Evaluation of hypertension in systemic sclerosis and systemic lupus erythematosus overlap

Abstract

Patients with systemic sclerosis and systemic lupus erythematosus serologies present a unique challenge to the clinician when hypertension is detected in the outpatient setting. Treatment choices for non-renal crisis hypertension are different for systemic sclerosis versus systemic lupus erythematosus. Urgent laboratory studies and, in the presence of certain symptoms, imaging assessment are indicated in systemic sclerosis and systemic lupus erythematosus overlap patients with systemic hypertension. Long-term assessment of systemic hypertension may be enhanced by advances in non-contrast imaging that serve as valuable biomarkers for progressive vasculopathy. In this review, the diagnostic approach to systemic sclerosis and systemic lupus erythematosus overlap patients presenting with hypertension is discussed.

Introduction

Autoimmune connective tissue diseases are clinical syndromes often classified by symptoms with a positive antinuclear antibody (ANA) and a supportive autoantibody. A common clinical symptom among autoimmune connective tissue disease patients is Raynaud’s phenomenon (RP), which is indicative of vasospasm. The evaluation of RP includes a detailed physical exam and laboratories that include specific autoimmune serologies. The presence of systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) overlap serologies is of particular importance when determining a treatment approach for systemic hypertension (HTN), especially when associated with renal dysfunction. The epidemiology of SSc–SLE overlap in large well-characterized cohorts ranges from 0.4% to 8.4%.^1,2 Screening patients for co-occurrence of SLE with SSc is important because it may affect prognosis and treatment. ³ The presence of HTN in a patient where there is a concern for SSc–SLE overlap, defined primarily by autoantibodies, has critical diagnostic and therapeutic considerations, which is directed primarily by whether kidney dysfunction is present, but also whether the patient has cardiovascular or neurologic symptoms. Hypertensive emergencies are defined by end-organ damage including cerebral infarction, intracerebral or subarachnoid hemorrhage, hypertensive encephalopathy, acute pulmonary edema, and acute congestive heart failure. ⁴ Thus, symptoms of headache, chest pain, dyspnea, and neurologic deficit should be elicited to guide urgent additional testing. While the prevalence of pulmonary HTN in SSc–SLE overlap is reported between 7% and 29%, the true prevalence of systemic HTN without renal crisis is unknown. ⁵ In this review, the assessment of patients with SSc–SLE overlap serologies that are noted to have HTN in the outpatient setting is discussed.

Causes of systemic HTN in SLE and SSc

Blood pressure (BP) control involves complex interactions among the kidneys, the central and peripheral nervous systems, the vascular endothelium, and in some situations, the pituitary and adrenal glands. ⁶ The ability of the kidney to handle sodium and volume is proposed as primary controller of BP and makes an understanding of renal involvement in SSc and SLE imperative when approaching systemic HTN. ⁷ Modifiable causes of systemic HTN in SSc and SLE include tobacco use and sedentary lifestyle.

Clinical assessment and serum tests in SLE–SSc overlap with systemic HTN

Vascular features are universally present in SSc, with RP being the most common. In fact, RP with a positive ANA, puffy fingers and abnormal nailfold capillaroscopy that represents microcirculatory abnormalities, has a high predictive value for developing SSc. ⁸ However, while an SSc-pattern of nailfold videocapillaroscopy (NVC) is described, this pattern is also found in SLE. ⁹ In addition, in ANA positive individuals, autoantibodies to self-antigens that are not traditionally captured by current screening techniques reveal that SLE patients specifically display reactivity to many autoantigens. ¹⁰ Patients with SSc–SLE overlap are younger at diagnosis, more frequently have pulmonary arterial HTN, and less frequently have cutaneous manifestations of SSc. ² It is well established that these SSc–SLE overlap patients should be monitored for interstitial lung disease (ILD), digital ulcers, and renal crisis; however, there are no clear guidelines on the routine evaluation and management of systemic HTN in this population.

