Antihypertensive effects of immunosuppressive therapy in autoimmune disease

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 (n=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 a follow-up visit. Our results suggest that MMF and hydroxychloroquine have beneficial effects on BP, independent of adjunctive antihypertensive therapies and existing renal disease.

INTRODUCTION

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that primarily affects women in their childbearing years. While the precise etiology of SLE is unknown, a complex interplay of genetic, hormonal, and environmental factors likely plays a role in the development and pathogenesis of the disease. SLE is characterized by aberrant activity of both the innate and adaptive immune systems, and central to the disease is B and T lymphocyte hyperreactivity leading to the formation of autoantibodies that can lead to progressive pathophysiology in multiple organ systems, including the skin, vasculature, central nervous system, and kidney.

Cardiovascular disease (CVD) is the most common cause of premature death in SLE patients (1), and hypertension (HTN) is a significant modifiable CVD risk factor. While the prevalence of HTN can vary widely depending on the cohort, SLE patients under the age of 40 have an approximately four times higher prevalence of HTN (~40%) compared to age-matched controls (~11%) (2). Both traditional (smoking, BMI, sedentary lifestyle) and non-traditional (immune system dysfunction, lupus nephritis, medications) risk factors likely contribute to the development and progression of HTN in SLE (3). However, despite the increased incidence of HTN and CVD, there are limited data on the outcomes or progression of SLE in patients with strict blood pressure (BP) management. Furthermore, specific recommendations for antihypertensive treatment and BP control in patients with SLE or other autoimmune diseases are currently unclear. A recent analysis of the impact of the new 2017 HTN ACC/AHA guidelines on cardiovascular events in SLE suggests that BP <130/80 mmHg decreases CVD morbidity and mortality (4).

While antihypertensive medications are important tools to control HTN in SLE patients, other therapies may also impact BP while also helping to manage SLE disease activity. Therapeutic regimens are wide ranging among the SLE patient population and are determined by the extent of the disease, the presence of lupus nephritis or renal disease, and whether a patient is experiencing recurrent flares (5). The most commonly prescribed SLE medications are immunomodulatory dugs, including glucocorticoids, antimalarials, immunosuppressive agents, and biologics. While some of these medications can potentially increase BP or exacerbate pre-existing HTN (6), there are little data on the effects of autoimmune disease treatment on BP control in SLE.

In support of the potential BP lowering effects of these therapies, several have been examined in animal models of autoimmunity that develop HTN, including mycophenolate mofetil (MMF) (7) and hydroxychloroquine (8). However, the possible additive benefits of these drugs for BP control in SLE patients has not been examined. In the present study, we retrospectively analyzed BP in SLE patients before and after the initial administration of a single SLE therapy.

MATERIALS AND METHODS

Study Patients

The Research Data Warehouse (RDW) from the University of Mississippi Medical Center (UMMC), a large academic health science center, contains >37 million electronic health records from >1 million unique patients. De-identified data are extracted from the electronic health record system (Epic) and are exempt from IRB approval (9). Data from 2013–2020 were retrieved from patients ≥16 years old with a clinical SLE diagnosis. To isolate the potential BP effects of an initial prescription of autoimmune therapy, the following pre-specified eligibility criteria were applied:

1. An initial clinical diagnosis of SLE was entered.

2. The patient had received no prior SLE therapy.

3. BP measurements were available from the initial encounter as well as a follow-up encounter within the window of at least 7 days and less than 90 days after the initial encounter.

4. As clinically indicated at the initial encounter, the patient did or did not have an autoimmune monotherapy prescribed. SLE therapies that were included in the study were: methotrexate sodium (2.5 – 25 mg), hydroxychloroquine (200 mg), azathioprine (50 – 100 mg), MMF (250 – 500 mg), and prednisone (1 – 20 mg). Additional therapies were queried from the RDW (rituximab, belimumab, adalimumab, cyclosporine, and cyclophosphamide), but there were not sufficient sample sizes to perform further analyses (<10 patients per drug).

5. Patients with clinical diagnoses of heart failure, circulatory shock, cardiac arrhythmia,valvular disease, end stage renal disease (ESRD), acute kidney injury, or liver failure were excluded as likely confounders for the assessment of BP control.

