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.

Anakinra and hepatotoxicity in pediatric rheumatology: a case series.

BACKGROUND: Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist used in systemic juvenile idiopathic arthritis (sJIA), refractory Kawasaki disease (KD) and cryopyrin-associated autoinflammatory syndrome (CAPS). Anakinra associated hepatotoxicity, while rare, has been described in several cases in daily practice. ​In this case series the authors describe three pediatric patients with this side effect in the setting of severe macrophage activation syndrome (MAS) in KD and sJIA. CASE PRESENTATION: The first patient was a 12-year-old boy who presented with fever, maculo-papular exanthema and polyarthralgia. Tonsillitis, distal limb induration and tender cervical lymph nodes were observed. Erythrocyte-sedimentation rate (ESR), C-reactive protein (CRP), ferritin (11,975 ng/mL), D-dimers (5,98 mg/L FEU) and soluble CD25 (3645 pg/mL) levels were elevated. Exclusion of sepsis / toxic shock syndrome warranted introduction of IV methylprednisolone and immunoglobulin (IG IV), with partial response. A MAS secondary to KD was assumed, and anakinra 2 mg/kg/day was introduced. Twenty days later he developed new-onset nausea and severe cyto-cholestasis, normalizing after 2 months of drug discontinuation. Posterior onset of polyarthritis and evanescent lead to a final diagnosis of sJIA. The second patient was a 2-year-old boy with a 10-day history of fevers, generalized rash, hepatosplenomegaly and strawberry tongue. Leucocytosis with neutrophilia and elevated CRP were observed. Initial treatment with IVIG in the setting of incomplete KD was ineffective. Mild anaemia, leukopenia and very high serum ferritin (maximum 26,128 ng/mL) ensued. Presumptive sJIA associated MAS was treated with IV methylprednisolone and anakinra 2 mg/kg/day, with prompt response. Four weeks later transaminitis was detected, and temporary anakinra suspension led to normalisation of laboratorial values. The third case related to a 4-year-old boy presenting with fever, maculopapular rash and cervical lymphadenopathy. CRP and ESR were elevated, and KD was diagnosed. IVIG and methylprednisolone were initiated with clinical worsening, warranting for anakinra introduction at 2 mg/kg/day. After three weeks, liver enzymes progressively elevated, resolving on 2 weeks of anakinra discontinuation. CONCLUSIONS: To the best of our knowledge, this is the first case series describing anakinra associated hepatotoxicity in pediatric patients with rheumatic diseases other than sJIA, bringing additional insight to therapeutic monitoring in patients undergoing this treatment.

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.

Cumulative dose and length of methotrexate treatment were not shown to be predictors of hepatic fibrosis by elastography - a monocentric cohort study.

OBJECTIVE: Methotrexate is used in several inflammatory diseases, such as rheumatoid arthritis (RA), spondyloarthritis (SpA) or inflammatory bowel disease (IBD). There has been some controversy regarding methotrexate liver toxicity, especially since the use of newer techniques. We aim to evaluate the prevalence of liver injury in methotrexate-treated patients with inflammatory diseases. METHODS: We performed a cross-sectional study where consecutive patients diagnosed with RA, SpA or IBD, treated with methotrexate, were submitted to liver elastography. The cutoff for fibrosis was ≥7.1 kPa. Comparisons between groups were evaluated using chi-square, t test and Mann-Whitney U test. Correlations were made between continuous variables using Spearman correlation. Logistic regression was performed to determine predictors of fibrosis. RESULTS: A total of 101 patients were included, 60 (59.4%) females, aged 46.2±12.6 years. Eleven patients (10.9%) had fibrosis, with a median score of 4.8 (4.1-5.9) kPa. Patients with fibrosis had higher rates of daily alcohol consumption (63.6% vs 31.1%, p=0.045). Methotrexate exposure time (OR 1.001, 95% CI 0.999-1.003, p=0.549) and cumulative dose (OR 1.000, 95% CI 1000-1000, p=0.629) were shown not to be predictors of fibrosis, unlike alcohol (OR 3.875, 95% CI 1.049-14.319, p=0.042). In multivariate logistic regression analysis, methotrexate cumulative and exposure times were not predictors of significant fibrosis, even when adjusted for alcohol consumption. CONCLUSIONS: In this study, we found that fibrosis detected on hepatic elastography was not associated with methotrexate, unlike alcohol. Therefore, it is of paramount importance to redefine risk factors for liver toxicity in patients with inflammatory diseases under treatment with methotrexate.

Demographic and clinical features of pediatric vasculitis: a single-center study.

