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Summary: In this study, we optimized the dissociation of synovial tissue biopsies for single-cell omics studies and created a single-cell atlas of human synovium in inflammatory arthritis. The optimized protocol allowed consistent isolation of highly viable cells from tiny fresh synovial biopsies, minimizing the synovial biopsy drop-out rate. The synovium scRNA-seq atlas contained over 100,000 unsorted synovial cells from 25 synovial tissues affected by inflammatory arthritis, including 16 structural, 11 lymphoid, and 15 myeloid cell clusters. This synovial cell map expanded the diversity of synovial cell types/states, detected synovial neutrophils, and broadened synovial endothelial cell classification. We revealed tissue-resident macrophage subsets with proposed matrix-sensing (FOLR2+COLEC12high) and iron-recycling (LYVE1+SLC40A1+) activities and identified fibroblast subsets with proposed functions in cartilage breakdown (SOD2highSAA1+SAA2+SDC4+) and extracellular matrix remodeling (SERPINE1+COL5A3+LOXL2+). Our study offers an efficient synovium dissociation method and a reference scRNA-seq resource, that advances the current understanding of synovial cell heterogeneity in inflammatory arthritis.

VEXAS syndrome is a recently described autoinflammatory syndrome caused by the somatic acquisition of UBA1 mutations in myeloid precursors and is frequently associated with hematologic malignancies, chiefly myelodysplastic syndromes. Disease presentation can mimic several rheumatologic disorders, delaying the diagnosis. We describe a case of atypical presentation resembling late-onset axial spondylarthritis, later progressing to a systemic inflammatory syndrome with chondritis, cutaneous vasculitis, and transfusion-dependent anemia, requiring high doses of steroids. Ruxolitinib was used as the first steroid-sparing strategy without response. However, azacitidine showed activity in controlling both inflammation and the mutant clone. This case raises the question of whether azacitidine’s anti-inflammatory effects are dependent on or independent of clonal control. We discuss the potential relevance of molecular remission in VEXAS syndrome and highlight the importance of a multidisciplinary team for the care of such complex patients.

Abstract Background Juvenile idiopathic arthritis (JIA) treatment is aimed at inducing remission to prevent joint destruction and disability. However, it is unclear what is the long-term impact on health-related outcomes of the timing of biological disease-modifying antirheumatic drug (bDMARD) initiation in JIA. Our aim was to evaluate the long-term impact of the time between JIA onset and the initiation of a bDMARD in achieving clinical remission, on physical disability and health-related quality of life (HRQoL). Methods Adult JIA patients registered in the Rheumatic Diseases Portuguese Register (Reuma.pt) and ever treated with bDMARD were included. Data regarding socio-demographic, JIA-related characteristics, disease activity, physical disability (HAQ-DI), HRQoL (SF-36), and treatments were collected at the last visit. Patients were divided into 3 groups (≤ 2 years, 2–5 years, or > 5 years), according to the time from disease onset to bDMARD initiation. Regression models were obtained considering remission on/off medication, HAQ-DI, SF-36, and joint surgeries as outcomes and time from disease onset to bDMARD start as an independent variable. Results Three hundred sixty-one adult JIA patients were evaluated, with a median disease duration of 20.3 years (IQR 12.1; 30.2). 40.4% had active disease, 35.1% were in remission on medication, and 24.4% were in drug-free remission; 71% reported some degree of physical disability. Starting a bDMARD > 5 years after disease onset decreased the chance of achieving remission off medication (OR 0.24; 95% CI 0.06, 0.92; p = 0.038). Patients who started a bDMARD after 5 years of disease onset had a higher HAQ and worse scores in the physical component, vitality, and social function domains of SF-36, and more joint surgeries when compared to an earlier start. Conclusion Later initiation of bDMARDs in JIA is associated with a greater physical disability, worse HRQoL, and lower chance of drug-free remission in adulthood.

Background Hepatitis B virus (HBV) vaccination is recommended for non-immunised patients with rheumatic diseases starting biological disease-modifying antirheumatic drugs (bDMARDs). There is some evidence that HBV vaccination is effective in patients under conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), but it is currently unclear whether this also applies to bDMARDs.Objectives To assess the efficacy and safety of HBV vaccination in patients with inflammatory arthritides treated with bDMARDs.Methods A prospective cohort with inflammatory arthritides treated with bDMARDs, negative for anti-HBs and anti-HBc and never vaccinated for HBV was recruited. Engerix B was administered at 0, 1 and 6 months and anti-HBs was reassessed ≥1 month after last dose. Response was defined as anti-HBs≥10 IU/L and compared against vaccinated healthy controls. Disease flare, serious adverse events and immune-related disorders not previously present were recorded.Results 62 patients, most treated with TNF inhibitors (TNFi), and 38 controls were recruited. Most patients were taking csDMARDs (67.7%) and were in remission/low disease activity (59.4%). Only 20/62 patients (32.3%) had a positive response to vaccination, in comparison to 36/38 age-matched controls (94.7%, p

Systemic lupus erythematosus (SLE) is a chronic, immune-mediated disease associated with significant morbidity and mortality. New evidence suggests that diet, gut microbiota, intestinal permeability, and endotoxemia may modulate chronic inflammation and disease activity in SLE. This review focus on what is known about the gut microbiota in lupus mouse models and SLE patients and the possible mechanisms that connect the gut microbiota with SLE. It included 29 studies (12 animal studies, 15 human studies, and 2 included data on both), with variable results regarding alpha and beta-diversity and gut microbiota composition between lupus-mouse models and SLE patients. Ruminococcus (R.) gnavus was significantly increased in lupus nephritis (LN) in one study, but this was not corroborated by others. Despite the different results, mechanistic lupus mouse model studies have shown that gut microbiota can modulate disease activity. Interestingly, pathobiont translocation in monocolonized and autoimmune-prone mice induced autoantibodies and caused mortality, which could be prevented by a vaccine targeting the pathobiont. Moreover, studies on fecal transplants and diet on different lupus mouse models showed an effect on disease activity. In SLE patients, a higher adherence to the Mediterranean diet was associated with lower disease activity, which may be explained by the connection between diet and gut microbiota. Although gut dysbiosis has been observed in SLE patients and lupus mouse models, it remains to clarify if it is a cause or a consequence of the disease or its treatments. Further studies with larger and well-characterized populations will undoubtedly contribute to deciphering the role of gut microbiota in SLE development, progression, and outcome.