All BP measurements consisted of office sphygmomanometer methods and were taken at University of Mississippi Medical Center clinics, which have standardized BP measurement procedures. Patients were classified as untreated if they had a clinical SLE diagnosis without record of SLE therapy, either at baseline or previously. Based on the 8^th Joint National Committee guidelines and an average age of 44 years in this study population, HTN was defined as a clinical diagnosis or a baseline SBP of ≥140 mmHg or DBP of ≥90 mmHg. Controlled HTN was defined as SBP of <140 and DBP <90 mmHg. Normotension was defined as no history of HTN and baseline visit systolic BP <140 mmHg and diastolic BP < 90 mmHg.

Statistical Analysis

Baseline characteristics were summarized as means, standard deviations, and 95% confidence intervals for continuous measures. Categorical factors are summarized as counts and percentages. Baseline characteristics were compared with t-tests for continuous factors and Fisher’s exact test for categorical factors stratified by HTN status. Stratified by initial immunomodulatory prescription, baseline characteristics were compared with ANOVA for continuous factors with two-sided Dunnett test adjustment for multiple comparisons compared to the control group of no immunomodulatory prescription indicated (No Rx). Similarly, baseline categorical factors stratified by initial immunomodulatory prescription were compared with Fisher-Freeman-Halton exact test and, when significant, stepdown Fisher exact tests compared to No Rx. Multivariable general linear regression models were used to evaluate the associations between change in mean arterial pressure (MAP) with initial prescription of immunomodulatory medications versus No Rx indicated. This association was further evaluated with models adjusting for demographics (age, gender, race), body mass index, and kidney disease (lupus nephritis, proteinuria), and baseline MAP. Two-sided Dunnett tests adjusted the p-values for multiple comparisons with the control No Rx indicated group. Logistic regression analyses were performed to evaluate the associations between and among baseline characteristics and initial immunomodulatory medication prescription. These are reported as odds ratios with 95% confidence limits. Detailed analysis of residuals confirmed satisfaction of the assumptions of the general and generalized linear models evaluated. All analyses were performed in SAS version 9.4 (Cary, NC, USA).

RESULTS

Of the 761,741 total patients in the RDW that were ≥16 years old, 3,168 had a clinical diagnosis of SLE (0.4% overall prevalence). Of those patients that had an SLE diagnosis, 976 were excluded due to heart failure, circulatory shock, ESRD, acute kidney injury, or liver failure. After further selecting patients that had at least two visits, and were prescribed either a single drug on the initial visit or given no medication, 811 were included in the study (Figure 1). Overall, the average age for the entire cohort was 44±16 years old, and the patients were 94% female and 65% black or African American, with an average BMI of 31±8 kg/m². The average MAP was 96±13 mmHg, and the overall prevalence of HTN in the cohort was 56%. Table 1 outlines the differences between normotensive and hypertensive SLE patients included in the study. The patients with HTN were older (average age 47±15 vs. 40±16, p<0.05) and more likely to have various comorbidities, including diabetes mellitus type II, atherosclerosis, and chronic kidney disease (CKD). Despite being hypertensive, only 9% of these patients were taking antihypertensive medication.

Figure 1.

Database flow chart for exclusion numbers and sample sizes for each drug class.

Table 1.

Characteristics of hypertensive and normotensive SLE patients

Variable	NTN (n=357)	HTN (n=454)
BP control baseline (%)	100	43*
BP control follow-up (%)	84	57*
Antihypertensive use (%)	0	9*
Age (yr)	40 ± 16	47 ± 15*
Female (%)	94	94
Black (%)	58	70*
SBP (mmHg)	118 ± 12	138±19*
DBP (mmHg)	74 ±9	84 ± 13*
PP (mmHg)	45 ± 10	55 ± 16*
BMI (kg/m2)	28 ±7	32 ±8*
Neutrophil %	63 ± 17	63 ± 14
Lymphocyte %	25 ± 13	26 ± 12
Comorbidities
T2D (%)	3.4	15.9*
Atherosclerosis (%)	0	5.7*
CKD (%)	2.5	10.8*
Nephritis (%)	3.9	6.8
Proteinuria (%)	3.6	9.7*

NTN indicates normal baseline BP; HTN, hypertension; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; BMI, body mass index; T2D, type II diabetes; and CKD, chronic kidney disease. Mean ± SD

^*p < 0.05 vs. NTN

The baseline characteristics of patients after separation into treatment groups for further analysis are outlined in Table 2. Treated and untreated groups were relatively similar in regards to age, sex, and race. Of note, the patients prescribed azathioprine were associated with a relative tachycardia, increased circulating neutrophil percentages and decreased lymphocyte percentages. There were no statistical differences among common adjunctive therapy use (glucocorticoids, antihypertensives, or statins).

