Seminars in Arthritis and Rheumatism 43 (2014) 666–672
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Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis—Results from the International Scleroderma Renal Crisis Survey Marie Hudson, MD, MPHa,b,n, Murray Baron, MDa,b, Solène Tatibouet, MSca, Daniel E. Furst, MDc, Dinesh Khanna, MD, MSd, International Scleroderma Renal Crisis Study Investigators1 a
Jewish General Hospital, Montreal, Quebec, Canada McGill University, Montreal, Quebec, Canada c Geffen School of Medicine, University of California, Los Angeles, CA d University of Michigan Scleroderma Program, Ann Arbor, MI b
a r t i c l e in f o
Keywords: Scleroderma Scleroderma renal crisis ACE inhibitors
abstract Objective: To determine whether exposure to angiotensin-converting enzyme (ACE) inhibitors prior to the onset of scleroderma renal crisis (SRC) leads to worse outcomes of SRC. Methods: Prospective cohort study of incident SRC subjects. The exposure of interest was ACE inhibitors prior to the onset of SRC. The outcomes of interest were death or dialysis during the first year after the onset of SRC. Results: A total of 87 subjects with incident SRC were identified and 1-year follow-up data were obtained in 75 (86%) subjects. Overall, 27 (36%) subjects died within the first year and an additional 19 (25%) remained on dialysis 1 year after the onset of SRC. In adjusted analyses, exposure to ACE inhibitors prior to the onset of SRC was associated with an increased risk of death (hazard ratio 2.42, 95% CI 1.02, 5.75, p o 0.05 in the primary analysis and 2.17, 95% CI 0.88, 5.33, p ¼ 0.09 after post-hoc adjustment for preexisting hypertension). Conclusion: Overall, the 1-year outcomes of SRC were poor. Prior exposure to ACE inhibitors was associated with an increased risk of death after the onset of SRC, although there was uncertainty around the magnitude of the risk and the possibility of residual confounding could not be ruled out. Further studies will be needed to confirm these findings. & 2014 Elsevier Inc. All rights reserved.
Scleroderma renal crisis (SRC) is an infrequent, but lifethreatening complication of systemic sclerosis (SSc) [1]. It was previously associated with significant morbidity, including chronic renal failure and dialysis, and high mortality. However, since the advent of angiotensin-converting enzyme (ACE) inhibitors, the outcome of SRC has improved [2]. In addition, there is some data to suggest that the incidence of SRC has fallen over the past years [3,4]. This has been hypothesized to be due, at least in part, to the more liberal use of ACE inhibitors to treat Raynaud's phenomenon and hypertension in SSc [5]. Given the benefits of ACE inhibitors in SRC and the perceived decrease in incidence in SRC, the prophylactic use of ACE inhibitors to prevent SRC has been considered [5]. However, there is no clear physiologic rationale for this since most SSc patients do not have Funding: This study was funded in part by the Fonds de la recherche en santé du Québec. Dr. Hudson is funded as a Chercheur-clinicien also by the Fonds de recherche en santé du Québec. n Corresponding author at: Jewish General Hospital, Room A-725, 3755 Côte Ste Catherine Rd, Montreal, Quebec, Canada H3T 1E2. E-mail address: [email protected] (M. Hudson). 1 Investigators of the International Scleroderma Renal Crisis Study are listed in the Appendix. 0049-0172/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2013.09.008
hyper-reninemia prior to the onset of SRC [3]. In addition, there is a theoretical concern that by masking hypertension, prophylactic ACE inhibitor use may lead to worse outcomes after the onset of SRC. Indeed, normotensive SRC patients have been reported to have a worse prognosis than hypertensive patients [6], possibly because diagnosis may be delayed in the absence of hypertension. In fact, retrospective data have provided some preliminary evidence suggesting that those exposed to ACE inhibitors prior to the onset of SRC may have worse outcomes, in particular more chronic dialysis, than those with SRC unexposed to these drugs [6–8]. To further elucidate this important clinical question, we undertook a prospective study to determine the outcomes after SRC and to compare those outcomes in SSc patients exposed to ACE inhibitors or not prior to the onset of SRC.
Methods Design We designed a prospective, international cohort study of subjects with incident SRC identified through a web-based survey.
M. Hudson et al. / Seminars in Arthritis and Rheumatism 43 (2014) 666–672
The study was registered with the Scleroderma Clinical Trials Consortium (http://www.sctc-online.org/studies.htm), and the detailed methodology has been previously published [9]. Central research ethics approval for this study was obtained from the ethics review board of the Jewish General Hospital, Montreal, Canada. Study subjects An e-mail list of physicians with an interest in SSc was compiled from the Canadian Scleroderma Research Group, the Scleroderma Clinical Trials Consortium (SCTC), the EULAR Scleroderma Trials and Research (EUSTAR) group, and other international collaborators, in particular from Colombia, Mexico, and Australia. The physicians were contacted and invited to participate in the web-based survey. Thereafter, 589 physicians who agreed to participate were sent an e-mail on every second Friday afternoon asking them simply “Have you diagnosed a case of SRC in the past two weeks?” They were asked to check a yes/no box. If the answer was no, and in most cases it was, then there was no further question. If the answer was yes, then they were asked to answer a simple, short survey about their case requiring about 5–10 min to complete. The survey was developed and conducted using SurveyMonkey, a simple, inexpensive, web-based survey tool.
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the signs and symptoms that the physicians relied on to make their diagnosis, namely (1) systolic blood pressure 4 140 mmHg; (2) a rise in systolic blood pressure of 430 mmHg compared to baseline; (3) diastolic blood pressure 4 90 mmHg; (4) a rise in diastolic blood pressure of 4 20 mmHg compared to baseline; (5) an increase in serum creatinine 450% from baseline or serum creatinine 4 120% of the upper limit normal for the local laboratory; (6) proteinuria 4 2þ by dipstick and confirmed by a protein:creatinine ratio 4 upper limit of normal; (7) hematuria 42þ by dipstick or 410 red blood cells/high power field (without menstruation); (8) thrombocytopenia o100,000 platelets/mm3; (9) hemolysis present on blood smear or presumed by an elevated reticulocyte count; and (10) hypertensive encephalopathy (Table 1). Exposures The primary exposure of interest was the use of ACE inhibitors prior to the onset of SRC. Exposure to angiotensin receptor blockers prior to the onset of SRC, as well as the reasons for exposure to ACE inhibitors or angiotensin receptor blockers (Raynaud's phenomenon, systemic hypertension, prophylaxis because of concurrent corticosteroid use, simple prophylaxis from renal crisis, and other), was also ascertained. Outcomes
Definition of SRC There is no gold standard to define SRC. Thus, for the purposes of this study, a report of SRC confirmed by a study physician was used to define that condition. We nevertheless collected data on
One year after a patient was identified, a simple follow-up case report form was sent to the recruiting physician. The outcomes of interest were death or dialysis during the first year after the onset of SRC.
Table 1 Proposed characteristics of scleroderma renal crisis in the ISRCS compared to those proposed by expert consensus [11] ISRCS
Expert consensus
Hypertensive SRC Any one of the following: a) Systolic blood pressure 4 140 mmHg, or
A. Hypertensive SRC (fulfills both A1 and A2) 1. New onset hypertension, defined as any of the following: a) Systolic blood pressure Z 140 mgHg
b) Diastolic blood pressure 4 90 mmHg, or c) Rise in systolic blood pressure 4 30 mmHg compared to baseline, or
b) Diastolic blood pressure Z 90 mgHg c) Rise in systolic blood pressure Z 30 mmHg
d) Rise in diastolic blood pressure 4 20 mmHg compared to baseline, or
d) Rise in diastolic blood pressure Z 20 mmHg
AND One of the following features: a) Increase in serum creatinine 4 50% over baseline OR serum creatinine 4 120% of upper limit of normal for local laboratory b) Proteinuria: 4 2þ by dipstick and confirmed by protein:creatinine ratio 4 upper limit of normal c) Hematuria: 4 2þ by dipstick or 4 10 RBCs/HPF (without menstruation) 3
d) Thrombocytopenia: o 100,000 platelets/mm e) Hemolysis: by blood smear or increased reticulocyte count f) Hypertensive encephalopathy Normotensive SRC Increase in serum creatinine 4 50% over baseline OR serum creatinine 4 120% of upper limit of normal for local laboratory AND One of the following features: a) Proteinuria: 4 2þ by dipstick and confirmed by protein:creatinine ratio 4 upper limits of normal b) Hematuria: 4 2þ by dipstick or 4 10 RBCs/HPF (without menstruation) 3 c) Thrombocytopenia: o 100,000 platelets/mm Hemolysis: by blood smear or increased reticulocyte count d)
e) Hypertensive encephalopathy
AND 2. One (1) of the following five (5) features: a) Increase in serum creatinine by 50 þ % over baseline OR serum creatinine Z120% of upper limit of normal for local laboratory b) Proteinuria Z2 þ by dipstick c) Hematuria Z2 þ by dipstick or Z10 RBCs/HPF 3 d) Thrombocytopenia: o100,000 platelets/mm e) Hemolysis defined as anemia not due to other causes and either of the following: (1) Schistocytes or other RBC fragments seen on blood smear (2) increased reticulocyte count B. Normotensive SRC (fulfills both B1 and B2) 1. Increase in serum creatinine 4 50% over baseline OR serum creatinine Z 120% of upper limit of normal for local laboratory AND 2. One (1) of the following five (5) features: a) Proteinuria Z2 þ by dipstick b) Hematuria Z2 þ by dipstick or Z10 RBCs/HPF 3 c) Thrombocytopenia: o100,000/mm d) Hemolysis defined as anemia not due to other causes and either of the following: (1) Schistocytes or other RBC fragments seen on blood smear (2) Increased reticulocyte count e) Renal biopsy findings consistent with scleroderma renal crisis (microangiopathy)
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Covariates Data on the following variables were also collected at baseline: 1. patient demographics (age, sex, and race/ethnicity); 2. disease characteristics (limited vs. diffuse cutaneous SSc, disease duration, and SSc-related autoantibodies); 3. blood pressure and renal function prior to the onset of SRC; and 4. concomitant medications, including glucocorticoids, cyclosporine, and nonsteroidal anti-inflammatory drugs prior to the onset of SRC.
