Assessment of calcinosis in Portuguese patients with systemic sclerosis - a multicenter study.

INTRODUCTION/OBJECTIVES: The study aims to define the clinical and subclinical calcinosis prevalence, the sensitivity of radiographed site and clinical method for its diagnosis, and the phenotype of Portuguese systemic sclerosis (SSc) patients with calcinosis. METHOD: A cross-sectional multicenter study was conducted with SSc patients fulfilling Leroy/Medsger 2001 or ACR/EULAR 2013 classification criteria, registered in the Reuma.pt. Calcinosis was assessed through clinical examination and radiographs of hands, elbows, knees, and feet. Independent parametric or non-parametric tests, multivariate logistic regression, and sensitivity calculation of radiographed site and clinical method for calcinosis detection were performed. RESULTS: We included 226 patients. Clinical calcinosis was described in 63 (28.1%) and radiological calcinosis in 91 (40.3%) patients, of which 37 (40.7%) were subclinical. The most sensitive location to detect calcinosis was the hand (74.7%). Sensitivity of the clinical method was 58.2%. Calcinosis patients were more often female (p = 0.008) and older (p < 0.001) and had more frequently longer disease duration (p < 0.001), limited SSc (p = 0.017), telangiectasia (p = 0.039), digital ulcers (p = 0.001), esophageal (p < 0.001) and intestinal (p = 0.003) involvements, osteoporosis (p = 0.028), and late capillaroscopic pattern (p < 0.001). In multivariate analysis, digital ulcers (OR 2.63, 95% CI 1.02-6.78, p = 0.045) predicted overall calcinosis, esophageal involvement (OR 3.52, 95% CI 1.28-9.67, p = 0.015) and osteoporosis (OR 4.1, 95% CI 1.2-14.2, p = 0.027) predicted hand calcinosis, and late capillaroscopic pattern (OR 7.6, 95% CI 1.7-34.9, p = 0.009) predicted knee calcinosis. Anti-nuclear antibody positivity was associated with less knee calcinosis (OR 0.021, 95% CI 0.001-0477, p = 0.015). CONCLUSIONS: Subclinical calcinosis high prevalence suggests that calcinosis is underdiagnosed and radiographic screening might be relevant. Multifactorial pathogenesis may explain calcinosis predictors' variability. Key Points • Prevalence of subclinical calcinosis in SSc patients is substantial. • Hand radiographs are more sensitive to detect calcinosis than other locations or clinical method. • Digital ulcers were associated with overall calcinosis, esophageal involvement and osteoporosis were associated with hand calcinosis, and late sclerodermic pattern in nailfold capillaroscopy was associated with knee calcinosis. • Anti-nuclear antibody positivity may be a protective factor for knee calcinosis.

Added value of lymphocyte subpopulations in the classification of Sjögren's syndrome.

Sjögren's Syndrome (SjS) is a chronic systemic immune-mediated inflammatory disease characterized by lymphocytic infiltration and consequent lesion of exocrine glands. SjS diagnosis and classification remains a challenge, especially at SjS onset, when patients may have milder phenotypes of the disease or uncommon presentations. New biomarkers are needed for the classification of SjS, thus, we aimed to evaluate the added-value of lymphocyte subpopulations in discriminating SjS and non-Sjögren Sicca patients. Lymphocyte subsets from 62 SjS and 63 Sicca patients were characterized by flow cytometry. The 2002 AECG and the 2016 ACR/EULAR SjS classification criteria were compared with clinical diagnosis. The added discriminative ability of joining lymphocytic populations to classification criteria was assessed by the area under the Receiver-Operating-Characteristic Curve (AUC). Considering clinical diagnosis as the gold-standard, we obtained an AUC = 0.952 (95% CI: 0.916-0.989) for AECG and an AUC = 0.921 (95% CI: 0.875-0.966) for ACR/EULAR criteria. Adding Tfh and Bm1 subsets to AECG criteria, performance increased, attaining an AUC = 0.985 (95% CI: 0.968-1.000) (p = 0.021). Th1/Breg-like CD24hiCD27+ and switched-memory B-cells maximized the AUC of ACR/EULAR criteria to 0.953 (95% CI: 0.916-0.990) (p = 0.043). Our exploratory study supports the potential use of lymphocyte subpopulations, such as unswitched memory B cells, to improve the performance of classification criteria, since their discriminative ability increases when specific subsets are added to the criteria.