Table 2.

Baseline characteristics of all Lupus patients

Variable	No Rx (n=405)	Prednisone (n=76)	MTX (n=33)	HCQ (n=256)	AZA (n=25)	MMF (n=16)
Age (yr)	45 ± 16	42± 15	46 ± 15	42 ± 15*	41 ± 22	41 ± 17
Female (%)	94	92	97	95	96	88
Black (%)	55	67	64	74*	68	69
SBP (mmHg)	128 ± 19	130 ± 20	126 ± 15	131 ± 19	129 ± 19	138 ± 21
DBP (mmHg)	78 ± 12	81 ± 13	75 ± 10	81 ± 13	80 ± 12	87 ± 14*
PP (mmHg)	50 ± 15	50 ± 15	51 ± 12	51 ± 15	50 ± 15	51 ± 15
HR (bpm)	84 ± 15	85 ± 15	83 ± 20	84 ± 15	90 ± 14	79 ± 15
BMI (kg/m2)	31 ± 8	29 ± 8	31 ± 7	31 ± 8	29 ± 7	32 ± 6
Follow up (days)	33 ± 21	36 ± 23	42 ± 24*	35 ± 20	43 ± 23*	34 ± 18
Neutrophil %	58 ± 14	60 ± 12	62 ± 23	57 ± 14	83 ± 8*	56 ± 11
Lymphocyte %	31 ± 12	29 ± 11	30 ± 21	31 ± 11	12 ± 5*	31 ± 6
Adjunctive therapy Glucocorticoid (%)	-	100	30	32	36	31
HTN (%)	-	11	6	11	8	6
Statin (%)	-	3	3	1	0	0

No Rx indicates no therapy group; MTX, methotrexate; HCQ, hydroxychloroquine; Az, Azathioprine; MMF, mycophenolate mofetil; SBP, systolic blood pressure; DBP, diastolic blood pressure; PP, pulse pressure; HR, heart rate; BMI, body mass index; and HTN, antihypertensive medication. Mean ± SD

^*p < 0.05 vs. No Rx

Comparisons between comorbidities in the treatment groups are shown in Figure 2. Patients within the prednisone, hydroxychloroquine, and MMF groups had a higher prevalence of HTN as compared to the untreated cohort. MMF therapy was also associated with an increased prevalence of CKD, lupus nephritis, and proteinuria. The odds ratio of being prescribed MMF was significantly higher in patients with baseline lupus nephritis (OR 15.5 [5 to 44 95% CI]) or in patients with baseline proteinuria (OR 6.5 [2 to 19 95% CI]). Patients taking azathioprine also had a higher incidence of nephritis and proteinuria as compared to the untreated group (Figure 2). In the entire cohort, proteinuria and lupus nephritis were highly corelated (OR 22.5 [11 to 44 95% CI]).

Figure 2.

Baseline comorbidity prevalence within each group. Patients were untreated (No Rx) or prescribed prednisone (Pred), methotrexate (MTX), hydroxychloroquine (HCQ), azathioprine (AZA), or mycophenolate mofetil (MMF). *, p<0.05 vs. No Rx; +, p<0.05 vs. indicated group.

Figure 3 shows the changes in MAP after treatment. Patients prescribed MMF (n=16) had a greater fall in MAP (−9.2 mm Hg [−15.3 to −3.2 95% CI]) as compared to the untreated group after controlling for age, sex, race, BMI, and kidney disease. Similarly, the patients treated with hydroxychloroquine (n=256) had a small but statistically significant decrease in MAP (−2.3 mm Hg [−4.1 to −0.4 95% CI]). These decreases in MAP in patients administered MMF and hydroxychloroquine were significant when adjusting for age, sex, race, BMI, and kidney disease. (Figure 3A). When also adjusting for baseline BP, age, BMI, baseline BP, and MMF therapy were associated with decreased BP at a follow-up visit (Table 3). Patients with proteinuria (n=57) at baseline were associated with a larger decrease in MAP (−3.8 mmHg [−7.5 to −0.1 95% CI]) than those without proteinuria (n=754) (−0.4 mmHg [−1.2 to 0.4 95% CI]). This was actually reversed in the MMF group: MMF treated patients without proteinuria (n=11) had a significant decrease in MAP (−11.3 mmHg [−20.1 to −2.5 95% CI]) but those with proteinuria did not (n=5) (−3.9 mmHg [−12.9 to 5.2 95% CI]). Lastly, the untreated, hydroxychloroquine, and MMF groups had significantly higher levels of BP control at follow up (Figure 3B). Age, gender, race, BMI, and kidney disease were not significantly associated with a change in MAP between baseline and follow-up visits in multivariable regression analyses both with and without adjustment for initial medication prescription, while hydroxychloroquine and MMF were associated with a fall in BP (Table 3, Model 1).