Abstract Autoantibodies are produced within germinal centers (GC), in a process regulated by interactions between B, T follicular helper (Tfh), and T follicular regulatory (Tfr) cells. The GC dysregulation in human autoimmunity has been inferred from circulating cells, albeit with conflicting results due to diverse experimental approaches. We applied a consistent approach to compare circulating Tfr and Tfh subsets in patients with different autoimmune diseases. We recruited 97 participants, including 72 patients with Hashimoto’s thyroiditis (HT, n = 18), rheumatoid arthritis (RA, n = 16), or systemic lupus erythematosus (SLE, n = 32), and 31 matched healthy donors (HD). We found that the frequency of circulating T follicular subsets differed across diseases. Patients with HT had an increased frequency of blood Tfh cells (p = 0.0215) and a reduced Tfr/Tfh ratio (p = 0.0338) when compared with HD. This was not observed in patients with systemic autoimmune rheumatic diseases (RA, SLE), who had a reduction in both Tfh (p = 0.0494 and p = 0.0392, respectively) and Tfr (p = 0.0003 and p = 0.0001, respectively) cells, resulting in an unchanged Tfr/Tfh ratio. Activated PD-1+ICOS+Tfh and CD4+PD-1+CXCR5–Tph cells were raised only in patients with SLE (p = 0.0022 and p = 0.0054), without association with disease activity. Our data suggest that GC dysregulation, assessed by T follicular subsets, is not uniform in human autoimmunity. Specific patterns of dysregulation may become potential biomarkers for disease and patient stratification.

Abstract Background Rheumatic diseases are associated with an increase in overall risks of tuberculosis (TB). The aim of this study was to evaluate the frequency of TB and the frequency of latent TB infection (LTBI), in clinical practice, for juvenile idiopathic arthritis (JIA) patients from high and low risk of TB incidence endemic countries. Methods This is an international, multicenter, cross-sectional, observational study of data collection from Brazil and Registry of Portugal at REUMA.PT. The inclusion criteria were patients with Juvenile Idiopathic Arthritis (JIA) with age ≤ 18 years who underwent screening for Mycobacterium tuberculosis infection [tuberculin skin test (TST) and/or interferon gamma release assay (IGRA)]. Chest X-rays and history of exposure to TB were also assessed. Results 292 JIA patients were included; mean age 14.3 years, mean disease duration 7.5 years, 194 patients (66.4%) performed only TST, 14 (4.8%) only IGRA and 84 (28.8%) both. The frequency of LTBI (10.6%) and TB was similar between the two countries. The reasons for TB screening were different; in Brazil it was performed more often at JIA onset while in Portugal it was performed when starting Disease Modified Anti-Rheumatic Drugs (DMARD) treatment (p

ObjectivesIdiopathic inflammatory myopathies (IIM) are a group of rare disorders that can affect the heart. This work aimed to find predictors of cardiac involvement in IIM.MethodsMulticenter, open cohort study, including patients registered in the IIM module of the Rheumatic Diseases Portuguese Register (Reuma.pt/Myositis) until January 2022. Patients without cardiac involvement information were excluded. Myo(peri)carditis, dilated cardiomyopathy, conduction abnormalities, and/or premature coronary artery disease were considered.Results230 patients were included, 163 (70.9%) of whom were females. Thirteen patients (5.7%) had cardiac involvement. Compared with IIM patients without cardiac involvement, these patients had a lower bilateral manual muscle testing score (MMT) at the peak of muscle weakness [108.0 ± 55.0 vs 147.5 ± 22.0, p=0.008] and more frequently had oesophageal [6/12 (50.0%) vs 33/207 (15.9%), p=0.009] and lung [10/13 (76.9%) vs 68/216 (31.5%), p=0.001] involvements. Anti-SRP antibodies were more commonly identified in patients with cardiac involvement [3/11 (27.3%) vs 9/174 (5.2%), p=0.026]. In the multivariate analysis, positivity for anti-SRP antibodies (OR 104.3, 95% CI: 2.5-4277.8, p=0.014) was a predictor of cardiac involvement, regardless of sex, ethnicity, age at diagnosis, and lung involvement. Sensitivity analysis confirmed these results.ConclusionAnti-SRP antibodies were predictors of cardiac involvement in our cohort of IIM patients, irrespective of demographical characteristics and lung involvement. We suggest considering frequent screening for heart involvement in anti-SRP-positive IIM patients.

Pre-clinical rheumatoid arthritis (RA) is a phase of the disease that occurs before the characteristic symptoms and clinical manifestations of RA become evident. One key aspect of pre-clinical RA research has been the identification of biomarkers that can predict the development of RA in individuals who are at risk. Rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs) are often detectable in the pre-clinical phase, sometimes years before clinical onset. These biomarkers, along with genetic and environmental factors contribute to the risk profile for RA development. Synovial biopsy, serum and peripheral blood cell characterization, magnetic resonance imaging (MRI) and ultrasound, have allowed researchers to capture subclinical joint inflammation in individuals who do not yet exhibit clinical symptoms. This has provided valuable insights into the progression of RA, as well as the potential for early intervention to prevent irreversible joint damage. Understanding the pathogenesis of pre-clinical RA has revealed the role of several initial pathways that are relevant for the onset of the disease, paving the way for new treatment intervention and new very early diagnostic strategies. Ongoing research will continue to refine our understanding of this phase of the disease and optimize strategies for its management.

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine and its overexpression has been implicated in the pathophysiology of several chronic immune-mediated inflammatory diseases. Biological therapies, like TNF inhibitors, have been revolutionizing the course of these disorders. Golimumab is a transgenic anti-TNF monoclonal antibody that acts primarily by targeting and neutralizing TNF, thus preventing inflammation. It is approved for the treatment of Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis, Nonradiographic axial Spondyloarthritis, Juvenile Idiopathic Arthritis, and Ulcerative Colitis. Clinical trials are also being conducted in other conditions. This review charts the clinical development of golimumab and outlines the data that support its potential use across several Immune-mediated inflammatory diseases.

In the last decades, the concept of preclinical rheumatoid arthritis (RA) has become established. In fact, the discovery that disease mechanisms start years before the onset of clinical RA has been one of the major recent insights in the understanding of RA pathogenesis. In accordance with the complex nature of the disease, preclinical events extend over several sequential phases. In a genetically predisposed host, environmental factors will further increase susceptibility for incident RA. In the initial steps of preclinical disease, immune disturbance mechanisms take place outside the joint compartment, namely in mucosal surfaces, such as the lung, gums or gut. Herein, the persistent immunologic response to altered antigens will lead to breach of tolerance and trigger autoimmunity. In a second phase, the immune response matures and is amplified at a systemic level, with epitope spreading and widening of the autoantibody repertoire. Finally, the synovial and bone compartment are targeted by specific autoantibodies against modified antigens, initiating a local inflammatory response that will eventually culminate in clinically evident synovitis. In this review, we discuss the elaborate disease mechanisms in place during preclinical RA, providing a broad perspective in the light of current evidence.

