Recent Advances in Management of Systemic Lupus Erythematosus (SLE).A Mini Review

Fatima Saqib Rashid ¹, Kasim Syed Jafri², Muhammad Mohsin Sial³, Abeerah Zainub⁴, Anab Rehan⁵, Taseer, Mercy Zhou⁶, Aishaa Hasan⁷, Nadeem Iqbal*⁸

1, 2. Shifa College of Medicine, Islamabad.

3. King Edward Medical University.

4. Riphah International University Riphah International University.

5. Ochsner Clinic Foundation, New Orleans, LA ; Nephrology.

6. University of Tennessee Health Science Center.

7. Avecenna Hospital Lahore.

*Correspondence to: Nadeem Iqbal, Dept of Urology and Kidney Transplant, Pakistan Kidney and Liver Institute Lahore, Pakistan.
Copyright
© 2024: Nadeem Iqbal. This is an open access article distributed under the Creative Commons Attribution  License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original  work is properly cited.

Received:  19 August 2024

Published: 01 Sept 2024

Abstract

Systemic lupus erythematosus (SLE) is a challenging and an undecipherable example of autoimmunity, it is still under research. It is an autoimmune ailment involving almost every system in the body. Although immunosuppressive and other options of treatments have been tried forlong time but still clinicins have seen intermittent  disease flares and remissions. We searched literature and summarized findings in such studies regarding the subject matter over the last few years.

Key Words:- SLE, autoimmune disease , treatment ,guidelines.

Introduction

Systemic lupus erythematosus (SLE) is an undecipherable example of autoimmunity, it is still under research. It is a kind of  multisystem autoimmune ailment involving almost every system in the body. Although immunosuppressive agents have been utilized but very challenging at the same time.Many options of treatments still have intermittent  disease flares and remissions (1,2,3).

There are numerous challenges owing to the mixture of clinical and biological heterogeneity in SLE behavious that has led to limited  breakthroughs regarding the treatment options of systemic lupus erythematosus (5,6,7,8).  In this review ,recent advances in research related to SLE have been summarized.

Methods

We searched PubMed, and Medline database publications and results of clinical trials presented at major international rheumatology conferences during the last decade using: SLE, autoimmune disease , treatment ,guidelines. The publications included were special communications, reviews, books, and research presentations and studies regarding the subject matter over the last few years.

Discussion

The incidence and prevalence of systemic lupus erythematosus has been highly variable among different regions in the world.These variations are because of environmental exposures,genetics factors and variability of the presenations of systemic lupus erythematosus (1). The female gender, specific populations such as African Americans, Amerindians, and Asians are at greater risk of SLE (2). Recently increasing trend in the prevalence of systemic lupus erythematosus has been witnessed in different regions including USA, Europe and Asia (3,4,5,6).

Different sets of classification criteria for systemic lupus erythematosus have been devised over time such as one  used American College of Rheumatology criteria, others include the systemic lupus international collaborating clinics (SLICC)  (9). Recently, another classification has been devised by collaboration between the American College of Rheumatology and the European Alliance of Associations for Rheumatology (EULAR) (10).

Although genetics research has been done in connection to SLE but despite progress in researchers ‘ comprehension of the underlying genetic risk factors for systemic lupus erythematosus, many of questions still remain un answered . Approximately near 100 gene loci have been implicated as risk factors in systemic lupus erythematosus,but there are still many gaps in our understanding of the pathogenesis at genetic level (11). In males, patients having an extra X chromosome, such as those with Klinefelter syndrome (47,XXY) and trisomy X syndrome (47,XXX), have relatively higher prevalence of systemic lupus erythematosus (12,13).

Sex hormones have been implicated in systemic lupus erythematosus as they affect more female than males, increased flares in timesof elevated estrogen levels in pregnancy, and higher chances of being affected by systemic lupus erythematosus in those postmenopausal women who get estrogen administration (8,14).

Autoantibodies are a essential  hallmark of systemic lupus erythematosus, and important for the initial diagnosis as well as monitoring of disease activity. The antinuclear antibody test is positive in most patients with systemic lupus erythematosus (15,16,17).

There is high variance in clinical symptoms. Constitutional symptoms include fever, brain clouding, ,fatigue which negatively impact patients’ quality of life suffering  from systemic lupus erythematosus (18,19). Inflammatory arthropathy,mucocutaneous disease affects many of these patients  while glomerulonephritis and hematological disease, less common. Neuropsychiatric lupus and cognitive dysfunction are other less commonly encountered issues in SLE patients (20,21).