Sample size considerations The main objective of this study was to determine whether there was harm associated with using ACE inhibitors prior to the onset of SRC. In computing an estimated sample size, we made the following assumptions: (1) estimated prevalence of ACE inhibitor exposure prior to the onset of SRC approximately 25% (ratio of exposed to nonexposed 1:3); (2) prevalence of death or dialysis after 1 year in the nonexposed of approximately 50%; (3) risk of death or dialysis associated with exposure approximately 2-fold; and (4) loss to follow-up of about 10%. We thus calculated that a total sample of approximately 60 subjects would be needed to have 80% power to detect the estimated increased risk in poor outcomes in those exposed compared to those unexposed to ACE inhibitors. Statistical analysis Descriptive statistics were used to summarize the baseline characteristics of the study cohort, as a group and by exposure status. Chi-square test, Fisher's exact test, and Mann–Whitney U tests were used as appropriate. Cumulative incidence rates were used to compare the rates of events (death or dialysis) by exposure status. Kaplan–Meier and Cox proportional hazard survival analysis were used to compare the survival of subjects by exposure status. The Cox proportional hazard model was adjusted for baseline characteristics that were statistically significant between the exposed and unexposed in univariate analysis. Post hoc, the possibility of confounding by indication was considered. Indeed, it is possible that the indications for ACE inhibitor, in particular pre-existing systemic hypertension and hypertensionrelated cardiac and renal diseases, could account for worse outcomes after SRC, rather than the drug itself. Thus, for the purposes of this post-hoc analysis, we constructed a proxy variable for preexisting hypertension. In the baseline survey, we asked the question “Prior to the onset of SRC, what was your patient's usual blood pressure (7 10 mmHg)?” We defined pre-existing hypertension as reports of systolic blood pressure 4 140 mmHg or diastolic blood pressure 4 90 mmHg. Using this variable, we also adjusted the Cox proportional hazard model for this additional potential confounder. p o 0.05 were considered statistically significant. All statistical analyses were performed with SAS v.9.2 (SAS Institute, USA).
Results Over a 2-year period, we identified 94 subjects with SRC, of which we excluded 6 because they had a diagnosis of SRC prior to the start of the study. We excluded these prevalent cases to avoid introducing a survivor bias in the data. Of the 88 incident subjects, 13 were lost to follow-up (85% follow-up rate). Thus, the final study sample included 75 incident SRC subjects, 70 with
hypertensive SRC and 5 with normotensive SRC according to the recruiting physician. All subjects identified as having had a hypertensive SRC but only 2 of the 5 identified as having had a normotensive SRC met the criteria for SRC proposed in this study (Table 1). Overall, the mean age was 53 years, 67% were women, 77% were white, and the median disease duration from onset of the first non-Raynaud's symptom to the diagnosis of SRC was 1.5 years (Table 2). Three-quarters (75%) of the patients had diffuse cutaneous disease. Approximately 20% were positive for an RNA polymerase autoantibody (although not all centers tested for this antibody) and 45% were positive for a speckled antinuclear antibody (Table 3). Of note, of the 19 subjects who were identified as having limited cutaneous disease (n ¼ 16) or systemic sclerosis sine scleroderma (n ¼ 3) at baseline, 6 were positive for antitopoisomerase antibodies and 2 were positive for anti-RNA polymerase III antibodies. Sixteen subjects (21%) were on an ACE inhibitor prior to the onset of the SRC (Table 3). The indications for exposure to ACE inhibitors (which were not mutually exclusive) included systemic hypertension (n ¼ 12), Raynaud's phenomenon (n ¼ 2), prophylaxis because of concurrent corticosteroid exposure (n ¼ 2), and chronic renal insufficiency (n ¼ 1). None of the subjects exposed to ACE inhibitors prior to SRC were on it as simple prophylaxis from SRC. Subjects exposed to ACE inhibitors prior to the onset of SRC were older (57 vs. 51 years, p ¼ 0.14), less likely to be women (50% vs. 71%, p ¼ 0.11), and exposed to lower doses of corticosteroids (mean prednisone daily dose 9.2 mg/day vs. 18.2 mg/day, p ¼ 0.03) compared to the unexposed. Subjects exposed to ACE inhibitors prior to the onset of SRC were also more likely to have had a normotensive SRC (13% in the exposed compared to 5% in the unexposed, p ¼ 0.29). There were no important differences in other markers of disease severity between the 2 study groups, including recent cardiac events, presence or size of pericardial effusion at the start of SRC, anemia, and presence of large joint contractures. The rates of events during the first year after the onset of SRC are presented in Table 4. Overall, 27/75 (36%) subjects died within the first year and an additional 19/75 (25%) survived but remained on dialysis at 1 year. The cumulative incidence rate of death during the first year after the onset of SRC in subjects exposed to ACE inhibitors prior to the onset of SRC was 1.56 (95% confidence interval [CI] 0.68, 3.57) compared to the unexposed. There was no difference in the rate of dialysis during the first year after the onset of SRC between exposed and unexposed subjects (cumulative incidence rate 0.94, 95% CI 0.43, 2.05). In unadjusted survival analysis, there was a trend toward an increase in the risk of death in subjects exposed to ACE inhibitors prior to the onset of SRC compared to unexposed subjects. Kaplan– Meier log-rank p value was 0.13 (Fig. 1) and crude Cox proportional hazard ratio [HR] was 1.88 (95% CI 0.82, 4.30; Table 5, model 1). After adjusting for baseline differences in daily prednisone dosage, the risk of death in subjects exposed to ACE inhibitor prior to the onset of SRC was more than twice that of the unexposed and the difference was statistically significant (HR 2.42, 95% CI 1.02, 5.75, p o 0.05; Table 5, model 2). In the adjusted analysis, there was also a statistically significant increase in the risk of death with increasing exposure to prednisone: for every milligram of prednisone, the risk of death increased by 4% (hazard ratio 1.04, 95% CI 1.02, 1.07, p o 0.01). In post-hoc analysis, we investigated the possibility that the poor outcomes in subjects exposed to ACE inhibitors might be due to confounding by indication. In fact, exposure to ACE inhibitors prior to SRC was reported for hypertension in 12/16 subjects and it is possible that the worse outcomes in that group were due to preexisting hypertension and concomitant hypertension-related cardiac or renal disease, rather than exposure to ACE inhibitors. Indeed, subjects exposed to ACE inhibitors prior to the onset of SRC had
M. Hudson et al. / Seminars in Arthritis and Rheumatism 43 (2014) 666–672
Table 2 Baseline characteristics of cohort (n ¼ 75) Mean (SD) age, years Women, n (%) Ethnic groups, n (%) White Black Asian Hispanic Native American Other Disease subsets, n (%) Diffuse Limited Sine scleroderma Disease duration (since first non-Raynaud's symptom) Median disease duration, years (IQR) Number (%) with disease duration o1 year ACE inhibitor prior to SRC onset, n (%) Mean (SD) ACE dose mg/day (captopril equivalents) Median (IQR) ACE dose mg/day (captopril equivalents) ARB prior to SRC onset, n (%) Mean (SD) ARB dose mg/day (losartan equivalents) Median (IQR) ARB dose mg/day (losartan equivalents) Glucocorticoids prior to SRC onset, n (%) Mean (SD) dose mg/day in prednisone equivalents Median (IQR) dose mg/day in prednisone equivalents Nonsteroidal anti-inflammatory drugs prior to SRC onset, n (%) Cyclosporine prior to SRC onset, n (%) Countries of origin of study subjects, n Australia Belgium Brazil Canada Denmark Dominican Republic France Germany Ghana Greece Haiti Hungary Israel Italy Korea Norway Poland Spain Switzerland The Netherlands Turkey USA
52.5 (12.2) 50 (66.7) 58 10 1 2 2 2
(77.3) (13.3) (1.3) (2.7) (2.7) (2.7)
56 (74.7) 16 (21.3) 3 (4.0) 1.5 24 16 77.3 62.5 5 65 50 33 16.5 10 11 1
(0.9, 3.7) (32.0) (21.3) (59.9) (25, 100) (6.7) (33.5) (50, 100) (44.0) (12.5) (10, 20) (14.7) (1.3)
2 1 1 13 2 1 5 1 1 1 2 3 1 2 1 3 3 3 2 1 3 23
higher “usual” blood pressures prior to the onset of SRC than those without prior exposure to ACE inhibitors (mean systolic blood pressure 139 7 25.7 mmHg vs. 124 7 16 mmHg and mean diastolic blood pressure 85 7 19 mmHg vs. 75 7 11 mmHg). Thus, for the purposes of this post-hoc analysis, we defined pre-existing systemic hypertension as “usual” systolic blood pressures 4 140 mmHg or diastolic blood pressure 4 90 mmHg. In a multivariate model adjusting for hypertension and daily prednisone dosage, exposure to ACE inhibitors was still associated with a greater than 2-fold increase in the risk of death, although statistical significance was lost (HR 2.17, 95% CI 0.88, 5.33, p ¼ 0.09; Table 5, model 3). The multivariate models were repeated including subjects exposed to either ACE inhibitors or angiotensin receptor blockers. The results were similar to those including subjects exposed to ACE inhibitors only (data not shown).