Psoriatic arthritis (PsA) is a phenotypically heterogeneous chronic inflammatory disease associated to type I major histocompatibility complex alleles whose complex pathogenesis is still not completely understood. The psoriatic synovium shares general features of chronic inflammation with rheumatoid arthritis (RA) and other arthritis, such as hyperplasia of the intimal lining layer, sublining influx of inflammatory cells and neoangiogenesis, but recognizing disease-specific histopathologic findings may help in diagnosis and definition of therapeutic targets. Available literature reports conflicting data regarding the extension of lining hyperplasia, that does not allow depiction from RA. Sublining inflammatory cells consist of T and B cells and macrophages, plasma cells, mast cells and follicular dendritic cells, with a higher amount of overall T, mast cell and IL-17 producing CD8+ T lymphocytes and lower proportion of plasma cells when compared to the rheumatoid synovium. The amount of synovium IL17+ CD8+ T cells correlates positively to measures of disease activity. Lymphoid follicles with characteristics of germinal centers have been identified, similar to the ones described in RA. Neoangiogenesis is more prominent in PsA but can also be an outstanding feature in some RA samples, and different molecules involved in the process appear to have different influence in each disease. IL-17 and IL-22 expression in the synovium does not allow depiction between diseases. Among other cytokines and molecules likely implicated in disease physiopathology, only IL-35 is demonstrated to be reduced in PsA when compared to RA.

ObjectiveTo 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.MethodsNationwide 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.Results162 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).ConclusionsTNFi 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.

Juvenile idiopathic arthritis (JIA) is a term that collectively refers to a group of chronic childhood arthritides, which together constitute the most common rheumatic condition in children. The International League of Associations for Rheumatology (ILAR) criteria define seven categories of JIA: oligoarticular, polyarticular rheumatoid factor (RF) negative (RF-), polyarticular RF positive (RF+), systemic, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. The ILAR classification includes persistent and extended oligoarthritis as subcategories of oligoarticular JIA, but not as distinct categories. JIA is characterized by a chronic inflammatory process affecting the synovia that begins before the age of 16 and persists at least 6 weeks. If not treated, JIA can cause significant disability and loss of quality of life. Treatment of JIA is adjusted according to the severity of the disease as combinations of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and/ or biological disease modifying anti-rheumatic drugs (DMARDs). Although the disease etiology is unknown, disturbances in innate and adaptive immune responses have been implicated in JIA development. B cells may have important roles in JIA pathogenesis through autoantibody production, antigen presentation, cytokine release and/ or T cell activation. The study of B cells has not been extensively explored in JIA, but evidence from the literature suggests that B cells might have indeed a relevant role in JIA pathophysiology. The detection of autoantibodies such as antinuclear antibodies (ANA), RF and anti-citrullinated protein antibodies (ACPA) in JIA patients supports a breakdown in B cell tolerance. Furthermore, alterations in B cell subpopulations have been documented in peripheral blood and synovial fluid from JIA patients. In fact, altered B cell homeostasis, B cell differentiation and B cell hyperactivity have been described in JIA. Of note, B cell depletion therapy with rituximab has been shown to be an effective and well-tolerated treatment in children with JIA, which further supports B cell intervention in disease development.

A synoptic overview of scientific methods applied in bone and associated research fields across species has yet to be published. Experts from the EU Cost Action GEMSTONE (“GEnomics of MusculoSkeletal Traits translational Network”) Working Group 2 present an overview of the routine techniques as well as clinical and research approaches employed to characterize bone phenotypes in humans and selected animal models (mice and zebrafish) of health and disease. The goal is consolidation of knowledge and a map for future research. This expert paper provides a comprehensive overview of state-of-the-art technologies to investigate bone properties in humans and animals – including their strengths and weaknesses. New research methodologies are outlined and future strategies are discussed to combine phenotypic with rapidly developing –omics data in order to advance musculoskeletal research and move towards “personalised medicine”.

Rheumatoid arthritis (RA) is the most common systemic inflammatory rheumatic disease. It is associated with significant burden at the patient and societal level. Extensive efforts have been devoted to identifying a potential cause for the development of RA. Epidemiological studies have thoroughly investigated the association of several factors with the risk and course of RA. Although a precise etiology remains elusive, the current understanding is that RA is a multifactorial disease, wherein complex interactions between host and environmental factors determine the overall risk of disease susceptibility, persistence and severity. Risk factors related to the host that have been associated with RA development may be divided into genetic; epigenetic; hormonal, reproductive and neuroendocrine; and comorbid host factors. In turn, environmental risk factors include smoking and other airborne exposures; microbiota and infectious agents; diet; and socioeconomic factors. In the present narrative review, aimed at clinicians and researchers in the field of RA, we provide a state-of-the-art overview of the current knowledge on this topic, focusing on recent progresses that have improved our comprehension of disease risk and development.

Background Despite vitamin K antagonists (VKA) being the gold standard in the prevention of thromboembolic events in antiphospholipid syndrome (APS), non-vitamin K antagonists oral anticoagulants/direct oral anticoagulants (DOACs) have been used off-label.Objective We aimed to perform a systematic review comparing DOACs to VKA regarding prevention of thromboembolic events, occurrence of bleeding events and mortality in patients with APS.Methods An electronic database search was performed through MEDLINE, CENTRAL and Web of Science. After data extraction, we pooled the results using risk ratio (RR) and 95% CI. Heterogeneity was assessed using the I². The outcomes considered were all thromboembolic events as primary, and major bleeding, all bleeding events and mortality as secondary. Evidence confidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology.Results We included 7 studies and a total of 835 patients for analyses. Thromboembolic events were significantly increased in DOACs arm, compared with VKA—RR 1.69, 95% CI 1.09 to 2.62, I²—24%, n=719, 6 studies. In studies using exclusively rivaroxaban, which was the most representative drug in all included studies, the thromboembolic risk was increased threefold (RR 3.36, 95% CI 1.53 to 7.37). The risks of major bleeding, all bleeding events and mortality were not significantly different from control arm. The grade of certainty of our results is very low.Conclusions Current evidence suggests DOACs use, particularly rivaroxaban, among patients with APS, is less effective than VKA since it is associated with 69% increased risk of thromboembolic events.Trial registration number CRD42020216178.

