CLINICAL AND LABORATORY FEATURES OF ANTICENTROMERE ANTIBODY-POSITIVE SJö GREN’S SYNDROME

Objective: to study the clinical and laboratory features of patients with anticentromere antibody (ACA) positive Sjö gren’s syndrome (SjS); to assess the spectrum of autoantibodies in patients of this group; to determine the frequency with which the SjS patients who are highly positive for ACA, meet the international classification criteria for SjS and systemic sclerosis (SS); to reveal the incidence of MALT lymphomas in this patient group; to estimate the incidence of primary biliary cirrhosis (PBC)/biliary lesions as part of autoimmune epithelitis in SjS in this patient group.

Material and methods. A total of 83 patients with ACA positive SjS were comprehensively examined at the V.A. Nasonova Research Institute of Rheumatology during the period 2012 to 2018. The inclusion criteria were con formity to the 2001 Russian SjS criteria and a high ACA level. MALT lymphomas were diagnosed on the basis of histological and immunohistochemical studies and polymerase chain reaction-based determination of B-cell clonality in the biopsy samples of affected organs according to the World Health Organization classification of Hematopoietic Tumors. The diagnosis of PBC/biliary lesions was made on the basis of histological and immunohistochemical studies of liver biopsy specimens.

Results and discussion. The investigation revealed low detection rates for anti-Ro antibodies (32.5%), anti-La antibodies (7.2%) and rheumatoid factor (RF) (21.7%), which were typical for the classical SjS immunophenotype), increased ESR (14%), leukopenia (7%), hypergammaglobulinemia (17.6%), elevated levels of IgG (9.5%) and IgA (18.7%), and hypocomplementemia (16.1%) in the ACA positive SjS patients. Despite the low detection rate of RF, 15 (18%) patients in this group developed MALT lymphomas: 14 patients had salivary gland MALT lymphoma and one patient had tonsil MALT lymphoma with peripheral lymph node involvement (generalized marginal zone lymphoma). Also, the patients of this group showed high detection rates for AMA antibodies (34.6%), increased IgM level (29.7%) and a higher risk for PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS (14.5%). AMA-antibodies were absent in only two patients who were diagnosed with liver disease according to biopsy specimens. Nervous system and renal lesions, antiphospholipid syndrome, rheumatoid arthritis, hypergammaglobulinemic purpura, and cryoglobulinemic vasculitis were much less common and sporadic. Also ACA-positive SjS patients often have Raynaud’s phenomenon (54.9%) with scleroderma-type capillaroscopic changes (68%) and a limited form of SS (24%) according to the 2013 ACR criteria.

Conclusion. ACA-positive SjS is a subtype of the disease, which is significantly different from the classic one in a number of clinical and laboratory signs and characterized by an increased risk for SS, MALT lymphomas, and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS which in some cases leads to the underdiagnosis of SjS. ACA should be considered as pathogenetically related to SjS autoantibodies; and all patients who are seropositive for ACA should be examined for SjS and PBC/biliary lesions as a manifestation of autoimmune epithelitis in SjS regardless of whether they have SS or not, as well as complaints of dry mouth and eyes. Patients with significantly enlarged salivary glands should undergo biopsy to rule out or confirm MALT lymphoma before initiating hormonal, antilymphoproliferative, and anti-B-cell therapy.

1. Selmi C, M. Gershwin ME. Chronic Autoimmune Epithelitis in Sjogren’s Syndrome and Primary Biliary Cholangitis: A Comprehensive Review. Rheumatol Ther. 2017;4:263-79. doi: 10.1007/s40744-017-0074-2

2. Tinazzi E, Patuzzo G, Lunardi C. Autoantigens and Autoantibodies in the Pathogenesis of Sjögren’s Syndrome. In: Gerli R, Bartoloni E, Alunno A, eds. Sjögren’s Syndrome. Academic Press; 2016. P. 141-56. doi: 10.1016/B978-0-12-803604-4.00009-5

3. Derksen VFAM, Huizinga TWJ, van der Woude D. The role of autoantibodies in the pathophysiology of rheumatoid arthritis. Semin Immunopathol. 2017;39:437-46. doi: 10.1007/s00281-017-0627-z

4. Arriens C, Wren JD, Munroe ME, Mohan C. Systemic lupus erythematosus biomarkers: the challenging quest. Rheumatology. 2017;56:i32i45. doi: 10.1093/rheumatology/kew407

5. Ananyeva LP, Aleksandrova EN. Autoantibodies in scleroderma systematica: Spectrum, clinical associations, and prognostic value. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(1):86-99 (In Russ.).