Antimalarials such as hydroxychloroquine is also used unless it is contraindicated. Then glucocorticoids are pivotal in managing acute as well as chronic forms of systemic lupus erythematosus. Glucocorticoids use lead to Cushingoid metabolic adverse effects. Immunosuppressants such as mycophenolate mofetil , mycophenolate sodium, azathioprine, methotrexate are also used in combination therapy regimens along with glucocorticoids and antimalarials. The optimal time duration for using immunosuppressants option in systemic lupus erythematosus is imperfectly evidenced. Treatment guidelines recommend treatment of histological class III or IV lupus nephritis with mycophenolate mofetil or cyclophosphamide for induction, and mycophenolate mofetil for maintenance treatment. The optimal duration of maintenance treatment is still not known but approximately it should be around four years (22,23).

Anti-CD20 B cell depleting chimeric monoclonal antibody, rituximab is also utilisedin management of SLE. Another novel calcineurin inhibitor voclosporin has been found to be effective compared with placebo in a phase 3 study of 357 patients with lupus nephritis (24). Tyrosine kinase 2 (TYK2) a member of family of intracellular signalling molecules. Various inhibitors of TYK2 have now been studied in human disease, and one of these inhibitors, deucravacitinib has shown  preliminary safety profile  Two other inhibitors of TYK2, brepocitinib and ropsacitinib, are also in earlier stages of clinical trials (25). Tolerogenic dendritic cells (tolDCs) are pivotal factors in the initiation and maintenance of immune tolerance and subsequent prevention of autoimmunity. Recent advances in treatment of autoimmune diseases including systemic lupus erythematosus (SLE) have focused on inducing specific tolerance to avoid long-term use of immunosuppressive drugs (26).

The treatment outcomes for SLE are always facing challenges. The main causes of death in patients suffering with systemic lupus erythematosus include infection secondary to immunosuppression, renal disease, and cardiovascular compications (27,28,29). The poor outcomes for patients with systemic lupus erythematosus which has been seen in many research studies underscores the fact that we still need for better options of treatments pathways for optimally controlling SLE. There are leading socities in world working on guidelineshowever we still need more application of advances in pathogenic understanding to identification and testing of therapeutic targets. We need more evidence based decision making in clinical practice. There is demand for robustness of goals gauging  in trials to better guide the utility of trials results and their possible application in clinical practices.

Conclusion

Although much of work has been done regarding devising optimal treatment goals and guidelines to achieve them. But there are still questions which need answers regarding SLE management.In future quest for combination of new treatment options and measures to reduce complications of SLE would be a main challenge for researchers.

References

1. Izmirly PM, Parton H, Wang L, et al. Prevalence of systemic lupus erythematosus in the United States: estimates from a meta-analysis of the centers for disease control and prevention national lupus registries. Arthritis Rheumatol 2021;73:991-6. doi:10.1002/ art.41632.

2. Duarte-García A, Hocaoglu M, Valenzuela-Almada M, et al. Rising incidence and prevalence of systemic lupus erythematosus: a population-based study over four decades. Ann Rheum Dis 2022;81:1260-6. doi:10.1136/annrheumdis-2022-222276.

3. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019;78:1151-9. doi:10.1136/annrheumdis-2018-214819.

4. Harley ITW, Sawalha AH. Systemic lupus erythematosus as a genetic disease. Clin Immunol 2022;236:108953. doi:10.1016/j. clim.2022.108953.

5. Barturen G, Babaei S, Català-Moll F, et al. Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases. Arthritis Rheumatol 2021;73:1073-85. doi:10.1002/art.41610.

6. Brown GJ, Cañete PF, Wang H, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature 2022;605:349-56. doi:10.1038/s41586-022-04642-z

7. Pyfrom S, Paneru B, Knox JJ, et al. The dynamic epigenetic regulation of the inactive X chromosome in healthy human B cells is dysregulated in lupus patients. Proc Natl Acad Sci U S A 2021;118:e2024624118. doi:10.1073/pnas.2024624118.

8. Rojas-Villarraga A, Torres-Gonzalez JV, Ruiz-Sternberg Á-M. Safety of hormonal replacement therapy and oral contraceptives in systemic lupus erythematosus: a systematic review and meta-analysis. PLoS One 2014;9:e104303. doi:10.1371/journal.pone.0104303.

9. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012;64:2677-86. doi:10.1002/art.34473.

10. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis 2019;78:1151-9. doi:10.1136/annrheumdis-2018-214819.

