Objective
To study the role of B lymphocytes in systemic sclerosis (SSc).
Methods
Peripheral B cell subpopulations and the production of interleukin‐6 (IL‐6) and transforming growth factor β (TGFβ) ...were analyzed using flow cytometry and multiplex assay. The fibroblast proliferation rate upon incubation with supernatants from B cells isolated from SSc patients or healthy controls was assessed using XTT, bromodeoxyuridine, and Ki‐67. Collagen production was assessed using a collagen assay.
Results
Ninety untreated patients (12 males) fulfilling the American College of Rheumatology/European League Against Rheumatism criteria for SSc (23 with diffuse cutaneous SSc dcSSc and 67 with limited cutaneous SSc lcSSc) and 30 healthy controls were recruited. Increased proportions of B cells expressing CD69 and CD95 were identified among the patients with SSc. B lymphocytes from dcSSc patients versus lcSSc patients and healthy controls expressed increased proportion of cells positive for CD5 (mean ± SD 24.12 ± 7.93% versus 14.09 ± 6.58% P = 0.03 and 14.21 ± 5.34% P = 0.01), CD86 (39.89 ± 22.11% versus 17.72 ± 13.98% P = 0.0007 and 11.68 ± 11.09% P < 0.001), IL‐6 receptor (IL‐6R; 33.64 ± 23.12% versus 17.91 ± 13.62% P < 0.0001 and 12.08 ± 8.68% P = 0.0009), or IL‐21R (32.55 ± 20.19% versus 5.76 ± 4.40% P < 0.0001 and 5.93 ± 3.29% P < 0.0001). In addition, the levels of IL‐6 (mean ± SD 314.3 ± 317.8 pg/ml versus 6.10 ± 2.58 pg/ml; P = 0.0007) and TGFβ (mean ± SD 1,020 ± 569 pg/ml versus 163.8 ± 98.69 pg/ml; P = 0.001) secreted by B lymphocytes from patients with SSc were increased compared to healthy controls. Fibroblast proliferation and collagen production were also significantly increased in the presence of B cell supernatant from SSc patients as compared to healthy controls.
Conclusion
The numbers of activated B cells were increased in SSc patients, and the up‐regulation of CD5, CD86, IL‐6R, and IL‐21R discriminated between patients with dcSSc and those with lcSSc. Peripheral B lymphocytes from SSc patients secreted both IL‐6 and TGFβ, and they activated fibroblasts in vitro.
Ischemic digital ulcers (DU) are frequent and severe complications of systemic sclerosis (SSc). The purpose of our study was to assess the effect of DU on hand disability and pain in patients with ...SSc.
The Evaluation of the Impact of Recurrent Ischemic DU on Hand Disability in Patients with SSc (ECLIPSE) is a prospective, multicenter, noninterventional study with a 2-year followup. Patients with SSc who experienced at least 1 DU in the previous year and received bosentan therapy were included between October 2009 and March 2011. This cohort is described at the time of inclusion.
There were 190 patients (132 females) from 53 centers. Mean age ± SD was 43 ± 15 years at SSc diagnosis and 53 ± 15 years at inclusion. In 105 patients (56.2%), DU were the first non-Raynaud symptoms of SSc. The mean time interval between the occurrence of Raynaud phenomenon and the first DU episode was 6.6 ± 9.1 years. The mean numbers of active DU and fingers affected per patient for both hands were 2.3 ± 1.8 and 2.2 ± 1.6, respectively. Presence of active DU at inclusion was significantly associated with pain and impaired hand function: Visual Analog Scale for pain (0 to 10) was 6.2 ± 2.6 versus 2.5 ± 2.4 (p < 0.0001) and Cochin Hand Function Scale for hand disability (0 to 90) was 38 ± 20 versus 25 ± 19 (p < 0.0001), respectively.
DU represent a major sign of SSc, often affecting multiple fingers and both hands. They are significantly associated with pain and hand disability.
Scleroderma renal crisis (SRC) is a major complication in patients with systemic sclerosis (SSc). It is characterized by malignant hypertension and oligo/anuric acute renal failure. SRC occurs in 5% ...of patients with SSc, particularly in the first years of disease evolution and in the diffuse form. The occurrence of SRC is more common in patients treated with glucocorticoids, the risk increasing with increasing dose. Left ventricular insufficiency and hypertensive encephalopathy are typical clinical features. Thrombotic microangiopathy is detected in 43% of the cases. Anti-RNA-polymerase III antibodies are present in one third of patients who develop SRC. Renal biopsy is not necessary if SRC presents with classical features. However, it can help to define prognosis and guide treatment in atypical forms. The prognosis of SRC has dramatically improved with the introduction of angiotensin-converting enzyme inhibitors (ACEi). However, 5 years survival in SSc patients who develop the full picture of SRC remains low (65%). SRC is often triggered by nephrotoxic drugs and/or intravascular volume depletion. The treatment of SRC relies on aggressive control of blood pressure with ACEi, if needed in combination with other types of antihypertensive drugs. Dialysis is frequently indicated, but can be stopped in approximately half of patients, mainly in those for whom a perfect control of blood pressure is obtained. Patients who need dialysis for more than 2 years qualify for renal transplantation.