Figure 3.

Impact of SLE therapy on MAP and BP control. A, Changes in mean arterial pressure (MAP) adjusted for age, gender, race, and BMI (mean ± 95% CI). B, Proportion of blood pressure control adjusted for age, gender, race, and BMI. *, p<0.05 vs. No Rx; #, p<0.05 vs. baseline.

Table 3.

Multivariable adjusted models for the decrease in blood pressure by medication

Model 1				Model 2
Factor	Estimate	Standard Error	p-value	Factor	Estimate	Standard Error	p-value
Age	0.032	0.028	0.253	Age	0.122	0.024	<0.0001*
Gender	0.121	1.756	0.945	Gender	−0.320	1.482	0.829
Race	−1.051	0.912	0.250	Race	0.529	0.773	0.494
BMI	0.012	0.052	0.824	BMI	0.133	0.045	0.003*
Proteinuria	−2.598	1.814	0.153	Proteinuria	−0.338	1.534	0.825
Nephritis	2.166	2.042	0.289	Nephritis	1.879	1.721	0.275
Prednisone	−0.660	1.462	0.652	Prednisone	0.764	1.236	0.537
MTX	3.602	2.112	0.089	MTX	1.911	1.784	0.284
HCQ	−2.268	0.948	0.017*	HCQ	−1.017	0.803	0.205
AZA	−1.914	2.463	0.437	AZA	−1.246	2.077	0.549
MMF	−9.244	3.066	0.003*	MMF	−5.363	2.593	0.039*
				Baseline BP	−0.494	0.027	<0.0001*

BMI indicates body mass index; MTX, methotrexate; HCQ, hydroxychloroquine; AZA, Azathioprine; MMF, mycophenolate mofetil; and BP, blood pressure.

Finally, we sought to address the effect of potential differences in baseline BP among individuals treated with different drugs as compared to those patients who were not prescribed a therapy. Thus, we analyzed the change in SBP, DBP, and PP while controlling for baseline SBP, DBP, and PP, respectively, as covariates along with the other standard variables (Figure S1). Patients who received hydroxychloroquine or MMF had a significant decrease in SBP compared to the No Rx group (Figure 4A), and patients who received hydroxychloroquine or azathioprine had a significant decrease in PP compared to the No Rx group (Figure 4C). The follow-up MAP and SBP were more likely to be lower if the patient was prescribed MMF (Table S1). Lower DBP at follow-up was more likely if the patient had lower baseline DBP, younger, and lower BMI (Table S1).

Figure 4.

Changes in systolic, diastolic, and pulse pressures after therapy versus placebo group when controlling for age, gender, race, BMI, renal disease, and baseline values. *, p<0.05 vs. baseline.

DISCUSSION

HTN and CVD are a significant burden in those diagnosed with autoimmune diseases including SLE and rheumatoid arthritis, among others (2, 10, 11). In this predominately black cohort of SLE patients, we found a substantial burden of HTN and limited antihypertensive medication use. The SLE patient cohort was 65% black, compared to the entire Research Data Warehouse which is comprised of 53% black and 42% white patients. The increased prevalence of SLE in black individuals is in agreement with previously published work; a large population-based study found that black women had an SLE incidence rate 3 times that of white women, and black men had a rate more than four times higher than white men (12). Patients prescribed hydroxychloroquine or MMF as an initial monotherapy immunomodulatory treatment of their SLE had significant decreases in MAP and improved BP control at their subsequent follow up visit within 3 months. These data indicate that certain drugs that control and manage SLE disease activity may have the added benefit of improving BP control.

Experimental and clinical evidence firmly establish a role for the immune system and inflammation in the development and progression of HTN (13). Thus, it is likely that the immune system dysfunction that is present in SLE plays a mechanistic role in the development of HTN. In support of this concept, studies in animal models of SLE have implicated B and T lymphocytes (14, 15) and autoantibodies (16) in the development of HTN. While the data on mechanisms of HTN in SLE patients are limited, several studies suggest that chronic inflammation is associated with elevated BP. An analysis of the Toronto SLE cohort positively correlated SLE disease activity scores with BP (17). Similarly, Sabio and colleagues found that increased circulating IL-6 and an elevated erythrocyte sedimentation rate were associated with elevated BP in SLE patients (2). In our analysis, we compared various immunological parameters in SLE patients, including circulating leukocytes, lymphocytes, and anti-dsDNA levels, among others, but there were insufficient data available to make comparisons or draw conclusions.