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease that ultimately leads to joint destruction and functional disability. Although the exact etiology of RA is not fully understood, it is well established that gut microbiota (GM) plays a vital role in the pathogenesis of RA, with accumulating evidence suggesting that gut dysbiosis induces a chronic inflammatory response that may be linked to disease development. Of interest, patients with RA have significant changes in the intestinal microbiota compared to healthy controls, and several studies have suggested the use of probiotics as a possible adjuvant therapy for RA. Benefits of probiotic supplementation were reported in animal models of arthritis and human studies, but the current evidence regarding the effect of probiotic supplementation in the management of RA remains insufficient to make definite recommendations. Several different strains of Lactobacillus and Bifidobacteria, as single species or in mixed culture, have been investigated, and some have demonstrated beneficial effects on disease activity in RA human subjects. As of now, L.casei probiotic bacteria seems to be the strongest candidate for application as adjuvant therapy for RA patients. In this review, we highlight the role of GM in the development and progression of RA and summarize the current knowledge on the use of probiotics as a potential adjuvant therapy for RA. We also review the proposed mechanisms whereby probiotics regulate inflammation. Finally, the role of fermented foods is discussed as a possible alternative to probiotic supplements since they have also been reported to have health benefits.

Background and Aims: Atherosclerosis and osteoporosis share common risk factors, as well as inflammatory mechanisms. Our aim was to understand how atherosclerotic lesions are related with disturbances in bone.Methods: Gene expression of pro-inflammatory and bone metabolism related proteins (IL-1β, IL-6, IL-17A, TNF, RANKL, OPG, COL1, CTSK, OCL, TRAP, CBFA1, DKK1, SOST, ADIPOQ, and ADIPOR1) were analyzed in arteries and bones from 45 deceased donors and adipose tissue was used as control. Additionally, in 139 patients with advanced atherosclerosis submitted to carotid endarterectomy we compared calcium content (Alizarin red) and plaque inflammatory scores (CD3+, CD68+, and adiponectin) of patients with normal bone mineral density (BMD) with those with low BMD and explored the associations between gene expression in atherosclerotic plaques and BMD. Serum levels of pro-inflammatory and bone related proteins were measured both in donors and patients. Associations were investigated by the Pearson or Spearman correlation tests, and multivariate regression analyzes were performed when justified.Results: Gene expression of bone remodeling and pro-inflammatory proteins correlated positively in bone and aorta, independently of age and sex of donors, but not in adipose tissue. The expression of bone formation genes was significantly higher in atheroma plaques from endarterectomized patients with normal vs. low BMD as well as inflammatory CD68+ scores, regardless of patients' age and sex, but not of body mass index. No relationship was observed between serum levels and gene expression levels of pro-inflammatory or bone remodeling proteins.Conclusions: Our results suggest that the relationship between bones and vessels in the context of atherosclerotic disease and osteoporosis may rely on the intrinsic connection between the tissues involved, independently of disease stage. Serum measurements of pro-inflammatory and bone-remodeling proteins do not accurately translate tissue pathologic processes.

A 64-year-old male presented with a 6-month history of symmetric polyarthritis involving proximal interphalangeal joints and metacarpophalangeal joints of the hands, wrists, and ankles. Associated symptoms included vomiting, progressive fatigue, and weight loss. Laboratory results showed microcytic anemia, leukocytosis, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, and rheumatoid factor (RF) and anti-cyclic citrullinated protein (ACPA) antibody positivity. Joints radiographs were normal, without erosions. Upper endoscopy and gastric endoscopic ultrasonography showed a gastric adenocarcinoma with lymphatic involvement. Intraoperatively, peritoneal carcinomatosis was documented, and the patient started palliative chemotherapy. A paraneoplastic seropositive arthritis was assumed, and treatment with low-dose prednisolone and hydroxychloroquine was started. Arthritis remission was achieved and sustained up to 18 months of follow-up, although gastric cancer progression was documented. We describe a unique phenotype of paraneoplastic arthritis (PA) presenting as a seropositive (RF and ACPA positivity) rheumatoid arthritis (RA) with a good response to both low dose corticosteroids and hydroxychloroquine therapy. We also review the literature of PA, mostly the RA-like pattern, and the association between PA and ACPA positivity. This case highlights the importance of considering underlying cancer in elderly male patients, presenting with polyarthritis and systemic symptoms, even in those with ACPA-positive RA-like arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic immune-mediated inflammatory disease that can lead to joint destruction, functional disability and substantial comorbidity due to the involvement of multiple organs and systems. B cells have several important roles in RA pathogenesis, namely through autoantibody production, antigen presentation, T cell activation, cytokine release and ectopic lymphoid neogenesis. The success of B cell depletion therapy with rituximab, a monoclonal antibody directed against CD20 expressed by B cells, has further supported B cell intervention in RA development. Despite the efficacy of synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs) in the treatment of RA, few patients reach sustained remission and refractory disease is a concern that needs critical evaluation and close monitoring. Janus kinase (JAK) inhibitors or JAKi are a new class of oral medications recently approved for the treatment of RA. JAK inhibitors suppress the activity of one or more of the JAK family of tyrosine kinases, thus interfering with the JAK-Signal Transducer and Activator of Transcription (STAT) signaling pathway. To date, there are five JAK inhibitors (tofacitinib, baricitinib, upadacitinib, peficitinib and filgotinib) approved in the USA, Europe and/ or Japan for RA treatment. Evidence from the literature indicates that JAK inhibitors interfere with B cell functions. In this review, the main results obtained in clinical trials, pharmacokinetic, in vitro and in vivo studies concerning the effects of JAK inhibitors on B cell immune responses in RA are summarized.

Synovial tissue can be safely and reliably collected for research and clinical purposes using arthroscopy. This technique offers the obvious advantage of allowing direct visualization, and targeted biopsy of specific areas of interest within the joint, as well as for the collection of tissue which will include a lining layer. Much has been learnt by studying the synovium retrieved using this technique concerning the pathobiology of inflammatory arthritis. Furthermore, recent evidence suggests that the tissue retrieved may enable the identification of unique pathotypes that will allow for a precise approach to treatment selection in individual patients. Although ultrasound guided techniques for sampling synovial tissue have gained in popularity over the last decade, both methodologies are expected to compliment each other, each having unique benefits and drawbacks. We present here a detailed description of the arthroscopy technique reporting on our collective experience at two centers in Europe.

Introduction: Several new treatments have been developed for psoriatic disease, an inflammatory condition that involves skin and joints. Notwithstanding, few studies have made direct comparisons between treatments and therefore it is difficult to select the ideal treatment for an individual patient. The aim of this systematic review with network meta-analysis (NMA) was to analyze available and approved biologic therapies for each domain of psoriatic disease: skin, peripheral arthritis, axial arthritis, enthesitis, dactylitis, and nail involvement.Methods: Data from randomized clinical trials (RCTs) were included. A systematic review was performed using the MEDLINE database (July 2020) using PICO criteria. Bayesian NMA was conducted to compare the clinical efficacy of biological therapy in terms of the American College of Rheumatology criteria (ACR, 24 weeks) and Psoriasis Area and Severity Index (PASI, 10–16 weeks).Results: Fifty-four RCTs were included in the systematic review. Due to the design of the RCTs, namely, outcomes and time points, network meta-analysis was performed for skin and peripheral arthritis domains. For the skin domain, 30 studies reporting PASI100 were included. The peripheral arthritis domain was analyzed through ACR70 in 12 studies. From the therapies approved for both domains, secukinumab and ixekizumab were the ones with the highest probability of reaching the proposed outcomes. There is a lack of outcome uniformization in the dactylitis, enthesitis, and nail domains, and therefore, an objective comparison of the studies was not feasible. Nevertheless, secukinumab was the treatment with the best compromise between the number of studies in each domain and the results obtained in the different outcomes.Conclusion: Secukinumab and ixekizumab were the treatments with the highest probability of reaching both PASI100 and ACR70 outcomes. Due to the lack of a standard evaluation of outcomes of the other psoriatic disease domains, a network meta-analysis for all the domains was not possible to perform.