Discussion Whether antecedent use of ACE inhibitors is associated with a worse prognosis for patients with SRC is an important clinical
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question, in particular given the widespread availability of these drugs and their perceived benefits in reducing the incidence of SRC. Using an international, web-based cohort study design, we identified 75 incident SRC cases. Overall, outcomes after the onset of SRC were poor, with over 60% deceased (36%) or still on dialysis (25%) at 1 year. Although the rates of dialysis did not differ, exposure to ACE inhibitors prior to the onset of SRC was associated with a greater than 2-fold increase in the risk of death after the onset of SRC in exposed compared to unexposed subjects. Of considerable interest, as well, was the finding that for every milligram of daily prednisone, the risk of death increased by 4% (hazard ratio 1.04, 95% CI 1.02, 1.07, p o 0.01). Retrospective data from the UK [7] and France [6] have suggested that exposure to ACE inhibitors prior to the onset of SRC was associated with worse outcomes [6,7]. In a combined analysis of those 2 case series, the odds ratio for permanent dialysis was 2.4 (95% CI 1.0, 5.7) in those exposed to ACE inhibitors compared to those not exposed prior to the onset of SRC [8]. However, another recent French retrospective study of 91 SRC cases, including 48 previously reported by Teixeira et al. [6], found that the rates of mortality and dialysis were similar in subjects exposed to ACE inhibitors prior to the onset of SRC compared to unexposed subjects [10]. There are several limitations of retrospective studies, including incomplete ascertainment of exposure status. Consistent with some, but not all, of these retrospective data, our prospectively collected data support the hypothesis that exposure to ACE inhibitor prior to the onset SRC may be associated with worse outcomes. Given the therapeutic role of ACE inhibitors in SRC, the results of this study may appear counterintuitive. On the other hand, only 3 subjects were on captopril 3 times a day and 2 on enalapril twice daily. The majority of the subjects were on daily dosing regimens with either lisinopril (n ¼ 6) or ramipril (n ¼ 5). In addition, the doses of ACE inhibitors were relatively low (Table 2). Thus, incomplete inhibition of the renin-angiotensin system, either due to incomplete drug coverage or insufficient dosing, may explain why subjects on ACE inhibitor may have nevertheless developed SRC. In addition, new or worsening systemic hypertension is one of the hallmarks of SRC. Thus, a possible explanation for worse outcomes in SRC in subjects exposed to ACE inhibitors relates to the fact that exposure may have masked, at least in part, this important clinical clue. Our data provide some support for this hypothesis. Indeed, there was a trend toward subjects exposed to ACE inhibitors having more normotensive SRC compared to unexposed subjects (13% in the exposed compared to 5% in the unexposed, Table 3), although the numbers were small. Two alternative explanations for our findings need to be considered. First, it is possible that the increased risk of death in those exposed to ACE inhibitors may have been due to pre-existing systemic hypertension and concomitant hypertension-related cardiac and renal disease, for which the ACE inhibitor was prescribed, rather than the drug itself. This would be a classic example of confounding by indication. Unfortunately, for the sake of simplicity, we did not collect comorbidity data in the baseline survey. However, we did inquire about the subject's “usual” blood pressure prior to the onset of SRC. We therefore used the data from this question to create a proxy variable for pre-existing systemic hypertension. In post-hoc analysis, we adjusted for hypertension using this proxy variable (in addition to daily prednisone dosage) and found that exposure to ACE inhibitor remained associated with a greater than 2-fold increase in the risk of death (HR 2.17, 95% CI 0.88, 5.33, p ¼ 0.09), although statistical significance was lost. Thus, the data were still consistent with an association between exposure to ACE inhibitors prior to the onset of SRC and death, although there was considerable uncertainty surrounding the estimate and the possibility of residual confounding persists.
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Table 3 Baseline characteristics by exposure group
Mean (SD) age, years Women, n (%) Disease subsets, n (%) Diffuse cutaneous Limited cutaneous (including sine) Disease duration (since first non-Raynaud's symptom) Median disease duration, years (IQR) Disease duration o 1 year, n (%) Glucocorticoids prior to SRC onset, n (%) Mean (SD) dose mg/day in prednisone equivalents Nonsteroidal anti-inflammatory drugs prior to SRC onset, n (%) Cyclosporine prior to SRC onset, n (%) Recent cardiac event, n (%) Pericardial effusion at diagnosis of SRC, n (%) Size of effusion, n (%) Small Moderate Large Recent anemia, n (%) Hemoglobin at diagnosis of SRC (g/dl) Large joint contractures, n (%) Autoantibodies, n (%) Anti-centromere Anti-topoisomerase Anti-RNA polymerase III Antinuclear antibody with speckled pattern Antinuclear antibody with nucleolar pattern Antinuclear antibody with other pattern
Prior ACE inhibitor (n ¼ 16)
No prior ACE inhibitor (n ¼ 59)
p Value
56.6 (9.9) 8 (50)
51.4 (12.5) 42 (71)
0.14 0.11
43 (73) 16 (27)
0.75
13 (81) 3 (19) 1.4 6 6 9.2 2 0 3 6 4 2 0 6 10.4 5 1 4 2 5 1 0 1 2
None of the above Unknown Renal crisis type, n (%) Hypertensive Normotensive
(0.7, 3.5) (38) (38) (3.4) (13) (0) (18.8) (42.9)
1.5 18 27 18.2 9 1 10 19
(66.7) (33.3)
9 9 1 22 9.9 14
(46.2) (2.4) (31.3) (6) (25) (13) (31) (6) (0) (6) (13)
2 15 13 14 3 3 8 1
14 (88) 2 (13)
(1.0, 4.2) (31) (46) (13.2) (15) (2) (17.0) (45.2)
0.61 0.59 0.55 0.03 1.00 1.00 1.00 0.88
(47.4) (47.4) (5.3) (47.8) (2.3) (24.6)
0.37 0.92 0.55 0.75
(3) (25) (22) (24) (5) (5) (14) (2)
0.52 1.00 0.50 0.53 1.00 1.00 0.67 0.11
56 (95) 3 (5)
0.29
The p values in bold were considered as statistically significant.
Second, it is possible that some patients who develop “systemic hypertension” during early SSc and are treated with ACE inhibitors may in fact have unrecognized SRC and treatment with ACE inhibitors may abort the renal crisis. Such milder cases may not have been recruited into the cohort. Rather, only more severe cases, refractory to ACE inhibitor treatment, may have been included in the exposed group and compared to a spectrum of unexposed subjects that included some with milder disease. Thus, a differential selection bias in favor of more severe disease in the exposed may have accounted for the worse outcomes in that group. However, the fact that the exposed and unexposed groups did not differ significantly in their baseline disease characteristics, and in fact those exposed to ACE inhibitors were exposed to lower doses of corticosteroids, argues against a systematic selection bias between the 2 groups. Our study was not designed to answer another important question, namely whether the use of ACE inhibitor is associated with a reduction in the incidence of SRC. We identified incident
SRC subjects, whereas answering that question would require prospectively following incident SSc subjects, some exposed and others unexposed to ACE inhibitors, until the occurrence of SRC. In fact, 1 motivation for this study was to determine if there might be safety issues surrounding the use of prophylactic ACE inhibitors in a large trial designed to address the question of incidence. Indeed, given the findings of this study, if such a trial were to take place, very careful follow-up would be required to avoid delayed diagnosis of SRC, in particular in subjects with normal blood pressures. The methodology used in this study was innovative and allowed the recruitment of a sizable cohort of incident SRC subjects in a timely manner. This underscores the importance and feasibility of inter-institutional and international collaboration to study infrequent vascular manifestations of SSc and other rare diseases. In addition, the successful case-finding strategy of this study suggests that a large study to investigate the effect of exposure to ACE inhibitor on the incidence of SRC would be feasible. Recruitment would most likely have to occur over several
Table 4 Cumulative incidence rates of events after the onset of SRCa Study subjects Death Any dialysis during the first year Ongoing dialysis at 1 year, among those who survived 1 year Death or ongoing dialysis at 1 year among survivors a
Dialysis status missing for 1 subject.
