Characteristics and outcome of ANCA-associated vasculitides induced by anti-thyroid drugs: a multicentre retrospective case-control study.

OBJECTIVE: Data on ANCA-associated vasculitis (AAV) induced by anti-thyroid drugs (ATD) are scarce. We aimed to describe the characteristics and outcome of these patients in comparison to primary AAV. METHODS: We performed a retrospective multicentre study including patients with ATD-induced AAV. We focused on ATD-induced microscopic polyangiitis (MPA) and compared them with primary MPA by matching each case with four controls by gender and year of diagnosis. RESULTS: Forty-five patients with ATD-induced AAV of whom 24 MPA were included. ANCA were positive in 44 patients (98%), including myeloperoxidase (MPO)-ANCA in 21 (47%), proteinase 3 (PR3)-ANCA in six (13%), and double positive MPO- and PR3-ANCA in 15 (33%). Main clinical manifestations were skin involvement (64%), arthralgia (51%) and glomerulonephritis (20%). ATD was discontinued in 98% of cases, allowing vasculitis remission in seven (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in four (11%). ATD were reintroduced in seven cases (16%) without any subsequent relapse. Compared with 96 matched primary MPA, ATD-induced MPA were younger at diagnosis (48 vs 65 years, P < 0.001), had more frequent cutaneous involvement (54 vs 25%, P = 0.007), but less frequent kidney (38 vs 73%, P = 0.02), and a lower risk of relapse (adjusted HR 0.07; 95% CI 0.01, 0.65, P = 0.019). CONCLUSION: ATD-induced AAV were mainly MPA with MPO-ANCA, but double MPO- and PR3-ANCA positivity was frequent. The most common manifestations were skin and musculoskeletal manifestations. ATD-induced MPA were less severe and showed a lower risk of relapse than primary MPA.

Sicca syndrome in systemic sclerosis: a narrative review on a neglected issue.

SSc is an auto-immune disease characterized by life-threatening manifestations such as lung fibrosis or pulmonary arterial hypertension. Symptoms with a detrimental impact on quality of life are also reported and sicca syndrome (xerostomia, xeropthalmia) is present in up to 80% of patients with SSc. Sicca syndrome can occur in the absence of overlap with Sjögren's disease and recent studies highlight that fibrosis of minor and major salivary glands, directly linked to the pathogenesis of SSc, could be a major contributor of xerostomia in SSc. This narrative review provides an overview of the clinical presentation, diagnostic strategies, management and future perspectives on sicca syndrome in patients with SSc.

In-depth characterization of pulmonary arterial hypertension in mixed connective tissue disease: a French national multicentre study.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a leading cause of death in MCTD. We aimed to describe PAH in well-characterized MCTD patients. METHODS: MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, SLE patients with PAH and SSc patients with PAH. Survival rates were estimated by the Kaplan-Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. RESULTS: Thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD) and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1, 5 and 10 years following PAH diagnosis were 83%, 67% and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. CONCLUSION: PAH is a rare and severe complication of MCTD associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as a predictor of mortality in MCTD-PAH.

Heart and systemic sclerosis-findings from a national cohort study.

OBJECTIVES: Heart involvement is one of the leading causes of death in systemic sclerosis (SSc). The prevalence of SSc-related cardiac involvement is poorly known. Our objective was to investigate the prevalence and prognosis burden of different heart diseases in a nationwide cohort of patients with SSc. METHODS: We used data from a multicentric prospective study using the French SSc national database. Focusing on SSc-related cardiac involvement, we aimed to determine its incidence and risk factors. RESULTS: Over the 3528 patients with SSc 312 (10.9%) had SSc-related cardiac involvement at baseline. They tended to have a diffuse SSc subtype more frequently, more severe clinical features, and presented more cardiovascular risk factors. From the 1646 patients available for follow-up analysis, SSc-related cardiac involvement was associated with an increased risk of death. There was no significant difference in overall survival between SSc-related cardiac involvement, ischaemic heart disease or pulmonary arterial hypertension. Regarding survival analysis, 98 patients developed SSc-related cardiac involvement at five years (5-year event rate: 11.15%). Regarding reduced LVEF < 50% and left ventricular diastolic dysfunction, the 5-year event rate was 2.49% and 5.84% respectively. Pericarditis cumulative incidence at five years was 3%. Diffuse SSc subtype was a risk factor for SSc-related cardiac involvement and pericarditis. Female sex was associated with less left ventricular diastolic dysfunction incidence. CONCLUSIONS: Our results describe the incidence and prognostic burden of SSc-related cardiac involvement at a large scale, with gender and diffuse SSc subtype as risk factors. Further analyses should assess the potential impact of treatment on these various cardiac outcomes.