Autoantibodies might be detectable before disease onset and serve as biomarkers enabling diagnosis and targeting of therapeutic interventions. ¹¹ Classification criteria serologies for SLE include positive antiphospholipid (aPL) antibodies by medium or high titer, anti-double stranded DNA (dsDNA), and anti-Smith (anti-Sm) antibodies. ¹² SSc-specific antibodies include anticentromere, antitopoisomerase (Scl70), and anti-RNA polymerase III (RNApol3), and are prognostically used in combination of skin involvement assessment by modified Rodnan skin score.^13,14 The anticentromere antibody can be detected in SLE without SSc features. ¹⁵ A home BP log can be helpful for understanding acuity, but basic laboratories are indicated as an initial evaluation in all patients (Figure 1). Based on a urinalysis result with hematuria and casts, additional testing—including antineutrophil cytoplasmic antibody (ANCA), dsDNA, and complement 3 and 4 (C3, C4)—is indicated. While ANCA-associated vasculitis is rare, it is an important consideration. ¹⁶ Symptoms and screening laboratories are essential for determining whether inpatient admission or renal biopsy is indicated.

Figure 1.

Assessment of hypertension in an SSc–SLE overlap patient.

CBC: complete blood count; CMP: comprehensive metabolic profile; UA: urinalysis; eGFR: estimated glomerular filtration rate; LDH: lactate dehydrogenase.

A challenge for determining inpatient assessment is that in SLE, HTN is highly prevalent, and while commonly associated with renal damage, it can also occur independently of nephropathy.^17,18 Similar to tobacco cessation counseling, a focus on detection of HTN is particularly important as a modifiable cardiovascular risk factor. ¹⁹ In addition to understanding acuity, ambulatory BP monitoring may have value in understanding the role of immune activation in cardiovascular disease. ²⁰ Standard renal assessment in an SLE patient with systemic HTN includes a complete blood count, complete metabolic profile, urinalysis with quantitative urine protein, and complement C3 and C4 levels. If these screening results suggest a glomerulonephritis, the gold standard for diagnosis is a kidney biopsy that documents various histopathological patterns depending on the location and severity of the glomerular injury. ²¹ Anemia and thrombocytopenia in the setting of acute kidney injury and HTN requires additional evaluation. Hemolysis is evaluated by a peripheral smear, ADAMTS13 level (for thrombotic thrombocytopenic purpura), direct antiglobulin (Coombs) test, lactate dehydrogenase (LDH), indirect bilirubin, and a haptoglobin level. Angiotensin II type 1 receptor agonist antibodies (AT1R-AAs) are reported in malignant and refractory HTN and have been associated with microvascular damage and HTN in SLE and SSc but are not commercially available.^22,23

The primary concern when systemic HTN is present in an SSc patient is scleroderma renal crisis (SRC). A challenge in determining SRC is that while it most commonly occurs early in diffuse cutaneous disease, it can also occur limited and sine cutaneous subsets, making all patients with a diagnosis of SSc at risk. ²⁴ The presence of recent cardiac events, palpable tendon friction rubs, glucocorticoid use in doses greater than 15 mg a day, large joint contractures, myopathy, and RNA-pol3 autoantibody, and the absence of anticentromere autoantibody are associated with higher risk of SRC.^25,26 Similar to SLE, for prevention of complications from HTN, SSc patients should be educated on home BP monitoring and indications for emergency assessments.^27,28 If elevation of BP is detected, a complete blood count, complete metabolic profile, and urinalysis are initially obtained to assess for acute kidney injury and microangiopathic hemolytic anemia (Figure 1). The urinalysis in SRC can reveal hematuria and/or proteinuria, but this is mild (<1 g/day) in contrast to that associated with SLE-associated glomerular nephritis. ²⁸ SRC appears histologically as the presence of obliterating endarteritis with onionskin appearance, narrowing of arterioles, and glomerular ischemia without inflammatory change or immune deposits. ²⁹ Small vessel thrombus are more prevalent than glomerular thrombus. ³⁰ While renal biopsy is not recommended in patients with SSc presenting with typical features of SRC, immunofluorescence is important for suspected overlap conditions or atypical presentations. ²⁶ Of interest in SSc, the extent of fibrosis does not reflect long-term renal outcome. ³¹

