Scand J Rheumatol 2011;iFirst article:1–5
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Scleroderma renal crisis in a Swedish systemic sclerosis cohort: survival, renal outcome, and RNA polymerase III antibodies as a risk factor R Hesselstrand, A Scheja, DM Wuttge
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Department of Clinical Sciences, Section for Rheumatology, Lund University, Lund, Sweden
Objectives: To study survival, renal outcome, and RNA polymerase III antibodies (RNAP Abs) as a risk factor for scleroderma renal crisis (SRC) in a Swedish cohort of systemic sclerosis (SSc) patients. Methods: SRC was diagnosed in 16 SSc patients during the period from 1982 to 2010. For comparison, 112 (seven for each SRC patient) SSc patients without SRC were included. RNAP Abs were detected by a fully automated fluoroenzymeimmunoassay (EliA). Values greater than 15 μg/L were considered positive. Frozen serum samples from the time of diagnosis of SSc were used. Results: The 5- and 10-year survival rates were, respectively, 58% and 40% for SRC patients and 90% and 76% for patients without SRC (p < 0.001). The odds ratio (OR) for mortality was 4.39 [95% confidence interval (CI) 2.10–9.16, p < 0.001] in patients with SRC compared to those without SRC. Renal outcome was good in three patients. Haemodialysis was started in 10 patients and peritoneal dialysis in three. Renal function improved in three patients and dialysis was terminated. Four patients underwent renal transplantation. Seven SRC patients and nine without SRC were positive for RNAP Abs. Anti-RNAP Abs was a strong predictor of SRC. The sensitivity and specificity for development of SRC were 0.44 and 0.92, respectively. The OR for development of SRC was 8.90 (95% CI 2.68–29.6, p ¼ 0.001) in RNAP-positive patients. Conclusions: RNAP positivity is a strong risk factor for SRC. Renal outcome was variable and survival is still notably decreased.
Systemic sclerosis (SSc, scleroderma) is a systemic connective tissue disease characterized by fibrosis of the skin and internal organs, progressive vascular obliteration, and the production of autoantibodies (1). SSc is associated with increased mortality (2–4) but prognosis is significantly variable. Scleroderma renal crisis (SRC) used to be the leading cause of death in SSc. However, with improved treatment of SRC, pulmonary involvement, either fibrotic or vascular, surpassed renal involvement as the most common cause of death in the 1990s (3, 5, 6). SRC affects 12% of SSc patients with diffuse cutaneous (dcSSc) involvement and 2% with limited cutaneous (lcSSc) involvement and still has a high mortality rate (7). The prevalence and outcome of SRC is well studied in large SSc centres (7– 10) but less so in smaller ones (11). Despite treatment with angiotensin-converting enzyme (ACE) inhibitors, dialysis, modern intensive care, and renal transplantation, 5-year survival after SRC was 59% in a large study of 110 SRC patients from the UK (7). The need for permanent
Roger Hesselstrand, Department of Rheumatology, Skåne University Hospital, S-221 85 Lund, Sweden. E-mail:
[email protected]
dialysis has a poor prognosis whereas patients with no, or only temporary, need of dialysis have survival rates comparable to SSc patients without SRC (7, 12). It is generally accepted that diffuse skin involvement, especially with rapid skin progression, is a risk factor for SRC. The presence of tendon friction rubs, contractures, anaemia, and new cardiac events are also proposed as risk factors, but it is still debated whether a high dose of corticosteroids increases and prophylactic treatment with ACE inhibitors decreases the risk of SRC (13). In SSc, autoantibodies may be used to predict both mortality and organ involvement (14). In summary, the presence of anti-centromere antibodies is associated with lcSSc and the development of pulmonary arterial hypertension and anti-Scl-70 with dcSSc and pulmonary fibrosis (14–16). There are several studies showing an association between SRC and the presence of anti-RNA polymerase III antibodies (anti-RNAP Abs) (7–11). There is, however, a striking difference between studies with a high incidence of both SRC and RNAP positivity (7–10) and others with a lower incidence (11, 12). It is unclear whether the reasons are ethnic, environmental, or related to patient selection. Recently, genetic studies have showed HLA-DRB1*0407 and *1304 to be risk factors for SRC (17).