Systemic sclerosis and rheumatoid arthritis overlap syndrome - management of severe cardiac, pulmonary and articular involvement.

Introduction: The presence of another rheumatological condition in patients with systemic sclerosis (SSc) is not uncommon. To report a case of a patient with SSc-RA overlap and perform a review of the cases reported in the literature. Material and methods: A chart review of the present case report was performed. After, we performed a literature search in MEDLINE, EMBASE and Cochrane databases. Results: We included 26 articles. Sixty-three patients were reviewed, 51 were female with a mean age of 45.03 years at the time of the first diagnosis. Sixty-three patients were diagnosed with limited cutaneous SSc. Regarding organ involvement, the most frequently reported were cutaneous, vascular, pulmonary and gastrointestinal involvement. Erosions were presenting 65.08% of patients. A panoply of treatments was used. Conclusions: The authors concluded that screening for an associated disease should be encouraged since the overlap with SSc may affect prognosis and treatment.

Risk Factors for Infection, Predictors of Severe Disease, and Antibody Response to COVID-19 in Patients With Inflammatory Rheumatic Diseases in Portugal-A Multicenter, Nationwide Study.

Objective: To identify risk factors for SARS-CoV-2 infection and for severe/critical COVID-19, and to assess the humoral response after COVID-19 in these patients. Methods: Nationwide study of adult patients with inflammatory RMDs prospectively followed in the Rheumatic Diseases Portuguese Register-Reuma.pt-during the first 6 months of the pandemic. We compared patients with COVID-19 with those who did not develop the disease and patients with mild/moderate disease with those exhibiting severe/critical COVID-19. IgG antibodies against SARS-CoV-2 were measured ≥3 months after infection and results were compared with matched controls. Results: 162 cases of COVID-19 were registered in a total of 6,363 appointments. Patients treated with TNF inhibitors (TNFi; OR = 0.160, 95% CI 0.099-0.260, P < 0.001) and tocilizumab (OR 0.147, 95% CI 0.053-0.408, P < 0.001) had reduced odds of infection. Further, TNFi tended to be protective of severe and critical disease. Older age, major comorbidities, and rituximab were associated with an increased risk of infection and worse prognosis. Most patients with inflammatory RMDs (86.2%) developed a robust antibody response. Seroconversion was associated with symptomatic disease (OR 13.46, 95% CI 2.21-81.85, P = 0.005) and tended to be blunted by TNFi (OR 0.17, 95% CI 0.03-1.05; P = 0.057). Conclusions: TNFi and tocilizumab reduced the risk of infection by SARS-CoV-2. Treatment with TNFi also tended to reduce rates of severe disease and seroconversion. Older age, general comorbidities and rituximab were associated with increased risk for infection and worse prognosis, in line with previous reports. Most patients with RMDs developed a proper antibody response after COVID-19, particularly if they had symptomatic disease.

Eosinophilic fasciitis (Shulman disease) with clinical, imaging and pathological correlation.

Eosinophilic fasciitis (EF) is a rare subacute fibrosing disorder of unknown aetiology, characterised by thickening of the muscular fascia and subcutaneous tissue, leading to swelling of limbs and trunk and sparing fingers and toes. Eosinophilic infiltration and degranulation may prompt tissue damage and consequent fibrosis due to the accumulation of collagen and extracellular matrix proteins. MRI is the best imaging modality for diagnosis, depicting fascial thickening and enhancement. MRI may also have a significant role in excluding alternative diagnosis and guiding the skin-muscle biopsy.We report a case of EF with clinical and pathological correlation, highlighting the diagnostic value of MRI for early diagnosis and further treatment.

Lymphocyte subpopulations in Sjögren's syndrome are distinct in anti-SSA-positive patients and related to disease activity.