Performance of finger systolic blood pressure measurement to detect digital occlusive arterial disease in systemic sclerosis.

OBJECTIVE: Digital ulcers related to digital occlusive arterial disease (DOAD) are frequent in patients with SSc. Finger systolic blood pressure (FSBP) and digital-brachial pressure index (DBI) using laser Doppler flowmetry constitute a non-invasive means of detecting DOAD in SSc, although thresholds have yet to be established for defining DOAD. The purpose of this study was to ascertain FSBP and DBI thresholds to detect DOAD in SSc patients. The intra/interday reproducibility of curve reading by four vascular physicians in relation to finger pressure measurement was also investigated. METHODS: SSc patients were followed in this single-centre study (Rennes University Hospital, France) between November 2017 and October 2019.These patients underwent tests before and after heating at two visits spaced 10 days apart. DOAD was diagnosed on the basis of post-warming skin blood flow of ≤206 arbitrary units measured by laser Doppler flowmetry, contingent on previous results validated by arteriography as a gold standard. An interday kappa coefficient with a 95% confidence interval was used to assess reproducibility. RESULTS: Sixteen [10 females; mean age: 63 (9) years] SSc patients were included. Mean time interval between visits was 9 (5) days. The best FSBP threshold for DOAD diagnosis was 76 mmHg and DBI was 0.74 after warming. FSBP and DBI sensitivity/specificity were 59.1% (95% CI: 49.6, 68.5%)/92.5% (95% CI: 85.3, 99.6%) and 73.3% (95% CI: 64.9, 81.8%)/83.0% (95% CI: 72.9, 93.1%), respectively. Intra/interday reproducibility ranged from fair to good. CONCLUSION: The conclusions drawn from this study suggest that FSBP ≤ 76 mmHg and DBI ≤ 0.74 thresholds are potentially reliable indicators of DOAD and demonstrate fair to good intra- and interday reproducibility. TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT03264820.

Efficacy and safety of TNF-α antagonists and tocilizumab in Takayasu arteritis: multicentre retrospective study of 209 patients.

OBJECTIVE: To assess the safety and the efficacy of TNF-α antagonists and tocilizumab in patients with Takayasu arteritis (TAK). METHODS: A total of 209 patients with TAK [median age 29 years (interquartile range 7-62)], 186 (89%) females] were included. They received either TNF-α antagonists [n = 132 (63%) with 172 lines; infliximab (n = 109), adalimumab (n = 45), golimumab (n = 8), certolizumab (n = 6) and etanercept (n = 5)] or tocilizumab [n = 77 (37%) with 121 lines; i.v. and s.c. in 95 and 26 cases, respectively]. RESULTS: A complete response at 6 months was evidenced in 101/152 (66%) patients on TNF-α antagonists and 75/107 (70%) patients on tocilizumab. Age ≥30 years [odds ratio 2.09 (95% CI 1.09, 3.99)] was associated with complete response, whereas vascular signs [OR 0.26 (95% CI 0.1, 0.65)], baseline prednisone ≥20 mg/day [OR 0.51 (95% CI 0.28, 0.93)] were negatively associated with the complete response to TNF-α antagonists or tocilizumab. During a median follow-up of 36 months, 103 relapses were noted. Supra-aortic branches and thoracic aorta involvement [HR 2.44 (95% CI 1.06, 5.65) and 3.66 (1.18, 11.4), respectively] and systemic signs at baseline [HR 2.01 (95% CI 1.30, 3.11)] were significantly associated with relapse. The cumulative incidence of treatment discontinuation and relapse were similar in TNF-α antagonists and tocilizumab. Fifty-eight (20%) adverse effects occurred on biologic targeted therapies [37 (21%) on TNF-α antagonists and 21 (17%) on tocilizumab (P = 0.4), respectively]. CONCLUSION: This large multicentre study shows high efficacy of biologic targeted treatments in refractory TAK. Efficacy, relapse and drug retention rate were equivalent with TNF-α antagonists and tocilizumab.