The coronavirus disease 2019 (COVID-19) pandemic has come with many challenges for healthcare providers and patients alike. In addition to the direct burden it has placed on societies and health systems, it had a significant impact in the care of patients with chronic diseases, as healthcare resources were deployed to fight the crisis, and major travel and social restrictions were adopted. In the field of rheumatology, this has required notable efforts from departments and clinicians to adapt to the novel status quo and assure the follow-up of patients with rheumatic and musculoskeletal diseases. In the present viewpoint, we provide a practical approach to tackle this reality. Key measures include setting up preventive team management strategies, optimising communication with patients and reorganising patient care in all its dimensions. We then anticipate the nuances of rheumatology practice as restrictive measures are progressively lifted, while an effective vaccine is still pending. This includes the need to reimpose the same strategy as further waves unfold. Finally, we look ahead and address the lessons we can incorporate into post-COVID-19 rheumatology.

Background: We previously demonstrated that celastrol has significant anti-inflammatory and bone protective effects when administered via the intraperitoneal route. For further preclinical evaluation, an effective oral administration of celastrol is crucial. Here we aimed to study the therapeutic dose range for its oral administration.Methods: Celastrol (1–25 μg/g/day, N = 5/group) was administrated orally to female adjuvant-induced arthritis (AIA) rats after 8 days of disease induction for a period of 14 days. A group of healthy (N = 8) and arthritic (N = 15) gender- and age-matched Wistar rats was used as controls. During the treatment period, the inflammatory score, ankle perimeter, and body weight were measured. At the end of the treatment, the animals were sacrificed, blood was collected for clinical pathology, necropsy was performed with collection of internal organs for histopathological analysis, and paw samples were used for disease scoring.Results: Doses higher than 2.5 μg/g/day of celastrol reduced the inflammatory score and ankle swelling, preserved joint structure, halted bone destruction, and diminished the number of synovial CD68+ macrophages. Bone resorption and turnover were also reduced at 5 and 7.5 μg/g/day doses. However, the dose of 7.5 μg/g/day was associated with thymic and liver lesions, and higher doses showed severe toxicity.Conclusion: Oral administration of celastrol above 2.5 μg/g/day ameliorates arthritis. This data supports and gives relevant information for the development of a preclinical test of celastrol in the setting of a chronic model of arthritis since rheumatoid arthritis is a long-term disease.

Objectives: To describe our experience with a coronavirus disease 2019 (COVID-19) outbreak within a large rheumatology department early in the pandemic.Methods: Symptomatic and asymptomatic healthcare workers (HCWs) had a naso-oropharyngeal swab for detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and were followed clinically. Reverse transcription polymerase-chain reaction (RT-PCR) was repeated to document cure, and serological response was assessed. Patients with risk contacts within the department in the 14 days preceding the outbreak were screened for COVID-19 symptoms.Results: 14/34 HCWs (41%; 40 ± 14 years, 71% female) tested positive for SARS-CoV-2, and 11/34 (32%) developed symptoms but were RT-PCR-negative. Half of RT-PCR-positive HCWs did not report fever, cough, or dyspnea before testing, which were absent in 3/14 cases (21%). Mild disease prevailed (79%), but 3 HCWs had moderate disease requiring further assessment, which excluded severe complications. Nevertheless, symptom duration (28 ± 18 days), viral shedding (31 ± 10 days post-symptom onset, range 15–51), and work absence (29 ± 28 days) were prolonged. 13/14 (93%) of RT-PCR-positive and none of the RT-PCR-negative HCWs had a positive humoral response Higher IgG indexes were observed in individuals over 50 years of age (14.5 ± 7.7 vs. 5.0 ± 4.4, p = 0.012). Of 617 rheumatic patients, 8 (1.3%) developed COVID-19 symptoms (1/8 hospitalization, 8/8 complete recovery), following a consultation/procedure with an asymptomatic (7/8) or mildly symptomatic (1/8) HCW.Conclusions: A COVID-19 outbreak can occur among HCWs and rheumatic patients, swiftly spreading over the presymptomatic stage. Mild disease without typical symptoms should be recognized and may evolve with delayed viral shedding, prolonged recovery, and adequate immune response in most individuals.

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Abstract High-resolution musculoskeletal ultrasound (MSUS) has been increasingly employed in daily rheumatological practice and in clinical research. In rheumatoid arthritis (RA), MSUS can be now considered a complement to physical examination. This method evaluates synovitis through gray-scale and power Doppler and it is also able to identify bone erosions. The utilization of MSUS as a marker of RA activity has received attention in recent literature. Current data account for good correlation of MSUS with classical measures of clinical activity; in some instances, MSUS appears to perform even better. Diagnosis of subclinical synovitis by MSUS might help the physician in RA management. With some variation, interobserver MSUS agreement seems excellent for erosion and good for synovitis. However, lack of MSUS score standardization is still an unmet need. In this review, we describe several MSUS scores, as well as their correlation with clinical RA activity and response to therapy. Finally, we look at the relationship of MSUS with synovial tissue inflammation and discuss future perspectives for a better interpretation and integration of this imaging method into clinical practice.

Abstract Individualising biologic disease-modifying anti-rheumatic drugs (bDMARDs) to maximise outcomes and deliver safe and cost-effective care is a key goal in the management of rheumatoid arthritis (RA). Investigation to identify predictive tools of bDMARD response is a highly active and prolific area of research. In addition to clinical phenotyping, cellular and molecular characterisation of synovial tissue and blood in patients with RA, using different technologies, can facilitate predictive testing. This narrative review will summarise the literature for the available bDMARD classes and focus on where progress has been made. We will also look ahead and consider the increasing use of ‘omics’ technologies, the potential they hold as well as the challenges, and what is needed in the future to fully realise our ambition of personalised bDMARD treatment.

