ACE inhibitors in SSc patients display a risk factor for scleroderma renal crisis—a EUSTAR analysis

ACE inhibitors (ACEi) are the mainstay of therapy in scleroderma renal crisis (SRC). Initiation of their use allowed for major increased survival rates of SRC over the last decades yet with mostly lasting sequelae [1]. Nevertheless, the incidence of SRC remained almost unchanged over the last decades and SRC risk factors are still poorly understood. Among those, the use of ACEi in hypertensive SSc patients prior to any SRC episode is meanwhile contradictorily discussed. While ACEi are supposed to lower the risk of SRC at the same time as they lower blood pressure, there are a few data that SRC outcome is worse in patients with prior ACEi intake.

A prospective online survey demonstrated a worse outcome in SRC patients when treated with ACEi prior to SRC onset [2]. On the other hand, pathophysiological reasoning cannot explain the phenomenon why a therapeutic agent should be discouraged when applied in a protective intention. The need for more valuable data is therefore often discussed among experts, but respective trials are rare, mostly retrospective, and difficult to conduct. One study by Guillevin et al. in as much as 91 patients pointed into the direction of favoring ACEi for SRC protection but was unable to draw firm conclusions [3].

Furthermore, besides some well-known factors for the risk of SRC, arterial hypertension is still discussed as bystander or promoting factor leaving the optimal choice for antihypertensive treatment unanswered.

Arterial hypertension in SSc patients might be present per se (i.e., independent from SSc itself) or at least in part due to hyperreninemia with activation of the renin-angiotensin-aldosterone system (RAAS)—which itself is discussed as a risk factor for SRC [4]. RAAS activation might therefore lead to the idea of initiating ACEi therapy.

The use of beta blockers and/or diuretics in the treatment of arterial hypertension in SSc patients is mostly precluded as they negatively affect the already reduced peripheral perfusion.

Calcium channel blockers (CCB) used to be the antihypertensive medication of choice in SSc patients due to their vasodilative effects and improvement in Raynaud’s phenomenon. Unfortunately, negative effects on, e.g., the esophagus, by smooth muscle relaxation [5] and sphincter pressures have been claimed although their clinical consequences on reflux and potential aspiration remain uncertain.

In the era of endothelin receptor antagonists (ERA) used for prevention of digital ulcers, the impact of CCBs at least in the indication for digital ulcer prevention might be vanishing. Furthermore, ERAs were supposed to be helpful in SRC as endothelin expression was shown to be high in kidney specimen from SRC patients [6]. Yet, they have only rarely been described in SRC case reports without convincing results [7].

The use of glucocorticoids (GC) especially in higher doses above 15 mg/d has long been known as important negative factor for the development of SRC, and the use of GC dosages above 15 mg/d is therefore discouraged [8]. However, the bias for indication cannot be ruled out in this setting with more severe patients having a higher propensity to receive high-dose corticosteroids. In addition, concomitant medication with, e.g., glucocorticoids in a situation of an activated RAAS additionally reduces renal flow by inhibiting synthesis of prostaglandins. Nevertheless, even recent data report on frequent if not routine use of GC in SSc patients for various reasons as, e.g., interstitial lung disease or progressive skin affection [9].

Data regarding incidence and influencing factors for SRC have and will always have limitations: they describe a very rare phenomenon in a rare disease with heterogeneous presentation and ongoing discussion about correct and/or consensus-driven diagnostic criteria [10]. The currently published data on possible classification criteria for SRC reflect this process [11]. The herein proposed core set of acute onset of hypertension, acute kidney injury, microangiopathic hemolytic anemia/thrombocytopenia, and target organ dysfunction is mainly consistent with the EUSTAR-based definition of SRC.

We therefore set out to analyze the European Scleroderma Trials and Research (EUSTAR) database representing the largest European and in part Extra-European prospective data collection from SSc patients, hereby focusing on ACEi, arterial hypertension, other anti-hypertensive medication, and glucocorticoids with respect to their influence on SRC.

Our work analyses the largest cohort of SSc patients with focus upon potentially influencing medication for the development of SRC.