6. Fayyaz A, Kurien BT, Scofield H. Autoantibodies in Sjö gren’s Syndrome. Rheum Dis Clin North Am. 2016 Aug;42(3):419-34. doi: 10.1016/j.rdc.2016.03.002

7. Vasil'ev VI, Probatova NA, Tupicyn NN, et al. Lymphoproliferative diseases in Sjogren's disease. Onkogemаtologiya. 2007;(3):16-26 (In Russ.).

8. Baer AN, Medrano L, McAdams-DeMarco M, Gniadek TJ. Anticentromere antibodies are associated with more severe exocrine glandular dysfunction in Sjö gren’s syndrome: Analysis of the Sjö gren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res. 2016 Oct;68(10):1554-9. doi: 10.1002/acr.22859

9. Moroi Y, Peebles C, Fritzler MJ, et al. Autoantibody to centromere (kinetochore) in scleroderma sera. Proc Natl Acad Sci USA. 1980;77:1627-31. doi: 10.1073/pnas.77.3.1627

10. Guseva NG. Systemic sclerosis. In: Sigidin YaA, Guseva NG, Ivanova MM. Diffuznye bolezni soedinitel'noi tkani [Diffuse connective tissue disease]. Moscow: Meditsina; 2004. P. 343-487 (In Russ.).

11. Hudson M, Mahler M, Pope J, et al; Canadian Scleroderma Research Group, and Fritzler M. Clinical Correlates of CENP-A and CENP-B Antibodies in a Large Cohort of Patients with Systemic Sclerosis. J Rheumatol. 2012;39(4):787-94. doi: 10.3899/jrheum.111133

12. Vlachoyiannopoulos PG, Drosos AA, Wiik A, Moutsopoulos HM. Patients with anticenromere antibodies, clinical features, diagnoses and evolution. Br J Rheumatol. 1993;32:297-301. doi: 10.1093/rheumatology/32.4.297

13. Yamagiwa S, Kamimura H, Takamura M, Aoyagi Y. Autoantibodies in primary biliary cirrhosis: Recent progress in research on the pathogenetic and clinical significance. World J Gastroenterol. 2014 Mar 14;20(10):2606-12. doi: 10.3748/wjg.v20.i10.2606

14. Jearn L-H, Kim T-Y. The influence of anti-cyclic citrullinated peptide on anticentromere antibody-positive rheumatoid arthritis patients. Arthritis Res Ther. 2010;12:406. doi: 10.1186/ar3153

15. Kuramoto N, Ohmura K, Ikari K, et al. Anti-centromere antibody exhibitsspecific distribution levels amonganti-nuclear antibodies and maycharacterize a distinct subset inrheumatoid arthritis. Sci Rep. 2017;7:6911. doi: 10.1038/s41598-017-07137-4

16. Varada M-G, Dhanesh ES. Digital Gangrene Associated with Anticentromere Antibodies. Indian J Dermatol. 2014 Mar-Apr;59(2):195-6. doi: 10.4103/0019-5154.127686

17. Elqatni M, Mekouar F, Amezyane T, Ghafir D. A Rare Entity: RACAND Syndrome. Intern Med. 2014;53:2749. doi: 10.2169/internalmedicine.53.2757

18. Bolster L, Taylor-Gjevre RM, Nair B, Gjevre JA. Digital gangrene associated with anticentromere antibodies: a case report. J Med Case Rep. 2010;4:189. doi: 10.1186/1752-1947-4-189

19. Takehara K, Soma Y, Igarashi A, et al. Longitudinal Study of Patients with Anticentromere Antibody. Dermatologie. 1990;181:202-6. doi: 10.1159/000247924

20. Lee S-L, Tsay GJ, Tsai R-T. Anticentromere antibodies in subjects with no apparent connective tissue disease. Ann Rheum Dis. 1993;52:586-9. doi: 10.1136/ard.52.8.586