INTRODUCTION: Vasculitides are rare systemic conditions which may occur in childhood. This study aims to document demographic and clinical features of systemic vasculitides in a tertiary center, comparing our outcomes with previously published studies of other international centers. METHODS: Patients presenting with systemic vasculitis before 18 years of age, admitted to a tertiary Portuguese center at diagnosis or during follow-up, from 2009 to 2020, were retrospectively included in this study. RESULTS: In our study, we included 138 patients. The youngest patients at diagnosis were in the Kawasaki's disease (KD) group, with a median age at diagnosis of 2.26 years old (IQR 1.07-6.20), as opposed to the Behçet's syndrome (BS) group with a median age at diagnosis of 13.41 years old (IQR 10.19-16.75), which was significantly higher (p 90% in both IgA Vasculitis (IgAV) and KD. Gastrointestinal symptoms were common in all groups (15-50%), rarer in BS (17%). Arthritis and arthralgia were highly prevalent in IgAV (65%). The American Heart Association criteria of diagnosis for complete KD were met in 62% of cases. No significant difference was found in age distribution between complete and incomplete diagnosis (p=0.616). Mean duration of fever in KD was 9.6 ±2.1 days, which was higher than anticipated. Renal manifestations in IgAV (11%) and ophthalmic involvement in BS (22%) were lower than expected. There was a notable number of children reporting joint involvement in KD (27%). We also noticed a slightly higher prevalence of vascular events in BS (30%). CONCLUSIONS: Each specific vasculitis assessed had different key symptoms, but there are several complaints and signs shown by our patients, some of them overlapping between vasculitides and others very atypical, such as recurrent epididymitis in BS due to microvasculitis. We can state that most of our findings are in concordance with current literature, with some notable exceptions. Pediatric multicentric population-based studies are warranted to increase research and design clinical trials concerning this field of knowledge.

Two Siblings With Recurrent Fevers: The Path to Mevalonate Kinase Deficiency Diagnosis.

Systemic autoinflammatory diseases (SAIDs) are a group of disorders that constitute a rare cause of recurrent fevers. Recurrent fevers are defined as periodic febrile episodes lasting from days to weeks, separated by symptom-free intervals of variable duration. They present multiple etiologies, representing a diagnostic challenge. Mevalonate kinase deficiency (MKD) is a genetic SAID, a rare hereditary recurrent fever syndrome (HRF) caused by pathogenic variants in the mevalonate kinase (MVK) gene. It is characterized by the early onset of periodic fever flares, frequently associated with joint, gastrointestinal, skin, and lymph node involvement. Although elevated serum immunoglobulin D (IgD) levels were previously considered an MKD's hallmark, normal values do not exclude it. High serum immunoglobulin A (IgA) is frequent. An acute-phase response and elevated urinary mevalonic acid (UAV) excretion during flares may aid in the diagnosis. Genetic testing is an essential tool to confirm the diagnosis. The authors report two siblings presenting with early infancy onset of recurrent febrile illness and characteristic associated symptoms, one of which was initially misdiagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. MKD diagnoses were only established at 12 and nine years old, respectively, after the identification of the same two MVKgene variants. The diagnosis in the eldest favored the earlier recognition of MKD in the youngest. Owing to its wide spectrum of manifestations, with many being nonspecific and/or shared with other more frequent entities, a significant proportion of MKD patients present a long delay until its final establishment. These cases illustrate the MKD diagnosis and management's difficulties, reinforcing the importance of a careful clinical history and HRF awareness for its prompt diagnosis and appropriate precocious referral.

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.

Comparison of non-criteria antiphospholipid syndrome with definite antiphospholipid syndrome: A systematic review.

Objectives: Patients with laboratory or clinical manifestations suggestive of antiphospholipid syndrome (APS) but not fulfilling the classification criteria constitute a clinical challenge. This study aims to compare non-criteria APS (NC-APS) with definite APS in terms of clinical manifestations, therapies, and outcomes. Methods: A systematic review of observational studies comparing definite and NC-APS was performed searching four electronic databases. Data on clinical manifestations, therapies and clinical outcomes was extracted. Results: Sixteen studies, assessing a total of 3,798 participants, were included. Seven out of 10 studies found no significant difference in the prevalence of arterial or venous thrombosis between definite and NC-APS, with two studies on seronegative APS also finding no difference in thrombosis recurrence. Seven out of 12 studies found no significant difference in the prevalence of obstetric manifestations between groups, with the remaining exhibiting conflicting results. In 9 studies comparing treatment frequency in obstetric patients, all but one described similar treatment frequency, with the percentage of NC-APS treated during pregnancy ranging from 26% to 100%. In 10 studies comparing pregnancy outcomes of NC-APS versus definite APS, 7 found similar successful pregnancies/live births. Additionally, 5 studies described improvement of live births in both groups with treatment, with three signalling aspirin monotherapy as efficacious as combination therapy in NC-APS. Conclusion: This review hints at an absence of marked differences in most evaluated parameters between definite and NC-APS, emphasizing the value of a more active follow-up of these patients. The low-quality available evidence highlights the need for well-defined NC-APS populations in future studies. Systematic Review Registration: https://www.crd.york.ac.uk/prospero, identifier CRD42020210674.

