Application of the new PRINTO classification criteria for juvenile idiopathic arthritis in a sample of Portuguese patients.

BACKGROUND: The International League of Associations for Rheumatology (ILAR) classification system for juvenile idiopathic arthritis (JIA) does not depict homogenous subgroups of disease. As to unify our language with the adult rheumatic diseases, the Pediatric Rheumatology International Trials Organization (PRINTO) is attempting to revise these criteria. OBJECTIVE: To reclassify a JIA sample according to the new provisional PRINTO subsets: systemic JIA (sJIA), RF-positive JIA (RF-JIA), early-onset ANA-positive JIA (eoANA-JIA), enthesitis/spondylitis-related JIA (ESR-JIA), "other JIA" and "unclassified JIA". METHODS: Retrospective study including JIA patients followed in a Pediatric Rheumatology Unit at a university hospital. Medical records were reviewed, and patients were reclassified as per the provisional PRINTO criteria. RESULTS: Of a total of 104 patients, 41 (39.4%) were reclassified as "other JIA", 36 (34.6%) as eoANA-JIA, 15 (14.4%) as ESR-JIA, 8 (7.7%) as sJIA and 4 (3.8%) as RF-JIA. More than 90% of the oligoarticular JIA were reclassified into either eoANA-JIA or "other JIA". Only one negative RF polyarticular JIA converted to RF-JIA due to the presence of a positive anti-citrulinated peptide antibody (ACPA). The psoriatic arthritis (PsA) subgroup disappeared into eoANA-JIA (25%), ESR-JIA (25%) or "other JIA" (50%). There were significant differences in age of onset, but not on the gender ratio or uveitis presence. Antinuclear antibody was more frequent in females (p=0.035) and younger patients (p<0.001). CONCLUSION: The number of affected joints and PsA features elapsed in favour of laboratory RF, ACPA and ANA traits. PsA and oligoarticular JIA were abolished. The "other JIA" entity is heterogenous and prevalent, claiming reformulation.

Touraine-Solente-Gole syndrome: pathogenic variant in SLCO2A1 presented with polyarthralgia and digital clubbing.

BACKGROUND: Primary Hypertrophic Osteoarthropathy (PHO), also known as Touraine-Solente-Gole Syndrome, is a rare, multisystemic autosomal recessive disorder caused by pathogenic variants in the 15-hydroxyprostaglandin dehydrogenase (HPGD) or Solute Carrier Organic Anion Transporter Family Member 2A1 (SLCO2A1) genes. However, autosomal dominant transmission has also been described in some families with incomplete penetrance. PHO usually starts in childhood or adolescence, presenting with digital clubbing, osteoarthropathy, and pachydermia. We described a complete form of the syndrome in a male patient with a homozygous variant in the SLCO2A1 gene (c.1259G > T). CASE PRESENTATION: A 20-year-old male was referred to our Pediatric Rheumatology Clinic with a five-year history of painful and swollen hands, knees, ankles and feet, prolonged morning stiffness and relief with non-steroidal antiinflammatory drugs. He also reported late onset facial acne and palmoplantar hyperhidrosis. Family history was irrelevant and parents were non-consanguineous. On clinical examination, he presented clubbing of the fingers and toes, moderate acne and marked facial skin thickening with prominent scalp folds. He had hand, knee, ankles and feet swelling. Laboratory investigations showed elevated inflammatory markers. Complete blood count, renal and hepatic function, bone biochemistry were normal, as well as immunological panel. Plain radiographs revealed soft tissue swelling, periosteal ossification and cortical thickening of the skull, phalanges, femur and toe acroosteolysis. Due to the absence of other clinical signs suggesting a secondary cause, we suspected PHO. A genetic study revealed a likely pathogenic variant, c.1259G > T(p.Cys420Phe), in homozygosity in the SLCO2A1 gene, thus confirming the diagnosis. The patient started oral naproxen with significant clinical improvement. CONCLUSIONS: PHO should be kept in the differential diagnosis of inflammatory arthritis affecting children, often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). To the best of our knowledge, this is the second genetically confirmed case of PHO in a Portuguese patient (first variant c.644 C > T), both made at our department.

Outcome of Uveitis in Juvenile Idiopathic Arthritis and Spondyloarthritis Patients - A 5-Year Follow-Up Study.

