Comparative characteristics of the main phenotypes of systemic sclerosis

Various clinical and immunological phenotypes of systemic sclerosis (SS) differ in the frequency and severity of manifestations of the disease, the progression of damage to internal organs, and prognosis. The detection rate of anti-U1-ribonucleoprotein (RNP) (anti-U1RNP) antibodies in SSD ranges from 5 to 30%. They are found in various rheumatic diseases (SS, systemic lupus erythematosus, rheumatoid arthritis, polymyositis, and Sjo gren’s syndrome) and are associated with a more favorable course, a good response to treatment (in particular, that with glucocorticoids), and a good prognosis. In SS, the clinical and laboratory associations of anti-U1RNP have been insufficiently investigated.

Objective: to compare clinical, laboratory, and instrumental findings in patients with SS positive for anti-U1RNP, anti-topoisomerase-I (anti-Scl70), and anticentromere antibodies (ACA).

Subjects and methods. Sixty-five anti-U1RNP antibody-positive patients were selected for a study group (Group 1) from the general database of patients who met the 2013 ACR/EULAR criteria for SS and who were followed up at the V.A. Nasonova Research Institute of Rheumatology in 2012 to 2017. The comparison groups included 50 anti-Scl70 antibody-positive patients with SS (Group 2) and 50 ACA-positive ones (Group 3). Anti-U1RNP negativity was confirmed in patients of the comparison groups.

Results and discussion. Most patients in Groups 1 and 3 had the limited type of SS (88 and 94%, respectively) and a chronic course of the disease (82 and 94%) while Group 2 patients showed an acute and subacute course (52%) and predominantly the diffuse type of SS (58%). All the patients with SS had a higher level of antinuclear factor. The feature of the anti-U1RNP positive group was a preponderance of the limited type of the disease with minimal skin damage concurrent with a more frequent involvement of the musculoskeletal system (damages to the joints (65%) and muscles (43%), as well as with the high rate of damage to internal organs (in particular, the lung, heart, and gastrointestinal tract). The patients of this group exhibited high inflammatory and immunological activities, hematological disorders (hypocomplementemia (15%) and leukopenia (14%)). Sjo gren’s syndrome was detected in one-third of these patients.

Conclusion. Further study of anti-U1RNP-positive SS will be able to create a management algorithm and to more clearly define the risks and prognosis of the disease for this group of patients.

1. Guseva NG. Sistemnaya sklerodermiya i psevdosklerodermicheskie sindromy [Systemic scleroderma and pseudoscleroderma syndromes]. Moscow: Meditsina; 1993 (In Russ.).

2. Hamaguchi Y. Autoantibody profiles in systemic sclerosis: Predictive value for clinical evaluation and prognosis. J Dermatol. 2010;37:42-53. doi: 10.1111/j.1346-8138.2009.00762.x

3. Starovoitova MN, Desinova OV, Koneva OA, et al. Profile of autoantibodies in systemic sclerosis. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(4):418-23 (In Russ.). doi: 10.14412/1995-4484-2016-418-423

4. Aleksandrova EN, Novikov AA, Nasonov EL. Current approaches to the laboratory diagnosis of rheumatic diseases: Role of molecular and cellular biomarkers. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(3):324-38 (In Russ.). doi: 10.14412/1995-4484-2016-324-338

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.). doi: 10.14412/1995-4484-2016-86-99

6. Kuwana M. Circulating Anti-Nuclear Antibodies in Systemic Sclerosis: Utility in Diagnosis and Disease Subsetting. J Nippon MedSch. 2017;84(2):56-63. doi: 10.1272/jnms.84.56

7. Hesselstrand R, Scheja A, Shen GQ, et al. The association of antinuclear antibodies with organ involvement and survival in systemic sclerosis. Rheumatology (Oxford). 2003;42:534-40. doi: 10.1093/rheumatology/keg170

8. Hamaguchi Y, Kodera M, Matsushita T, et al. Clinical and immunological predictors of scleroderma renal crisis for Japanese systemic sclerosis patients with anti-RNA polymerase III autoantibodies. Arthritis Rheum. 2015;67:1045-52. doi: 10.1002/art.38994

9. Moinzadeh P, Fonseca C, Hellmich M, et al. Association of anti-RNA polymerase III autoantibodies and cancer in scleroderma. Arthritis Res Ther. 2014;16:R53. doi: 10.1186/ar4486

