Hypertension in Rheumatic Diseases: A Closer Look at Immune Mediators and Hormone Changes

Compared with the general population, individuals with autoimmune rheumatic disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have an especially high risk for cardiovascular disease (CVD) and associated mortality.¹ In patients with RA, for example, CVD causes 50% of premature deaths.² This high prevalence has been linked to the elevated risk for hypertension in patients with autoimmune rheumatic disorders, including up to 40% of patients with SLE younger than 40 (vs 11% of age-matched controls).²

Several medications used in RA treatment such as glucocorticoids and certain disease-modifying antirheumatic drugs can lead to increased blood pressure or affect blood pressure control.³ In addition, the high prevalence of chronic kidney disease in patients with autoimmune rheumatic diseases (40% to 70% of patients with SLE) further hampers blood pressure control.¹

“Hypertension invariably reflects kidney involvement commonly seen in SLE and scleroderma, but much less frequently in patients with other [autoimmune rheumatic diseases] such as RA, myositis, and Sjogren syndrome,” David Isenberg, MD, FRCP, FAMS, the Arthritis Research UK Diamond Jubilee Professor of Rheumatology at University College London, told Rheumatology Advisor. “The need to prescribe medication to normalize blood pressure adds to the disease burden in these patients.”

However, clinical trials and guidelines regarding hypertension treatment have not addressed the particular needs of patients with rheumatic diseases, and many of these individuals do not receive the appropriate medication or do not achieve treatment targets.

Angiotensin converting enzyme (ACE) inhibitors are often used to treat hypertension and renal disease in SLE.¹ These are “generally well tolerated and associated with a delay in the onset of renal involvement and a decline in the risk of disease relapse…that likely occurs from both the decrease in angiotensin II and the immunomodulatory impact of renin-angiotensin system blockade,” as explained in a review published in Current Hypertension Reports.¹ The use of ACE inhibitors in patients with SLE is also associated with a delay in the development of renal involvement and a reduced risk for disease activity.⁴

“Work from our laboratory and others suggests that innate and adaptive immunity are important regulators of [the] physiological systems [that influence blood pressure] and therefore have important mechanistic implications for the development of hypertension,” wrote the authors.¹ The review focused on the potential mechanisms by which the chronic inflammation in autoimmune diseases can lead to hypertension, with a special emphasis on risk factors specific to SLE “as a disease model of autoimmune-associated hypertension,” they stated. Many of these risk factors are highlighted below.

Environmental factors: Several studies have identified vitamin D deficiency in a substantial number of patients with autoimmune diseases, including SLE.¹ Vitamin D deficiency may lead to increased production of autoantibodies due to reductions in regulatory T cells (Treg) and increased activation of autoreactive B cells. Other findings point to a connection between vitamin D deficiency and a non-dipping pattern of nocturnal blood pressure, including a study involving 77 women with SLE.⁵

Sex-specific factors: Sex hormones have immunomodulatory functions, and manipulation of these hormones was found to influence disease progression in experimental models of autoimmunity.¹ While estrogens are generally believed to buffer against hypertension and other CVD risk factors, mouse studies have observed divergent effects of ovariectomy on hypertension based on the age of the mice, indicating that the effect of estrogen on SLE pathogenesis and hypertension is not straightforward.¹

Metabolic factors: Adipokines such as leptin, resistin, and adiponectin have been implicated in the development of low-grade inflammation and hypertension in patients with autoimmune disease.¹ Earlier findings demonstrated that leptin, a known immodulatory hormone, affected blood pressure via alterations in sympathetic outflow and renal sodium retention, and the results of more recent studies suggest proinflammatory effects of leptin in SLE, RA, psoriasis, and multiple sclerosis.^6,7

Immune system dysfunction (B and T cells): In a mouse model, the depletion of B cells with mycophenolate mofetil (MMF) and the mouse equivalent of rituximab reduced hypertension.¹ Small studies have found similar evidence for MMF in humans. In addition, both clinical and experimental studies have noted that reductions in circulating Treg cells are associated with SLE pathogenesis, and adoptive transfer of Treg was shown to reduce blood pressure in hypertensive mice. “These studies further strengthen the link between autoimmunity and blood pressure control,” the authors concluded.¹

Renal hemodynamics: An estimated 50% to 75% of patients with SLE have renal involvement “in the form of immune complex mediated glomerulonephritis,”¹ according to the investigators. It is unlikely that nephritis-induced renal injury is the cause of hypertension in these individuals, as researchers have observed hypertension in 53% of patients with lupus nephritis who had been in remission for a minimum of 6 months.⁸

Overall, clinical and experimental data “suggest the possibility that early immunological changes during autoimmunity may impact renal hemodynamic and tubular function to cause hypertension before there are clear signs of renal injury,” the review stated.¹

Blood pressure control should be considered an important part of treatment in patients with autoimmune diseases. “In SLE, controlling blood pressure is vital to maintaining kidney function and kidney survival,” said Dr Isenberg. Overall, however, the “issue of high blood pressure is really secondary to improving our understanding and treatment of [rheumatic disease]s,”he continued.

References

1. Wolf VL, Ryan MJ.  Autoimmune disease-associated hypertension. Curr Hypertens Rep. 2019;21(1):10.
2. Taylor EB, Wolf VL, Dent E, Ryan MJ. Mechanisms of hypertension in autoimmune rheumatic diseases [published online February 3, 2019]. Br J Pharmacol.  doi:10.1111/bph.14604
3. Panoulas VF, Metsios GS, Pace AV, et al. Hypertension in rheumatoid arthritis. Rheumatology (Oxford). 2008;47(9):1286-1298.
4. Durán-Barragán S, McGwin G, Vilá LM, Reveille JD, Alarcón GS, LUMINA (LIX).  Angiotensin-converting enzyme inhibitors delay the occurrence of renal involvement and are associated with a decreased risk of disease activity in patients with systemic lupus erythematosus–results from LUMINA (LIX): a multiethnic US cohort. Rheumatology (Oxford). 2008;47(7):1093-1096.
5. Sabio JM, Vargas-Hitos JA, Martinez Bordonado J, Mediavilla Garcia JD. Association between non-dipper hypertension and vitamin D deficiency in women with systemic lupus erythematosus. Clin Exp Rheumatol. 2018;37(2):286-292.
6. Bravo PE, Morse S, Borne DM, Aguilar EA, Reisin E. Leptin and hypertension in obesity. Vasc Health Risk Manag. 2006;2(2):163-169.
7. Tian G, Liang JN, Wang ZY, Zhou D.  Emerging role of leptin in rheumatoid arthritis. Clin Exp Immunol. 2014;177(3):557-570.
8. 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(1):93-97.