Patients with systemic sclerosis (SSc) are prone to disease-specific or treatment-related life-threatening complications that may warrant intensive care unit (ICU) admission. We assessed the ...characteristics and current outcome of patients with SSc admitted to the ICU.
We performed a single-center retrospective study over 6 years (November 2006-December 2012). All patients with SSc admitted to the ICU were enrolled. Short-term (in-ICU and in-hospital) and longterm (6-mo and 1-yr) mortality rates were studied, and the prognostic factors were analyzed.
Forty-one patients with a median age of 50 years interquartile range (IQR) 40-65 were included. Twenty-nine patients (72.5%) displayed diffuse cutaneous SSc. The time from diagnosis to ICU admission was 78 months (IQR 34-128). Twenty-eight patients (71.7%) previously had pulmonary fibrosis, and 12 (31.5%) had pulmonary hypertension. The main reason for ICU admission was acute respiratory failure in 27 patients (65.8%). Noninvasive ventilation was first attempted in 13 patients (31.7%) and was successful in 8 of them, whereas others required endotracheal intubation within 24 h. Altogether, 13 patients (31.7%) required endotracheal intubation and mechanical ventilation. The overall in-ICU, in-hospital, 6-month, and 1-year mortality rates were 31.8%, 39.0%, 46.4%, and 61.0%, respectively. Invasive mechanical ventilation was the worst prognostic factor, associated with an in-hospital mortality rate of 84.6%.
This study provides reliable prognostic data in patients with SSc who required ICU admission. The devastating outcome of invasive mechanical ventilation in patients with SSc requires a reappraisal of indications for ICU admission and early identification of patients likely to benefit from noninvasive ventilation.
Summary Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc) mainly encountered in patients with diffuse disease. Unlike idiopathic interstitial pneumonias (IIP), SSc ...associated ILD corresponds to non-specific interstitial pneumonia (NSIP) in most cases, whereas usual interstitial pneumonia (UIP) is encountered less frequently. This explains the better prognosis of SSc associated ILD compared to IIP. However, severe restrictive lung disease represents one of the two main causes of disease-related death in SSc patients. The treatment of SSc associated ILD is not very well established. Anti-fibrosing treatments have failed to demonstrate any benefit and cyclophosphamide, which has been used in the treatment of this condition for about 15 years, has recently been evaluated in two prospective randomised studies which showed a significant but modest effect on respiratory function. Since none of the patients included in retrospective or prospective studies were selected on the basis of progression of ILD, and since only a minority of SSc patients develop severe ILD, further studies should focus on the subgroup of SSc patients with worsening ILD. A subgroup of patients with rapidly progressive ILD might benefit from pulsed intravenous cyclophosphamide combined with prednisone 15 mg daily but this remains to be confirmed.
Scleroderma renal crisis (SRC) is characterized by malignant hypertension, oliguric/anuric acute renal failure, and important mortality, with a 5-year survival rate of 65%. SRC occurs in 2% to 5% of ...patients with systemic sclerosis (SSc), particularly those with diffuse cutaneous SSc in the first years of disease evolution. Several retrospective studies have found high-dose corticosteroid therapy to be associated with increased risk of SRC, and anti-RNA-polymerase III antibodies have been detected in one third of patients with SRC. Treatment relies on the early control of blood pressure with increasing doses of angiotensin-converting enzyme inhibitors, eventually associated with calcium channel blockers together with dialysis if necessary. After 2 years on dialysis, eligible patients should be considered for renal transplantation. The strategy for prevention of SRC lacks consensus. However, corticosteroids and/or nephrotoxic drugs should be avoided in patients with diffuse cutaneous SSc.
To assess changes over time and responsiveness of the Cochin Hand Function Scale (CHFS) and Mouth Handicap In Systemic Sclerosis (MHISS) scale in patients with systemic sclerosis (SSc).
This was a ...prospective longitudinal study.