Pharmacist-led medication reconciliation at patient discharge: a tool to reduce healthcare utilization? an observational study in patients 65 years or older.

BACKGROUND: Older patients often experience adverse drug events (ADEs) after discharge that may lead to unplanned readmission. Medication Reconciliation (MR) reduces medication errors that lead to ADEs, but results on healthcare utilization are still controversial. This study aimed to assess the effect of MR at discharge (MRd) provided to patients aged over 65 on their unplanned rehospitalization within 30 days and on both patients' experience of discharge and their knowledge of their medication. METHODS: An observational multicenter prospective study was conducted in 5 hospitals in Brittany, France. RESULTS: Patients who received both MR on admission (MRa) and MRd did not have significantly fewer deaths, unplanned rehospitalizations and/or emergency visits related to ADEs (OR = 1.6 [0.7 to 3.6]) or whatever the cause (p = 0.960) 30 days after discharge than patients receiving MRa alone. However, patients receiving both MRa and MRd were more likely to feel that their discharge from the hospital was well organized (p = 0.003) and reported more frequently that their community pharmacist received information about their hospital stay (p = 0.036). CONCLUSIONS: This study found no effect of MRd on healthcare utilization 30 days after discharge in patients over 65, but the process improved patients' experiences of care continuity. Further studies are needed to better understand this positive impact on their drug care pathway in order to improve patients' ownership of their drugs, which is still insufficient. Improving both the interview step between pharmacist and patient before discharge and the transmission of information from the hospital to primary care professionals is needed to enhance MR effectiveness. TRIAL REGISTRATION: NCT04018781 July 15, 2019.

Sacroiliac joint in sarcoidosis on computed tomography: a monocentric retrospective study (SISTER).

Sacroiliitis and spondyloarthritis (SpA) have been associated to sarcoidosis. Sarcoidosis bone involvement of the sacral or iliac bones has been reported to mimic SpA. We aimed to evaluate the prevalence of structural sacroiliitis and structural changes of the sacroiliac joints (SIJ) in patients with sarcoidosis by abdominal-pelvic computed tomography (AP-CT). In this monocentric retrospective study, three blinded readers evaluated AP-CT that had already been performed on patients with sarcoidosis and classified them as normal, degenerative, or inflammatory. A consensus was reached for the divergent cases. Erosion, ankylosis, and sclerosis, classically associated with sacroiliitis, were noted. SpA was defined according to the ASAS 2009 classification criteria. We identified 217 patients with proven sarcoidosis who underwent AP-CT. Only three patients had sacroiliitis by CT and four had SpA, representing 1.38% and 1.85% of the patients, respectively. Degenerative SIJs represented 28.1% of patients and were significantly associated with age, at least one pregnancy, rural lifestyle, ankylosis, diffuse idiopathic skeletal hyperostosis, sclerosis, and the presence of osteophytes. Four patients had axial bone sarcoidosis. Sacroiliitis, SpA, and degenerative changes of the SIJ have been highlighted by AP-CT in patients with sarcoidosis. Osteoarthritis of the SIJ in sarcoidosis was associated with age, pregnancy, and rural lifestyle. Further studies are needed to assess the link between SpA and sarcoidosis.

A descriptive, retrospective case series of patients with factitious disorder imposed on self.