OBJECTIVES: Sjögren's syndrome (SjS) patients exhibit great phenotypical heterogeneity, reinforced by the positiveness of anti-SSA antibody. We aimed to evaluate lymphocyte subpopulations in SSA-positive (SSA+SjS) and SSA-negative (SSA-SjS) SjS patients, Sicca patients, and healthy controls (HC), and to investigate associations between lymphocyte subpopulations and disease activity in SjS. METHODS: According to the fulfilment of the ACR/EULAR 2016 classification criteria, patients were included as SjS or as Sicca. HC were selected from the Ophthalmology outpatient clinic. Lymphocyte subpopulations were characterized by flow cytometry. Statistical analysis was performed with GraphPad PrismTM, with statistical significance concluded if p < 0.05. RESULTS: We included 53 SjS patients (38 SSA+ and 15 SSA-), 72 Sicca, and 24 HC. SSA+SjS patients presented increased IL-21+CD4+ and CD8+ T cells compared to Sicca and HC, whereas compared to SSA-SjS patients, only IL-21+CD4+ T cell percentages were increased and Tfh17 percentages and numbers were decreased. Compared to Sicca and HC, SSA+SjS patients had higher levels of CD24HiCD38Hi B cells, naïve B cells, and IgM-/+CD38++ plasmablasts, and lower levels of memory B cells, including CD24HiCD27+ B cells. SSA+SjS patients with clinically active disease had positive correlations between ESSDAI and IL-21+CD4+ (p = 0.038, r = 0.456) and IL-21+CD8+ T cells (p = 0.046, r = 0.451). CONCLUSIONS: In SjS, a distinct lymphocyte subset distribution profile seems to be associated with positive anti-SSA. Moreover, the association between ESSDAI and IL-21+CD4+ and IL-21+CD8+ (follicular) T cells in SSA+SjS patients suggests the involvement of these cells in disease pathogenesis and activity, and possibly their utility for the prognosis and assessment of response to therapy. Key Points • SSA+SjS patients have a pronounced naïve/memory B cell imbalance. • SSA+SjS patients have more active disease associated with IL-21+CD4+ and IL-21+CD8+ follicular T cell expansion. • IL-21+CD4+ and IL-21+CD8+ T cell quantification may be useful for the prognosis and assessment of response to therapy.

Safety and Effectiveness of Biologic Disease-Modifying Antirheumatic Drugs in Older Patients with Rheumatoid Arthritis: A Prospective Cohort Study.

BACKGROUND AND OBJECTIVE: The number of older patients with rheumatoid arthritis is increasing, but data on drug effectiveness and safety in these patients are scarce. This study assessed the effectiveness and safety of biologic disease-modifying antirheumatic drugs in older patients with rheumatoid arthritis. METHODS: This prospective cohort study was based on data recorded in the Rheumatic Diseases Portuguese Register (Reuma.pt). Treatment persistence, European League Against Rheumatism response at 6 and 12 months, and adverse events were compared between adult (age < 65 years), old (age 65-74 years), and very old (age ≥ 75 years) patients. RESULTS: In total, 2401 patients were included, of which 379 were old and 83 were very old. Older patients had higher disease activity at baseline (Disease Activity Score 28: 5.5 in adults, 5.7 in old patients, and 6 in very old patients; p = 0.02) and more comorbidities, with patients aged 65-74 years beginning biologic disease-modifying antirheumatic drugs later in the course of rheumatoid arthritis. Treatment persistence was similar in the three patient groups (p = 0.07). The European League Against Rheumatism response rates were comparable in the three groups at 6 months (81.6% of adults, 75.2% of old patients, and 81.8% of very old patients; p = 0.19), and inferior in old patients at 12 months. The proportion of patients who experienced adverse events was also similar in the three groups (21% of adults, 22.5% of old patients, and 22.9% of very old patients; p = 0.76), but the rate of serious adverse events was higher in old patients (1.94/100 patient-years) and very old patients (4.29/100 patient-years) compared with 1.03/100 patient-years in adult patients with rheumatoid arthritis (p < 0.05). CONCLUSIONS: Adults, old patients, and very old patients with rheumatoid arthritis benefit similarly from biologic disease-modifying antirheumatic drug treatments, although older patients have more active disease at baseline and more comorbidities. However, it is necessary to consider the risk of serious adverse events in older patients when prescribing a biologic.

