No immunomodulatory drug has been approved for primary Sjögren's syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 ...receptor in patients with Sjögren's syndrome-related systemic complications.
Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren's syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren's Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician's global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment.
110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of -11.4% (95% credible interval -30.6 to 9.0) (PrToc >Pla=0.14).
Among patients with primary Sjögren's syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo.
NCT01782235.
Objective
Studies assessing the prevalence of anti–RNA polymerase III (anti–RNAP III) antibodies in systemic sclerosis (SSc) have yielded a wide range of results. The aim of the present study was to ...describe a new SSc cohort tested for presence of anti–RNAP III and perform a systematic review and meta‐analysis to assess the prevalence of anti–RNAP III in patients worldwide and the potential factors of variability.
Methods
Seropositivity for anti–RNAP III was evaluated in a French cohort of SSc patients. A systematic review of the literature was carried out in PubMed and EMBase. Meta‐analysis was performed using available data on prevalence, clinical characteristics of SSc patients, and the types of assays used for anti–RNAP III testing.
Results
One hundred thirty‐three French SSc patients were tested for anti–RNAP III, and a prevalence of 6–9% was found in these patients. Thirty studies representing a total population of 8,437 SSc patients were included in the meta‐analysis. Prevalence of anti–RNAP III in this population was highly variable (range 0–41%). The overall pooled prevalence of anti–RNAP III was 11% (95% confidence interval 8–14), but heterogeneity was high among studies (I2 = 93%, P < 0.0001). Geographic factors such as continent or country of study origin partially explained this heterogeneity and correlated with the prevalence. No other baseline SSc characteristics were significantly correlated with the prevalence of anti–RNAP III.
Conclusion
Data on our new cohort and our meta‐analysis of the literature confirmed that anti–RNAP III prevalence in SSc varies among centers. Geographic factors were significantly associated with prevalence, which underscores the probable implication that genetic background and environmental factors play a role. Heterogeneity among studies remained largely unexplained.
Objective
To evaluate the association of ulnar artery occlusion (UAO) assessed using Doppler ultrasound (DUS) with the severity markers of systemic sclerosis (SSc).
Methods
Two hundred four ...unselected patients fulfilling the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria for SSc were included in this cross‐sectional multicenter study. All patients underwent bilateral hand DUS to evaluate the presence of UAO and clinical/paraclinical visceral evaluation according to current guidelines. Univariable and multivariable ordinal regression models were applied, grading the severity of UAO as “no UAO,” “only one UAO,” and “UAO on both hands,” and assessing its association with clinical features of SSc. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.
Results
UAO was found in 76 patients (37.3%) and was bilateral in 49 patients (24%). UAO as an ordinal event was significantly associated with disease duration, history of fingertip ulcers, telangiectasia, higher modified Rodnan skin thickness score (MRSS), worse diffusing capacity for carbon monoxide (DLco) values, higher tricuspid jet velocity, late capillaroscopic pattern, and positivity for anticentromere antibodies (ACAs) (univariable analysis). In the adjusted multivariable ordinal model, UAO was less frequent in women (OR 0.35 95% CI 0.15–0.83, P = 0.017) and in patients receiving steroids (OR 0.24 95% CI 0.09–0.62, P = 0.0034). In multivariable analyses, significant association with UAO was retained for history of fingertip ulcers (OR 2.55 95% CI 1.24–5.21, P = 0.011), higher MRSS (OR 1.65 95% CI 1.06–2.56, P =0.025), lower DLco values (OR 0.85 95% CI 0.78–0.94, P = 0.0015), and ACA positivity (OR 2.89 95% CI 1.36–6.11, P = 0.0056).
Conclusion
UAO may represent a relevant severity marker of vasculopathy in SSc. Its predictive value for the onset of severe vascular manifestations such as pulmonary arterial hypertension, and its association with mortality, remain to be determined in longitudinal studies.
Systemic sclerosis-related interstitial lung disease (SSc-ILD) is the leading cause of death in SSc. In this study, we aimed to describe the baseline severity and evolution of forced vital capacity ...(FVC) and diffusing capacity for carbon monoxide (DLCO) in patients with SSc-ILD and to assess the baseline clinical, biological and high-resolution CT scan (HRCT) predictors of this evolution. Baseline and serial FVC and DLCO were collected in 75 SSc-ILD patients followed during 6.4±4.2 years (n = 557 individual data). FVC and DLCO evolution was modelled using a linear mixed model with random effect. During follow-up, FVC was stable while DLCO significantly decreased (-1.5±0.3%/year (p<0.0001). Baseline NYHA functional class III/IV, extensive SSc-ILD on HRCT and DLCO<80% were associated with a lower baseline FVC. Absence of digital ulcers extensive SSc-ILD, and FVC<80% and were associated with a lower baseline DLCO. Presence or history of digital ulcers and presence of pulmonary hypertension at baseline or during follow-up were associated with a faster decline of DLCO overtime. Neither age, gender, subtype of SSc nor specificity of autoantibodies were associated with baseline severity or outcome of lung function tests. In this SSc-ILD population, FVC was therefore stable while DLCO significantly declined over time. ILD extension was associated with baseline FVC and DLCO but not with their evolution. Presence or history of digital ulcers and pulmonary hypertension were predictors of a faster decline of DLCO over time.
