Jean Cabane

Mortality and risk factors of scleroderma renal crisis: a French retrospective study of 50 patients

Objectives: To describe presentation and outcome of patients with scleroderma renal crisis (SRC). Methods: SRC was defined as rapidly progressive oliguric renal insufficiency and/or rapidly progressive arterial hypertension occurring during the course of systemic sclerosis (SSc). Chronic dialysis-free survival was analysed using multivariate Cox proportional hazards regression models. The risk for developing SRC associated with corticosteroid (CS) exposure during the preceding 1- or 3-month periods was analysed according to a case–crossover design. Results: A total of 50 SSc patients aged 53.3 (14.5) (mean (SD)) years were included in the study. SRC occurred between 1979 and 2003, after a mean (SD) disease duration of 27.7 (49.1) months. A total of 43 (86%) patients had diffuse SSc, 5 (10%) had limited cutaneous SSc and 2 (4%) had SSc sine scleroderma. At the time of SRC, 10 (20%) patients were taking angiotensin converting enzyme inhibitors, and mean creatininaemia was 468 (293) μmol/l. A total of 28 (56%) patients required haemodialysis. In all, 11 patients underwent a renal biopsy, all of them had specific vascular lesions of SRC. Multivariate analyses retained age >53 years and normal blood pressure as independent predictors of decreased dialysis-free survival. Exposure to CS prior to SRC was identified in 30 (60%) patients. The odds ratios for developing SRC associated with CS exposure during the preceding 1- or 3-month periods were 24.1 (95% CI 3.0–193.8) and 17.4 (95% CI 2.1–144.0), respectively. Conclusion: SRC remains associated with severe morbidity and mortality. CS might increase the risk of developing SRC. Further studies are needed to confirm these results.

The three-year incidence of pulmonary arterial hypertension associated with systemic sclerosis in a multicenter nationwide longitudinal study in France.

OBJECTIVE An algorithm for the detection of pulmonary arterial hypertension (PAH), based on the presence of dyspnea and the findings of Doppler echocardiographic evaluation of the velocity of tricuspid regurgitation (VTR) and right-sided heart catheterization (RHC), which was applied in a large multicenter systemic sclerosis (SSc) population, estimated the prevalence of PAH to be 7.85%. The aim of this observational study was to investigate the incidence of PAH and pulmonary hypertension (PH) during a 3-year followup of patients from the same cohort (the ItinérAIR-Sclérodermie Study). METHODS Patients with SSc and without evidence of PAH underwent evaluation for dyspnea and VTR at study entry and during subsequent visits. Patients in whom PAH was suspected because of a VTR of 2.8-3.0 meters/second and unexplained dyspnea or a VTR of >3.0 meters/second underwent RHC to confirm the diagnosis. RESULTS A total of 384 patients were followed up for a mean+/-SD of 41.03+/-5.66 months (median 40.92 months). At baseline, 86.7% of the patients were women, and the mean+/-SD age of the patients was 53.1+/-12.0 years. The mean+/-SD duration of SSc at study entry was 8.7+/-7.6 years. After RHC, PAH was diagnosed in 8 patients, postcapillary PH in 8 patients, and PH associated with severe pulmonary fibrosis in 2 patients. The incidence of PAH was estimated to be 0.61 cases per 100 patient-years. Two patients who exhibited a mean pulmonary artery pressure of 20-25 mm Hg at baseline subsequently developed PAH. CONCLUSION The estimated incidence of PAH among patients with SSc was 0.61 cases per 100 patient-years. The high incidence of postcapillary PH highlights the value of RHC in investigating suspected PAH.

Corticosteroid-induced clinical adverse events: frequency, risk factors and patient's opinion.

Background  More than 50 years after the introduction of corticosteroids, few studies have focused on corticosteroid‐induced adverse events after long‐term systemic therapy.

Corticosteroid-induced adverse events in adults: frequency, screening and prevention.

Corticosteroids represent the most important and frequently used class of anti-inflammatory drugs and are the reference therapy for numerous neoplastic, immunological and allergic diseases. However, their substantial efficacy is often counter-balanced by multiple adverse events. These corticosteroid-induced adverse events represent a broad clinical and biological spectrum from mild irritability to severe and life-threatening adrenal insufficiency or cardiovascular events.The purpose of this article is to provide an overview of the available data regarding the frequency, screening and prevention of the adverse events observed in adults during systemic corticosteroid therapy (topically administered corticosteroids are outside the remit of this review). These include clinical (i.e. adipose tissue redistribution, hypertension, cardiovascular risk, osteoporosis, myopathy, peptic ulcer, adrenal insufficiency, infections, mood disorders, ophthalmological disorders, skin disorders, menstrual disorders, aseptic necrosis, pancreatitis) and biological (i.e. electrolytes homeostasis, diabetogenesis, dyslipidaemia) events. Lastly, data about the prescription of corticosteroids during pregnancy are provided. This review underscores the absence of data on many of these adverse events (e.g. lipodystrophy, dyslipidaemia).Our intent is to present to practitioners data that can be used in a practical way to both screen and prevent most of the adverse events observed during systemic corticosteroid therapy.