Effectiveness of switching between TNF inhibitors in patients with axial spondyloarthritis: is the reason to switch relevant?

BACKGROUND: To investigate whether the reason to discontinue the first TNF inhibitor (TNFi) affects the response to the second TNFi in axial spondyloarthritis (axSpA). METHODS: Patients with axSpA from the Rheumatic Diseases Portuguese Register (ReumaPt), who discontinued their first TNFi and started the second TNFi between June 2008 and May 2018, were included. Response was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement (ASDAS-CII), major important improvement (ASDAS-MI), low disease activity (ASDAS-LDA), and inactive disease (ASDAS-ID). The reason for discontinuation of the first TNFi was defined, according to ASDAS-CII as primary failure (no response ≤ 6 months), secondary failure (response ≤ 6 months but lost thereafter), adverse events, and others. The association between the reason for discontinuation of the first TNFi and response to the second TNFi over time was assessed in multivariable generalized equation (GEE) models. RESULTS: In total, 193 patients were included. The reason for discontinuation of the first TNFi did not influence the response to the second TNFi, according to the ASDAS-CII. However, a difference was found with more stringent outcomes, e.g., there was a higher likelihood to achieve ASDAS-ID with the second TNFi for patients discontinuing the first TNFi due to secondary failure (OR 7.3 [95%CI 1.9; 27.7]), adverse events (OR 9.1 [2.5; 33.3]), or other reasons (OR 7.7 [1.6; 37.9]) compared to primary failure. CONCLUSION: Patients with axSpA with secondary failure to their first TNFi, compared to those with primary failure, have a better response to the second TNFi according to stringent outcomes.

Reuma.pt/vasculitis - the Portuguese vasculitis registry.

BACKGROUND: The vasculitides are a group of rare diseases with different manifestations and outcomes. New therapeutic options have led to the need for long-term registries. The Rheumatic Diseases Portuguese Register, Reuma.pt, is a web-based electronic clinical record, created in 2008, which currently includes specific modules for 12 diseases and > 20,000 patients registered from 79 rheumatology centres. On October 2014, a dedicated module for vasculitis was created as part of the European Vasculitis Society collaborative network, enabling prospective collection and central storage of encrypted data from patients with this condition. All Portuguese rheumatology centres were invited to participate. Data regarding demographics, diagnosis, classification criteria, assessment tools, and treatment were collected. We aim to describe the structure of Reuma.pt/vasculitis and characterize the patients registered since its development. RESULTS: A total of 687 patients, with 1945 visits, from 13 centres were registered; mean age was 53.4 ± 19.3 years at last visit and 68.7% were females. The most common diagnoses were Behçet's disease (BD) (42.5%) and giant cell arteritis (GCA) (17.8%). Patients with BD met the International Study Group criteria and the International Criteria for BD in 85.3 and 97.2% of cases, respectively. Within the most common small- and medium-vessel vasculitides registered, median [interquartile range] Birmingham Vasculitis Activity Score (BVAS) at first visit was highest in patients with ANCA-associated vasculitis (AAV) (17.0 [12.0]); there were no differences in the proportion of patients with AAV or polyarteritis nodosa who relapsed (BVAS≥1) or had a major relapse (≥1 major BVAS item) during prospective assessment (p = 1.00, p = 0.479). Biologic treatment was prescribed in 0.8% of patients with GCA, 26.7% of patients with AAV, and 7.6% of patients with BD. There were 34 (4.9%) deaths reported. CONCLUSIONS: Reuma.pt/vasculitis is a bespoke web-based registry adapted for routine care of patients with this form of rare and complex diseases, allowing an efficient data-repository at a national level with the potential to link with other international databases. It facilitates research, trials recruitment, service planning and benchmarking.

Eligibility criteria for biologic disease-modifying antirheumatic drugs in axial spondyloarthritis: going beyond BASDAI.