Participants were drawn from a convenience sample of individuals with SSc, who were attending the annual Congress of the Association des Sclérodermiques de France, the French SSc patients' association.
Participants were evaluated twice by the CHFS, MHISS scale, Health Assessment Questionnaire, McMaster-Toronto Arthritis Patient Preference Disability Questionnaire, and other outcome measures. Differences in measures over time were evaluated using the Wilcoxon signed rank test. Responsiveness was assessed by the effect size and standardized response mean. Nonparametric Spearman rank correlation (r) was used to assess correlation between outcome measures.
Forty-nine patients were assessed. The CHFS and MHISS scores worsened over time (mean SD differences 2.7 10.7, P = 0.08, and 3.5 9.8, P = 0.14, respectively). The CHFS effect size and standardized response mean values were -0.16 and -0.24, respectively, and MHISS values were -0.53 and -0.52, respectively. The correlation between change in the CHFS score and change in Health Assessment Questionnaire and McMaster-Toronto Arthritis Patient Preference Disability Questionnaire scores was fair to moderate, whereas changes in MHISS score were poorly or not correlated to other measures. For patients considering their state deteriorated, the MHISS scale was the most responsive instrument.
The CHFS and MHISS scores may be useful in detecting changes in location-specific limitations in activity for SSc patients.
Objective:
To explore pharmacokinetic/pharmacodynamic relationship between mycophenolic acid area under the curve and clinical response at 1 year on skin involvement or interstitial lung disease in ...patients with systemic sclerosis.
Method:
Retrospective, monocentric study based on French Scleroderma Database in patients receiving mycophenolate mofetil who experienced a limited sampling strategy to estimate individual mycophenolic acid area under the curve plus two pulmonary function tests and skin evaluation after 1 month and 1 year. Efficacy criterions were variations of modified Rodnan skin score, forced vital capacity, and diffusing lung capacity for carbon monoxide at 1 year.
Results:
We included 52 patients; mean age was 49 years (range 17–79), and 36 (69%) were females. Fifty patients (96%) had skin sclerosis, 39 (75%) had diffuse skin involvement with a median modified Rodnan skin score of 14 (0–38). Thirty-eight (76%) had interstitial lung disease, with median forced vital capacity and diffusing lung capacity for carbon monoxide of 81% (37–127) and 56% (28–103) from predicted values, respectively. Twenty-five (51%) patients had pulmonary fibrosis. Mycophenolate mofetil was given for 10 months (0–173) at a median dose of 2000 mg/day (500–3000). In the entire population, no relationship was found between area under the curve and modified Rodnan skin score (p = 0.085), forced vital capacity (p = 0.80), or diffusing lung capacity for carbon monoxide (p = 0.72) variations at 1 year.
Conclusion:
In this retrospective study, we failed to document any relationship between mycophenolic acid area under the curve and skin involvement or interstitial lung disease evolution. Routine monitoring of mycophenolic acid in systemic sclerosis patients treated with mycophenolate mofetil cannot be recommended based on our results.
Objectives To report a patient with systemic ANCA-associated vasculitis, under maintenance treatment, who had persistent microscopic hematuria and developed recurrent pelvic pain due to ...Corynebacterium urealyticum encrusting cystitis. The relevant literature on this infection is reviewed. Methods Descriptive case report and a review of the literature (PubMed search). Results A 39-year-old woman on maintenance therapy for systemic ANCA-associated vasculitis, diagnosed 10 months earlier and with persistent microscopic hematuria, developed recurrent pelvic pain. She had received several immunosuppressants (including cyclophosphamide and rituximab) since the onset of her vasculitis, as well as cycles of broad-spectrum antibiotics during the acute initial phase of her disease. Computerized tomography of the pelvis and cystoscopy showed several encrusted calcifications in the bladder mucosa, and, finally, urine culture (selective media) led to the diagnosis of C. urealyticum infection. Most of the bladder-encrusted stones were removed during cystoscopy and daily intramuscular teicoplanin injections were given for 14 days. Her symptoms disappeared rapidly and completely. On reviewing the literature, immunosuppression, previous broad-spectrum antibiotics, urogenital alkaline pH, and prolonged bladder catheterization are predisposing factors for this rare infection. C. urealyticum encrusting cystitis has been reported in patients with systemic diseases but not yet in ANCA-associated vasculitis. Outcome is almost always good under adequate antibiotic therapy, mainly glycopeptides. Conclusion Physicians should be aware of this unusual but potentially emerging infectious complication that can be challenging in ANCA-associated vasculitis, because the urinary tract can be affected by the vasculitis or as a complication of previous cyclophosphamide therapy.
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