Additional evaluation for end-organ damage includes assessment for hypertensive retinopathy confirmed by ophthalmology, as well as assessment for acute heart failure and pericarditis. ³² Vasculopathy, unlike vasculitis, is defined by tissue histology in which there is endothelial damage, but the histological finding of leukocytoclasia is absent. ³³ Vasculitis is a general term for inflammation of blood vessel walls which can result in stenosis, occlusion, aneurysm, or rupture, and is responsive to therapeutics that modulate circulating cytokines. ³⁴ Unlike, vasculopathy, vasculitis is associated with low serum complement 3 and 4 levels. ³⁵ Low complement levels are also associated with active aPL. ³⁶ Thus, while renal biopsy is useful in SSc–SLE overlap, often more immediate diagnostics are often needed to more expeditiously direct therapy if there is a concern for vasculitis due to important treatment implications regarding corticosteroid use. ³³

Imaging considerations in HTN assessment in SSc–SLE overlap

SLE patients with systemic HTN who present with headache, seizures, loss of vision, and altered mental function are a risk for posterior reversible encephalopathy syndrome (PRES) and require cranial magnetic resonance imaging (MRI) for identification of posterior cerebral hyperintensities on T2-weighted images. ³⁷ In these patients, the documentation of aPL is important. ³⁸ Similarly, the assessment of SRC requires further assessment of hypertensive encephalopathy if headache, seizures, and visual changes are present. Hypertensive encephalopathy can mimic cerebral vasculitis. Digital subtraction angiography (DSA) is more sensitive than MRI for the detection of vasculitic luminal changes of small- and medium-sized peripheral arteries. However, DSA does not visualize the vessel walls and is reserved to diagnose cerebral vasculitis because it is invasive with relatively low specificity regarding the underlying pathology of the luminal changes. ³⁹

Renal Doppler ultrasound is indicated in SSc–SLE patients with acute kidney injury and can assess for the presence of renal artery stenosis (RAS), which is important to determine prior to treatment with an angiotensin-converting enzyme (ACE) inhibitor.^28,40,41 Renal Doppler ultrasound with intrarenal hemodynamic parameters of renal resistive index (RRI) is obtained through the Doppler spectrum analysis of renal small arteries, and is established for determining renovascular damage in non-obstructive renal diseases where it correlates with biopsy findings. ⁴² In SSc, RRI is associated with asymptomatic renal dysfunction and may be useful in the assessment of systemic vasculopathy.^43,44 From a vasculopathy standpoint, RRI is correlated to NVC change and digital ulcer, and may have serial monitoring implications for patients with HTN.^45,46

Acute heart failure, characterized by typical symptoms and signs (i.e. elevated jugular venous pressure, pulmonary crackles, and peripheral edema), is diagnosed by echocardiography. Acute pericarditis is diagnosed by symptoms and echocardiogram or new widespread ST segment elevation or PR segment depression of electrocardiogram. ³² Additional hypertensive vascular imaging may include carotid ultrasound, left ventricle angiography (conventional and Technetium-99m myocardial perfusion imaging), cardiac magnetic resonance imaging (CMR), and electron beam CT (to quantify coronary artery calcification). While catheter angiography is used to evaluate the coronary arteries, in a patient with HTN and possible renal disease, imaging choices may be limited by ability administer contrast as part of a diagnostic imaging evaluation. In addition, cardiac biomarkers have different cut-off values in end stage renal disease. ⁴⁷

