Clinical and immunological phenotypes of systemic lupus erythematosus, identified based on cluster analysis of data from 400 patients from V.A. Nasonova Research Institute of Rheumatology

Objective: to identify clinical and immunological variants (phenotypes) of systemic lupus erythematosus (SLE) using cluster analysis.

Patients and methods. The study included 400 patients with diagnosis of SLE according to the 2012 SLICC classification criteria. Patients underwent laboratory and immunological workup according to accepted standards of medical care for patients with SLE, and therapy was prescribed in accordance with disease activity.

Results and discussion. Among patients, most were females (ratio of men and women – 1:10), and people of young age (34.2±11.5 years), with an average duration of illness of 6 [3; 12] years. In 98 (25%) patients with SLE, the disease debuted before the age of 18 years. Lupus nephritis (LN) was detected in 192 (48%) patients, SLE with antiphospholipid syndrome (APS) – in 48 (12%), SLE with Sjцgren's syndrome – in 44 (11%). For cluster analysis 30 clinical, 4 laboratory, 12 immunological and 10 therapeutic parameters were selected and a dendrogram was constructed with the calculation of the Euclidean distance using the Ward method. As a result, five clusters of SLE were identified: with the development of LN; with predominantly extrarenal manifestations; SLE combined with APS; SLE combined with Sjцgren's syndrome; SLE with a debut in childhood (up to 18 years of age). Clusters differed in clinical, laboratory and immunological parameters, as well as in therapy.

Conclusion. Cluster analysis data made it possible to group the selected signs into five clinical and immunological variants (phenotypes) of SLE. Identification of SLE phenotypes as a set of characteristics that, individually or in combination, make it possible to determine differences between patients based on clinical, laboratory and immunological parameters, variants of the onset and course of the disease, response to therapy and prognosis, will contribute to a personalized approach in choosing the therapy, improving its long-term results, as well as quality of life and prognosis in patients with SLE.

1. Nasonov EL, editor. Rossiiskie klinicheskie rekomendatsii. Revmatologiya [Russian clinical guidelines. Rheumatology]. Moscow: GEOTAR-Media; 2017. 464 s.

2. Solov'ev SK, Aseeva EA, Zotkin EG, et al. Problems of low activity and remission in systemic lupus erythematosus. Nauchno-prakticheskaya revmatologiya. 2019;57(2):218-21. (In Russ.).

3. Solov'ev SK, Aseeva EA, Popkova TV, et al. Systemic lupus erythematosus: new horizons of diagnosis and therapy. Nauchno-prakticheskaya revmatologiya. 2020;58(1):5-14. (In Russ.).

4. Dörner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet. 2019 Jun 8;393(10188):2344-58. doi: 10.1016/S0140-6736(19)30546-X.

5. Durcan L, O'Dwyer T, Petri M. Management strategies and future directions for systemic lupus erythematosus in adults. Lancet. 2019 Jun 8;393(10188):2332-43. doi: 10.1016/S0140-6736(19)30237-5. Epub 2019 Jun 6.

6. Jorge A, Lu N, Zhang Y, Rai S, et al. Unchanging premature mortality trends in systemic lupus erythematosus: a general population-based study (1999-2014). Rheumatology (Oxford). 2018 Feb 1;57(2):337-44. doi: 10.1093/rheumatology/kex412.

7. Solov'ev SK, Aseeva EA, Popkova TV, et al. Recommendations of the international working group and comments of Russian experts. Nauchno-prakticheskaya revmatologiya. 2015; 53(1):9-16. (In Russ.).

8. Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020 Jun;79(6): 713-23. doi: 10.1136/annrheumdis-2020-216924. Epub 2020 Mar 27.

9. Fanouriakis A, Tziolos N, Bertsias G, et al. Update n the diagnosis and management of systemic lupus erythematosus. Ann Rheum Dis. 2021 Jan;80(1):14-25. doi: 10.1136/annrheumdis-2020-218272. Epub 2020 Oct 13.

10. Han M, Agusti A, Calverley P, et al. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med. 2010 Sep 1;182(5):598-604. doi: 10.1164/rccm.200912-1843CC. Epub 2010 Jun 3.

11. Nenasheva NM. Phenotypes of bronchial asthma and the choice of therapy. Prakticheskaya pul'monologiya. 2014;(2):2-11. (In Russ.).

12. Trushenko NV, Sopova MI, Sopova VI. Phenotypes of chronic obstructive pulmonary disease – the way to personalized therapy. Prakticheskaya pul'monologiya. 2019;(3):32-9. (In Russ.).

13. Lazzaroni M, Marasco E, Campochiaro C, et al; EUSTAR co-authors. The clinical phenotype of systemic sclerosis patients with anti-PM/Scl antibodies: results from the EUSTAR cohort. Rheumatology (Oxford). 2021 Nov 3;60(11):5028-41. doi: 10.1093/rheumatology/keab152.

14. Bettiol A, Hatemi G, Vannozzi L, et al. Treating the Different Phenotypes of Behcet's Syndrome. Front Immunol. 2019 Dec 6; 10:2830. doi: 10.3389/fimmu.2019.02830.