Prior ACE inhibitor
No prior ACE inhibitor
Cumulative incidence rate
95% Confidence intervals
27/75 (36%) 39/74 (53%) 19/47 (40%)
8/16 (50%) 8/16 (50%) 3/8 (38%)
19/59 (32%) 31/58 (53%) 16/39 (41%)
1.56 0.94 0.93
0.68, 3.57 0.43, 2.05 0.27, 3.18
46/74 (62%)
11/16 (69%)
35/58 (60%)
1.15
0.58, 2.26
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Fig. 1. Kaplan–Meier curves for subjects exposed and unexposed to ACE inhibitors prior to the onset of SRC followed for 1 year after diagnosis of SRC (log-rank p ¼ 0.13).
years and strategies to maintain interest in recruitment would have to be developed. On the other hand, the costs of maintaining an ongoing web-based survey are minimal. Ten study subjects underwent kidney biopsies. Unfortunately, we were not able to review the slides centrally since we did not have ethics approval to transfer biological specimens. Nevertheless, we were able to review the pathological reports of these 10 subjects. All who underwent kidney biopsy had been diagnosed with hypertensive SRC. Of those, 3 were exposed to ACE inhibitors prior to the onset of SRC and their biopsies were reported as showing the following: (1) severe changes consistent with scleroderma/malignant hypertension, (2) mild but diffuse ischemic changes, and (3) changes consistent with thrombotic microangiopathy. Six biopsies done in patients who were not exposed to ACE inhibitors prior to the onset of SRC were reported as showing changes consistent with thrombotic microangiopathy and one of scleroderma-related kidney disease without widespread features of SRC possibly related to sampling issues. In all, these reports provide some external validity for the diagnosis of SRC in our cohort. This study is not without limitations. First, there is no accepted gold standard to define SRC. Given that many of the recruiting physicians were identified through SSc research groups and had an apparent interest in SSc, we chose to rely on their “expert” Table 5 Cox proportional hazard models to compare the risk of death of SRC patients exposed to ACE inhibitors prior to the onset of SRC compared to those unexposed. Model 1 is the crude analysis, model 2 is the pre-specified adjusted model, controlling for baseline differences significant at the p o 0.05 level, and model 3 is the post-hoc analysis also adjusting for pre-existing systemic hypertension Hazard ratio 95% Confidence intervals p Values Model 1 ACE inhibitor prior to SRC 1.88 Model 2
0.82, 4.30
0.14
ACE inhibitor prior to SRC 2.42 Prednisone (mg/day) 1.04 Model 3
1.02, 5.75 1.02, 1.07
o0.05 o0.01
ACE inhibitor prior to SRC 2.17 Prednisone (mg/day) 1.05 Hypertension 1.98
0.88, 5.33 1.02, 1.08 0.64, 6.13
0.09 o0.01 0.24
The p values in bold were considered as statistically significant.
opinion. However, we also collected data on the signs and symptoms that they relied on to make their diagnosis. All of the patients diagnosed with hypertensive SRC satisfied the criteria for hypertensive SRC presented in Table 1, although only 2 out of the 5 who were diagnosed with normotensive SRC satisfied the proposed criteria. Experts have also, in the past, proposed criteria to define SRC [11]. Those differ from the criteria used in this study mainly by the absence of “hypertensive encephalopathy” as a diagnostic feature of either hypertensive or normotensive SRC and by the inclusion of “renal biopsy findings consistent with SRC (microangiopathy)” as an additional diagnostic feature for normotensive SRC only (Table 1). None of the 5 subjects identified as having had a normotensive SRC in this study had a kidney biopsy. Thus, we were able to test the validity of the expert criteria, except for the fact that we had no data on kidney biopsies for those with normotensive SRC. Again, all of the subjects with hypertensive SRC met the expert criteria for SRC and 2/5 met those for normotensive SRC. This is the first study to validate proposed criteria for SRC in an incident cohort. The current definitions of hypertensive SRC are highly sensitive but additional work will be required to improve the definition of normotensive SRC and to determine the value of kidney biopsy in this patient subset. Second, it is possible that some cases were seen but not entered into the survey and it is conceivable that their disease characteristics may have been different from those of the cases included in the survey (e.g., some may have had worse and others milder disease). Thus, the response rate and the effect of a non-response bias in this study are uncertain. Similarly, patients who did not have access to, or were not referred to, a participating physician (e. g., those treated by nephrologists) and those with sub-clinical disease (e.g., normotensive SRC) whose SRC may have been overlooked by a physician were not captured in this survey. On the other hand, the characteristics of the SRC subjects included in this study are consistent with those of samples included in prior studies of SRC and suggest that the results of the study are largely generalizable. In conclusion, in this international, prospective cohort study, we identified 75 incident SRC cases and found that outcomes after the onset of SRC were poor. We also found that exposure to ACE inhibitors prior to the onset of SRC was associated with a greater than 2-fold increase in the risk of death at 1 year, after adjusting
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for prednisone exposure and hypertension using a proxy variable. However, the wide confidence intervals indicating considerable uncertainty around the precise magnitude of the risk and the possibility of residual confounding remained important limitations. Ideally, a randomized controlled trial with a large sample would be needed to confirm the findings and avoid the pitfalls of confounding.
Appendix International Scleroderma Renal Crisis Study Investigators (numbers enrolled) – Laura Hummers (7): Johns Hopkins University, Baltimore, Maryland, USA; Eric Hachulla (4): Université de Lille, Lille, France; Thomas Medsger (4): University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Virginia Steen (4): Georgetown University, Washington, DC, USA; Firas Alkassab (3): University of Massachusetts, Worcester, Massachusetts, USA; Sindhu Johnson (3): University Health Network, University of Toronto, Toronto, Ontario, Canada; Oyvind Midtvedt (3): Oslo UniversitetssykehusRikshospitalet, Oslo, Norway; Gabriella Szucs (3): University of Debrecen, Debrecen, Hungary; Elena Schiopu (3): University of Michigan, Ann Arbor, Michigan, USA; Patricia E. Carreira (2): Hospital Universitario 12 de Octubre, Madrid, Spain; Chris T. Derk (2): Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Oliver Distler (2): University Hospital Zurich, Zurich, Switzerland; Murat Inanc (2): University of Istanbul, Istanbul, Turkey; Nader Khalidi (2): McMaster University, Hamilton, Ontario, Canada; Tafazzul H. Mahmud (2): Shaikh Zayed Medical Complex and Federal Postgraduate Medical Institute, Lahore, Pakistan; Maureen D. Mayes (2): University of Texas Medical Center, Houston, Texas, USA; Kevin McKown (2): University of Wisconsin, Madison, Wisconsin, USA; Susanna Proudman (2): Royal Adelaide Hospital, Adelaide, South Australia; Lidia Rudnicka (2): Faculty of Medical Sciences, Medical University of Warsaw, Warsaw, Poland; Stuart Seigel (2): Hospital of Kelowna, British Columbia, Canada; Jack Stein (2): Scarborough General Hospital, Scarborough, Ontario, Canada; Gabriele Valentini (2): Second University of Naples, Naples, Italy; Sule Yavuz (2): Marmara University School of Medicine, Istanbul, Turkey; Hector Arbillaga (1): Chinook Regional Hospital, Lethbridge, Alberta, Canada; Murray Baron (1): McGill University, Montreal, Quebec, Canada; Milton Baker (1): Victoria, British Columbia, Canada; Mike Becker (1): Humboldt University, Berlin, Germany; Jean Cabane (1): Hôpital Saint-Antoine, Paris, France; Andrew Chow (1): McMaster University, Hamilton, and University of Toronto, Toronto, Ontario, Canada; Romy Christmann (1): University of Sao Paulo, Brazil, and Boston University, Boston, Massachusetts, USA; Philip Clements (1): David Geffen School of Medicine at UCLA, Los Angeles, California, USA; Mary Ellen Csuka (1): Medical College Wisconsin, Milwaukee, Wisconsin, USA; Daniel E. Furst (1): UCLA, Los Angeles, California, USA; Katharina Hanke (1): Humboldt University Berlin, Berlin, Germany; Beth
Hazel (1): McGill University, Montreal, Quebec, Canada; Ina Kötter (1): University of Tübingen, Tübingen, Germany; Soren Jacobsen (1): Copenhagen University Hospital, Copenhagen, Denmark; Jason Kur (1): University of British Columbia, Vancouver, Canada; Edward V. Lally (1): Brown University School of Medicine, Providence, Rhode Island, USA; Sophie Ligier (1): Hôpital MaisonneuveRosemont, Montreal, Quebec, Canada; Shikha Mittoo (1): University of Manitoba, Winnipeg, Manitoba, Canada; Paloma Garcia De La Pena-Lefebvre (1): Hospital Ramon y Cajal, Madrid, Spain; Christine Peschken (1): University of Manitoba, Winnipeg, Manitoba, Canada; Viviane Queyrel (1): Centre Hospitalier Universitaire de Nice, Nice, France; Jan Schulz (1): McGill University, Montreal, Quebec, Canada; Richard Silver (1): Medical University of South Carolina, Charleston, South Carolina, USA; Robert Simms (1): Boston University School of Medicine, Boston, Massachusetts, USA; Klaus Sondergaard (1): Aarhus University Hospital, Aarhus, Denmark; Yves Troyanov (1): Hôpital Sacré-Coeur, Montreal, Quebec, Canada; Maria C. Turi (1): University of Chieti, Chieti, Italy; John Varga (1): Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Panayiotis G. Vlachoyiannopoulos (1): National University of Athens, Athens, Greece; Alexandre E. Voskuyl (1): Vrije Universiteit, Nijmegen, The Netherlands; Carol Yeadon (1): Université de Montréal, Montreal, Quebec, Canada; Rene Westhovens (1): University Hospitals KU, Leuven, Belgium.