In the present study, we evaluated BP responses to therapeutics commonly prescribed to SLE patients and have known effects on immunological parameters. There were no significant changes in BP in the untreated, prednisone, methotrexate, and azathioprine groups. Corticosteroids such as prednisone are commonly used in SLE disease management because of their potent inhibitory effects on innate and adaptive immune cells. Unfortunately, chronic prednisone use can also increase BP (18). Indeed, excess glucocorticoid can activate the renal mineralocorticoid receptor, leading to sodium retention and increased BP (19). Glucocorticoids also likely affect BP via glucocorticoid receptors in extrarenal tissues such as the vasculature, CNS, and adipose tissue (18). In the current study, we included patients that received a daily dose of 1–20 mg of prednisone. Generally, daily doses of <7.5 mg/day are considered to be associated with less risk of adverse side effects, but chronic glucocorticoid use can have side effects even at low doses (20). Because the follow-up BP measurement was within a short time frame (<3 months), it is unlikely that the time on glucocorticoid therapy had a significant deleterious impact on BP control. Nevertheless, a recent study in SLE patients with resistant HTN did find that prednisone use was associated with the development of HTN (21). Thus, it is important for SLE patients who take prednisone to be monitored carefully and given strict BP management.

The use of methotrexate in rheumatoid or psoriatic arthritis is associated with lower risk of CVD and myocardial infarction (22). Further, previous studies have shown that methotrexate lowers BP in rheumatoid arthritis patients (23). Studies in SLE patients have demonstrated methotrexate use was associated with decreased lupus disease activity and circulating dsDNA levels (24). However, no studies have evaluated the effect of methotrexate on BP in SLE patients. Although BP was below hypertensive levels and patients had a low incidence of comorbidities at baseline, methotrexate use in the current SLE population was associated with trends of increased BP and decreased BP control, although neither reached statistical significance (Figure 3). Additionally, azathioprine was found to have no significant improvements in BP or BP control.

Hydroxychloroquine and other antimalarial drugs are considered a front-line treatment for mild SLE disease and are now recommended for all SLE patients to prevent disease flares, maintain remission, and reduce complications (25). Hydroxychloroquine has been shown to prevent accelerated CVD (26), but there are no human data available on the effect of hydroxychloroquine on BP control. Hydroxychloroquine has been investigated in animal models of both essential HTN and hypertensive SLE. For example, McCarthy et al. treated both young and old spontaneously hypertensive rats with hydroxychloroquine and found that treatment lowers BP and improves vascular function in old rats with established HTN, but does not prevent the development of HTN in young animals (27). Evidence using the NZBWF1 mouse model of SLE demonstrated that treatment with hydroxychloroquine lowers BP and improves endothelial function, without any changes in SLE disease activity such as anti-dsDNA autoantibody levels (8). Consistent with these studies, we found that hydroxychloroquine use was associated with significant decreases in BP and improvements in BP control. These data suggest that hydroxychloroquine could enhance BP control in SLE patients similar to those seen in this study (e.g., middle aged black women with no signs of overt kidney disease).

MMF is an immunosuppressive drug that is commonly given to SLE patients, including those with progressive lupus nephritis (28, 29). The role of MMF in renal function and long-term BP control in SLE patients has never been investigated. In the present analysis, patients prescribed MMF had significant decrease in BP as compared to untreated patients, despite the high prevalence of renal disease (Figure 2), which is well-documented to antagonize BP control. This beneficial effect on BP may have been due to amelioration of renal inflammation. In a study by our laboratory using the NZBWF1 mouse model of SLE, MMF was found to significantly lower BP. Concomitant with the decrease in BP, the animals had lower levels of renal immune cell infiltration (7). Even without existing renal disease, MMF has been shown to significantly decrease BP, as shown in a small 3-month clinical trial in RA and psoriasis patients (30). Again, this decrease in BP was correlated with decreased urinary markers of renal inflammation, TNF-ɑ and RANTES (30). In the current study, the superior effect on BP control in the MMF group could have been through its impact on nephritis, as more lupus nephritis patients were in the MMF group. However, clinical evidence has been inconclusive, as some show MMF efficacy to be similar to azathioprine and cyclophosphamide in maintaining renal function and halting CKD progression (31, 32). Notwithstanding, clinical studies have identified a disconnect between lupus nephritis and HTN (33). In the current study, patients with proteinuria at baseline had a significantly greater decrease in MAP than those without proteinuria, suggesting that greater benefits may be seen if the target SLE population is proteinuric. However, this was not the case in the MMF group. A larger sample size is needed to confirm these results and to pinpoint the exact mechanisms of the antihypertensive effects of MMF and to elucidate the possible role of renal inflammation in SLE HTN.