BACKGROUND: Despite cases of factitious disorder imposed on self being documented in the literature for decades, it appears to remain an under-identified and under-diagnosed problem. The present study aimed to explore factitious disorder imposed on self in a series of French patients. METHODS: Patients 18 years old and over with factitious disorder imposed on self were retrospectively included by two independent reviewers according to DSM-5 criteria in Rennes University Hospital for the period 1995 to 2019. Patients were identified from a clinical data warehouse. RESULTS: 49 patients with factitious disorder imposed on self were included. Among them, 36 (73.5%) were female. The average age at diagnosis was 38.4 years. The 16 patients with a health-related profession were all female. Direct evidence of falsification was found in 20.4% of cases. Falsification was mainly diagnosed on the basis of indirect arguments: history of factitious disorder diagnosed in another hospital (12.2%), extensive use of healthcare services (22.4%), investigations that were normal or inconclusive (69.4%), inconsistent or incomplete anamnesis and/or patient refusal to allow access to outside information sources (20.4%), atypical presentation (59.2%), evocative patient behaviour or comments (32.7%), and/or treatment failure (28.6%). Dermatology and neurology were the most frequently involved specialities (24.5%). Nine patients were hospitalized in intensive care. Some of them received invasive treatments, such as intubations, because of problems that were only reported or feigned. The diagnosis of factitious disorder imposed on self was discussed with the patient in 28 cases (57.1%). None of them admitted to making up the disorder intentionally. Two suicide attempts occurred within 3 months after the discussion of the diagnosis. No deaths were recorded. 44.9% of the patients returned to the same hospital at least once in relation to factitious disorder imposed on self. CONCLUSIONS: The present study reinforces data in favour of a predominance of females among patients with factitious disorder imposed on self. This diagnosis is difficult and is based on a range of arguments. While induced cases can be of low severity, cases that are only feigned can lead to extreme medical interventions, such as intubation.

Hand ultrasound for the diagnosis of scleroderma: a scoring strategy including US items and items from the EULAR/ACR classification.

OBJECTIVES: To evaluate the diagnostic value of hand ultrasound (US) in systemic sclerosis (SSc) and to explore its relevance within a combined diagnostic approach. METHODS: 224 patients with suspected SSc were consecutively included. They all had US evaluation assessing the presence of fibrotic tenosynovitis (fibrotic TS) and ulnar artery occlusion (UAO). The final diagnosis of SSc was based on the clinical evaluation of a board of experts independently of any pre-established classification criteria. RESULTS: 166 patients were finally diagnosed as SSc according to the experts as reference standard. 62 SSc and 8 non-SSc patients had UAO (uni or bilateral) (p=0.001). 23 SSc patients and 1 non-SSc patient had US fibrotic TS (p=0.007). A US SSc-pattern (presence of UAO and/or fibrotic TS) was reported in 73 SSc patients and 9 non-SSc patients (p<0.001). UAO had an area under ROC curve (AUC) for the diagnosis of SSc of 0.618 (95%CI 0.539- 0.697); with Se=0.373 (0.304-0.449) and Sp=0.862 (0.751-0.928). Fibrotic TS had an AUC of 0.561 (0.480-0.643); with Se=0.139 (0.094-0.199) and Sp=0.983 (0.909-0.997). The US-SSc pattern had a AUC of 0.641 (0.563- 0.695), with Se=0.440 (0.367-0.516) and Sp=0.845 (0.731-0.916). A scoring system including these US parameters and items from ACR/EULAR classification criteria had an AUC of 0.979 (0.962-0.996)) and allows the substitution of capillaroscopy by US parameters with similar performances. CONCLUSIONS: The use of hand US parameters may help to refine the diagnostic strategy of SSc and their inclusion in a combined diagnostic approach could be discussed.

Efferocytosis capacities of blood monocyte-derived macrophages in systemic sclerosis.