Abstract
Objectives
Onset of primary SS is usually between 40 and 60 years of age, with severe systemic complications in 15% of cases. We sought to determine whether early-onset disease is related to ...a specific phenotype and if it is predictive of a poor outcome.
Methods
Biological and clinical data from 393 patients recruited in the ASSESS cohort, a French multicentre prospective cohort, were compared according to age at diagnosis.
Results
Fifty-five patients had early-onset disease, defined as age ⩽35 years at diagnosis, and presented a significantly higher frequency of salivary gland enlargement (47.2% vs 33.3%, P = 0.045), adenopathy (25.5% vs 11.8%, P = 0.006), purpura (23.6% vs 9.2%, P = 0.002) and renal involvement (16.4% vs 4.4%, P = 0.003). They had a higher frequency of hypergammaglobulinaemia (60.8% vs 26.6%, P < 0.001), RF positivity (41.5% vs 20.2%, P < 0.001), low C3 level (18.9% vs 9.1%, P = 0.032), low C4 level (54.7% vs 40.2%, P = 0.048) and autoantibodies 84.6% with anti-SSA vs 54.4% (P < 0.001) and 57.7% with anti-SSB vs 29.7% (P < 0.001). The change in ESSDAI scores between baseline and the 5-year follow-up was significantly different (P = 0.005) with a trend for worsening in the early-onset group (0.72, P = 0.27) and a significant improvement in the later onset group (−1.27, P < 0.0001).
Conclusion
Early-onset primary SS is associated with a specific phenotype defined by clinical and biological features known to be predictive factors of severe systemic disease. Interestingly, we showed a different evolution of the ESSDAI score depending on the age at disease onset, patients with early-onset disease tending to worsen over time.
Objectives The aims of the present study were to (1) assess clinical features and long-term outcome in anti-Jo1-positive patients with anti-Ro52 antibody; (2) compare characteristics of ...anti-Jo1-positive patients with and without anti-Ro52 antibody; and (3) compare features of anti-Ro52-positive patients with and without anti-Jo1 antibody. Methods The medical records of 89 consecutive anti-Jo1-positive patients with antisynthetase syndrome (ASS) were reviewed; 36 of these patients had coexistent anti-Ro52 antibody. Furthermore, the medical records of 13 consecutive anti-Ro52-positive patients without anti-Jo1 antibody were also reviewed. Results Nine anti-Jo1-positive patients (25%) with anti-Ro-52 antibody achieved remission of ASS, whereas 19 other patients (52.8%) improved and 8 patients (22.2%) worsened their clinical status. Anti-Jo1-positive patients with anti-Ro52 antibody experienced ASS-related complications: interstitial lung disease ( n = 28), esophageal dysfunction ( n = 9), and joint manifestations ( n = 25), including periarticular hydroxyapatite calcifications and erosions of metacarpophalangeal and interphalangeal joints and wrists ( n = 3); 7 anti-Ro52-positive patients (19.4%) had cancer. Anti-Jo1-positive patients with anti-Ro52 antibody, compared with those without, more commonly experienced deterioration of myositis and joint involvement, symptomatic form of ILD, and cancer; they also had decreased survival rate ( P = 0.05). We further found that anti-Ro52-positive patients with anti-Jo1 antibody, compared with those without, were younger and more frequently exhibited ILD with poorer prognosis. Conclusions Our series underlines that the presence of anti-Ro52 antibody is associated with a particular phenotype of ASS, leading to more severe myositis and joint impairment. Moreover, the coexistence of anti-Ro52 antibody seems to be associated with an increased risk of cancer. We therefore suggest that anti-Jo1-positive patients should routinely undergo the search for anti-Ro52 antibody, as this autoantibody appears to impact patients' prognosis.
To determine whether the severity of salivary-gland involvement, assessed using salivary gland ultrasonography SGUS, histological focus score, or the unstimulated whole salivary flow UWSF, was ...associated with the response to rituximab in patients with primary Sjögren's syndrome pSS.
Among the 120 patients with pSS enrolled in the randomised TEARS trial of rituximab versus placebo, 35 underwent either centralised minor salivary-gland biopsy or SGUS at inclusion. The echostructure of each parotid and submandibular gland was graded on a scale of 0 to 4. Histologic minor salivary gland involvement was assessed by the focus score. Among rituximab-treated patients with available data (n = 14), half met the Sjögren's Syndrome Responder Index SSRI-30 definition of a response at week 24.