To our surprise, ACEi independently and very prominently enhanced the hazard for SRC. Assuming that the main reason for the prescription of ACEi is arterial hypertension the latter was analyzed separately. We hereby wanted to rule out arterial hypertension itself as the main influence for SRC. Contrariwise ACEi and arterial hypertension proved independent risk factors and even more: both factors add up the risk for SRC. These results lead us to perform subanalyses regarding other potentially influencing factors finally confirming the initial results even more. In line with our main finding are the results of the QUINS trial [13]. Within this controlled trial, the ACE inhibition by long-term application of quinapril was not able to control vascular damage in SSc patients with limited cutaneous disease.

One of the questions is whether our cohort is different from other SRC cohorts. We found a SRC incidence of 3.72 (3.06–4.51) per 1000 py. Some of the first analyses by Steen et al. in 1984 could demonstrate an incidence of as high as 18% within their retrospective cohort of rapidly progressing SSc patients [14]. Since then SRC incidence considerably declined: In a recent large meta-analysis, an overall SRC prevalence of 4% was found during the last 30 years consistent with findings from the EUSTAR group describing a prevalence of 4.2% in the diffuse cutaneous (dc) SSc group [15, 16]. Mainly, most SRC risk factors as, e.g., dSSc, male sex, and rapid disease progression as displayed in our cohort are of course well-known risk factors for SRC [17, 18] with a longer duration of disease tending to reduce the risk of SRC as the counterpart. In addition, glucocorticoids given in higher dosages have already been described extensively as negatively influencing SRC incidence and outcome [19]. Here, our data could demonstrate a minimal effect of GC only, yet the average dosage was low with only 3% receiving more than 15 mg of prednisolone per day. So most physicians must have implemented this negative impact when deciding for immunosuppression of any kind. Furthermore, our data were collected prospectively in a standardized manner which allows for adequate documentation with only few missings.

Given a thorough analysis of a well-defined, prospectively collected cohort, what reasoning might at least in part explain our findings? Possibly, in SSc patients with long standing ACEi therapy, an aldosterone breakthrough mechanism with elevated aldosterone and renin levels therapy might come into account [20] leading to further unwanted vasoconstriction and endothelial cell proliferation. In this case, direct renin inhibition seems to be an option. Yet, this inhibition was not able to prevent from breakthrough mechanisms so far [21]. Furthermore, renin inhibition has only infrequently been used in SSc patients [22] which is as well reflected in our analysis as no EUSTAR patient had received renin inhibitors.

Therefore, regarding angiotensin II, its direct blockade appears to be an option, which might guide therapy into the direction of ARBs. This hypothesis is clearly supported by our data: as more than 600 patients were treated with ARBs, we judge the results valuable: In clear contrast to the use of ACEi, ARBs demonstrated a slightly positive effect on the hazard of SRC and definitely no negative effect at all.

Other medication analyzed within our cohort had a neutral effect on SRC occurrence as, e.g., CCBs: they showed no additional influence in concomitant arterial hypertension. This is in agreement with a recent analysis of the Canadian Scleroderma Research Group, which did not find any association of CCB with SRC [23].

Secondly, some medication was given in few patients only. ERA for example might have some indication in SRC treatment as ET receptors can be expressed within SRC [24] and rare cases with positive effects of ET receptor blocking therapy in SRC have been observed [25]. No data exist on their preventive potential and our study does not contribute enough evidence to allow for a clear description of any influence on SRC incidence in either way.

Overall, our data clearly demonstrate an increased risk for SRC when ACEi are used in SSc patients prior to the onset of any SRC. Nevertheless, the significant and independent negative influence of arterial hypertension on the risk of SRC demands antihypertensive treatment. Unfortunately, the list of acceptable antihypertensive medications in SSc patients is short and—after removal of ACEi—mostly CCB and ARBs are left. The large number of SSc patients with ARB treatment in our cohort without a negative signal on SRC incidence might make it a valuable alternative to ACEi at present. We hope that a more frequent use of newer antihypertensive drugs in the future will broaden our understanding of their potential influence and safety regarding SRC in hypertensive SSc patients.

ACEi in SSc patients with concomitant arterial hypertension display an independent risk factor for the development of SRC. Still, they are the mainstay of treatment once SRC is established. ARBs might be a safe option in the treatment of arterial hypertension with a possibly lower risk for development of SRC. Yet, the overall safety of alternative antihypertensive drugs in SSc patients needs to be studied.