21. Nasonov EL. Rossyskiye klinicheskiye rekomendatsii. Revmatologiya [Russian clinical guidelines. Rheumatology]. Moscow: GEOTAR-Media; 2017 (In Russ.). http://www.rosmedlib.ru/book/ISBN9785970442616.html

22. Swerdlow SH, Campo E, Pilery SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375-90.

23. Shiboski SC, Shiboski CH, Criswell LA, et al, for the Sjö gren’s International Collaborative Clinical Alliance (SICCA) Research Groups. American College of Rheumatology Classification Criteria for Sjö gren’s Syndrome: A Data-Driven, Expert Consensus Approach in the SICCA Cohort. Arthritis Care Res (Hoboken). 2012;64(4):475-87. doi: 10.1002/acr.21591

24. Shiboski CH, Shiboski SC, Seror R, et al; and the International Sjogren’s Syndrome Criteria Working Group. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjogren’s Syndrome. Arthritis Rheum. 2016. doi: 10.1002/art.39859

25. Van den Hoogen F, Khanna D, Fransen J, et al. Classification Criteria for Systemic Sclerosis: An ACR-EULAR Collaborative Initiative. Arthritis Rheum. 2013 Nov;65(11):2737-47. doi: 10.1002/art.38098

26. Martire MV, Santiago ML, Cazenave T, Gutierrez M. Latest Advances in Ultrasound Assessment of Salivary Glands in Sjö gren Syndrome. J Clin Rheumatol. 2018 Jun;24(4):218-23. doi: 10.1097/RHU.0000000000000625

27. Baldini C, Mosca M, Della Rossa A, et al. Overlap of ACA-positive systemic sclerosis and Sjö gren’s syndrome: a distinct clinical entity with mild organ involvement but at high risk of lymphoma. Clin Exper Rheumatol. 2013;31:272-80.

28. Nakamura H, Kawakami A, Hayashi T, et al. Anticentromere antibody-seropositive Sjö gren's syndrome differs from conventional subgroup in clinical and pathological study. BMC Musculoskelet Disord. 2010;11:140. doi: 10.1186/1471-2474-11-140

29. Bournia VKK, Diamanti KD, Vlachoyiannopoulos PG, Moutsopoulos HM. Anticentromere antibody positive Sjö gren’s Syndrome: a retrospective descriptive analysis. Arthritis Res Ther. 2010;12:R47. doi: 10.1186/ar2958

30. Capobianco KG, Xavier RM, Bredemeier M, et al. Nailfold capillaroscopic findings in primary Sjö gren's syndrome: clinical and serological correlations. Clin Exp Rheumatol. 2005 Nov-Dec;23(6):789-94.

31. Tektonidou M, Kaskani E, Skopouli FN, Moutsopoulos HM. Microvascular abnormalities in Sjö gren's syndrome: nailfold capillaroscopy. Rheumatology. 1999;38(9):826-30. doi: 10.1093/rheumatology/38.9.826

32. Tanaka N, Muro Y, Suzuki Y, et al. Anticentromere antibodypositive primary Sjö gren's syndrome: Epitope analysis of a subset of anticentromere antibody-positive patients. Mod Rheumatol. 2017;27(1):115-21. doi: 10.1080/14397595.2016.1176327

33. Reina D, Roig Vilaseca D, Torrente-Segarra V, et al. Sjö gren's syndrome-associated interstitial lung disease: A multicenter study. Reumatol Clin. 2016 Jul-Aug;12(4):201-5. doi: 10.1016/j.reuma.2015.09.003

34. Kyung-Eun LEE, Ji-Hyoun KANG, Jeong-Won LEE, et al. Anticentromere antibody-positive Sjogren’s syndrome: A distinct clinical subgroup? Int J Rheum Dis. 2015;18:776-82. doi: 10.1136/annrheumdis-2013-eular.2753

35. Selmi C, M. Gershwin ME. Chronic Autoimmune Epithelitis in Sjogren’s Syndrome and Primary Biliary Cholangitis: A Comprehensive Review. Rheumatol Ther. 2017;4:263-79. doi: 10.1007/s40744-017-0074-2