The SGUS score correlated positively to the focus score r = 0.61 and negatively to the UWSF r = -0.68. The focus score was not correlated to the UWSF. The median total SGUS grade at inclusion was 9 6-11 in responders versus 16 11-16 in non-responders p = 0.04. The proportion of SSRI-30 responders was 0% among patients with SGUS grade 4 and 88% among those with SGUS grade ≤3. Low baseline SGUS scores were associated with sicca-related outcomes improvement, but not with fatigue or biological improvement. Median baseline focus score was 0.3 0.0-1.3 in the responders versus 4.0 2.7-5.3 in the non-responders p = 0.02. Baseline UWSF was not associated with the response rate.
In patients with pSS, the highest SGUS grade or a high histological focus score is associated with absence of a response to a single rituximab course after 6 months. Further studies, including more patients and different treatment strategies, are required to confirm the clinical utility of these potential biomarkers in pSS.
To describe the natural history of ischemic digital ulcers (DU) in systemic sclerosis (SSc).
This single-center, retrospective, longitudinal study identified patients by demographic data, SSc history ...and type, Rodnan score, tobacco use, presence of autoantibodies, ongoing treatment, and DU history.
One hundred three patients were enrolled, 46 with DU history and 57 without; 2 with DU were excluded. The mean duration of followup from the first non-Raynaud SSc symptoms was 12.3 +/- 6.3 years in patients with DU history and 12.1 +/- 7.0 years in patients without. In 43% of cases, first DU occurred within 1 year following first non-Raynaud SSc symptoms, and within 5 years in 73% of cases. In a multivariate analysis, younger patients at occurrence of first non-Raynaud SSc symptoms (HR = 0.77 per each 5 years older, 95% CI 0.66-0.90) with higher Rodnan scores (HR = 1.21 per 5 points, 95% CI 1.05-1.47) experienced earlier DU occurrences, which were delayed by vasodilator therapy (HR = 0.17, 95% CI 0.09-0.32). Patients with shorter durations between first and second DU episodes, particularly with a second episode within 2 years of the first, experienced a higher yearly incidence of DU episodes (0.85 +/- 0.57 and 0.48 +/- 0.26, respectively, if less or more than 2 yrs; p = 0.04). Throughout the duration of followup, the incidence of finger amputation was 1.2% per patient-year in patients with DU history.
Patients who are young at first sign of SSc, with high Rodnan scores and without vasodilator therapy, are at high risk of developing DU. Development of DU typically occurred within 5 years of the first non-Raynaud clinical symptom of SSc in the majority of patients.
Cogan syndrome is mainly treated with steroids. We aimed to determine the place of DMARDs and biologic-targeted treatments.
We conducted a French nationwide retrospective study of patients with Cogan ...syndrome (n=40) and a literature review of cases (n=22) and analyzed the efficacy of disease-modifying anti-rheumatic drugs (DMARDs) and tumor necrosis factor α (TNF-α) antagonists.
We included 62 patients (31 females) (median age 37years range 2–76. At diagnosis, 61 patients (98%) had vestibulo-auditory symptoms, particularly bilateral hearing loss in 41% and deafness in 31%. Ocular signs were present in 57 patients (92%), with interstitial keratitis in 31 (51%). The first-line treatment consisted of steroids alone (n=43; 70%) or associated with other immunosuppressive drugs (n=18; 30%). Overall, 13/43 (30%) and 4/18 (22%) patients with steroids alone and with associated immunosuppressive drugs, respectively (p=0.8), showed vestibulo-auditory response; 32/39 (82%) and 15/19 (79%) ocular response; and 23/28 (82%) and 10/14 (71%) general response. Overall 61 patients had used a total of 126 lines of treatment, consisting of steroids alone (n=51 lines), steroids with DMARDs (n=65) and infliximab (n=10). Vestibulo-auditory response was significantly more frequent with infliximab than DMARDs or steroids alone (80% vs 39% and 35%, respectively), whereas ocular, systemic and acute-phase reactant response rates were similar. Infliximab was the only significant predictor of vestibulo-auditory improvement (odds ratio 20.7 95% confidence interval 1.65; 260, p=0.019).
Infliximab could lead to vestibulo-auditory response in DMARDS and steroid-refractory Cogan syndrome, but prospective studies are necessary.
•Vestibulo-auditory response was similar with DMARDs and steroids alone.•Infliximab could lead to vestibulo-auditory response in DMARDS and steroid-refractory Cogan syndrome.•The 5 and 10-years incidence of relapse increased under steroids and DMARDS, while it stayed stable with infliximab.
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