15. Jung S, Park K, Kim K, et al. Clinical phenotype with high risk for initiation of biologic therapy in rheumatoid arthritis: a datadriven cluster analysis. Clin Exp Rheumatol. 2021 Nov-Dec;39(6):1282-90. Epub 2021 Feb 9.

16. FitzGerald O, Haroon M, Giles J, et al. Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype. Arthritis Res Ther. 2015 May 7;17(1):115. doi: 10.1186/s13075-015-0640-3.

17. Dooley M, Aranow C, Ginzler E. Review of ACR renal criteria in systemic lupus erythematosus. Lupus. 2004;13(11): 857-60. doi: 10.1191/0961203304lu2023oa.

18. Miyakis S, Lockshin M, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006 Feb;4(2):295-306. doi: 10.1111/j.1538-7836.2006.01753.x.

19. Bokemeyer B, Thiele K. Cluster analysis of the classification of disseminated lupus erythematosus. Z Rheumatol. 1984 Sep-Oct; 43(5):462-74.

20. Bokemeyer B, Thiele K. Cluster analysis of 109 patients with systemic lupus erythematosus. Klin Wochenschr. 1985 Jan 15;63(2): 79-83. doi: 10.1007/BF01733072.

21. Stenszky V, Kozma L, Szegedi G, et al. Heterogeneity of systemic lupus erythematosus elucidated by cluster analysis. The influence of HLA. J Immunogenet. 1986 Aug; 13(4):327-40. doi: 10.1111/j.1744-313x.1986.tb01117.x.

22. Sedzimirska M, Jacak A, Laba C, et al. Variants of SLE — a statistical approach for discrimination of a group of SLE cases into different subgroups sharing symptomatology. A pilot study. Arch Immunol Ther Exp (Warsz). 1991;39(4):397-404.

23. Аrtim-Esen B, Cene E, Sahinkaya Y, et al. Cluster analysis of autoantibodies in 852 patients with systemic lupus erythematosus from a single center. J Rheumatol. 2014 Jul; 41(7):1304-10. doi: 10.3899/jrheum.130984. Epub 2014 May 15.

24. Coit P, Ruffalo L, Sawalha A. Clinical subgroup clustering analysis in a systemic lupus erythematosus cohort from Western Pennsylvania. Eur J Rheumatol. 2022 Jan;9(1):3-7. doi: 10.5152/eurjrheum.2020.21225.

25. Font J, Cervera R, Ramos-Casals M, et al. Clusters of clinical and immunologic features in systemic lupus erythematosus: analysis of 600 patients from a single center. Semin Arthritis Rheum. 2004 Feb;33(4):217-30. doi: 10.1053/s0049-0172(03)00133-1.

26. To C, Mok C, Tang S, et al. Prognostically distinct clinical patterns of systemic lupus erythematosus identified by cluster analysis. Lupus. 2009 Dec;18(14):1267-75. doi: 10.1177/0961203309345767. Epub 2009 Oct 27.

27. Martin-Gutierrez L, Peng J, Thompson N, et al. Stratification of Patients With Sjögren's Syndrome and Patients With Systemic Lupus Erythematosus According to Two Shared Immune Cell Signatures, With Potential Therapeutic Implications. Arthritis Rheumatol. 2021 Sep;73(9):1626-37. doi: 10.1002/art.41708. Epub 2021 Aug 6.

28. Wu C, Li C, Wu Q, et al; CSTAR co-authors. Chinese Systemic Lupus Erythematosus Treatment and Research Group Registry IX: Clinical Features and Survival of ChildhoodOnset Systemic Lupus Erythematosus in China. Chin Med J (Engl). 2017 Jun 5;130(11): 1276-82. doi: 10.4103/0366-6999.206346.

29. Hiraki L, Feldman C, Liu J, et al. Prevalence, incidence, and demographics of systemic lupus erythematosus and lupus nephritis from 2000 to 2004 among children in the US Medicaid beneficiary population. Arthritis Rheum. 2012 ;64(8):2669-76. doi: 10.1002/art.34472.

30. Kaleda MI, Nikishina IP. Neuropsychic disorders in systemic lupus erythematosus with juvenile onset. Nauchno-prakticheskaya revmatologiya. 2020;58(4):437-42. (In Russ.).

31. Hersh A, Trupin L, Yazdany J, et al. Childhood-onset disease as a predictor of mortality in an adult cohort of patients with systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2010 Aug;62(8):1152-9. doi: 10.1002/acr.20179.

32. Holland M, Beresford M, Feldman B, et al; PRINTO and PRCSG Investigators. Measuring Disease Damage and Its Severity in Childhood-Onset Systemic Lupus Erythematosus. Arthritis Care Res (Hoboken). 2018 Nov;70(11):1621-9. doi: 10.1002/acr.23531.

33. Heshin-Bekenstein M, Trupin L, Yelin E, et al. Longitudinal disease- and steroid-related damage among adults with childhood-onset systemic lupus erythematosus. Semin Arthritis Rheum. 2019 Oct;49(2):267-72. doi: 10.1016/j.semarthrit.2019.05.010. Epub 2019 Jun 3.