Children with extended oligoarticular and polyarticular juvenile idiopathic arthritis have alterations in B and T follicular cell subsets in peripheral blood and a cytokine profile sustaining B cell activation.

OBJECTIVES: The main goal of this study was to characterise the frequency and phenotype of B, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in peripheral blood and the cytokine environment present in circulation in children with extended oligoarticular juvenile idiopathic arthritis (extended oligo JIA) and polyarticular JIA (poly JIA) when compared with healthy controls, children with persistent oligoarticular JIA (persistent oligo JIA) and adult JIA patients. METHODS: Blood samples were collected from 105 JIA patients (children and adults) and 50 age-matched healthy individuals. The frequency and phenotype of B, Tfh and Tfr cells were evaluated by flow cytometry. Serum levels of APRIL, BAFF, IL-1ß, IL-2, IL-4, IL-6, IL-10, IL-17A, IL-21, IL-22, IFN-γ, PD-1, PD-L1, sCD40L, CXCL13 and TNF were measured by multiplex bead-based immunoassay and/or ELISA in all groups included. RESULTS: The frequency of B, Tfh and Tfr cells was similar between JIA patients and controls. Children with extended oligo JIA and poly JIA, but not persistent oligo JIA, had significantly lower frequencies of plasmablasts, regulatory T cells and higher levels of Th17-like Tfh cells in circulation when compared with controls. Furthermore, APRIL, BAFF, IL-6 and IL-17A serum levels were significantly higher in paediatric extended oligo JIA and poly JIA patients when compared with controls. These immunological alterations were not found in adult JIA patients in comparison to controls. CONCLUSIONS: Our results suggest a potential role and/or activation profile of B and Th17-like Tfh cells in the pathogenesis of extended oligo JIA and poly JIA, but not persistent oligo JIA.

Eosinophilic Granulomatosis with Polyangiitis - description of a pediatric patient with severe disease.

INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare vasculitis of small and medium sized blood vessels. CASE DESCRIPTION: Thirteen-year-old male, with history of rhinitis and asthma, who presented to the emergency room with one week of asthenia, arthralgias and myalgias and two days of fever. A diffuse petechial rash, palpable purpura and polyarthritis were detected on examination. Leukocytosis (34990/µL) with eosinophilia (66%) and elevated C-reactive protein were identified. The patient was admitted and ceftriaxone and doxycycline were started. The clinical status deteriorated in the following days. The patient developed myopericarditis, bilateral pulmonary infiltrates and pleural effusion, requiring mechanical ventilation and aminergic support. Non-clonal eosinophils were detected on the bone marrow aspiration and the skin biopsy showed leukocytoclastic vasculitis with eosinophils. Antineutrophil cytoplasmic antibodies and genetic analysis for hypereosinophilic syndrome mutations were negative. After treatment with methylprednisolone for three days a fast clinical, laboratory and radiological improvement occurred. The patient started azatiophrine and reduced steroids progressively. No relapses occurred since diagnosis five years ago. DISCUSSION: Clinical suspicion and early treatment of EGPA are crucial to improve prognosis.

The 2021 Portuguese Society of Ophthalmology joint guidelines with Paediatric Rheumatology on the screening, monitoring and medical treatment of juvenile idiopathic arthritis-associated uveitis.

AIM: To develop the first Ophthalmology joint guidelines with Paediatric Rheumatology with recommendations on the screening, monitoring and medical treatment of juvenile idiopathic arthritis-associated uveitis (JIA-U), endorsed by the Portuguese Society of Ophthalmology (SPO). METHODS: A systematic literature review was conducted to include publications up to July 14th 2020, with no language restrictions, in order to include all the international position papers/guidelines concerning the medical management of JIA-U and randomised clinical trials assessing the efficacy and safety of medical treatment in this field. We searched through MEDLINE (PubMed), Scopus, Web of Science and Cochrane Library. The Delphi modified technique to generate consensus was used. Preliminary evidence statements were subject to an anonymous agreement assessment and discussion process using an online survey, followed by further discussion and update at a national meeting. A draft of the manuscript with all recommendations was then circulated among all participants and suggestions were incorporated. The final version was again circulated before publication. RESULTS: Twenty-six recommendations were developed focusing on the following topics: general management (3), screening and follow-up of uveitis (4), treatment (17) and health education in JIA-U among patients and families (2). CONCLUSION: These guidelines were designed to support the shared medical management of patients with JIA-U and emphasize the need for a multidisciplinary approach between Ophthalmology and Paediatric Rheumatology regarding the comprehensive care of JIA-U. We acknowledge that updating these recommendations will be warranted in the future, as more evidence becomes available. KEY-WORDS: juvenile idiopathic arthritis, uveitis, biological treatment, conventional immunosuppressive treatment, multidisciplinary management, guidelines, consensus, review, Delphi Technique.

