was included. Of the pS patients, 54% developed one or more EGM. Antibodies quantitated were IgM-RF, IgA-RF, IgG-RF, anti-Ro52, and anti-Ro60. Upon analysis of RF isotypes, pS patients generally displayed higher IgA-RF concentrations than RA patients (126 versus 49 U/ml, p = 0.015), while the dominant RF isotype in RA patients was IgM-RF (82.5 versus 38 U/ml, p = 0.012). No differences were observed regarding IgG-RF concentrations. In pS without/with EGM, the median RF IgM concentrations were similar, while RF IgA and IgG concentrations tended to be lower in pS patients with EGM > 1. Both Ro epitopes were strongly recognized by almost all pS patients, independent from EGM, while these antibodies were absent in RA patients. Primary Sjögren syndrome and RA patients have distinct serological profiles when analysing RF and Ro-specific antibodies. A longitudinal study of switched RF isotypes in pS patients is worthwhile from an immunological point of view, but its value is limited regarding identification of pS patients prone to developing EGM or RA patients prone to developing secondary sicca symptoms.
KeywordsSjögren Extraglandular manifestations Rheumatoid factor Ro Rheumatoid arthritis Isotype
We thank Anne Thus and Anja van Heugten-Roelink for their technical contributions.
All authors have substantially contributed to the submitted work. BM performed the research, collected and analysed the data, and wrote the manuscript. JK collected and analysed the data and edited the manuscript. AC supervised performance of the study and edited the manuscript. AJvH co-designed the study, provided expertise, co-supervised the project, and edited the manuscript. EJtB designed the study, collected the clinical data, supervised the project, and edited the manuscript.
Compliance with ethical standards
Conflict of interest
No conflicts of interest.
All procedures followed were in accordance with the Declaration of Helsinki. This is a retrospective study with the aim to improve clinical interpretation of routine laboratory diagnostic procedures using clinical data and samples from a published cohort, for which no additional informed consent is required.
- 9.Tsuboi H, Asashima H, Takai C, Hagiwara S, Hagiya C, Yokosawa M, Hirota T, Umehara H, Kawakami A, Nakamura H, Sano H, Tsubota K, Ogawa Y, Takamura E, Saito I, Inoue H, Nakamura S, Moriyama M, Takeuchi T, Tanaka Y, Hirata S, Mimori T, Yoshifuji H, Ohta A, Matsumoto I, Sumida T (2014) Primary and secondary surveys on epidemiology of Sjogren’s syndrome in Japan. Mod Rheumatol 24:464–470CrossRefPubMedGoogle Scholar
- 14.Ramos-Casals M, Solans R, Rosas J, Camps MT, Gil A, Del Pino-Montes J, Calvo-Alen J, Jimenez-Alonso J, Mico ML, Beltran J, Belenguer R, Pallares L, GEMESS Study Group (2008) Primary Sjogren syndrome in Spain: clinical and immunologic expression in 1010 patients. Medicine (Baltimore) 87:210–219CrossRefGoogle Scholar
- 20.Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH, European Study Group on Classification Criteria for Sjogren’s Syndrome (2002) Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Falkenburg WJJ, von Richthofen HJ, Koers J, Weykamp C, Schreurs MWJ, Bakker-Jonges LE, Haagen IA, Lems WF, Hamann D, van Schaardenburg D, Rispens T (2018) Clinically relevant discrepancies between different rheumatoid factor assays. Clin Chem Lab Med. https://doi.org/10.1515/cclm-2017-0988 PubMedGoogle Scholar