OBJECTIVES: To compare definitions of high disease activity of the Ankylosing Spondylitis Disease Activity Score (ASDAS) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in selecting patients for treatment with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: Patients from Rheumatic Diseases Portuguese Register (Reuma.pt) with a clinical diagnosis of axial spondyloarthritis (axSpA) were included. Four subgroups (cross-tabulation between ASDAS (≥2.1) and BASDAI (≥4) definitions of high disease activity) were compared regarding baseline characteristics and response to bDMARDs at 3 and 6 months estimated in multivariable regression models. RESULTS: Of the 594 patients included, the majority (82%) had both BASDAI≥4 and ASDAS ≥2.1. The frequency of ASDAS ≥2.1, if BASDAI<4 was much larger than the opposite (ie, ASDAS <2.1, if BASDAI≥4): 62% vs 0.8%. Compared to patients fulfilling both definitions, those with ASDAS ≥2.1 only were more likely to be male (77% vs 51%), human leucocyte antigen B27 positive (79% vs 65%) and have a higher C reactive protein (2.9 (SD 3.5) vs 2.1 (2.9)). Among bDMARD-treated patients (n=359), responses across subgroups were globally overlapping, except for the most 'stringent' outcomes. Patients captured only by ASDAS responded better compared to patients fulfilling both definitions (eg, ASDAS inactive disease at 3 months: 61% vs 25% and at 6 months: 42% vs 25%). CONCLUSION: The ASDAS definition of high disease activity is more inclusive than the BASDAI definition in selecting patients with axSpA for bDMARD treatment. The additionally 'captured' patients respond better and have higher likelihood of predictors thereof. These results support using ASDAS≥2.1 as a criterion for treatment decisions.

Remission and low disease activity matrix tools: results in real-world rheumatoid arthritis patients under anti-TNF therapy.

BACKGROUND: Remission/ low disease activity (LDA) are the main treatment goals in rheumatoid arthritis (RA) patients. Two tools showing the ability to predict golimumab treatment outcomes in patients with RA were published. OBJECTIVES: To estimate the real-world accuracy of two quantitative tools created to predict RA remission and low disease activity. METHODS: Multicenter, observational study, using data from the Rheumatic Diseases Portuguese Register (Reuma.pt), including biologic naïve RA patients who started an anti-TNF as first-line biologic and with at least 6 months of follow-up. The accuracy of two matrices tools was assessed by likelihood-ratios (LR), sensitivity (SN), specificity (SP), positive predictive value (PPV), negative predictive value (NPV) and area under the ROC curve (AUC). RESULTS: 674 RA patients under first-line anti-TNF (266 etanercept, 186 infliximab, 131 adalimumab, 85 golimumab, 6 certolizumab pegol) were included. The median (IQR) age was 53.4 (44.7-61.1) years and the median disease duration was 7.7 (3.7-14.6) years. The majority were female (72%). Most patients were RF and/or ACPA positive (75.5%) and had erosive disease (54.9%); 58.6% had comorbidities. At 6-months, 157 (23.3%) patients achieved remission (DAS28 ESR < 2.6) and 269 (39.9%) LDA (DAS28 ESR ≤ 3.2). Area under the curve for remission in this real-world sample was 0.756 [IC 95% (0.713-0.799)] and for LDA was 0.724 [IC 95% (0.686 -0.763)]. The highest LR (8.23) for remission state was obtained at a cut-off ≥ 67%, with high specificity (SP) (99.6%) but low sensitivity (SN) (3.2%). A better balance of SN and SP (65.6% and 73.9%, respectively) was observed for a cut-off >30%, with a LR of 2.51, PPV of 43.3% and NPV of 87.6%. CONCLUSION: In this population, the accuracy of the prediction tool was good for remission and LDA. Our results corroborate the idea that these matrix tools could be helpful to select patients for anti-TNF therapy.

Subacute cutaneous lupus erythematosus in a patient with Sjögren's syndrome taking terbinafine for onychomycosis.

We report the case of a 40-year old woman followed at our Rheumatology department for a 14-year history of a relatively well controlled Sjögren's syndrome who developed, for the first time in life, lesions suggestive of subacute cutaneous lupus erythematosus, nine weeks after taking oral terbinafine prescribed for onychomycosis. She denied additional symptoms, namely systemics, and no other clinical finding besides cutaneous lesions were detected. No laboratory findings were in favour of a flare of her connective tissue disease. Here we explore the possibility of terbinafine-induced subacute cutaneous lupus erythematosus in the context of previous autoimmunity. This clinical case highlights the importance of avoiding the prescription of terbinafine in this kind of patients.