The Added Value of a Multidisciplinary Clinic for Systemic Autoinflammatory Diseases.

Background: Systemic autoinflammatory diseases (SAID) are characterized by inappropriate activation of the innate immune system and include not only monogenic periodic fever syndromes but also multifactorial conditions. As SAID are rare and represent a diagnostic challenge, a multidisciplinary approach is important to ensure successful diagnosis and adequate follow-up of these patients. Objective: To describe the organization of our multidisciplinary SAID clinic and to characterize our clinical experience, highlighting the benefits of multidisciplinary team management. Methods: Our SAID clinic takes place monthly and is managed by pediatric rheumatologists closely collaborating with pediatricians specialized in infectious diseases and immunodeficiencies and one medical geneticist. Patients' data are systematically incorporated in the Rheumatic Diseases Portuguese Register (Reuma.pt). Biological samples are stored in a biobank. We describe our clinical experience based on SAID patients registered into Reuma.pt/SAID between July 2011 and June 2020. Results: We have registered 176 patients, with a median age of disease onset of 3.1 ± 4.4 years and median age at disease diagnosis of 4.7 ± 4.0 years. Most patients were diagnosed with periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA) (n=133), 20 with undefined SAID (uSAID) and 13 with monogenic SAID, including familial Mediterranean fever (FMF) (n=5), tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (n=1), cryopyrin-associated periodic disease (CAPS) (n=1), and hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD) (n=2). A genetic test was performed in 31 patients (18%), and in 26% of these a mutation responsible for the phenotype was found. Thirty-four patients (19%) achieved remission. Conclusion: FMF was the most common monogenic SAID and the percentage of patients with an identified causal mutation was low. A structured electronic clinical record coupled with a biobank and a multidisciplinary approach are crucial to ensure successful diagnosis and adequate follow-up of these patients.

Spotlight on latent tuberculosis infection screening for juvenile idiopathic arthritis in two countries, comparing high and low risk patients

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 < 0.001). Isoniazid therapy was prescribed in 40 (13.7%) patients (31 with LTBI and 9 with epidemiologic risks and/or due to contact with sick people). Only three patients (1%) developed active TB. Conclusion: We found nearly 10% of patients with LTBI, a small percentage of patients with treatment due to epide-miologic risks and only 1% with active TB. Distinct reasons and screening methods for LTBI were observed between the two countries.

Sinus node disfunction in an adolescent with systemic lupus erythematosus.

Cardiac involvement in systemic lupus erythematosus (SLE) is well documented. The pericardium, myocardium and endocardium, as well as the coronary arteries, the valves and the conduction system can all be affected. While pericarditis is common, arrythmias are less frequently described.We present a 13-year-old male, who had fatigue, anorexia, weight loss, myalgias and arthralgias for four months. On physical examination, we identified bradycardia (heart rate 31-50 bpm), oral and nasal ulcers and polyarthritis. The laboratory results showed hemolytic anemia, hypocomplementemia, antinuclear and anti-dsDNA antibodies, hematuria and non-nephrotic proteinuria. Renal function was normal. Lupus nephritis class II was diagnosed by kidney biopsy. On the transthoracic echocardiogram we identified a minimal pericardial effusion, suggesting pericarditis, and, on the electrocardiogram, we detected sinus arrest with junctional rhythm, denoting sinus node dysfunction. The patient was diagnosed with juvenile SLE with cardiac, renal, musculoskeletal and hematologic involvement. Disease remission and cardiac rhythm control were obtained with steroids and mycophenolate mofetil. Currently, the patient is asymptomatic, with normal sinus rhythm.We described an adolescent with SLE who had sinus node dysfunction upon diagnosis. Other cases have been reported in adults but none in juvenile SLE. All SLE patients should have a thorough cardiac examination to promptly diagnose and treat the innumerous cardiac manifestations of this disease.

Spondyloepiphyseal dysplasia type Stanescu: Expanding the clinical and molecular spectrum of a very rare type II collagenopathy.