Autologous bone marrow transplantation in the treatment of refractory systemic sclerosis: early results from a French multicentre phase I-II study.

Summary. Haematopoietic stem cell transplantation (HSCT) has been proposed for refractory autoimmune diseases, including systemic sclerosis (SSc). A sequential Bayesian phase I–II clinical trial was conducted in SSc patients to assess the feasibility, the tolerance and the efficacy of autologous HSCT. Peripheral blood stem cells (PBSC) were collected using cyclophosphamide (4 g/m2) and recombinant human granulocyte colony‐stimulating factor (5 µg/kg/d) and reinfused after positive CD34+ selection. Conditioning used cyclophosphamide (200 mg/kg) or melphalan (140 mg/m2) according to cardiac function. The main end‐point was the failure of the procedure, defined by failure of either PBSC mobilization, CD34+ selection or intensification procedure, or by procedure‐related death. Among the 12 enrolled patients, three failures occurred: one PBSC mobilization, one CD34+ selection and one CD34+ intensification. Probability of graft failure was estimated at 0·286 (95% confidence interval: 0·095–0·54). Autologous PBSC (n = 10) or bone marrow (n = 1) transplantation was actually performed in 11 patients with one procedure‐related death. Median time to neutrophil (> 0·5 × 109/l) and platelet (> 25 × 109/l) haematopoietic reconstitution was 12 and 10 d respectively. After 18 months (range 1–26), eight out of 11 patients have shown major or partial response. Non‐myeloablative conditioning, followed by a T cell‐depleted autologous PBSC or bone marrow transplantation, appears feasible with low toxicity in severe SSc with short‐term clinical benefits.

Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis

Objectives: There is increasing concern about heart and pulmonary vascular involvement in systemic sclerosis (SSc). One of the most severe complications of SSc is pulmonary arterial hypertension (PAH). There has been an increased awareness of left ventricular (LV) diastolic abnormalities in SSc patients. However, previous studies have generally been conducted in small populations. The aims of this study were to prospectively screen for PAH and to describe echocardiographic parameters in a large group of SSc patients. Methods: This prospective study was conducted in 21 centres for SSc in France. Patients without severe pulmonary function abnormalities, severe cardiac disease and known PAH underwent Doppler echocardiography performed by a reference cardiologist. Results: Of the 570 patients evaluated, PAH was suspected in 33 patients and was confirmed in 18 by right heart catheterisation. LV systolic dysfunction was rare (1.4%). LV hypertrophy was found in 22.6%, with LV diastolic dysfunction in 17.7%. These LV abnormalities were influenced by age, gender and blood pressure. We identified a small group of 21 patients with a restrictive mitral flow pattern in the absence of any other cardiopulmonary diseases, suggesting a specific cardiac involvement in SSc. Conclusions: Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.

Baclofen therapy for chronic hiccup.

Chronic hiccup is a rare but potentially severe condition, that can be symptomatic of a variety of diseases, or idiopathic. Many therapeutic interventions have been reported, most often as case reports. Among other drugs, baclofen has been suggested as a therapy for chronic hiccup. In a large series of patients, we have evaluated its therapeutic position. In patients with chronic hiccup, defined as hiccup spell or recurring hiccup attacks lasting more than 7 days, investigation of the upper gastro-oesophageal tract (fibroscopy, manometry, and pH monitoring) was systematically performed. Most patients had tried numerous drugs in the past, without success. Baclofen was used as a first treatment in patients without evidence of any gastro-oesophageal disease (n = 17), and was undertaken only after full treatment of such disease (n = 55) had failed to solve the hiccup problem (n = 20). Baclofen has, therefore, been administered to 37 patients with chronic hiccup (average duration 4.6 yrs). Baclofen produced a long-term complete resolution (18 cases) or a considerable decrease (10 cases) of hiccups in 28 of the 37 patients. There was no significant difference between patients with or without gastro-oesophageal disease. We conclude that so-called idiopathic chronic hiccup often results from gastro-oesophageal abnormalities. Also, if controlled studies confirm our encouraging results, baclofen can be a major element in the treatment of chronic hiccup that is idiopathic, or that cannot be helped by treatment of gastro-oesophageal diseases.

Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls

OBJECTIVE Scleroderma renal crisis (SRC) is a severe manifestation of SSc, whose prognosis remains severe, despite treatment with angiotensin-converting-enzyme inhibitor and dialysis. This study was undertaken to describe SRC characteristics, prognosis and outcome, and evaluate the responsibility of CSs in its occurrence. METHODS Analysis concerned 91 SSc patients with SRC who were compared with 427 non-SRC-SSc patients taken as controls. RESULTS Among the 91 SRC patients, 71 (78.0%) had high blood pressure, 53 (58.2%) hypertensive encephalopathy and 51 (56.0%) thrombotic microangiopathy; 64 (70.3%) had received CSs before or concomitantly with SRC vs 156 (36.5%) non-SRC-SSc patients (P < 0.001). Treated SRC patients also received more prednisone 29.3 (28.4) vs 3.6 (9.9) mg than controls (P < 0.001). SRC clinical outcomes were poor: 49 (53.8%) patients required dialysis, which was definitive for 38. Thirty-seven (40.7%) SRC patients died vs 10.8% of the controls (P < 0.001). Death was most frequent among dialysed patients who never recovered renal function (22 vs 2) and 13 never-dialysed SRC patients died. CONCLUSIONS Although SRC prognosis has improved markedly, SRC remains a severe manifestation of SSc, despite treatment with angiotensin-converting enzyme inhibitor and dialysis. CSs contributed significantly to SRC occurrence.

Development and validation of a scale for mouth handicap in systemic sclerosis: the Mouth Handicap in Systemic Sclerosis scale

Objective: To develop and assess the reliability and construct validity of a scale assessing disability involving the mouth in systemic sclerosis (SSc). Methods: We generated a 34-item provisional scale from mailed responses of patients (n = 74), expert consensus (n = 10) and literature analysis. A total of 71 other SSc patients were recruited. The test–retest reliability was assessed using the intraclass coefficient correlation and divergent validity using the Spearman correlation coefficient. Factor analysis followed by varimax rotation was performed to assess the factorial structure of the scale. Results: The item reduction process retained 12 items with 5 levels of answers (total score range 0–48). The mean total score of the scale was 20.3 (SD 9.7). The test–retest reliability was 0.96. Divergent validity was confirmed for global disability (Health Assessment Questionnaire (HAQ), r = 0.33), hand function (Cochin Hand Function Scale, r = 0.37), inter-incisor distance (r = −0.34), handicap (McMaster-Toronto Arthritis questionnaire (MACTAR), r = 0.24), depression (Hospital Anxiety and Depression (HAD); HADd, r = 0.26) and anxiety (HADa, r = 0.17). Factor analysis extracted 3 factors with eigenvalues of 4.26, 1.76 and 1.47, explaining 63% of the variance. These 3 factors could be clinically characterised. The first factor (5 items) represents handicap induced by the reduction in mouth opening, the second (5 items) handicap induced by sicca syndrome and the third (2 items) aesthetic concerns. Conclusion: We propose a new scale, the Mouth Handicap in Systemic Sclerosis (MHISS) scale, which has excellent reliability and good construct validity, and assesses specifically disability involving the mouth in patients with SSc.

Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome

OBJECTIVE A very low percentage of glycosylated ferritin (<20%) has only been reported in association with adult-onset Stills disease (AOSD), a disease classically associated with hemophagocytic syndrome. We undertook this study to determine whether hemophagocytic syndrome outside the context of AOSD is also associated with a very low percentage of glycosylated ferritin. METHODS From October 2006 to September 2007, the serum level of glycosylated ferritin was determined in all consecutive patients seen in 3 departments and for whom the diagnosis of hemophagocytic syndrome was suspected. The level of glycosylated ferritin in these patients was compared with that in age- and sex-matched controls with a marked inflammatory syndrome not associated with hemophagocytic syndrome. We assessed the value of glycosylated ferritin as a marker for the diagnosis of hemophagocytic syndrome. RESULTS Forty-two patients were included in the study (14 with confirmed hemophagocytic syndrome, 7 with suspected but unconfirmed hemophagocytic syndrome, and 21 controls). The median level (interquartile range [IQR]) of total serum ferritin was significantly higher in patients with confirmed hemophagocytic syndrome (3,344 microg/liter [2,074-7,334]) than in patients with suspected but unconfirmed hemophagocytic syndrome (555 microg/liter [464-1,420]) (P = 0.02) or in controls (451 microg/liter [126-929]) (P < 0.001). The median (IQR) percentage of glycosylated ferritin was significantly lower in patients with confirmed hemophagocytic syndrome (10% [3-14]) than in patients with suspected but unconfirmed hemophagocytic syndrome (40% [36-47]) (P < 0.001) or in controls (36% [26-49]) (P < 0.001). The diagnostic performance of glycosylated ferritin tended to be higher than that of total serum ferritin for the diagnosis of hemophagocytic syndrome (area under the receiver operating characteristic curve [95% confidence interval] 0.97 [0.92-1.00] versus 0.79 [0.59-1.00]; P = 0.10). CONCLUSION These results suggest that glycosylated ferritin may be a helpful marker for the diagnosis of hemophagocytic syndrome.