A defect in the apoptotic cell clearance (efferocytosis) by phagocytic cells may participate in autoimmunity and chronic inflammation. The mechanisms leading to the emergence of autoimmunity in systemic sclerosis (SSc) are still to be determined. In this study, the efferocytosis capacities of blood monocyte-derived macrophages (MDM) from patients with SSc were evaluated. Blood monocytes obtained from patients with SSc and healthy donors (HD) were differentiated in vitro into macrophages. The capacities of MDM to engulf CFSE+ apoptotic Jurkat human T lymphocytes were compared between SSc MDM and HD using flow cytometry. The expression of classical engulfing receptors in SSc MDM and HD MDM was also evaluated and their involvement in the modulation of efferocytosis was confirmed using a siRNA approach. The mean phagocytic index (PI) reflecting efferocytosis capacities of SSc MDM (PI = 19.3 ± 3.0; n = 21) was significantly decreased in comparison with the PI of HD MDM (PI = 35.9 ± 3.0; n = 31; P < 0.001). In comparison with HD, SSc MDM exhibited a downregulated expression of scavenger receptor (SR)-B1, SR-A1 and integrin ß5 (ITGß5). In HD MDM, the extinction of these receptors was followed by a reduction of efferocytosis only for the repression of ITGß5, suggesting a possible selective role of this integrin in the impaired efferocytosis observed in SSc. As efferocytosis may be at the crossroads of inflammation, autoimmunity and fibrosis, in showing impaired efferocytosis capacities of blood MDM in SSc, our study offers new pathogenesis considerations for the involvement of macrophages in the autoimmune processes driving this disorder.

Orbital mass in ANCA-associated vasculitides: data on clinical, biological, radiological and histological presentation, therapeutic management, and outcome from 59 patients.

OBJECTIVE: Orbital mass is a rare and sight-threatening manifestation of ANCA-associated vasculitides, which remains a therapeutic challenge. We aimed to describe the presentation, therapeutic management and outcome of ANCA-associated vasculitides-related orbital mass. METHODS: We conducted a French nationwide retrospective study of patients with orbital mass in the setting of ANCA-associated vasculitides according to ACR criteria and/or Chapel Hill Consensus Conference definitions. RESULTS: Fifty-nine patients [33 women, median age 46 (range 7-90) years] were included. Fifty-six (95%) patients had granulomatosis with polyangiitis, two eosinophilic granulomatosis with polyangiitis and one microscopic polyangiitis. Orbital mass was unilateral in 47 (80%) cases, and seemed to develop from ENT involvement in most cases. Orbital mass biopsy was available in 32 (54%) patients, showing lymphoplasmacytic infiltration in 65%, fibrosis in 55%, granulomas in 48% and vasculitis in 36%. All patients but one received glucocorticoids as first-line therapy associated with immunosuppressive agents in 82%, mainly cyclophosphamide. Response to therapy was noted in 52% of patients treated with cyclophosphamide compared with 91% of those treated with rituximab. Twenty-seven (46%) patients required a second-line therapy because of relapse (59%) or refractory course (41%). Sequelae included visual impairment in 28%, with definitive blindness in 17%. Refractory course was associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis. CONCLUSION: Orbital mass is associated with refractory course and high frequency of sequelae, especially blindness. Refractory course is associated with PR3-ANCA positivity, visual loss and contiguous pachymeningitis.

Six months versus two years of oral anticoagulation after a first episode of unprovoked deep-vein thrombosis. The PADIS-DVT randomized clinical trial.