Our analyses suggest adequate BP in SLE control remains an important clinical concern. The overall prevalence of HTN in this SLE patient cohort was 56% when using the <140/90 definition. However, using the new ACC/AHA guidelines of <130/80, the prevalence of HTN at baseline was 72% at an average age of 44. While the prevalence of HTN varies depending on the cohort examined, the consensus is that SLE populations can be 2–4 times more hypertensive when compared to age-matched controls (2, 10, 33). In the present study, 70% of the SLE patients with HTN were black, which was significantly different from the normotensive SLE group (58% black, p<0.05). The hypertensive group was also older and had higher BMI, which both deleteriously impacted the BP response in these patients (Table 3, Table S1). Black patients with SLE have also been shown to have a higher frequency of lupus nephritis and also are more likely to progress to ESRD as compared to the white population (34, 35). The current standard of care for SLE patients with lupus nephritis involves the use of both glucocorticoids as well as additional medications such as MMF, cyclophosphamide, or azathioprine. Blockade of the renin-angiotensin system is also commonly used to control HTN in SLE patients. Unfortunately, despite the increased age, comorbidities such as obesity and renal disease, and other risks shown to exacerbate HTN, only 9% of the hypertensive patients in this cohort were on antihypertensive medication. Our current findings highlight the need for greater attention to BP control in this understudied population, which would most likely translate into lower long-term cardiovascular risk (4).

This study has several limitations. The retrospective design leads to variable lengths of follow-up between initial diagnosis of SLE, baseline BP measurement, potential prescription of immunomodulatory medication, and ascertainment of follow-up BP. Hence, >7 days and <90 days was selected a priori as a clinically meaningful time window for assessing BP change. This shorter window was also chosen to limit the bias selection of patients with poor drug adherence, limited routine medical care, and potentially confounding changes in underlying disease progressions. Despite these limitations of this retrospective study, we believe the current findings can inform future clinical studies on BP control in autoimmune disease, which has not yet been formally addressed in prospective studies. While all UMMC clinics have standardized BP measurement procedures consistent with societal guidelines, the retrospective design does not assure that these were rigorously adhered to in routine daily practice. Patients with clinical conditions that would be expected to confound BP change over time were a priori excluded including heart failure, cardiac arrhythmia, valvular disease, ESRD, acute kidney injury, liver failure, or shock based on clinical expertise. Also, for the n=405 patients where no initial immunomodulatory prescription was prescribed, we must assume this was not clinically indicated given the retrospective design. This is a single center study in central Mississippi with a high proportion of African Americans dissimilar to most of the United States. While this suggests epidemiological observations from our cohort concerning BP control may not be broadly representative, they appear consistent with other published studies. Also, this was a single center study with multiple exclusion criteria intended to isolate newly diagnosed SLE patients receiving prescription of initial monotherapy immunomodulatory treatment or not as clinically indicated, and an a priori but retrospectively specified follow-up timeframe. Thus, the total study sample size was limited to n=811. Hence there were large differences in the sample sizes of specific initial immunomodulatory medication prescriptions, ranging from n=16 for MMF to n=256 for hydroxychloroquine. Our analysis has limited power to detect effects for some agents. Finally, although there may have been a possibility of a regression to the mean phenomenon in comparing initial to follow-up BP, the major results of this study were still persistent when controlling for baseline BP. Future work will focus on the impact of different treatment regimens and drug combinations on the long-term progression of SLE disease and BP control.

Supplementary Material

Figure S1

Supplementary Figure S1. Changes in systolic, diastolic, and pulse pressures after therapy when controlling for placebo, age, gender, race, BMI, kidney disease, and baseline values.

Figure S2

Supplementary Figure S2. Blood pressure responses and control (unadjusted) and comorbidities in all untreated patients and in untreated patients with hypertension and lupus nephritis.

Table S1

Supplementary Table S1. Multivariable adjusted models predicting the pressure at follow-up with bolded effects from respective baseline systolic, mean, diastolic, or pulse pressures and the effect of MMF.

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.