Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Antihypertensive effects of immunosuppressive therapy in autoimmune disease

Subjects

Abstract

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disorder that primarily affects women of childbearing age. While immune system dysfunction has been implicated in the development of hypertension (HTN) in SLE, the effect of immunomodulatory drugs on blood pressure (BP) control in SLE patients is unknown. In the present study, we hypothesized that first-line immunomodulatory therapies prescribed to SLE patients would have a beneficial impact on BP. We retrospectively analyzed the Research Data Warehouse containing de-identified patient data (nā€‰=ā€‰1,075,406) from the University of Mississippi Medical Center for all patients with a clinical diagnosis of SLE. BP responses were analyzed in SLE patients that were initially prescribed a single therapy (methotrexate, hydroxychloroquine, azathioprine, mycophenolate mofetil (MMF), or prednisone). Of the 811 SLE patients who met criteria, most were hypertensive (56%), female (94%), and black (65%). Individuals prescribed MMF or hydroxychloroquine had significantly decreased BP and improved BP control at follow-up (>7 days and <3 months after initial visit). Our results suggest that MMF and hydroxychloroquine have beneficial effects on BP, independent of adjunctive antihypertensive therapies and existing renal disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Database flow chart for exclusion numbers and sample sizes for each drug class.
Fig. 2: Baseline comorbidity prevalence within each group.
Fig. 3: Impact of SLE therapy on MAP and BP control.

Similar content being viewed by others

Data availability

The data generated during this study is contained within the manuscript and in supplemental files. Any additional data is available from the corresponding author on reasonable request.

References

  1. Fors Nieves CE, Izmirly PM. Mortality in Systemic Lupus Erythematosus: an Updated Review. Curr Rheumatol Rep. 2016;18:21.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  2. Sabio JM, Vargas-Hitos JA, Navarrete-Navarrete N, Mediavilla JD, Jimenez-Jaimez J, Diaz-Chamorro A, et al. Prevalence of and factors associated with hypertension in young and old women with systemic lupus erythematosus. J Rheumatol 2011;38:1026ā€“32.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  3. Tselios K, Koumaras C, Urowitz MB, Gladman DD. Do current arterial hypertension treatment guidelines apply to systemic lupus erythematosus patients? a critical appraisal. Semin Arthritis Rheum. 2014;43:521ā€“5.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  4. Tselios K, Gladman DD, Su J, Urowitz M. Impact of the new American College of Cardiology/American Heart Association definition of hypertension on atherosclerotic vascular events in systemic lupus erythematosus. Ann Rheum Dis. 2020;79:612ā€“7.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  5. Fanouriakis A, Kostopoulou M, Alunno A, Aringer M, Bajema I, Boletis JN, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019;78:736ā€“45.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  6. Grossman E, Messerli FH. Secondary hypertension: interfering substances. J Clin Hypertens. 2008;10:556ā€“66.

    ArticleĀ  CASĀ  Google ScholarĀ 

  7. Taylor EB, Ryan MJ. Immunosuppression with mycophenolate mofetil attenuates hypertension in an experimental model of autoimmune disease. J Am Heart Assoc. 2017;6:e005394.

  8. Gomez-Guzman M, Jimenez R, Romero M, Sanchez M, Zarzuelo MJ, Gomez-Morales M, et al. Chronic hydroxychloroquine improves endothelial dysfunction and protects kidney in a mouse model of systemic lupus erythematosus. Hypertension 2014;64:330ā€“7.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  9. UMMC. University of Mississippi Medical Center, Center for Informatics and Analytics. Patient Cohort Explorer (2020). https://doi.org/10.6084/m9.figshare.12252737.v2.

  10. Al-Herz A, Ensworth S, Shojania K, Esdaile JM. Cardiovascular risk factor screening in systemic lupus erythematosus. J Rheumatol. 2003;30:493ā€“6.

    PubMedĀ  Google ScholarĀ 

  11. Panoulas VF, Metsios GS, Pace AV, John H, Treharne GJ, Banks MJ, et al. Hypertension in rheumatoid arthritis. Rheumatology. 2008;47:1286ā€“98.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  12. Lim SS, Bayakly AR, Helmick CG, Gordon C, Easley KA, Drenkard C. The incidence and prevalence of systemic lupus erythematosus, 2002-2004: The Georgia Lupus Registry. Arthritis Rheumatol. 2014;66:357ā€“68.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  13. Rodriguez-Iturbe B, Pons H, Johnson RJ. Role of the immune system in hypertension. Physiol Rev. 2017;97:1127ā€“64.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  14. Taylor EB, Wolf VL, Dent E, Ryan MJ. Mechanisms of hypertension in autoimmune rheumatic diseases. Br J Pharmacol. 2019;176:1897ā€“913.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  15. Nikpour M, Urowitz MB, Ibanez D, Harvey PJ, Gladman DD. Importance of cumulative exposure to elevated cholesterol and blood pressure in development of atherosclerotic coronary artery disease in systemic lupus erythematosus: a prospective proof-of-concept cohort study. Arthritis Res Ther. 2011;13:R156.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  16. Goodwin JE, Geller DS. Glucocorticoid-induced hypertension. Pediatr Nephrol. 2012;27:1059ā€“66.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  17. Baid S, Nieman LK. Glucocorticoid excess and hypertension. Curr Hypertens Rep. 2004;6:493ā€“9.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  18. Ruiz-Irastorza G, Danza A, Khamashta M. Glucocorticoid use and abuse in SLE. Rheumatology. 2012;51:1145ā€“53.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  19. Gandelman JS, Khan OA, Shuey MM, Neal JE, McNeer E, Dickson A, et al. Increased incidence of resistant hypertension in patients with systemic lupus erythematosus: a retrospective cohort study. Arthritis Care Res. 2020;72:534ā€“43.