Abstract There are currently no robust noninvasive markers of fragility fractures. Secreted frizzled related protein‐1 (sFRP‐1), dickkopf‐related protein 1 (DKK1) and DKK2, and sclerostin (SOST) inhibit Wnt signaling and interfere with osteoblast‐mediated bone formation. We evaluated associations of serum levels of sFRP‐1, DKK1, DKK2, and SOST with incident low‐impact fracture and BMD in 828 women aged ≥65 years from EpiDoC, a longitudinal population‐based cohort. A structured questionnaire during a baseline clinical appointment assessed prevalent fragility fractures and clinical risk factors (CRFs) for fracture. Blood was collected to measure serum levels of bone turnover markers and Wnt regulators. Lumbar spine and hip BMD were determined by DXA scanning. Follow‐up assessment was performed through a phone interview; incident fragility fracture was defined by any new self‐reported low‐impact fracture. Multivariate Cox proportional hazard models were used to analyze fracture risk adjusted for CRFs and BMD. During a mean follow‐up of 2.3 ± 1.0 years, 62 low‐impact fractures were sustained in 58 women. A low serum DKK2 level (per 1 SD decrease) was associated with a 1.5‐fold increase in fracture risk independently of BMD and CRFs. Women in the two lowest DKK2 quartiles had a fracture incidence rate of 32 per 1000 person‐years, whereas women in the two highest quartiles had 14 fragility fractures per 1000 person‐years. A high serum sFRP1 level was associated with a 1.6‐fold increase in fracture risk adjusted for CRFs, but not independently of BMD. Serum levels of SOST (r = 0.191; p = 0.0025) and DKK1(r = −0.1725; p = 0.011) were correlated with hip BMD, but not with incident fragility fracture. These results indicate that serum DKK2 and sFRP1 may predict low‐impact fracture. The low number of incident fractures recorded is a limitation and serum levels of Wnt regulators should be further studied in other populations as potential noninvasive markers of fragility fractures. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

Background: We aimed to assess efficacy and safety of anti-tumor necrosis factor (TNF) drugs for adult chronic non-infectious uveitis (NIU).Methods: CENTRAL, MEDLINE, and EMBASE, were searched from inception to January 2019. Double-masked randomized placebo-controlled trials, assessing any anti-TNF vs. best medical intervention/standard of care in adults with chronic NIU were considered. The PRISMA and SAMPL guidelines were followed. The risk of bias was assessed using the Cochrane risk of bias tool. Overall quality of the evidence was assessed according to GRADE. PROSPERO registration: #CRD42016039068. The primary efficacy and safety outcomes were preservation of visual acuity (VA) and withdrawals due to adverse events, respectively. Meta-analysis of efficacy analysis was not performed due to significant clinical heterogeneity between studies' population and interventions.Results: A total of 1,157 references were considered and 3 studies were included. The overall risk of bias was moderate. In active NIU, adalimumab group showed an increased likelihood of VA preservation (risk ratio (RR) 1.75, 95%CI 1.32 to 2.32, n = 217), whereas the etanercept group did not (RR 0.81, 95%CI 0.57 to 1.14, n = 20). In inactive NIU, adalimumab was associated with increased likelihood of VA preservation (RR 1.31, 95%CI 1.12 to 1.53, n = 226). The rate of adverse events did not differ between anti-TNF and control arms (RR 1.03, 95%CI 0.94 to 1.13, n = 410).Conclusions: There is high quality evidence that adalimumab decreases the risk of worsening VA in active and inactive NIU and very low quality evidence that the risk of etanercept worsening VA in inactive NIU is not different from placebo. Moderate quality evidence suggests that anti-TNF agents are not different from placebo on the risk of study withdrawal.

PurposeTo demonstrate the production of inflammatory mediators by cells located in bone marrow spaces inside rodent menisci.MethodsMice subjected to transection of the medial collateral and anterior cruciate ligaments and meniscotomy (osteoarthritis model) or to a sham procedure, as well as non-operated (naive) mice and rats, had knee joints excised. Tissues were stained with hematoxylin-eosin and tartrate-resistant acid phosphatase (TRAP). CD68+ cells, inducible nitric oxide synthase (iNOS), interleukin (IL)-1β, and tumor necrosis factor (TNF) expression were detected using immunohistochemistry.ResultsLamellar ossified areas, bone-entrapped osteocytes and bone marrow spaces were found inside menisci of one week up to 6 months-old naïve mice, regardless of gender. Menisci from naive rats also showed the same pattern with bone marrow areas. CD68+ cells were identified in bone marrow areas inside the meniscus of mice. TRAP+ osteoclasts, and hematogenous precursors expressing IL-1β, TNF, and iNOS were identified inside bone marrow areas in meniscal samples from both naïve and sham operated mice. Quantitative immunoexpression of IL-1 β, TNF and iNOS was more intense, P = 0.0194, 0.0293, 0.0124, respectively, in mouse knees from mice sacrificed 49 days after being subjected to an osteoarthritis (OA) model as compared to sham operated animals.ConclusionWe provide novel data showing that rodent menisci display bone marrow areas with cells able to produce inflammatory mediators. Immunoexpression of inflammatory mediators in those bone marrow areas is significantly more pronounced in mice subjected to experimental OA.

Growing experimental and clinical evidence suggests that a chronic inflammatory response induced by gut dysbiosis can critically contribute to the development of rheumatic diseases, including rheumatoid arthritis (RA). Of interest, an adherence to a Mediterranean diet has been linked to a reduction in mortality and morbidity in patients with inflammatory diseases. Diet and intestinal microbiota are modifying factors that may influence intestinal barrier strength, functional integrity, and permeability regulation. Intestinal microbiota may play a crucial role in RA pathogenesis, but up to now no solid data has clarified a mechanistic relationship between gut microbiota and the development of RA. Nonetheless, microbiota composition in subjects with RA differs from that of controls and this altered microbiome can be partially restored after prescribing disease modifying antirheumatic drugs. High levels of Prevotella copri and similar species are correlated with low levels of microbiota previously associated with immune regulating properties. In addition, some nutrients can alter intestinal permeability and thereby influence the immune response without a known impact on the microbiota. However, critical questions remain to be elucidated, such as the way microbiome fluctuates in relation to diet, and how disease activity may be influenced by changes in diet, microbiota or diet-intestinal microbiota equilibrium.

Rheumatoid arthritis (RA) is a chronic immune-driven inflammatory disease characterised by synovial inflammation, leading to progressive cartilage and bone destruction, impacting patients’ functional capacity and quality of life. Patients with RA have significant differences in gut microbiota composition when compared to controls. Intestinal dysbiosis influences the intestinal barrier strength, integrity and function, and diet is considered the main environmental factor impacting gut microbiota. Over the last few years, researchers have focused on the influence of single components of the diet in the modulation of intestinal microbiota in RA rather than whole dietary patterns. In this review, we focus on how the Mediterranean diet (MD), a whole dietary pattern, could possibly act as an adjuvant therapeutic approach, modulating intestinal microbiota and intestinal barrier function in order to improve RA-related outcomes. We also review the potential effects of particular components of the MD, such as n-3 polyunsaturated fatty acids (PUFAs), polyphenols and fibre.