OBJECTIVE: Uveitis is a frequent complication of juvenile idiopathic arthritis (JIA) and spondyloarthritis (SpA). The aim of this study is to evaluate the prevalence and risk factors for complications associated with uveitis in patients with JIA and SpA. METHODS: A longitudinal, monocentric cohort study that included patients diagnosed with JIA and SpA who developed uveitis. Demographic, laboratory, and clinical data were collected including complications of uveitis, HLA-B27, antinuclear antibodies, erythrocyte sedimentation rate, C-reactive protein, visual acuity and DMARD treatment. Comparison between groups (complicated versus uncomplicated uveitis) was evaluated using chi-square, t test and Mann-Whitney U test. Logistic regression was performed to determine predictors of complications. RESULTS: A total of 270 patients were evaluated, of which 37 patients (13.7%) had uveitis and were included in this study. Twenty patients were female (54.1%), aged 11.9±8.7 years at diagnosis of SpA/JIA and 15.3±9.9 years at diagnosis of uveitis. Twenty-seven patients (73.0%) had a diagnosis of JIA (23 with oligoarticular disease) and in 12 patients (32.4%) uveitis was the first manifestation. Fifteen (40.5%) patients exhibited complications during follow-up period. Eleven patients (29.7%) underwent ophthalmologic surgery. Complications were significantly higher in patients with JIA (51.9% vs 10.0% in SpA, p=0.03), as was the need for surgery (40.7% vs 0%, p=0.02). Complications in JIA were significantly more frequent in patients who had uveitis as the initial presentation (50.0% vs 7.7%, p=0.03); no significant differences were found between the groups in the other variables studied. Univariate logistic regression analysis showed that uveitis as the first manifestation of JIA (OR 12.0, confidence interval 95% 1.21-118.89, p=0.03) is a significant predictor of complications. CONCLUSION: We found higher rates of complications and need for ophthalmologic surgery in patients with JIA-associated uveitis. The initial presentation of JIA as uveitis is significantly associated with the occurrence of uveitis complications, so it is essential that there is a collaboration between ophthalmologist and rheumatologist in the diagnosis and treatment of these patients.

Biotechnological therapeutic in Juvenile Idiopathic Arthritis: Pathophysiological implications and targeted therapies.

Objective In this retrospective cohort study, we aim to investigate the most used biological disease modifying anti-rheumatic drugs (bDMARDs) in Juvenile Idiopathic Arthritis (JIA) patients in a pediatric rheumatologic unit from a Portuguese tertiary hospital, along with their effectiveness and safety. We also intended to link their effectiveness and the pathophysiology of the disease. Methods The medical records of JIA patients exposed to bDMARDs, between January 2018 and January 2023, in a pediatric rheumatologic unit from a Portuguese tertiary hospital were reviewed. Therapy effectiveness was accessed based on achievement of inactive disease according to Wallace Criteria. Effectiveness of different bDMARDs in the several JIA subtypes was linked to the disease´s pathophysiology. Adverse effects were also reviewed. Results Thirty-four patients were included in the study. Overall, nineteen patients (67,9%) had inactive disease at last evaluation. Six patients with missing data on inactive disease status were excluded from this analysis. Number of affected joints, ESR and CRP were significantly lower at 3, 6, 12 and 24 months after bDMARD therapy. All systemic JIA patients (n=10) were initially treated with Anakinra. Six (60%) achieved inactive disease. Two (20%) switched to Tocilizumab due to ineffectiveness in the control of articular features. Patients who switched to tocilizumab achieved inactive disease until the end of the follow-up. All patients with the other subtypes of JIA (n=24) were treated with TNF inhibitors. Inactive disease was achieved in 55,6%. Adverse effects occurred in eight patients (23,5%). Conclusions The results of the present study demonstrate the effectiveness of bDMARs in the study population. bDMARDs reduced the number of affected joints, CRP and ESR after three months of treatment, and this effectiveness was sustained over the two years of follow-up. For systemic JIA, preferred drug was Anakinra, an interleukin 1 inhibitor, and its effectiveness was consistent with previous studies. In the other JIA subtypes, TNF inhibitors were the most used bDMARDs, and showed an effectiveness consistent with previous studies. The most used bDMARDs for each JIA subtype are in line with pathophysiological differences. Our results demonstrated the safety of these drugs.

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.

Two cases of ADA2 deficiency presenting as childhood polyarteritis nodosa: novel ADA2 variant, atypical CNS manifestations, and literature review.

Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease resulting from loss-of-function pathogenic variants in ADA2 gene, which might resemble polyarteritis nodosa (PAN). The authors present two pediatric cases of ADA2 deficiency with phenotypic manifestations of PAN, including an unusual presentation with spinal cord ischemia. Also described is an assessment of ADA2 activity and gene expression profiling with description of a previously unreported homozygous variant, c.1226C > A (p.(Pro409His)), detected in a patient with consanguineous parents, confirmed by near-absent ADA2 plasma enzymatic activity. The authors suggest to first obtain enzymatic activity, whenever DADA2 is suspected, before proceeding to genetic testing, due to its excellent cost-effective results. Moreover, physicians must be aware of this monogenic disorder, especially in the case of early-onset PAN-like manifestations, having a family member with similar manifestations or having consanguineous parents suggesting an autosomal recessive inheritance pattern. Given the multi-organ involvement, recognizing the diverse manifestations is a crucial step towards timely diagnosis and management of this potentially fatal but often treatable syndrome.

Bone biopsy: an ally in the management of fragility fractures in chronic kidney disease.

Patients with chronic kidney disease (CKD) have an increased susceptibility to fracture and this risk gradually rises as renal disease progresses. Chronic Kidney Disease-Mineral and Bone Disorder (CKD- MBD) encompasses the mineral, bone, hormonal and calcific cardiovascular abnormalities that develop in these patients. Renal osteodystrophy (ROD) corresponds to the histopathologic description of bone lesions associated with CKD-MBD. Fragility fracture approach in CKD stages 1-3a may be similar to that of the general population. However, in stages 3b-5, osteoporosis cannot be established by the World Health Organization (WHO) criteria based on bone mineral density (BMD) or the presence of fragility fractures, because low BMD and fractures can also occur in the different forms of ROD. The gold standard for the diagnosis and classification of ROD is tetracycline double-labelled transiliac bone biopsy, with bone histology and histomorphometric analysis. By informing on bone turnover, mineralization and volume, it is a valuable tool that may help guide the management of CKD patients with fragility fractures, as therapeutic measures are distinct depending if the patient has osteoporosis or one of the forms of ROD. For patients with stages 1-3 CKD, without biochemical abnormalities suggestive of CKD-MBD, who sustained low-trauma fractures, any therapeutic approved for use in osteoporosis could be used. However, there is little evidence for the efficacy and safety of conventional anti-osteoporotic agents in patients with more advanced CKD stages, so currently the approach is opinion-based and must be patient-tailored depending on the presence or absence of ROD.

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.

Trombose intracardíaca na doença de Behçet: evento com risco de vida.

An adolescent with a recent diagnostic of Behçet's Disease (BD) was admitted with fever and intracardiac lesions detected on a routine transthoracic echocardiography, suggestive of endocarditis. Due to the absence of improvement after several rounds of antibiotics the patient was submitted to contrast-enhanced cardiac MRI that showed signs of intracardiac thrombosis, superior vena cava syndrome and pulmonary thromboembolism. The patient underwent surgery to excise the lesions and has been treated with cyclophosphamide and high dose prednisolone achieving complete remission. Intracardiac thrombosis is a rare manifestation of BD, and is associated with a poor prognosis. These patients usually require a combination of anticoagulation and immunosuppression to achieve remission.

Amyloidosis secondary to rheumatic diseases - 16 cases.

INTRODUCTION: Secondary amyloidosis (SA) results of tissue deposition of an acute phase reactant protein produced by chronic inflammation. Its incidence appears to be declining, following the improvement of medical care to primary diseases. Our aim is to assess a group of Portuguese patients with amyloidosis secondary to inflammatory rheumatic diseases, and their evolution over the past 10 years. METHODS: The study comprised 16 patients with SA confirmed by tissue biopsy, hospitalized in the Rheumatology Department of Hospital São João in Oporto in the last 10 years. We made a protocol on epidemiological, clinical and analytical data focusing the rheumatic disease and SA, and possible elements of connection between them. RESULTS: Of the 16 patients, mainly women (81,2%), with mean age at entry of 56 years, 68,8% had rheumatoid arthritis. Amyloidosis was diagnosed in average at 13,5 years of primary rheumatic disease, and its main manifestation was kidney involvement, which together with infection and orthopaedic surgery or its complications, were the leading causes of hospitalization. In this time interval, 6 patients died. They were older, with longer duration and lower rate of treatment of the primary rheumatic disease, and had SA diagnosed 1,5 years before death (different of the 5 years of those that still alive). They had higher rate of gastrointestinal, neurological and serious kidney involvement, and hospitalizations. CONCLUSIONS: Improving medical care in rheumatic inflammatory diseases has reduced the incidence of SA. Also, biotherapy appears to be achieving positive results in established amyloidosis, whatever the mechanisms involved. Our data, on Portuguese patients, seems to follow this trend.