11. Lu X, Chen X, Forney C, et al. Global discovery of lupus genetic risk variant allelic enhancer activity. Nat Commun 2021;12:1611. doi:10.1038/s41467-021-21854-5.

12. Scofield RH, Bruner GR, Namjou B, et al. Klinefelter’s syndrome (47,XXY) in male systemic lupus erythematosus patients: support for the notion of a gene-dose effect from the X chromosome. Arthritis Rheum 2008;58:2511-7. doi:10.1002/art.23701.

13.  Liu K, Kurien BT, Zimmerman SL, et al. X chromosome dose and sex bias in autoimmune diseases: increased prevalence of 47,XXX in systemic lupus erythematosus and Sjögren’s syndrome. Arthritis Rheumatol 2016;68:1290-300. doi:10.1002/art.39560.

14. Eudy AM, Siega-Riz AM, Engel SM, et al. Effect of pregnancy on disease flares in patients with systemic lupus erythematosus. Ann Rheum Dis 2018;77:855-60. doi:10.1136/ annrheumdis-2017-212535.

15. Dinse GE, Parks CG, Weinberg CR, et al. Antinuclear antibodies and mortality in the National Health and Nutrition Examination Survey (1999-2004). PLoS One 2017;12:e0185977. doi:10.1371/journal. pone.0185977.

16. Solow EB, Vongpatanasin W, Skaug B, Karp DR, Ayers C, de Lemos JA. Antinuclear antibodies are associated with all-cause mortality and cardiovascular outcomes in the general population. J Am Coll Cardiol 2015;65:2669-70. doi:10.1016/j.jacc.2015.03.578.

17. Fernandez-Ruiz R, Belmont HM. The role of anticomplement therapy in lupus nephritis. Transl Res 2022;245:1-17. doi:10.1016/j. trsl.2022.02.001.

18. Raghunath S, Guymer EK, Glikmann-Johnston Y, et al. Fibromyalgia,mood disorders, cognitive test results, cognitive symptoms and quality of life in systemic lupus erythematosus. Rheumatology (Oxford) 2022;62:190-9. doi:10.1093/rheumatology/keac207.

19. Golder V, Ooi JJY, Antony AS, et al. Discordance of patient and physician health status concerns in systemic lupus erythematosus. Lupus 2017;32:961203317722412-506. doi:10.1177/0961203317722412.

20. Hanly JG, Gordon C, Bae SC, et al. Neuropsychiatric events in systemic lupus erythematosus: predictors of occurrence and resolution in a longitudinal analysis of an international inception cohort. Arthritis Rheumatol 2021;73:2293-302. doi:10.1002/art.41876.

21. Raghunath S, Glikmann-Johnston Y, Hanly JG, et al. Cognitive dysfunction in systemic lupus erythematosus: how do we advance our understanding?Lancet Rheumatol 2022;4:e293-302. doi:10.1016/S2665-9913(21)00331-3.

22. Rovin BH, Adler SG, Barratt J, et al, Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int 2021;100(4S):S1-276. doi:10.1016/j. kint.2021.05.021.

23. 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;79:713-23. doi:10.1136/ annrheumdis-2020-216924.

24. Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet 2021;397:2070-80. doi:10.1016/S0140- 6736(21)00578-X.

25. Morand E, Merola JF, Tanaka Y, Gladman D, Fleischmann R. TYK2: an emerging therapeutic target in rheumatic disease. Nat Rev Rheumatol. 2024;20(4):232-240. doi: 10.1038/s41584-024-01093-w.

26. Ritprajak P, Kaewraemruaen C, Hirankarn N. Current Paradigms of Tolerogenic Dendritic Cells and Clinical Implications for Systemic Lupus Erythematosus. Cells. 2019;8(10):1291. doi: 10.3390/cells8101291.

27. Tektonidou MG, Lewandowski LB, Hu J, Dasgupta A, Ward MM. Survival in adults and children with systemic lupus erythematosus: a systematic review and Bayesian meta-analysis of studies from 1950 to 2016. Ann Rheum Dis 2017;76:2009-16. doi:10.1136/ annrheumdis-2017-211663.

28. Franklyn K, Hoi A, Nikpour M, Morand EF. The need to define treatment goals for systemic lupus erythematosus. Nat Rev Rheumatol 2014;10:567-71. doi:10.1038/nrrheum.2014.118.

29. Schmeding A, Schneider M. Fatigue, health-related quality of life and other patient-reported outcomes in systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2013;27:363-75. doi:10.1016/j. berh.2013.07.009..