References [1] Steen VD. Scleroderma renal crisis. Rheum Dis Clin North Am 2003;29:315–33. [2] Steen VD, Medsger TA Jr.. Long-term outcomes of scleroderma renal crisis. Ann Intern Med 2000;133:600–3. [3] Steen VD, Medsger TA Jr., Osial TA Jr., Ziegler GL, Shapiro AP, Rodnan GP. Factors predicting development of renal involvement in progressive systemic sclerosis. Am J Med 1984;76:779–86. [4] Walker UA, Tyndall A, Czirjak L, Denton C, Farge-Bancel D, Kowal-Bielecka O, et al. Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group database. Ann Rheum Dis 2007;66:754–63. [5] Denton C, Black C. Scleroderma—clinical and pathological advances. Best Pract Res Clin Rheumatol 2004;18:271–90. [6] Teixeira L, Mouthon L, Mahr A, Berezne A, Agard C, Mehrenberger M, et al. Mortality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients. Ann Rheum Dis 2008;67:110–6. [7] Penn H, Howie AJ, Kingdon EJ, Bunn CC, Stratton RJ, Black CM, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 2007;100:485–94. [8] Penn H, Denton CP. Diagnosis, management and prevention of scleroderma renal disease. Curr Opin Rheumatol 2008;20:692–6. [9] Hudson M, Baron M, Lo E, Weinfeld J, Furst D, Khanna D. An international, web-based, prospective cohort study to determine if the use of ACE inhibitors prior to the onset of scleroderma renal crisis is associated with worse outcome —methodology and preliminary results. Int J Rheumatol 2010 [Article ID 347402]. [10] Guillevin L, Berezne A, Seror R, Teixeira L, Pourrat J, Mahr A, et al. Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls. Rheumatology (Oxford) 2012;51:460–7. [11] Steen VD, Mayes MD, Merkel PA. Assessment of kidney involvement. Clin Exp Rheumatol 2003;21(3 Suppl. 29):S29–31.
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Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis—Results from the International Scleroderma Renal Crisis Survey Marie Hudson, MD, MPHa,b,n, Murray Baron, MDa,b, Solène Tatibouet, MSca, Daniel E. Furst, MDc, Dinesh Khanna, MD, MSd, International Scleroderma Renal Crisis Study Investigators1 a
Jewish General Hospital, Montreal, Quebec, Canada McGill University, Montreal, Quebec, Canada c Geffen School of Medicine, University of California, Los Angeles, CA d University of Michigan Scleroderma Program, Ann Arbor, MI b
a r t i c l e in f o
Keywords: Scleroderma Scleroderma renal crisis ACE inhibitors
abstract Objective: To determine whether exposure to angiotensin-converting enzyme (ACE) inhibitors prior to the onset of scleroderma renal crisis (SRC) leads to worse outcomes of SRC. Methods: Prospective cohort study of incident SRC subjects. The exposure of interest was ACE inhibitors prior to the onset of SRC. The outcomes of interest were death or dialysis during the first year after the onset of SRC. Results: A total of 87 subjects with incident SRC were identified and 1-year follow-up data were obtained in 75 (86%) subjects. Overall, 27 (36%) subjects died within the first year and an additional 19 (25%) remained on dialysis 1 year after the onset of SRC. In adjusted analyses, exposure to ACE inhibitors prior to the onset of SRC was associated with an increased risk of death (hazard ratio 2.42, 95% CI 1.02, 5.75, p o 0.05 in the primary analysis and 2.17, 95% CI 0.88, 5.33, p ¼ 0.09 after post-hoc adjustment for preexisting hypertension). Conclusion: Overall, the 1-year outcomes of SRC were poor. Prior exposure to ACE inhibitors was associated with an increased risk of death after the onset of SRC, although there was uncertainty around the magnitude of the risk and the possibility of residual confounding could not be ruled out. Further studies will be needed to confirm these findings. & 2014 Elsevier Inc. All rights reserved.
Scleroderma renal crisis (SRC) is an infrequent, but lifethreatening complication of systemic sclerosis (SSc) [1]. It was previously associated with significant morbidity, including chronic renal failure and dialysis, and high mortality. However, since the advent of angiotensin-converting enzyme (ACE) inhibitors, the outcome of SRC has improved [2]. In addition, there is some data to suggest that the incidence of SRC has fallen over the past years [3,4]. This has been hypothesized to be due, at least in part, to the more liberal use of ACE inhibitors to treat Raynaud's phenomenon and hypertension in SSc [5]. Given the benefits of ACE inhibitors in SRC and the perceived decrease in incidence in SRC, the prophylactic use of ACE inhibitors to prevent SRC has been considered [5]. However, there is no clear physiologic rationale for this since most SSc patients do not have Funding: This study was funded in part by the Fonds de la recherche en santé du Québec. Dr. Hudson is funded as a Chercheur-clinicien also by the Fonds de recherche en santé du Québec. n Corresponding author at: Jewish General Hospital, Room A-725, 3755 Côte Ste Catherine Rd, Montreal, Quebec, Canada H3T 1E2. E-mail address: [email protected] (M. Hudson). 1 Investigators of the International Scleroderma Renal Crisis Study are listed in the Appendix. 0049-0172/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2013.09.008
hyper-reninemia prior to the onset of SRC [3]. In addition, there is a theoretical concern that by masking hypertension, prophylactic ACE inhibitor use may lead to worse outcomes after the onset of SRC. Indeed, normotensive SRC patients have been reported to have a worse prognosis than hypertensive patients [6], possibly because diagnosis may be delayed in the absence of hypertension. In fact, retrospective data have provided some preliminary evidence suggesting that those exposed to ACE inhibitors prior to the onset of SRC may have worse outcomes, in particular more chronic dialysis, than those with SRC unexposed to these drugs [6–8]. To further elucidate this important clinical question, we undertook a prospective study to determine the outcomes after SRC and to compare those outcomes in SSc patients exposed to ACE inhibitors or not prior to the onset of SRC.
Methods Design We designed a prospective, international cohort study of subjects with incident SRC identified through a web-based survey.
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The study was registered with the Scleroderma Clinical Trials Consortium (http://www.sctc-online.org/studies.htm), and the detailed methodology has been previously published [9]. Central research ethics approval for this study was obtained from the ethics review board of the Jewish General Hospital, Montreal, Canada. Study subjects An e-mail list of physicians with an interest in SSc was compiled from the Canadian Scleroderma Research Group, the Scleroderma Clinical Trials Consortium (SCTC), the EULAR Scleroderma Trials and Research (EUSTAR) group, and other international collaborators, in particular from Colombia, Mexico, and Australia. The physicians were contacted and invited to participate in the web-based survey. Thereafter, 589 physicians who agreed to participate were sent an e-mail on every second Friday afternoon asking them simply “Have you diagnosed a case of SRC in the past two weeks?” They were asked to check a yes/no box. If the answer was no, and in most cases it was, then there was no further question. If the answer was yes, then they were asked to answer a simple, short survey about their case requiring about 5–10 min to complete. The survey was developed and conducted using SurveyMonkey, a simple, inexpensive, web-based survey tool.
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the signs and symptoms that the physicians relied on to make their diagnosis, namely (1) systolic blood pressure 4 140 mmHg; (2) a rise in systolic blood pressure of 430 mmHg compared to baseline; (3) diastolic blood pressure 4 90 mmHg; (4) a rise in diastolic blood pressure of 4 20 mmHg compared to baseline; (5) an increase in serum creatinine 450% from baseline or serum creatinine 4 120% of the upper limit normal for the local laboratory; (6) proteinuria 4 2þ by dipstick and confirmed by a protein:creatinine ratio 4 upper limit of normal; (7) hematuria 42þ by dipstick or 410 red blood cells/high power field (without menstruation); (8) thrombocytopenia o100,000 platelets/mm3; (9) hemolysis present on blood smear or presumed by an elevated reticulocyte count; and (10) hypertensive encephalopathy (Table 1). Exposures The primary exposure of interest was the use of ACE inhibitors prior to the onset of SRC. Exposure to angiotensin receptor blockers prior to the onset of SRC, as well as the reasons for exposure to ACE inhibitors or angiotensin receptor blockers (Raynaud's phenomenon, systemic hypertension, prophylaxis because of concurrent corticosteroid use, simple prophylaxis from renal crisis, and other), was also ascertained. Outcomes
Definition of SRC There is no gold standard to define SRC. Thus, for the purposes of this study, a report of SRC confirmed by a study physician was used to define that condition. We nevertheless collected data on
One year after a patient was identified, a simple follow-up case report form was sent to the recruiting physician. The outcomes of interest were death or dialysis during the first year after the onset of SRC.
Table 1 Proposed characteristics of scleroderma renal crisis in the ISRCS compared to those proposed by expert consensus [11] ISRCS
Expert consensus
Hypertensive SRC Any one of the following: a) Systolic blood pressure 4 140 mmHg, or
A. Hypertensive SRC (fulfills both A1 and A2) 1. New onset hypertension, defined as any of the following: a) Systolic blood pressure Z 140 mgHg
b) Diastolic blood pressure 4 90 mmHg, or c) Rise in systolic blood pressure 4 30 mmHg compared to baseline, or
b) Diastolic blood pressure Z 90 mgHg c) Rise in systolic blood pressure Z 30 mmHg
d) Rise in diastolic blood pressure 4 20 mmHg compared to baseline, or
d) Rise in diastolic blood pressure Z 20 mmHg
AND One of the following features: a) Increase in serum creatinine 4 50% over baseline OR serum creatinine 4 120% of upper limit of normal for local laboratory b) Proteinuria: 4 2þ by dipstick and confirmed by protein:creatinine ratio 4 upper limit of normal c) Hematuria: 4 2þ by dipstick or 4 10 RBCs/HPF (without menstruation) 3
d) Thrombocytopenia: o 100,000 platelets/mm e) Hemolysis: by blood smear or increased reticulocyte count f) Hypertensive encephalopathy Normotensive SRC Increase in serum creatinine 4 50% over baseline OR serum creatinine 4 120% of upper limit of normal for local laboratory AND One of the following features: a) Proteinuria: 4 2þ by dipstick and confirmed by protein:creatinine ratio 4 upper limits of normal b) Hematuria: 4 2þ by dipstick or 4 10 RBCs/HPF (without menstruation) 3 c) Thrombocytopenia: o 100,000 platelets/mm Hemolysis: by blood smear or increased reticulocyte count d)
e) Hypertensive encephalopathy
AND 2. One (1) of the following five (5) features: a) Increase in serum creatinine by 50 þ % over baseline OR serum creatinine Z120% of upper limit of normal for local laboratory b) Proteinuria Z2 þ by dipstick c) Hematuria Z2 þ by dipstick or Z10 RBCs/HPF 3 d) Thrombocytopenia: o100,000 platelets/mm e) Hemolysis defined as anemia not due to other causes and either of the following: (1) Schistocytes or other RBC fragments seen on blood smear (2) increased reticulocyte count B. Normotensive SRC (fulfills both B1 and B2) 1. Increase in serum creatinine 4 50% over baseline OR serum creatinine Z 120% of upper limit of normal for local laboratory AND 2. One (1) of the following five (5) features: a) Proteinuria Z2 þ by dipstick b) Hematuria Z2 þ by dipstick or Z10 RBCs/HPF 3 c) Thrombocytopenia: o100,000/mm d) Hemolysis defined as anemia not due to other causes and either of the following: (1) Schistocytes or other RBC fragments seen on blood smear (2) Increased reticulocyte count e) Renal biopsy findings consistent with scleroderma renal crisis (microangiopathy)
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Covariates Data on the following variables were also collected at baseline: 1. patient demographics (age, sex, and race/ethnicity); 2. disease characteristics (limited vs. diffuse cutaneous SSc, disease duration, and SSc-related autoantibodies); 3. blood pressure and renal function prior to the onset of SRC; and 4. concomitant medications, including glucocorticoids, cyclosporine, and nonsteroidal anti-inflammatory drugs prior to the onset of SRC.