    ArticleĀ  CASĀ  Google ScholarĀ 

  20. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:480ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  21. Mangoni AA, Baghdadi LR, Shanahan EM, Wiese MD, Tommasi S, Elliot D, et al. Methotrexate, blood pressure and markers of arterial function in patients with rheumatoid arthritis: a repeated cross-sectional study. Ther Adv Musculoskelet Dis. 2017;9:213ā€“29.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  22. Sakthiswary R, Suresh E. Methotrexate in systemic lupus erythematosus: a systematic review of its efficacy. Lupus. 2014;23:225ā€“35.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  23. Dorner T. Therapy: hydroxychloroquine in SLE: old drug, new perspectives. Nat Rev Rheumatol. 2010;6:10ā€“1.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  24. Stojan G, Petri M. Atherosclerosis in systemic lupus erythematosus. J Cardiovasc Pharmacol. 2013;62:255ā€“62.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  25. McCarthy CG, Wenceslau CF, Goulopoulou S, Ogbi S, Matsumoto T, Webb RC. Autoimmune therapeutic chloroquine lowers blood pressure and improves endothelial function in spontaneously hypertensive rats. Pharm Res. 2016;113:384ā€“94.

    ArticleĀ  CASĀ  Google ScholarĀ 

  26. Allison AC. Mechanisms of action of mycophenolate mofetil. Lupus. 2005;14:s2ā€“8.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  27. Fanouriakis A, Bertsias G. Changing paradigms in the treatment of systemic lupus erythematosus. Lupus Sci Med. 2019;6:e000310.

    ArticleĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  28. Georgianos PI, Agarwal R. Resistant Hypertension in Chronic Kidney Disease (CKD): prevalence, treatment particularities, and research agenda. Curr Hypertens Rep. 2020;22:84.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  29. Herrera J, Ferrebuz A, MacGregor EG, Rodriguez-Iturbe B. Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis. J Am Soc Nephrol. 2006;17:S218ā€“25.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  30. Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009;20:1103ā€“12.

    ArticleĀ  CASĀ  PubMedĀ  PubMed CentralĀ  Google ScholarĀ 

  31. Houssiau FA, Dā€™Cruz D, Sangle S, Remy P, Vasconcelos C, Petrovic R, et al. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial. Ann Rheum Dis. 2010;69:2083ā€“9.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  32. Shaharir SS, Mustafar R, Mohd R, Mohd Said MS, Gafor HA. Persistent hypertension in lupus nephritis and the associated risk factors. Clin Rheumatol. 2015;34:93ā€“7.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

  33. Alarcon GS, Friedman AW, Straaton KV, Moulds JM, Lisse J, Bastian HM, et al. Systemic lupus erythematosus in three ethnic groups: III. A comparison of characteristics early in the natural history of the LUMINA cohort. LUpus in MInority populations: NAture vs. Nurture. Lupus. 1999;8:197ā€“209.

    ArticleĀ  CASĀ  PubMedĀ  Google ScholarĀ 

  34. Seligman VA, Lum RF, Olson JL, Li H, Criswell LA. Demographic differences in the development of lupus nephritis: a retrospective analysis. Am J Med. 2002;112:726ā€“9.

    ArticleĀ  PubMedĀ  Google ScholarĀ 

Download references

Funding

This work was supported by grants from the National Institute on Minority Health and Health Disparities (K99 MD014738) to JSC, National Heart, Lung, and Blood Institute (K99 HL146888) to EBT, National Institute of General Medical Sciences (P20 GM104357) and IDeA grant (U54 GM115428) to WBH, and the National Heart, Lung, and Blood Institute (P01 HL051971) and National Institute of General Medical Sciences (P20 GM104357) to the UMMC Department of Physiology and Biophysics.

Author information

Authors and Affiliations

Authors

Contributions

JSC, EBT, and WBH contributed to the conception and design of the study. EBT and JSC drafted the manuscript. WBH performed statistical analyses. JSC created all tables and figures. EBT, JSC, and WBH revised the manuscript and approved the final manuscript.

Corresponding author

Correspondence to Erin B. Taylor.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

Data from this study was generated using the University of Mississippi Medical Center Research Data Warehouse. The data is in this repository is extracted from the electronic health record system (Epic) and de-identified and are thus exempt from IRB approval.

Additional information

Publisherā€™s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Clemmer, J.S., Hillegass, W.B. & Taylor, E.B. Antihypertensive effects of immunosuppressive therapy in autoimmune disease. J Hum Hypertens 37, 300ā€“306 (2023). https://doi.org/10.1038/s41371-022-00682-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41371-022-00682-0

This article is cited by

Search

Quick links