- 27.Pascual V, Victor K, Randen I, Thompson K, Steinitz M, Forre O, Fu SM, Natvig JB, Capra JD (1992) Nucleotide sequence analysis of rheumatoid factors and polyreactive antibodies derived from patients with rheumatoid arthritis reveals diverse use of VH and VL gene segments and extensive variability in CDR-3. Scand J Immunol 36:349–362CrossRefPubMedGoogle Scholar
- 29.Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, Rasmussen A, Scofield H, Vitali C, Bowman SJ, Mariette X, International Sjogren’s Syndrome Criteria Working Group (2017) 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjogren’s Syndrome: a consensus and data-driven methodology involving three international patient cohorts. Arthritis Rheumatol 69:35–45CrossRefPubMedGoogle Scholar
- 30.Rasmussen A, Ice JA, Li H, Grundahl K, Kelly JA, Radfar L, Stone DU, Hefner KS, Anaya JM, Rohrer M, Gopalakrishnan R, Houston GD, Lewis DM, Chodosh J, Harley JB, Hughes P, Maier-Moore JS, Montgomery CG, Rhodus NL, Farris AD, Segal BM, Jonsson R, Lessard CJ, Scofield RH, Sivils KL (2014) Comparison of the American-European Consensus Group Sjogren’s syndrome classification criteria to newly proposed American College of Rheumatology criteria in a large, carefully characterised sicca cohort. Ann Rheum Dis 73:31–38CrossRefPubMedGoogle Scholar
- 36.Barone F, Nayar S, Campos J, Cloake T, Withers DR, Toellner KM, Zhang Y, Fouser L, Fisher B, Bowman S, Rangel-Moreno J, Garcia-Hernandez Mde L, Randall TD, Lucchesi D, Bombardieri M, Pitzalis C, Luther SA, Buckley CD (2015) IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs. Proc Natl Acad Sci USA 112:11024–11029CrossRefPubMedGoogle Scholar
- 41.Seror R, Bootsma H, Saraux A, Bowman SJ, Theander E, Brun JG, Baron G, Le Guern V, Devauchelle-Pensec V, Ramos-Casals M, Valim V, Dorner T, Tzioufas A, Gottenberg JE, Solans Laque R, Mandl T, Hachulla E, Sivils KL, Ng WF, Fauchais AL, Bombardieri S, Priori R, Bartoloni E, Goeb V, Praprotnik S, Sumida T, Nishiyama S, Caporali R, Kruize AA, Vollenweider C, Ravaud P, Meiners P, Brito-Zeron P, Vitali C, Mariette X, EULAR Sjogren’s Task Force (2016) Defining disease activity states and clinically meaningful improvement in primary Sjogren’s syndrome with EULAR primary Sjogren’s syndrome disease activity (ESSDAI) and patient-reported indexes (ESSPRI). Ann Rheum Dis 75:382–389CrossRefPubMedGoogle Scholar
- 44.Bergum B, Koro C, Delaleu N, Solheim M, Hellvard A, Binder V, Jonsson R, Valim V, Hammenfors DS, Jonsson MV, Mydel P (2016) Antibodies against carbamylated proteins are present in primary Sjogren’s syndrome and are associated with disease severity. Ann Rheum Dis 75:1494–1500CrossRefPubMedGoogle Scholar
- 45.Li H, Reksten TR, Ice JA, Kelly JA, Adrianto I, Rasmussen A, Wang S, He B, Grundahl KM, Glenn SB, Miceli-Richard C, Bowman S, Lester S, Eriksson P, Eloranta ML, Brun JG, Goransson LG, Harboe E, Guthridge JM, Kaufman KM, Kvarnstrom M, Cunninghame Graham DS, Patel K, Adler AJ, Farris AD, Brennan MT, Chodosh J, Gopalakrishnan R, Weisman MH, Venuturupalli S, Wallace DJ, Hefner KS, Houston GD, Huang AJW, Hughes PJ, Lewis DM, Radfar L, Vista ES, Edgar CE, Rohrer MD, Stone DU, Vyse TJ, Harley JB, Gaffney PM, James JA, Turner S, Alevizos I, Anaya JM, Rhodus NL, Segal BM, Montgomery CG, Scofield RH, Kovats S, Mariette X, Ronnblom L, Witte T, Rischmueller M, Wahren-Herlenius M, Omdal R, Jonsson R, Ng WF, Nordmark G, Lessard CG, Sivils KL, for UK Primary Sjogren’s Syndrome Registry (2017) Identification of a Sjogren’s syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons. PLoS Genet 13:e1006820CrossRefPubMedPubMedCentralGoogle Scholar