Sample size considerations The main objective of this study was to determine whether there was harm associated with using ACE inhibitors prior to the onset of SRC. In computing an estimated sample size, we made the following assumptions: (1) estimated prevalence of ACE inhibitor exposure prior to the onset of SRC approximately 25% (ratio of exposed to nonexposed 1:3); (2) prevalence of death or dialysis after 1 year in the nonexposed of approximately 50%; (3) risk of death or dialysis associated with exposure approximately 2-fold; and (4) loss to follow-up of about 10%. We thus calculated that a total sample of approximately 60 subjects would be needed to have 80% power to detect the estimated increased risk in poor outcomes in those exposed compared to those unexposed to ACE inhibitors. Statistical analysis Descriptive statistics were used to summarize the baseline characteristics of the study cohort, as a group and by exposure status. Chi-square test, Fisher's exact test, and Mann–Whitney U tests were used as appropriate. Cumulative incidence rates were used to compare the rates of events (death or dialysis) by exposure status. Kaplan–Meier and Cox proportional hazard survival analysis were used to compare the survival of subjects by exposure status. The Cox proportional hazard model was adjusted for baseline characteristics that were statistically significant between the exposed and unexposed in univariate analysis. Post hoc, the possibility of confounding by indication was considered. Indeed, it is possible that the indications for ACE inhibitor, in particular pre-existing systemic hypertension and hypertensionrelated cardiac and renal diseases, could account for worse outcomes after SRC, rather than the drug itself. Thus, for the purposes of this post-hoc analysis, we constructed a proxy variable for preexisting hypertension. In the baseline survey, we asked the question “Prior to the onset of SRC, what was your patient's usual blood pressure (7 10 mmHg)?” We defined pre-existing hypertension as reports of systolic blood pressure 4 140 mmHg or diastolic blood pressure 4 90 mmHg. Using this variable, we also adjusted the Cox proportional hazard model for this additional potential confounder. p o 0.05 were considered statistically significant. All statistical analyses were performed with SAS v.9.2 (SAS Institute, USA).
Results Over a 2-year period, we identified 94 subjects with SRC, of which we excluded 6 because they had a diagnosis of SRC prior to the start of the study. We excluded these prevalent cases to avoid introducing a survivor bias in the data. Of the 88 incident subjects, 13 were lost to follow-up (85% follow-up rate). Thus, the final study sample included 75 incident SRC subjects, 70 with
hypertensive SRC and 5 with normotensive SRC according to the recruiting physician. All subjects identified as having had a hypertensive SRC but only 2 of the 5 identified as having had a normotensive SRC met the criteria for SRC proposed in this study (Table 1). Overall, the mean age was 53 years, 67% were women, 77% were white, and the median disease duration from onset of the first non-Raynaud's symptom to the diagnosis of SRC was 1.5 years (Table 2). Three-quarters (75%) of the patients had diffuse cutaneous disease. Approximately 20% were positive for an RNA polymerase autoantibody (although not all centers tested for this antibody) and 45% were positive for a speckled antinuclear antibody (Table 3). Of note, of the 19 subjects who were identified as having limited cutaneous disease (n ¼ 16) or systemic sclerosis sine scleroderma (n ¼ 3) at baseline, 6 were positive for antitopoisomerase antibodies and 2 were positive for anti-RNA polymerase III antibodies. Sixteen subjects (21%) were on an ACE inhibitor prior to the onset of the SRC (Table 3). The indications for exposure to ACE inhibitors (which were not mutually exclusive) included systemic hypertension (n ¼ 12), Raynaud's phenomenon (n ¼ 2), prophylaxis because of concurrent corticosteroid exposure (n ¼ 2), and chronic renal insufficiency (n ¼ 1). None of the subjects exposed to ACE inhibitors prior to SRC were on it as simple prophylaxis from SRC. Subjects exposed to ACE inhibitors prior to the onset of SRC were older (57 vs. 51 years, p ¼ 0.14), less likely to be women (50% vs. 71%, p ¼ 0.11), and exposed to lower doses of corticosteroids (mean prednisone daily dose 9.2 mg/day vs. 18.2 mg/day, p ¼ 0.03) compared to the unexposed. Subjects exposed to ACE inhibitors prior to the onset of SRC were also more likely to have had a normotensive SRC (13% in the exposed compared to 5% in the unexposed, p ¼ 0.29). There were no important differences in other markers of disease severity between the 2 study groups, including recent cardiac events, presence or size of pericardial effusion at the start of SRC, anemia, and presence of large joint contractures. The rates of events during the first year after the onset of SRC are presented in Table 4. Overall, 27/75 (36%) subjects died within the first year and an additional 19/75 (25%) survived but remained on dialysis at 1 year. The cumulative incidence rate of death during the first year after the onset of SRC in subjects exposed to ACE inhibitors prior to the onset of SRC was 1.56 (95% confidence interval [CI] 0.68, 3.57) compared to the unexposed. There was no difference in the rate of dialysis during the first year after the onset of SRC between exposed and unexposed subjects (cumulative incidence rate 0.94, 95% CI 0.43, 2.05). In unadjusted survival analysis, there was a trend toward an increase in the risk of death in subjects exposed to ACE inhibitors prior to the onset of SRC compared to unexposed subjects. Kaplan– Meier log-rank p value was 0.13 (Fig. 1) and crude Cox proportional hazard ratio [HR] was 1.88 (95% CI 0.82, 4.30; Table 5, model 1). After adjusting for baseline differences in daily prednisone dosage, the risk of death in subjects exposed to ACE inhibitor prior to the onset of SRC was more than twice that of the unexposed and the difference was statistically significant (HR 2.42, 95% CI 1.02, 5.75, p o 0.05; Table 5, model 2). In the adjusted analysis, there was also a statistically significant increase in the risk of death with increasing exposure to prednisone: for every milligram of prednisone, the risk of death increased by 4% (hazard ratio 1.04, 95% CI 1.02, 1.07, p o 0.01). In post-hoc analysis, we investigated the possibility that the poor outcomes in subjects exposed to ACE inhibitors might be due to confounding by indication. In fact, exposure to ACE inhibitors prior to SRC was reported for hypertension in 12/16 subjects and it is possible that the worse outcomes in that group were due to preexisting hypertension and concomitant hypertension-related cardiac or renal disease, rather than exposure to ACE inhibitors. Indeed, subjects exposed to ACE inhibitors prior to the onset of SRC had
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Table 2 Baseline characteristics of cohort (n ¼ 75) Mean (SD) age, years Women, n (%) Ethnic groups, n (%) White Black Asian Hispanic Native American Other Disease subsets, n (%) Diffuse Limited Sine scleroderma Disease duration (since first non-Raynaud's symptom) Median disease duration, years (IQR) Number (%) with disease duration o1 year ACE inhibitor prior to SRC onset, n (%) Mean (SD) ACE dose mg/day (captopril equivalents) Median (IQR) ACE dose mg/day (captopril equivalents) ARB prior to SRC onset, n (%) Mean (SD) ARB dose mg/day (losartan equivalents) Median (IQR) ARB dose mg/day (losartan equivalents) Glucocorticoids prior to SRC onset, n (%) Mean (SD) dose mg/day in prednisone equivalents Median (IQR) dose mg/day in prednisone equivalents Nonsteroidal anti-inflammatory drugs prior to SRC onset, n (%) Cyclosporine prior to SRC onset, n (%) Countries of origin of study subjects, n Australia Belgium Brazil Canada Denmark Dominican Republic France Germany Ghana Greece Haiti Hungary Israel Italy Korea Norway Poland Spain Switzerland The Netherlands Turkey USA
52.5 (12.2) 50 (66.7) 58 10 1 2 2 2
(77.3) (13.3) (1.3) (2.7) (2.7) (2.7)
56 (74.7) 16 (21.3) 3 (4.0) 1.5 24 16 77.3 62.5 5 65 50 33 16.5 10 11 1
(0.9, 3.7) (32.0) (21.3) (59.9) (25, 100) (6.7) (33.5) (50, 100) (44.0) (12.5) (10, 20) (14.7) (1.3)
2 1 1 13 2 1 5 1 1 1 2 3 1 2 1 3 3 3 2 1 3 23
higher “usual” blood pressures prior to the onset of SRC than those without prior exposure to ACE inhibitors (mean systolic blood pressure 139 7 25.7 mmHg vs. 124 7 16 mmHg and mean diastolic blood pressure 85 7 19 mmHg vs. 75 7 11 mmHg). Thus, for the purposes of this post-hoc analysis, we defined pre-existing systemic hypertension as “usual” systolic blood pressures 4 140 mmHg or diastolic blood pressure 4 90 mmHg. In a multivariate model adjusting for hypertension and daily prednisone dosage, exposure to ACE inhibitors was still associated with a greater than 2-fold increase in the risk of death, although statistical significance was lost (HR 2.17, 95% CI 0.88, 5.33, p ¼ 0.09; Table 5, model 3). The multivariate models were repeated including subjects exposed to either ACE inhibitors or angiotensin receptor blockers. The results were similar to those including subjects exposed to ACE inhibitors only (data not shown).