Impact of Hyaluronic Acid Treatment on Rhizarthrosis: a Systematic Review.

PURPOSE: Trapeziometacarpal (TMC) joint osteoarthritis (OA) is a common disabling condition. Current treatments do not have a significant impact on symptom relief or disease progression and the benefit of visco-supplementation remains uncertain. We aim to evaluate the efficacy of hyaluronic acid (HA) intra-articular injection in rhizarthrosis. METHODS: A systematic review of the literature addressing the efficacy of HA on pain reduction, functional capacity or pinch strength in patients with rhizarthrosis was performed. Pain at rest, functional capacity and pinch strength were assessed at baseline, 4th, 12th and 24th weeks Results: Sixteen trials were included with a total of 587 patients treated with HA injections (9 randomized controlled trials (RCTs), 5 single-arm studies and 2 non-randomized comparative trials). Despite important heterogeneity among trials, HA injections lead to a reduction in pain at rest (decrease of 0.65-3.5 points and 0.8-4.03 points on Visual Analogue Score after 4th and 24th weeks respectively, compared to baseline). Regarding disability, as assessed by functional scales, all studies reported improvement on functionality. An increase in pinch strength of 0.1-1.4 kg and 0.4-2kg was also reported at 4th and 24th weeks respectively. CONCLUSION: HA injections can be a valid therapeutic option inducing remission of pain with improvement of functionality and strength in patients suffering from TMC joint AO.

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.

Lupus Pneumonitis: Case Report of a Rare Manifestation of Neonatal Lupus.

Neonatal lupus is a rare entity, secondary to placental transfer of antibodies from mothers with immune-mediated conditions. While pulmonary involvement is common in lupus, its incidence in neonates is extremely rare, with very few cases being reported in the literature. The authors report a case of a neonate whose mother was diagnosed with systemic lupus erythematosus, with a prenatal diagnosis of third-degree atrioventricular block. While initially admitted in the neonatal intensive care unit with no need for organ support, he presented progressive respiratory failure, initially attributed to sepsis. Favorable clinical progression after pacemaker placement allowed ventilatory weaning, but respiratory failure was again apparent. Chest computer tomography revealed areas of ground-glass lesions, raising the suspicion for lupus pneumonitis. He was started on immunoglobulin and corticosteroids, with clinical improvement. The authors consider this case to be relevant due to the rarity of acute lupus pneumonitis in neonates, alerting that it must be considered a differential diagnosis in neonates with prolonged ventilator dependency.

Kidney Function, Age, and Education as Contributors to Depression and Anxiety in Juvenile Systemic Lupus Erythematosus.

Juvenile systemic lupus erythematosus (JSLE) is diagnosed in children younger than 18 years of age. Depression and anxiety are common, but not well understood in JSLE. We investigated the clinical and psychological factors associated with the psychological manifestations of JSLE. Twenty-nine JSLE patients were recruited for the study. Patients completed surveys evaluating their psychological status and perceptions about their health. Medical records were used to obtain laboratory results. The JSLE patient population was compared with adult-onset SLE (ASLE) patients and unaffected controls. Kidney involvement was associated with depression in the JSLE patients. The BUN levels, BUN/creatinine ratio, and leukocyturia were all significantly associated with depressive symptoms. Multivariate analysis found that the BUN/creatinine ratio was the most predictive value for both depression and anxiety. Depressive symptoms in JSLE were less pronounced than in ASLE, although anxiety was not different. Age and education are likely to be protective against depression in the JSLE patients. These findings may indicate that symptomatology is an important indicator of whether the patient needs psychiatric care.

Tricorhinophalangeal Syndrome type 1: a novel variant and Perthes-like hip changes as first manifestation.

We report a case of Trichorhinophalangeal syndrome type I (TRPS1) in a 16-year-old boy who was referred due to painless finger deformities over the last year. Legg-Calvé-Perthes disease (LGP) had been diagnosed at age 7 and required surgical treatment at age 12. Parents were healthy and non consanguineous; there was family history of pectus carinatum of maternal lineage. On examination the patient presented a bulbous nose, thin and sparse scalp hair; pectus carinatum; clinodactyly of the first and fifth fingers and hard painless swelling of all of the proximal interphalangeal joints; brachydactyly of the toes. Laboratory tests were unremarkable and radiographic studies revealed distinctive abnormalities of the hands (e.g., epiphyseal coning). This diagnosis was confirmed by gene sequencing, which identified in heterozygosity a pathogenic variant c.124G>T (p.Glu42Ter) in the exon 3 of the TRPS1 gene. The diagnosis of TRPS1 may be suspected upon identification of characteristic physical features, a compatible clinical history and imaging findings.