ObjectivesThe classification of disease activity states in rheumatoid arthritis (RA) can be achieved through disease activity indices, such as the Disease Activity Score in 28 joints erythrocyte sedimentation rate (DAS28-ESR), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI). Subjective measurements, such as patient reported outcomes have been incorporated into several of these indices alongside more objective assessments, such as increases in the ESR and C-reactive protein. Moreover, while they use similar criteria, different indices weight these criteria to different extents. Therefore, the classifications based on each evaluation may not always be the same. We aim to compare the performance of the three indices and their individual components in two different populations.MethodsData from Dutch and Portuguese adherent centers were extracted from the METEOR database, a multinational collaboration on RA. We included a total of 24,605 visits from Dutch centers (from 5,870 patients) and 20,120 visits from Portuguese centers (from 3,185 patients). We compared the disease activity states as evaluated by the DAS28-ESR, CDAI, and SDAI across the two populations. In addition, we analyzed the individual components of each evaluation, including their respective contributions to the outcome, in each population.ResultsWe found significant differences in the disease activity states classified with the DAS28-ESR between the two populations. SDAI and CDAI had more congruous results. While the proportion of visits to Dutch and Portuguese centers that were classified as “in remission” was very similar between the CDAI and SDAI, the DAS28-ESR gave discordant results. Dutch patients had lower ESRs, which is more heavily weighted in the DAS28-ESR. In addition, even though the mean physicians’ global assessment values did not vary significantly for Dutch vs Portuguese physicians, we found that doctors at Portuguese centers overall scored the physician’s global assessment lower than Dutch physicians for patient visits classified by disease activity state.ConclusionWhile the CDAI and SDAI assigned disease activity states that were largely similar, the DAS28-ESR was often discordant across the two populations. Moreover, we found that physicians, more than patients, evaluated disease activity differently among the Portuguese and Dutch populations.

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The Portuguese Society of Rheumatology and the Portuguese Society of Pulmonology have updated the guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (ATB) in patients with inflammatory joint diseases (IJD) that are candidates to therapy with tumour necrosis factor alpha (TNFá) antagonists. In order to reduce the risk of tuberculosis (TB) reactivation and the incidence of new infections, TB screening is recommended to be done as soon as possible, ideally at the moment of IJD diagnosis, and patient assessment repeated before starting anti -TNFá therapy. Treatment for ATB and LTBI must be done under the care of a TB specialist. When TB treatment is indicated, it should be completed prior to starting anti-TNFá therapy. If the IJD activity justifies the need for immediate treatment, anti-TNFá therapy can be started two months after antituberculous therapy has been initiated, in the case of ATB, and one month after in the case of LTBI. Chest X -ray is mandatory for all patients. If Gohn’s complex is present, the patient should be treated for LTBI; healed lesions require the exclusion of ATB. In cases of suspected active lesions, ATB should be excluded/confirmed and adequate therapy initiated. Tuberculin skin test, with two units of RT23, should be performed in all patients. If the induration is A Sociedade Portuguesa de Reumatologia e a Sociedade Portuguesa de Pneumologia actualizaram as recomendações para o diagnóstico e a terapêutica das tuberculoses latente (TL) e activa (TD) em doentes com doenças inflamatórias articulares (DIA), candidatos a tratamento com antagonistas do factor de necrose tumoral alfa (TNFá). Com o objectivo de reduzir o risco de reactivação da tuberculose (TB) ou nova infecção, recomenda-se o rastreio de TD e TL tão precocemente quanto possível, preferencialmente no momento do diagnóstico da DIA, e repetir a avaliação do doente antes de iníciar terapêutica anti-TNFá. O tratamento da TD e TL deve ser sempre supervisionado por um especialista em TB. Quando houver indicação para terapêutica de TB, esta deverá ser cumprida integralmente antes de se iniciar o anti -TNFá. No caso da actividade da DIA o exigir, o anti -TNFá poderá ser iniciado ap��s dois meses de terapêutica antibacilar, no caso de TD, ou após um mês, no caso de TL. Todos os doentes devem realizar radiografia do tórax. Alterações compatíveis com complexo de Gohn devem ser tratadas como TL. Lesões residuais obrigam a excluir TB activa. Se se suspeitar de lesões em actividade, o diagnóstico de TD deve ser excluido e o tratamento adequado instituído. A prova tuberculínica (PT), com 2 unidades de tuberculina RT23, deverá ser efectuada em todos os doentes. Se a induração for

Introduction. This study aimed to assess the genetic determinants of poor outcome in Portuguese patients with juvenile idiopathic arthritis (JIA). Methods. Our study was conducted in Reuma.pt, the Rheumatic Diseases Portuguese Register, which includes patients with JIA. We collected prospectively patient and disease characteristics and a blood sample for DNA analysis. Poor prognosis was defined as CHAQ/HAQ >0.75 at the last visit and/or the treatment with biological therapy. A selected panel of single nucleotide polymorphisms (SNPs) associated with susceptibility was studied to verify if there was association with poor prognosis. Results. Of the 812 patients with JIA registered in Reuma.pt, 267 had a blood sample and registered information used to define “poor prognosis.” In univariate analysis, we found significant associations with poor prognosis for allele A of TNFA1P3/20 rs6920220, allele G of TRAF1/C5 rs3761847, and allele G of PTPN2 rs7234029. In multivariate models, the associations with TRAF1/C5 (1.96 [1.17–3.3]) remained significant at the 5% level, while TNFA1P3/20 and PTPN2 were no longer significant. Nevertheless, none of associations found was significant after the Bonferroni correction was applied. Conclusion. Our study does not confirm the association between a panel of selected SNP and poor prognosis in Portuguese patients with JIA.

We have previously found in the chronic SKG mouse model of arthritis that long standing (5 and 8 months) inflammation directly leads to high collagen bone turnover, disorganization of the collagen network, disturbed bone microstructure and degradation of bone biomechanical properties. The main goal of the present work was to study the effects of the first days of the inflammatory process on the microarchitecture and mechanical properties of bone.Twenty eight Wistar adjuvant-induced arthritis (AIA) rats were monitored during 22 days after disease induction for the inflammatory score, ankle perimeter and body weight. Healthy non-arthritic rats were used as controls for compar-ison. After 22 days of disease progression rats were sacrificed and bone samples were collected for histomorphometrical, energy dispersive X-ray spectroscopical analysis and 3-point bending. Blood samples were also collected for bone turnover markers.AIA rats had an increased bone turnover (as inferred from increased P1NP and CTX1, p = 0.0010 and p = 0.0002, respectively) and this was paralleled by a decreased mineral content (calcium p = 0.0046 and phos-phorus p = 0.0046). Histomorphometry showed a lower trabecular thickness (p = 0.0002) and bone volume (p = 0.0003) and higher trabecular sepa-ration (p = 0.0009) in the arthritic group as compared with controls. In addition, bone mechanical tests showed evidence of fragility as depicted by diminished values of yield stress and ultimate fracture point (p = 0.0061 and p = 0.0279, re-spectively) in the arthritic group.We have shown in an AIA rat model that arthritis induc-es early bone high turnover, structural degradation, mineral loss and mechanical weak-ness.