The optimal duration of anticoagulation after a first episode of unprovoked deep-vein thrombosis is uncertain. We aimed to assess the benefits and risks of an additional 18 months of treatment with warfarin versus placebo, after an initial 6 months of anticoagulation for a first unprovoked proximal deep-vein thrombosis. We conducted a multicenter, randomized, double-blind, controlled trial comparing an additional 18 months of warfarin with placebo in patients with a unprovoked proximal deep-vein thrombosis initially treated for 6 months (treatment period: 18 months; follow up after treatment period: 24 months). The primary outcome was the composite of recurrent venous thromboembolism or major bleeding at 18 months. Secondary outcomes were the composite at 42 months, as well as each component of the composite, and death unrelated to pulmonary embolism or major bleeding, at 18 and 42 months. All outcomes were centrally adjudicated. A total of 104 patients, enrolled between July 2007 and October 2013 were analyzed on an intention-to-treat basis; no patient was lost to follow-up. During the 18-month treatment period, the primary outcome occurred in none of the 50 patients in the warfarin group and in 16 out of 54 patients (cumulative risk, 29.6%) in the placebo group (hazard ratio, 0.03; 95% confidence interval: 0.01 to 0.09; P<0.001). During the entire 42-month study period, the composite outcome occurred in 14 patients (cumulative risk, 36.8%) in the warfarin group and 17 patients (cumulative risk, 31.5%) in the placebo group (hazard ratio, 0.72; 95% confidence interval: 0.35-1.46). In conclusion, after a first unprovoked proximal deep-vein thrombosis initially treated for 6 months, an additional 18 months of warfarin therapy reduced the composite of recurrent venous thrombosis and major bleeding compared to placebo. However, this benefit was not maintained after stopping anticoagulation. Clinical registration: this trial was registered at www.clinicaltrials.gov as #NCT00740493.

Risk factors for recurrent venous thromboembolism after unprovoked pulmonary embolism: the PADIS-PE randomised trial.

We aimed to identify risk factors for recurrent venous thromboembolism (VTE) after unprovoked pulmonary embolism.Analyses were based on the double-blind randomised PADIS-PE trial, which included 371 patients with a first unprovoked pulmonary embolism initially treated during 6 months who were randomised to receive an additional 18 months of warfarin or placebo and followed up for 2 years after study treatment discontinuation. All patients had ventilation/perfusion lung scan at inclusion (i.e. at 6 months of anticoagulation).During a median follow-up of 41 months, recurrent VTE occurred in 67 out of 371 patients (6.8 events per 100 person-years). In main multivariate analysis, the hazard ratio for recurrence was 3.65 (95% CI 1.33-9.99) for age 50-65 years, 4.70 (95% CI 1.78-12.40) for age >65 years, 2.06 (95% CI 1.14-3.72) for patients with pulmonary vascular obstruction index (PVOI) ≥5% at 6 months and 2.38 (95% CI 1.15-4.89) for patients with antiphospholipid antibodies. When considering that PVOI at 6 months would not be available in practice, PVOI ≥40% at pulmonary embolism diagnosis (present in 40% of patients) was also associated with a 2-fold increased risk of recurrence.After a first unprovoked pulmonary embolism, age, PVOI at pulmonary embolism diagnosis or after 6 months of anticoagulation and antiphospholipid antibodies were found to be independent predictors for recurrence.

Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients.

OBJECTIVES: To assess the efficacy of tocilizumab in patients with Takayasu arteritis (TA). METHODS: We conducted a retrospective multicenter study in 46 TA patients treated with tocilizumab. We analyzed factors associated with response to tocilizumab (assessed using NIH score). RESULTS: Forty-six patients with TA were included, with a median age of 43 years [29-54], and 35 (76%) females. We observed a decrease in the median NIH scale (from 3 [2-3] at baseline to 0 [0-1] and 0 at 3 and 6 months, respectively; p < 0.0001). The daily prednisone dose also decreased from 15 mg [8-19] at baseline to 4 mg [5-21] and 5 mg [4.5-9] at 3 and 6 months, respectively (p < 0.0001) under tocilizumab. The overall tocilizumab failure free survival was 81% [CI 95%; 0.7-0.95], 72% [CI 95%; 0.55-0.95] and 48% [CI 95%; 0.2-0.1] at 12, 24 and 48 months, respectively. The presence of constitutional symptoms (HR 5.6 [CI 95%; 1.08-29], p = 0.041), and C-reactive protein level (HR 1.16 [CI 95%; 1.01-1.31], P = 0.003) at the time of tocilizumab initiation were significantly associated with tocilizumab event-free survival. The event-free survival was significantly better under tocilizumab therapy in comparison to DMARDs (p = 0.02). CONCLUSION: This large multicenter study shows that tocilizumab is efficient and may reduce the incidence of relapses in TA.