In systemic HTN, CMR is the gold standard for imaging cardiac anatomy, function, and advanced myocardial tissue characterization. Advances in parametric mapping enable direct, quantitative comparisons that can detect both focal and diffuse perfusion defects, myocardial fibrosis, and myocardial edema, without the need for contrast agents. ⁴⁸ CMR is helpful for detecting subendocardial perfusion defects. ⁴⁹ While the clinical and prognostic significance of subclinical findings remains unclear, obtaining CMR to further SSc–SLE overlap patients who are at high risk of significant conduction and rhythm disturbances, may guide therapeutic or prophylactic intervention. ⁵⁰ CMR with parametric mapping may improve the understanding of hypertensive cardiac changes and reduce the need for invasive myocardial biopsy.^51,52

Potential role for renal biopsy

Renal biopsy results will most effectively determine immunosuppressive choice for lupus nephritis. ⁵³ The treatment of lupus nephritis should aim for a significant reduction of proteinuria by 6–12 months with stable or improved glomerular filtration rate, prevention of flares, and minimization of exposure to glucocorticoids. ⁵⁴ Lupus nephritis with renal thrombotic microangiopathy (TMA) responds to therapy similarly to those without TMA. ⁵⁵ While immunosuppression is not in SRC treatment algorithms, if indicated for concurrent inflammatory skin, lung, or muscle (including myocardial) disease, these agents should be considered. This highlights the value of systematic cardiovascular studies in SSc–SLE overlap patients with systemic HTN.

Systemic HTN treatment considerations in SSc–SLE overlap

Management of SSc–SLE overlap often requires both a plan for vasodilatation, immunosuppression, and, in the setting of aPL antibodies with thrombosis, anticoagulation. The identification of potential offending agents, controlling HTN, and treating active disease to reverse symptoms and normalize laboratory and imaging abnormalities are the goal. Targeting endothelial vascular dysfunction is of value in both SLE and SSc. Education on tobacco cessation is critical. First-line treatment for RP and concurrent HTN is a calcium channel blocker. ⁵⁶ Empiric use of ACE inhibitors for SSc in the absence of SRC is not recommended. ²⁸ ACE inhibitor use in women of child-bearing age requires additional counseling with a “black-box” warning for use during second and third trimester.^57,58 This is an important consideration for SSc–SLE overlap patients with proteinuria.

SRC is considered a medical emergency, and intensive care admission is needed if seizures, pulmonary edema, tachyarrhythmia, and severe acute kidney injury with hyperkalemia are present. ²⁸ Hyperplasia of the juxtaglomerular apparatus leads to sustained renin–aldosterone–angiotensin (RAA) axis activation in SRC. Thus, while early, aggressive treatment with ACE inhibitors has improved prognosis in SRC, steroid use is guided by renal pathology in overlap cases. ³⁴ If suboptimal BP control, addition of short-acting calcium channel blockers to ACE inhibitors is indicated. This is followed by centrally acting alpha-blockers, which have a risk of hypotension, and diuretics, which may further stimulate renin release. In the United Kingdom, continuous low-dose iloprost is used. ²⁸ Importantly, beta-blockers should be avoided due to their well-known vasospastic effects on the microcirculation. ⁵⁹ Plasma exchange may be considered in refractory cases with TMA. ⁶⁰ There is positive anecdotal evidence to treat lupus nephritis and SRC patients with eculizumab, a fully humanized IgG2/IgG4 monoclonal antibody directed at C5 that prevents the formation of the terminal complement complex, when complement-mediated TMA is suspected.^30,61

Summary

SSc–SLE overlap patients present an important cohort of patients where characterization of systemic HTN etiology and timely management is critical. If SRC is absent, first-line therapy for HTN is a calcium channel blocker, which also treats RP. If SRC is diagnosed, prompt initiation of an ACE inhibitor is indicated. TMA always requires hospitalization and may require plasma exchange and eculizumab. Renal biopsy is important in non-classical SRC, especially when significant proteinuria and hematuria are present. Brain, kidney, and cardiac imaging are helpful for assessing severe organ damage. Advances in RRI and CMR parametric mapping that enables direct, quantitative comparisons without the need for contrast agents has implications for an improved understanding of HTN in this unique SSc–SLE overlap population. Longitudinal imaging studies in SSc–SLE overlap patients may better inform HTN management in terms of targeting disease activity versus assessing severe damage.