Accepted 31 July 2011 © 2011 Taylor & Francis on license from Scandinavian Rheumatology Research Foundation DOI: 10.3109/03009742.2011.610032
www.scandjrheumatol.dk
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R Hesselstrand et al
RNAP Abs can be analysed by immunoprecipitation (IP) (18) and also by enzyme-linked immunosorbent assay (ELISA). Several commercially available ELISA tests for the determination of RNAP Abs exist and have been tested to be concordant with IP, which is important when transferring conclusions reached from studies of IP. The aim of this study was to analyse the survival and outcome after SRC and to analyse RNAP Abs as a risk factor for SRC in a Swedish cohort of SSc patients.
severe cardiac failure with a left ejection fraction of 25% (normal 6 months earlier), pulmonary oedema, renal failure with a serum creatinine level of 850 μmol/L, and anuria. The reason for normal blood pressure was thus probably the inability of the left ventricle to respond to the activated renin–angiotensin system. He was too ill to undergo a renal biopsy. Eight of the 16 SRC cases underwent renal biopsy. Seven showed changes in line with SRC whereas one was inconclusive due to insufficient material.
Methods Analyses of RNAP Abs
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Patients and clinical characterization This retrospective case–control study was approved by the regional ethics committee. SRC was diagnosed in 16 SSc patients during the period from 1 January 1982 to 31 October 2010. For comparison, 112 (seven for each SRC case) SSc controls without SRC were randomly selected from the total SSc cohort comprising 675 patients. Cases and controls were matched by year of first examination in our department. The disease was classified as dcSSc or lcSSc according to the extent of skin involvement (1), which was determined by the modified Rodnan skin score (mRss) (19). Disease onset was defined as the first non-Raynaud’s manifestation. Data were obtained from the patients’ files and the Lund SSc patient database. Data on survival were obtained from the central population registry. Patients were followed until death or 31 October 2010. Pulmonary function tests were performed on all patients using a body plethysmograph (Erich Jaeger GmbH, Hoechberg, Germany). The clinical diagnosis of SRC was defined as rapidly progressive renal insufficiency and accelerated hypertension. One patient with normotensive SRC had additional signs including microangiopathic haemolytic anaemia on blood smear, retinopathy typical of acute hypertensive crisis, new onset of urinary red blood cells, and anuria (7). He was probably hypertensive before arriving at our unit. He had a 10-month history of skin changes and a 6-week history of severe illness. When arriving he had entered a state of
Serum samples stored in aliquots at 70 C were used for analyses. RNAP Abs were detected by the fully automated EliA RNA Pol III fluoroenzymeimmunoassay test (Phadia AB, Uppsala, Sweden). Values >15.0 μg/L were considered positive. Data on RNAP Ab status using IP were available in 55 (six with SRC, 49 without) of the 128 patients.
Statistical methods Differences between groups were analysed using the Mann–Whitney U-test or Fisher’s exact test. The results are presented as mean (SD) or odds ratio (OR) with 95% confidence interval (CI). The agreement between tests was assessed by the kappa value. Survival was estimated with the Kaplan–Meier method, differences in estimated survival was analysed using the log rank test, and the hazard ratio was estimated with the Cox proportional hazards model.
Results Demographic features Cases and controls were matched by year of first examination in our department and the demographic features are shown in Table 1.
Table 1. Demographic features of cases and controls at baseline. Cases:controls n Alive at exit, yes:no mRss, mean (SD) VC (%p), mean (SD) DLCO (%p), mean (SD) Age (years), mean (SD) Disease duration (years), mean (SD) Time to SRC (years), mean (SD)
SRC
SSc without SRC
p
16 6:10 23.1 (9.8) 82.3 (23.5) 48.5 (22.6) 52.5 (14.8) 1.9 (2.6) 2.0 (2.1)
112 81:31 11.7 (10.1) 87.5 (19.0) 72.4 (20.0) 52.2 (14.1) 6.0 (8.0)
0.008*