Discussion Whether antecedent use of ACE inhibitors is associated with a worse prognosis for patients with SRC is an important clinical
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question, in particular given the widespread availability of these drugs and their perceived benefits in reducing the incidence of SRC. Using an international, web-based cohort study design, we identified 75 incident SRC cases. Overall, outcomes after the onset of SRC were poor, with over 60% deceased (36%) or still on dialysis (25%) at 1 year. Although the rates of dialysis did not differ, exposure to ACE inhibitors prior to the onset of SRC was associated with a greater than 2-fold increase in the risk of death after the onset of SRC in exposed compared to unexposed subjects. Of considerable interest, as well, was the finding that for every milligram of daily prednisone, the risk of death increased by 4% (hazard ratio 1.04, 95% CI 1.02, 1.07, p o 0.01). Retrospective data from the UK [7] and France [6] have suggested that exposure to ACE inhibitors prior to the onset of SRC was associated with worse outcomes [6,7]. In a combined analysis of those 2 case series, the odds ratio for permanent dialysis was 2.4 (95% CI 1.0, 5.7) in those exposed to ACE inhibitors compared to those not exposed prior to the onset of SRC [8]. However, another recent French retrospective study of 91 SRC cases, including 48 previously reported by Teixeira et al. [6], found that the rates of mortality and dialysis were similar in subjects exposed to ACE inhibitors prior to the onset of SRC compared to unexposed subjects [10]. There are several limitations of retrospective studies, including incomplete ascertainment of exposure status. Consistent with some, but not all, of these retrospective data, our prospectively collected data support the hypothesis that exposure to ACE inhibitor prior to the onset SRC may be associated with worse outcomes. Given the therapeutic role of ACE inhibitors in SRC, the results of this study may appear counterintuitive. On the other hand, only 3 subjects were on captopril 3 times a day and 2 on enalapril twice daily. The majority of the subjects were on daily dosing regimens with either lisinopril (n ¼ 6) or ramipril (n ¼ 5). In addition, the doses of ACE inhibitors were relatively low (Table 2). Thus, incomplete inhibition of the renin-angiotensin system, either due to incomplete drug coverage or insufficient dosing, may explain why subjects on ACE inhibitor may have nevertheless developed SRC. In addition, new or worsening systemic hypertension is one of the hallmarks of SRC. Thus, a possible explanation for worse outcomes in SRC in subjects exposed to ACE inhibitors relates to the fact that exposure may have masked, at least in part, this important clinical clue. Our data provide some support for this hypothesis. Indeed, there was a trend toward subjects exposed to ACE inhibitors having more normotensive SRC compared to unexposed subjects (13% in the exposed compared to 5% in the unexposed, Table 3), although the numbers were small. Two alternative explanations for our findings need to be considered. First, it is possible that the increased risk of death in those exposed to ACE inhibitors may have been due to pre-existing systemic hypertension and concomitant hypertension-related cardiac and renal disease, for which the ACE inhibitor was prescribed, rather than the drug itself. This would be a classic example of confounding by indication. Unfortunately, for the sake of simplicity, we did not collect comorbidity data in the baseline survey. However, we did inquire about the subject's “usual” blood pressure prior to the onset of SRC. We therefore used the data from this question to create a proxy variable for pre-existing systemic hypertension. In post-hoc analysis, we adjusted for hypertension using this proxy variable (in addition to daily prednisone dosage) and found that exposure to ACE inhibitor remained associated with a greater than 2-fold increase in the risk of death (HR 2.17, 95% CI 0.88, 5.33, p ¼ 0.09), although statistical significance was lost. Thus, the data were still consistent with an association between exposure to ACE inhibitors prior to the onset of SRC and death, although there was considerable uncertainty surrounding the estimate and the possibility of residual confounding persists.
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Table 3 Baseline characteristics by exposure group
Mean (SD) age, years Women, n (%) Disease subsets, n (%) Diffuse cutaneous Limited cutaneous (including sine) Disease duration (since first non-Raynaud's symptom) Median disease duration, years (IQR) Disease duration o 1 year, n (%) Glucocorticoids prior to SRC onset, n (%) Mean (SD) dose mg/day in prednisone equivalents Nonsteroidal anti-inflammatory drugs prior to SRC onset, n (%) Cyclosporine prior to SRC onset, n (%) Recent cardiac event, n (%) Pericardial effusion at diagnosis of SRC, n (%) Size of effusion, n (%) Small Moderate Large Recent anemia, n (%) Hemoglobin at diagnosis of SRC (g/dl) Large joint contractures, n (%) Autoantibodies, n (%) Anti-centromere Anti-topoisomerase Anti-RNA polymerase III Antinuclear antibody with speckled pattern Antinuclear antibody with nucleolar pattern Antinuclear antibody with other pattern
Prior ACE inhibitor (n ¼ 16)
No prior ACE inhibitor (n ¼ 59)
p Value
56.6 (9.9) 8 (50)
51.4 (12.5) 42 (71)
0.14 0.11
43 (73) 16 (27)
0.75
13 (81) 3 (19) 1.4 6 6 9.2 2 0 3 6 4 2 0 6 10.4 5 1 4 2 5 1 0 1 2
None of the above Unknown Renal crisis type, n (%) Hypertensive Normotensive
(0.7, 3.5) (38) (38) (3.4) (13) (0) (18.8) (42.9)
1.5 18 27 18.2 9 1 10 19
(66.7) (33.3)
9 9 1 22 9.9 14
(46.2) (2.4) (31.3) (6) (25) (13) (31) (6) (0) (6) (13)
2 15 13 14 3 3 8 1
14 (88) 2 (13)
(1.0, 4.2) (31) (46) (13.2) (15) (2) (17.0) (45.2)
0.61 0.59 0.55 0.03 1.00 1.00 1.00 0.88
(47.4) (47.4) (5.3) (47.8) (2.3) (24.6)
0.37 0.92 0.55 0.75
(3) (25) (22) (24) (5) (5) (14) (2)
0.52 1.00 0.50 0.53 1.00 1.00 0.67 0.11
56 (95) 3 (5)
0.29
The p values in bold were considered as statistically significant.
Second, it is possible that some patients who develop “systemic hypertension” during early SSc and are treated with ACE inhibitors may in fact have unrecognized SRC and treatment with ACE inhibitors may abort the renal crisis. Such milder cases may not have been recruited into the cohort. Rather, only more severe cases, refractory to ACE inhibitor treatment, may have been included in the exposed group and compared to a spectrum of unexposed subjects that included some with milder disease. Thus, a differential selection bias in favor of more severe disease in the exposed may have accounted for the worse outcomes in that group. However, the fact that the exposed and unexposed groups did not differ significantly in their baseline disease characteristics, and in fact those exposed to ACE inhibitors were exposed to lower doses of corticosteroids, argues against a systematic selection bias between the 2 groups. Our study was not designed to answer another important question, namely whether the use of ACE inhibitor is associated with a reduction in the incidence of SRC. We identified incident
SRC subjects, whereas answering that question would require prospectively following incident SSc subjects, some exposed and others unexposed to ACE inhibitors, until the occurrence of SRC. In fact, 1 motivation for this study was to determine if there might be safety issues surrounding the use of prophylactic ACE inhibitors in a large trial designed to address the question of incidence. Indeed, given the findings of this study, if such a trial were to take place, very careful follow-up would be required to avoid delayed diagnosis of SRC, in particular in subjects with normal blood pressures. The methodology used in this study was innovative and allowed the recruitment of a sizable cohort of incident SRC subjects in a timely manner. This underscores the importance and feasibility of inter-institutional and international collaboration to study infrequent vascular manifestations of SSc and other rare diseases. In addition, the successful case-finding strategy of this study suggests that a large study to investigate the effect of exposure to ACE inhibitor on the incidence of SRC would be feasible. Recruitment would most likely have to occur over several
Table 4 Cumulative incidence rates of events after the onset of SRCa Study subjects Death Any dialysis during the first year Ongoing dialysis at 1 year, among those who survived 1 year Death or ongoing dialysis at 1 year among survivors a
Dialysis status missing for 1 subject.