Synovial involvement assessed by power Doppler ultra-sonography in systemic sclerosis: results of a cross-sectional study.

Objectives: To characterize hand synovial manifestations assessed by power Doppler ultrasonography (PDUS) in a cohort of unselected patients fulfilling the 2013 ACR/EULAR classification criteria for SSc and to evaluate the associations of these synovial manifestations with the main general clinical and biological features of SSc. Methods: One hundred and three SSc patients were consecutively included and underwent PDUS evaluation of both hands assessing synovial and tenosynovial manifestations according to the OMERACT definitions. Clinical, biological and immunological SSc characteristics were recorded at the same time. Results: Thirty-three patients (32%) had ultrasonographic synovial/tenosynovial involvement. The two main PDUS features were Doppler-positive/inflammatory synovitis (n = 18, 17.5%) and sclerosing tenosynovitis (TS) (n = 19, 18.4%). Inflammatory synovitis was more frequent in the wrist and MCP joints. Sclerosing TS was more frequent in men [odds ratio (OR) = 6.32, 95% CI: 2.17, 18.41; P = 0.001] and was associated with anti-RNA polymerase III antibodies (OR = 10.93, 95% CI: 1.84, 65.12; P = 0.01), diffuse SSc (OR = 18.24, 95% CI: 4.80, 69.32; P < 0.0001), interstitial lung disease (OR = 6.09, 95% CI: 1.86, 19.98; P = 0.001) and inflammatory arthralgia (OR = 14.64, 95% CI: 2.58, 83.10; P = 0.002). Inflammatory TS or synovitis were associated with CRP levels >5 mg/l (OR = 5.50, 95% CI: 1.81, 16.70; P = 0.001), pericarditis (OR = 7.81, 95% CI: 1.58, 38.71; P = 0.017) and inflammatory arthralgia (OR = 15.96, 95% CI: 2.80, 91.02; P = 0.002). Inflammatory synovitis and sclerosing TS were not significantly associated within an individual patient (OR = 2.77, 95% CI: 0.88, 8.70; P > 0.05). Conclusions: Ultrasonographic synovial involvement is frequent in patients fulfilling the 2013 ACR/EULAR classification criteria and PDUS may have a part to play in a more accurate and precise description of musculoskeletal manifestations of the disease, especially as the question of a treat-to-target approach is arising for SSc.

Distinct Properties of Human M-CSF and GM-CSF Monocyte-Derived Macrophages to Simulate Pathological Lung Conditions In Vitro: Application to Systemic and Inflammatory Disorders with Pulmonary Involvement.

Macrophages play a central role in the pathogenesis of inflammatory and fibrotic lung diseases. However, alveolar macrophages (AM) are poorly available in humans to perform in vitro studies due to a limited access to broncho-alveolar lavage (BAL). In this study, to identify the best alternative in vitro model for human AM, we compared the phenotype of AM obtained from BAL of patients suffering from three lung diseases (lung cancers, sarcoidosis and Systemic Sclerosis (SSc)-associated interstitial lung disease) to human blood monocyte-derived macrophages (MDMs) differentiated with M-CSF or GM-CSF. The expression of eight membrane markers was evaluated by flow cytometry. Globally, AM phenotype was closer to GM-CSF MDMs. However, the expression levels of CD163, CD169, CD204, CD64 and CD36 were significantly higher in SSc-ILD than in lung cancers. Considering the expression of CD204 and CD36, the phenotype of SSc-AM was closer to MDMs, from healthy donors or SSc patients, differentiated by M-CSF rather than GM-CSF. The comparative secretion of IL-6 by SSc-MDMs and SSc-AM is concordant with these phenotypic considerations. Altogether, these results support the M-CSF MDM model as a relevant in vitro alternative to simulate AM in fibrotic disorders such as SSc.

Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study.

OBJECTIVE: To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc). METHODS: Randomised, placebo-controlled study in patients with SSc to assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05). RESULTS: Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12). CONCLUSIONS: The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit. TRIAL REGISTRATION NUMBER: NCT01295736.