Spondyloepiphyseal dysplasia type Stanescu (SED-S) is a very rare type II collagenopathy. We describe an 8-year-old boy who presented with short trunk, C2-C3 vertebral fusion, hand, foot, leg and thigh pain, stiffness and limited joint mobility, and waddling gait. Radiographs showed platyspondyly with anterior wedging and endplate irregularities, broad femoral necks, and large epiphyses and epiphyseal equivalents. Differential diagnosis included progressive pseudorheumatoid dysplasia and SED-S. A skeletal dysplasia custom-designed NGS panel was performed and the heterozygous pathogenic variant c.620G>A; p.(Gly207Glu) in COL2A1 was detected, establishing the diagnosis of SED-S. Vertebral fusions, observed in our patient, have not been previously described in this dysplasia. This variant has not been previously associated with SED-S, but was reported in two other families with spondyloepiphyseal dysplasia. Thus, this case expands the clinical and mutational spectrum of SED-S and demonstrates that SED-S significantly overlaps with other skeletal dysplasias.

Tubulointerstitial nephritis and uveitis (TINU) syndrome: a review.

Inflammation of renal interstitium and uveal tissue establishes the two components of tubulointerstitial nephritis and uveitis (TINU) syndrome. Although believed to occur more frequently in young females, a broad spectrum of patients can be affected. Both renal and eye disease can be asymptomatic and may not manifest simultaneously, having independent progressions. Renal disease manifests as acute kidney injury and may cause permanent renal impairment. Eye inflammation can manifest in different anatomical forms, most commonly as bilateral anterior uveitis and may progress to a chronic course. TINU syndrome accounts for approximately 1%-2% of uveitis in tertiary referral centres. A literature review covering the clinical features, pathogenesis, diagnosis and treatment is presented.

Portuguese recommendations for the use of methotrexate in rheumatic diseases - 2016 update.

BACKGROUND: Methotrexate (MTX) is the first-line drug in the treatment of rheumatoid arthritis (RA) and the most commonly prescribed disease modifying anti-rheumatic drug. Moreover, it is also used as an adjuvant drug in patients under biologic therapies, enhancing the efficacy of biologic agents. OBJECTIVES: To review the literature and update the Portuguese recommendations for the use of MTX in rheumatic diseases first published in 2009. METHODS: The first Portuguese guidelines for the use of MTX in rheumatic diseases were published in 2009 and were integrated in the multinational 3E Initiative (Evidence Expertise Exchange) project. The Portuguese rheumatologists based on literature evidence and consensus opinion formulated 13 recommendations. At a national meeting, the recommendations included in this document were further discussed and updated. The document resulting from this meeting circulated to all Portuguese rheumatologists, who anonymously voted online on the level of agreement with the updated recommendations. RESULTS: Results presented in this article are mainly in accordance with previous guidelines, with some new information regarding hepatitis B infection during MTX treatment, pulmonary toxicity monitoring, hepatotoxicity management, association with hematologic neoplasms, combination therapy and tuberculosis screening during treatment. CONCLUSION: The present recommendations combine scientific evidence with expert opinion and attained desirable agreement among Portuguese rheumatologists. The regular update of these recommendations is essential in order to keep them a valid and useful tool in daily practice.

Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma.pt.

OBJECTIVES: Assess the effectiveness and safety of biologic therapy as well as predictors of response at 1 year of therapy, retention rate in biologic treatment and predictors of drug discontinuation in JIA patients in the Portuguese register of rheumatic diseases. METHODS: We prospectively collected patient and disease characteristics from patients with JIA who started biological therapy. Adverse events were collected during the follow-up period. Predictors of response at 1 year and drug retention rates were assessed at 4 years of treatment for the first biologic agent. RESULTS: A total of 812 JIA patients [65% females, mean age at JIA onset 6.9 years (s.d. 4.7)], 227 received biologic therapy; 205 patients (90.3%) were treated with an anti-TNF as the first biologic. All the parameters used to evaluate disease activity, namely number of active joints, ESR and Childhood HAQ/HAQ, decreased significantly at 6 months and 1 year of treatment. The mean reduction in Juvenile Disease Activity Score 10 (JADAS10) after 1 year of treatment was 10.4 (s.d. 7.4). According to the definition of improvement using the JADAS10 score, 83.3% respond to biologic therapy after 1 year. Fourteen patients discontinued biologic therapies due to adverse events. Retention rates were 92.9% at 1 year, 85.5% at 2 years, 78.4% at 3 years and 68.1% at 4 years of treatment. Among all JIA subtypes, only concomitant therapy with corticosteroids was found to be univariately associated with withdrawal of biologic treatment (P = 0.016). CONCLUSION: Biologic therapies seem effective and safe in patients with JIA. In addition, the retention rates for the first biologic agent are high throughout 4 years.