10. Jung M, Baron M, Hudson M, et al. Myopathy is a poor prognostic feature in systemic sclerosis: results from the Canadian Scleroderma Research Group (CSRG) cohort. Scand J Rheumatol. 2014;43(3):217-20. doi: 10.3109/03009742.2013.868512

11. Hoffmann AM, Gunnarsson R, Garen T, et al. Performance of the 2013 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis (SSc) in Large, Well-defined Cohorts of SSc and Mixed Connective Tissue Disease. J Rheumatol. 2015;42:60-3. doi: 10.3899/jrheum.140047

12. Hamaguchi Y, Hasegawa M, Fujimoto M, et al. The clinical relevance of serum antinuclear antibodies in Japanese patients with systemic sclerosis. Br J Dermatol. 2008;158(3):487-95. doi: 10.1111/j.1365-2133.2007.08392.x

13. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum. 2005;35:35-42. doi: 10.1016/j.semarthrit.2005.03.005

14. Reveille JD, Fischbach M, McNearney T, et al. Systemic sclerosis in 3 US ethnic groups: a comparison of clinical sociodemographic, serologic, and immunogenetic determinants. Semin Arthritis Rheum. 2001;30:332-46. doi: 10.1053/sarh.2001.20268

15. Kuwana M, Kaburaki J, Okano Y, et al. Clinical and prognostic associations based on serum antinuclear antibodies in Japanese patients with systemic sclerosis. Arthritis Rheum. 1994;37:75-83. doi: 10.1002/art.1780370111

16. Shayakhmetova RU, Ananyeva LP, Koneva OA, et al. Clinical and laboratory characteristics of patients with systemic sclerosis positive for anti-ribonucleoprotein antibodies. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2019;57(5):539-44 (In Russ.). doi: 10.14412/1995-4484-2019-539-544

17. Carpintero MF, Martinez L, Fernandez I, et al. Diagnosis and risk stratification in patients with anti-RNP autoimmunity. Lupus. 2015;24(10):1057-66. doi: 10.1177/0961203315575586

18. Brahms H, Raker VA, van Venrooij WJ, et al. A major, novel systemic lupus erythematosus autoantibody class recognizes the E, F, and G SmsnRNP proteins as an E—F—G complex but not in their denatured states. Arthritis Rheum. 1997;40:672-82. doi: 10.1002/art.1780400412

19. Lokesh S, Kadavanu T, Raghupathy, et al. A Rare Case of Mixed Connective Tissue Disease (MCTD) with Intricate Features of Lupus, Polymyositis and Rheumatoid Arthritis Presenting with Severe Myositis. J Clin Diagn Res. 2015;9(3):5-7.

20. Desinova OV, Starovoytova MN, Guseva IA, et al. Features of systemic sclerosis-rheumatoid arthritis overlap syndrome (SS-RA overlap syndrome). Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2007;45(4):18-23 (In Russ.). doi: 10.14412/1995-4484-2007-18-23

21. Brennan P, Silman A, Black C and the UK Scleroderma Study Group. Realiability of skin score measures in scleroderma. Br J Rheumatol. 1992;31:457-60. doi: 10.1093/rheumatology/31.7.457

22. Nasonov EL, editor. Rossiiskie klinicheskie rekomendatsii. Revmatologiya [Russian clinical recommendations. Rheumatology]. Moscow: GEOTAR-Media; 2017. P. 150-66 (In Russ.). ISBN 978-5-9704-4261-6

23. Hamaguchi Y, Takehara K. Anti-nuclear autoantibodies in systemic sclerosis?: News and perspectives. J Scler Relat Disord. 2018;3(3):201-13. doi: 10.1177/2397198318783930

24. Steen V, Domsic RT, Lucas M, et al. A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis. Arthritis Rheum. 2012;64(9): 2986-994. doi: 10.1002/art.34482

25. Ihn H, Yamane K, Yazawa N, et al. Distribution and antigen specificity of anti-U1RNP antibodies in patients with systemic sclerosis. Clin Exp Immunol. 1999;117(2):383-7. doi: 10.1046/j.1365-2249.1999.00961.x

26. Sobanski V, Giovannelli J, Lynch BM. Characteristics and survival of anti-U1 RNP antibody-positive patients with connective tissue disease-associated pulmonary arterial hypertension. Arthritis Rheum. 2016;68:484-93. doi: 10.1002/art.39432

27. Lundberg I, Hedfors E. Clinical course of patients with anti-RNP antibodies. A prospective study of 32 patients. J Rheumatol. 1991;18:1511-9.

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