Prior ACE inhibitor
No prior ACE inhibitor
Cumulative incidence rate
95% Confidence intervals
27/75 (36%) 39/74 (53%) 19/47 (40%)
8/16 (50%) 8/16 (50%) 3/8 (38%)
19/59 (32%) 31/58 (53%) 16/39 (41%)
1.56 0.94 0.93
0.68, 3.57 0.43, 2.05 0.27, 3.18
46/74 (62%)
11/16 (69%)
35/58 (60%)
1.15
0.58, 2.26
M. Hudson et al. / Seminars in Arthritis and Rheumatism 43 (2014) 666–672
671
Fig. 1. Kaplan–Meier curves for subjects exposed and unexposed to ACE inhibitors prior to the onset of SRC followed for 1 year after diagnosis of SRC (log-rank p ¼ 0.13).
years and strategies to maintain interest in recruitment would have to be developed. On the other hand, the costs of maintaining an ongoing web-based survey are minimal. Ten study subjects underwent kidney biopsies. Unfortunately, we were not able to review the slides centrally since we did not have ethics approval to transfer biological specimens. Nevertheless, we were able to review the pathological reports of these 10 subjects. All who underwent kidney biopsy had been diagnosed with hypertensive SRC. Of those, 3 were exposed to ACE inhibitors prior to the onset of SRC and their biopsies were reported as showing the following: (1) severe changes consistent with scleroderma/malignant hypertension, (2) mild but diffuse ischemic changes, and (3) changes consistent with thrombotic microangiopathy. Six biopsies done in patients who were not exposed to ACE inhibitors prior to the onset of SRC were reported as showing changes consistent with thrombotic microangiopathy and one of scleroderma-related kidney disease without widespread features of SRC possibly related to sampling issues. In all, these reports provide some external validity for the diagnosis of SRC in our cohort. This study is not without limitations. First, there is no accepted gold standard to define SRC. Given that many of the recruiting physicians were identified through SSc research groups and had an apparent interest in SSc, we chose to rely on their “expert” Table 5 Cox proportional hazard models to compare the risk of death of SRC patients exposed to ACE inhibitors prior to the onset of SRC compared to those unexposed. Model 1 is the crude analysis, model 2 is the pre-specified adjusted model, controlling for baseline differences significant at the p o 0.05 level, and model 3 is the post-hoc analysis also adjusting for pre-existing systemic hypertension Hazard ratio 95% Confidence intervals p Values Model 1 ACE inhibitor prior to SRC 1.88 Model 2
0.82, 4.30
0.14
ACE inhibitor prior to SRC 2.42 Prednisone (mg/day) 1.04 Model 3
1.02, 5.75 1.02, 1.07
o0.05 o0.01
ACE inhibitor prior to SRC 2.17 Prednisone (mg/day) 1.05 Hypertension 1.98
0.88, 5.33 1.02, 1.08 0.64, 6.13
0.09 o0.01 0.24
The p values in bold were considered as statistically significant.
opinion. However, we also collected data on the signs and symptoms that they relied on to make their diagnosis. All of the patients diagnosed with hypertensive SRC satisfied the criteria for hypertensive SRC presented in Table 1, although only 2 out of the 5 who were diagnosed with normotensive SRC satisfied the proposed criteria. Experts have also, in the past, proposed criteria to define SRC [11]. Those differ from the criteria used in this study mainly by the absence of “hypertensive encephalopathy” as a diagnostic feature of either hypertensive or normotensive SRC and by the inclusion of “renal biopsy findings consistent with SRC (microangiopathy)” as an additional diagnostic feature for normotensive SRC only (Table 1). None of the 5 subjects identified as having had a normotensive SRC in this study had a kidney biopsy. Thus, we were able to test the validity of the expert criteria, except for the fact that we had no data on kidney biopsies for those with normotensive SRC. Again, all of the subjects with hypertensive SRC met the expert criteria for SRC and 2/5 met those for normotensive SRC. This is the first study to validate proposed criteria for SRC in an incident cohort. The current definitions of hypertensive SRC are highly sensitive but additional work will be required to improve the definition of normotensive SRC and to determine the value of kidney biopsy in this patient subset. Second, it is possible that some cases were seen but not entered into the survey and it is conceivable that their disease characteristics may have been different from those of the cases included in the survey (e.g., some may have had worse and others milder disease). Thus, the response rate and the effect of a non-response bias in this study are uncertain. Similarly, patients who did not have access to, or were not referred to, a participating physician (e. g., those treated by nephrologists) and those with sub-clinical disease (e.g., normotensive SRC) whose SRC may have been overlooked by a physician were not captured in this survey. On the other hand, the characteristics of the SRC subjects included in this study are consistent with those of samples included in prior studies of SRC and suggest that the results of the study are largely generalizable. In conclusion, in this international, prospective cohort study, we identified 75 incident SRC cases and found that outcomes after the onset of SRC were poor. We also found that exposure to ACE inhibitors prior to the onset of SRC was associated with a greater than 2-fold increase in the risk of death at 1 year, after adjusting
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for prednisone exposure and hypertension using a proxy variable. However, the wide confidence intervals indicating considerable uncertainty around the precise magnitude of the risk and the possibility of residual confounding remained important limitations. Ideally, a randomized controlled trial with a large sample would be needed to confirm the findings and avoid the pitfalls of confounding.
Appendix International Scleroderma Renal Crisis Study Investigators (numbers enrolled) – Laura Hummers (7): Johns Hopkins University, Baltimore, Maryland, USA; Eric Hachulla (4): Université de Lille, Lille, France; Thomas Medsger (4): University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Virginia Steen (4): Georgetown University, Washington, DC, USA; Firas Alkassab (3): University of Massachusetts, Worcester, Massachusetts, USA; Sindhu Johnson (3): University Health Network, University of Toronto, Toronto, Ontario, Canada; Oyvind Midtvedt (3): Oslo UniversitetssykehusRikshospitalet, Oslo, Norway; Gabriella Szucs (3): University of Debrecen, Debrecen, Hungary; Elena Schiopu (3): University of Michigan, Ann Arbor, Michigan, USA; Patricia E. Carreira (2): Hospital Universitario 12 de Octubre, Madrid, Spain; Chris T. Derk (2): Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Oliver Distler (2): University Hospital Zurich, Zurich, Switzerland; Murat Inanc (2): University of Istanbul, Istanbul, Turkey; Nader Khalidi (2): McMaster University, Hamilton, Ontario, Canada; Tafazzul H. Mahmud (2): Shaikh Zayed Medical Complex and Federal Postgraduate Medical Institute, Lahore, Pakistan; Maureen D. Mayes (2): University of Texas Medical Center, Houston, Texas, USA; Kevin McKown (2): University of Wisconsin, Madison, Wisconsin, USA; Susanna Proudman (2): Royal Adelaide Hospital, Adelaide, South Australia; Lidia Rudnicka (2): Faculty of Medical Sciences, Medical University of Warsaw, Warsaw, Poland; Stuart Seigel (2): Hospital of Kelowna, British Columbia, Canada; Jack Stein (2): Scarborough General Hospital, Scarborough, Ontario, Canada; Gabriele Valentini (2): Second University of Naples, Naples, Italy; Sule Yavuz (2): Marmara University School of Medicine, Istanbul, Turkey; Hector Arbillaga (1): Chinook Regional Hospital, Lethbridge, Alberta, Canada; Murray Baron (1): McGill University, Montreal, Quebec, Canada; Milton Baker (1): Victoria, British Columbia, Canada; Mike Becker (1): Humboldt University, Berlin, Germany; Jean Cabane (1): Hôpital Saint-Antoine, Paris, France; Andrew Chow (1): McMaster University, Hamilton, and University of Toronto, Toronto, Ontario, Canada; Romy Christmann (1): University of Sao Paulo, Brazil, and Boston University, Boston, Massachusetts, USA; Philip Clements (1): David Geffen School of Medicine at UCLA, Los Angeles, California, USA; Mary Ellen Csuka (1): Medical College Wisconsin, Milwaukee, Wisconsin, USA; Daniel E. Furst (1): UCLA, Los Angeles, California, USA; Katharina Hanke (1): Humboldt University Berlin, Berlin, Germany; Beth
Hazel (1): McGill University, Montreal, Quebec, Canada; Ina Kötter (1): University of Tübingen, Tübingen, Germany; Soren Jacobsen (1): Copenhagen University Hospital, Copenhagen, Denmark; Jason Kur (1): University of British Columbia, Vancouver, Canada; Edward V. Lally (1): Brown University School of Medicine, Providence, Rhode Island, USA; Sophie Ligier (1): Hôpital MaisonneuveRosemont, Montreal, Quebec, Canada; Shikha Mittoo (1): University of Manitoba, Winnipeg, Manitoba, Canada; Paloma Garcia De La Pena-Lefebvre (1): Hospital Ramon y Cajal, Madrid, Spain; Christine Peschken (1): University of Manitoba, Winnipeg, Manitoba, Canada; Viviane Queyrel (1): Centre Hospitalier Universitaire de Nice, Nice, France; Jan Schulz (1): McGill University, Montreal, Quebec, Canada; Richard Silver (1): Medical University of South Carolina, Charleston, South Carolina, USA; Robert Simms (1): Boston University School of Medicine, Boston, Massachusetts, USA; Klaus Sondergaard (1): Aarhus University Hospital, Aarhus, Denmark; Yves Troyanov (1): Hôpital Sacré-Coeur, Montreal, Quebec, Canada; Maria C. Turi (1): University of Chieti, Chieti, Italy; John Varga (1): Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; Panayiotis G. Vlachoyiannopoulos (1): National University of Athens, Athens, Greece; Alexandre E. Voskuyl (1): Vrije Universiteit, Nijmegen, The Netherlands; Carol Yeadon (1): Université de Montréal, Montreal, Quebec, Canada; Rene Westhovens (1): University Hospitals KU, Leuven, Belgium.
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