A Sociedade Portuguesa de Reumatologia (SPR) e a Sociedade Portuguesa de Pneumologia (SPP) elaboraram recomendações para o diagnóstico e terapêutica da tuberculose latente (TL) e activa (TD) em doentes com doenças inflamatórias articulares (DIA), nomeadamente artrite reumatóide, artrite psoriática e espondilite anquilosante, tratadas com antagonistas do factor de necrose tumoral alfa (TNF-á). Devido ao elevado risco de tuberculose (TB) em doentes com DIA deverá proceder-se ao rastreio de TD e TL tão precocemente quanto possível, preferencialmente no momento do diagnóstico da doença reumática. No entanto, e mesmo que o rastreio já tenha sido efectuado no início da doença, a avaliação deverá ser repetida antes do início da terapêutica anti-TNFá. Sempre que houver indicação para terapêutica de tuberculose (TL ou TD), esta deverá ser, de preferência, cumprida integralmente antes de se iniciar o anti-TNF-á. No caso da actividade da DIA o exigir, o anti-TNF-á poderá ser iniciado ao fim de dois meses de terapêutica antibacilar, no caso de TD, ou ao fim de um mês, no caso de TL. Todos os doentes devem realizar radiografia do tórax. Alterações compatíveis com complexo de Gohn devem ser tratadas como TL. Lesões residuais obrigam a excluir TB em actividade e se se detectar história anterior de TB não tratada ou tratada de forma incorrecta ou incompleta, esta deverá ser tratada como TL. Se se suspeitar de lesões em actividade, o diagnóstico de TD deve ser confirmado e o tratamento adequado instituído. A prova tuberculínica (PT), com 2 Unidades de Tuberculina RT23, deverá ser efectuada em todos os doentes. Se a induração for inferior a 5 mm, a prova deve ser repetida 1 a 2 semanas depois, no antebraço oposto, e considerada negativa se o segundo resultado for igualmente inferior a 5 mm. As PT positivas obrigam a tratamento de TL. Se a PT é realizada em fase de imunodepressão, o doente deve ser submetido a tratamento de TL antes de iniciar terapêutica anti-TNF-á, mesmo que a prova seja negativa.The Portuguese Society of Rheumatology (SPR) and the Portuguese Society of Pulmonology (SPP) have developed guidelines for the diagnosis and treatment of latent tuberculosis infection (LTBI) and active tuberculosis (AT) in patients with inflammatory joint diseases (IJD), namely rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis, treated with tumour necrosis factor alpha (TNF-á) antagonists. Due to the high risk of tuberculosis (TB) in patients with IJD, LTBI and AT screening should be performed as soon as possible, ideally at the moment of IJD diagnosis. Even if TB screening was performed at the beginning of the disease, the evaluation should be repeated before starting anti-TNF-á therapy. When TB (LTBI or AT) treatment is indicated, it should be performed before the beginning of anti-TNF-á therapy. If the IJD activity requires urgent anti-TNF-á therapy, these drugs can be started after two months of antituberculosis therapy in AT cases, or after one month in LTBI cases. Chest X-ray is mandatory for all patients. If abnormal, e.g. Gohn complex, the patient should be treated as LTBI; residual lesions require the exclusion of AT and patients with history of untreated or incomplete TB treatment should be treated as LTBI. In cases of suspected active lesions, AT diagnosis should be confirmed and adequate therapy initiated. Tuberculin skin test (TST), with two units of RT23, should be performed in all patients. If induration is less than 5 mm, the test should be repeated after 1 to 2 weeks, on the opposite forearm, and should be considered negative if the result is again inferior to 5 mm. Positive TST implicates LTBI treatment. If TST is performed in immunosupressed IJD patients, LTBI treatment should be offered to the patient before starting anti-TNFá therapy, even in the presence of a negative test.

INTRODUÇÃO “Without publication, science is dead”. Scientific American, Gerard Piel. A actividade científica é tradicionalmente medida pelo número de artigos publicados em revistas com arbitragem científica (peer review). Publish or Perish - todos nós já ouvimos ou lemos estas palavras. O número e qualidade de artigos publicados são factores relevantes que podem decidir uma carreira. A autoria de publicações peer reviewed é uma métrica de sucesso. Aprender a estruturar, submeter e rever um artigo, são competências que desde cedo devem ser desenvolvidas nas Escolas Médicas. Produzir um mau manuscrito só atrasará ou evitará a publicação de bom material científico. Investigação que não é nova, inovadora ou interessante, também não será publicada numa revista de reputação. Com este documento pretendemos dinamizar a publicação de bons artigos científicos realçando que há muitas maneiras de se certificar que um manuscrito não é rejeitado antes de ser submetido ao peer review.

Introduction: Osteoporosis is a bone metabolic disease with increasing prevalence in ageing societies. Herein we reviewed recent epidemiologic findings and their impact in the individual patient management. In addition we dissected the major disease mechanisms which have uncovered new potential therapeutic strategies. Material and Methods: Using MeSH terms (osteoporosis, epidemiology, Portugal, Europe, pathogenesis, osteoblasts, osteoclasts, osteocytes, immune system, obesity, therapy, randomized controlled trial, efficacy, safety) as keywords. We have reviewed original studies, reviews and position papers indexed in PubMed. Results: Osteoporosis is increasingly prevalent, but recently an age-adjusted rate of fracture plateau was reached. A new fracture risk assessment tool was developed, FRAX™, which integrates the contribution of clinical risk factors associated with fragility fractures. It can be used either independently or in combination with bone mineral density. Osteoporosis treatment is offered only to a fraction of the affected individuals. In addition, 40% of the patients receiving Osteoporosis medication had a previous fracture. Relevant safety issues of different drugs used in Osteoporosis have been detected in post-marketing experience. Finally, advances in the understanding of the molecular pathways involved in Osteoporosis led to the development of new drugs. Discussion and Conclusion: Despite the existence of diagnostic tools and several effective treatments, Osteoporosis treatment is still offered only to a fraction of the affected individuals and mainly to a population with advanced disease. New and more effective treatments might change this scenario.