Validation of Rheumatoid Arthritis Quality of Life (RAQoL) Questionnaire into Portuguese Language.

BACKGROUND: Rheumatoid Arthritis (RA) is a chronic inflammatory disease with high impact on patients´ quality of life (QoL). The Rheumatoid Arthritis Quality of Life Questionnaire (RAQoL) is a self-completed questionnaire designed to assess QoL in patients with RA. A Portuguese adaptation of the RAQoL was available but required formal validation. AIM: To validate the RAQoL into the Portuguese language. METHODS: Patients with diagnosis of RA were included. The Portuguese RAQoL was administered on two occasions, 14 days apart. Participants also completed the Nottingham Health Profile (NHP) and Health Assessment Questionnaire (HAQ) at Time 1. Internal consistency was assessed using Cronbach's alpha and reliability through Spearman's Correlation Coefficient. Construct validity was evaluated through Spearman's correlation analyses between RAQoL, NHP and HAQ. Known-group validity was tested comparing the RAQoL across different groups, considering self-perceived general health status, flare symptoms and RA severity through non-parametric tests. RESULTS: 178 RA patients (mean age 56.6, 82% female, mean disease duration 13.6 years) were included. The mean score of RAQoL was 11, with low rates of missing data (3.9%), floor (4.5%) and ceiling (2.2%) effects. Cronbach's α was 0.95 and test-retest reliability 0.92. RAQoL scores correlated moderately with scores on the NHP Physical Mobility (r=0.77), Emotional reactions (r=0.69), Pain (r=0.68) and Energy (r=0.65) section scores. RAQoL showed to be discriminative for groups according to self-perceived general health status, flare of arthritis and disease severity. CONCLUSION: The Portuguese version of the RAQoL is a valid, feasible and reliable questionnaire, suitable for use in clinical practice and research purposes.

Osteopoikilosis: case series from Portuguese Rheumatology Centers.

Osteopoikilosis (OPK) is a rare, hereditary, usually asymptomatic disease characterized by the presence of multiple, well-defined sclerotic lesions distributed in peri-articular locations, frequently diagnosed as an incidental finding. Differential diagnosis with osteoblastic metastases is fundamental. This article reports six cases of OPK diagnosed in Portuguese Rheumatology Centers.

Biologic therapy use and pregnancy outcomes in women with immune-mediated inflammatory rheumatic diseases.

INTRODUCTION: Concerns about the side effects and interactions of biologic drugs with reproduction and pregnancy have been always an issue between experts. The safety of these therapies during conception and/or pregnancy is not fully understood. The aim of this study was to assess the exposure to biologic drugs before and/or during conception/pregnancy and the risk of adverse pregnancy outcomes in women with rheumatic diseases. METHODS: We conducted a cohort study of pregnancies reported in women with immune-mediated rheumatic diseases registered at the Rheumatic Diseases Portuguese Registry (Reuma.pt) and exposed to biologic drugs. Data concerning fetal and maternal outcomes (live birth, spontaneous abortion, neonatal and intrauterine death, intrauterine growth restriction, premature delivery, congenital malformations, neonatal lupus, voluntary or medical interruption of pregnancy, disease flares and need for treatment with other drugs) was extracted. RESULTS: In total, 69 pregnancies from 56 females were analysed, the majority with the diagnosis of spondyloarthritis or rheumatoid arthritis. In almost half of the cases (n=32, 46.4%) the biologic was stopped for pregnancy planning, in 31 cases (44.9%) it was stopped when pregnancy was diagnosed and in 6 pregnancies (8.7%) biologic therapy was maintained, at least until the 2nd trimester. There were 76.8% of live births and 22% of spontaneous abortions. Congenital anomalies were reported in 2 newborns. CONCLUSIONS: In half cases, it was decided to stop biologic therapy in the family planning period. Using biologic disease-modifying anti-rheumatic drugs before and/or during pregnancy doesn't seem to affect the overall maternal and fetal outcomes. Pregnancy planning and treatment options should be discussed and a shared decision should be established between physician and patient.