Tumor necrosis factor-alpha -308 genotypes influence inflammatory activity and TNF-alpha serum concentrations in children with juvenile idiopathic arthritis.

OBJECTIVE: Considering the relevance of tumor necrosis factor-alpha (TNF-alpha) in the pathophysiology of juvenile idiopathic arthritis (JIA), it is likely that polymorphisms in its promoter area may be relevant in disease susceptibility and activity. We investigated if clinical measures of JIA activity and TNF-alpha serum concentrations were associated with TNF-alpha -308 genotypes. METHODS: Portuguese patients with JIA in 5 pediatric rheumatology centers were recruited consecutively, along with a control group of healthy subjects. Demographic and clinical data and blood samples were collected from each patient. DNA was extracted for analysis of TNF-alpha gene promoter polymorphisms at position -308 by restriction fragment-length polymorphism. RESULTS: One hundred fourteen patients and 117 controls were evaluated; 57% of patients presented the oligoarticular subtype, 25% the polyarticular subtype, 8% the systemic subtype, and 9% had enthesitis-related arthritis and 5% psoriatic arthritis. Twenty-four percent of the patients presented the -308 GA/AA genotypes and 76% the -308 GG genotype, similar to findings in controls. Patients with the -308 GA/AA genotype had higher degree of functional impairment, erythrocyte sedimentation rate, 100-mm visual analog scale score for disease activity, and TNF-alpha levels compared to those with the -308 GG genotype. CONCLUSION: TNF-alpha -308 GA/AA genotypes were found to be related to higher inflammatory activity and worse measures of disease activity in Portuguese patients with JIA. They were not associated with susceptibility to JIA.

[Six clinical cases of relapsing polychondritis: review]. / Policondrite recidivante: estudo retrospectivo de seis casos.

INTRODUCTION: Relapsing Polycondritis is a rare connective tissue disease of unknown aetiology that is manifested by inflammatory changes in cartilaginous tissues but the immune damage can spread and involve other tissues. MATERIAL AND METHODS: Six patients with relapsing poycondritis treated in our service, between 1990 and 2003, were reviewed. The clinical features, age of onset, time from onset to diagnosis, disease associations and treatment were focused. RESULTS: The female-to-male ratio in our series was 2:4, The median age onset of symptoms was 52 years. A diagnosis delay varied from 8 months to 4 years, with a median time of 18 months. All the five patients had auricular and nasal condritis, laringotracheal involvement was detected in four patients, arthralgia and arthritis also in four patients, cardiac involvement was present in two patients, myelodysplastic syndrome in one patient and ocular disease in four patients. CONCLUSION: This is small sample study that differs from other studies in sex distribution. This disease is more frequent in females and in our sample men were more affected. The clinical manifestations and disease associations were similar to other populations. Calling attention is the best way to diminish time to diagnosis of this rare pathology.

Systemic lupus erythematosus (SLE) presenting with nephrotic syndrome and membranous glomerulopathy in a 10-year-old girl.

UNLABELLED: The authors report the case of a 10-y-old girl with clinical diagnosis of systemic lupus erythematosus (SLE), made at the age of 6 y, based upon arthritis, serositis, haematological disorder and positive antinuclear antibody. The first manifestation of disease--Raynaud's phenomenon--appeared at the age of 4 y. Seven months after the diagnosis, she developed nephrotic proteinuria with haematuria. Percutaneous renal biopsy showed membranous glomerulonephritis, the least common form of lupus nephritis. CONCLUSION: Intravenous cyclophosphamide therapy associated with oral prednisolone proved effective in inducing complete remission of nephrotic syndrome.

[Synovial lipoma arborescens]. / Lipoma arborescente da sinovial.

Lipoma arborescens is a rare intraarticular lesion of unknown etiology. The disorder usually presents as painless swelling and recurrent joint effusion. It is typically located in the knee (especially the suprapatellar bursa), though it has also been described in other joints. Laboratory test results are normal, as well as aspirated synovial fluid. Synovectomy is curative in most cases. The authors report a review of the literature, highlighting the importance of magnetic resonance imaging in the diagnosis of this pathology. Although it is a rare lesion, synovial lipoma arborescens should be included in the differential diagnosis of patients with a chronic swollen joint or recurrent joint effusions.