Severe hypertransaminasemia during mild SARS-CoV-2 infection: A pediatric case report and literature review.

Introduction: Liver injury during SARS-CoV-2 infection has a multifactorial pathogenesis and it is frequent in pediatric cases. Case presentation: We report a case with severe hypertransaminasemia associated with mild SARS-CoV-2 infection. Conclusion: This highlights the potential need of hepatic function evaluation during acute illness and follow-up even in non-critically ill children with COVID-19.

Childhood multisystem inflammatory syndrome associated with COVID-19 (MIS-C): a diagnostic and treatment guidance from the Rheumatology Study Group of the Italian Society of Pediatrics.

BACKGROUND: Italy was the first Western country to be hit by the SARS-CoV-2 epidemic. There is now mounting evidence that a minority of children infected with SARS-CoV2 may experience a severe multisystem inflammatory syndrome, called Multisystem inflammatory Syndrome associated with Coronavirus Disease 2019 (MIS-C). To date no universally agreed approach is available for this disease. MAIN BODY: as Italy is now facing a second hity of COVID-19 cases, we fear a recrudescence of MIS-C cases. We have, therefore, decided to prepare a report that will help clinicians to face this novel and challenging disease. We propose a diagnostic algorithm, to help case definition and guide work-up, and a therapeutic approach. MIS-C should be promptly recognized, based on the presence of systemic inflammation and specific organ involvement. Early treatment is crucial, and it will be based on the combined use of corticosteroids, high-dose immunoglobulins and anti-cytokine treatments, depending on the severity of the disease. Ancillary treatments (such as. aspirin and thrombo-profilaxis) will be also discussed. CONCLUSIONS: we propose a document that will help physicians to diagnose and treat MIS-C patients. Given the level of evidence available and the methodology used, this document should not be interpreted as a guideline; the final decision about the optimal management should still be taken by the caring physician, on an individual basis.

Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study.

BACKGROUND: Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. METHODS: We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. FINDINGS: Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0-27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2-4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89-408·12]), followed by weight loss (59·88 [6·34-565·53]), thrombocytopenia (12·67 [2·40-66·92]), monoarticular involvement (11·30 [4·09-31·19]), hip involvement (3·30 [1·13-9·61]), and male sex (2·40 [1·03-5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01-0·20]), joint swelling (0·03 [0·01-0·09]), and involvement of the small hand joints (0·02 [0-1·05]). INTERPRETATION: Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis. FUNDING: Associazione Lorenzo Risolo.

Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial.

BACKGROUND: Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. METHODS: We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m2; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. FINDINGS: Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. INTERPRETATION: Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. FUNDING: Italian Agency of Drug Evaluation.

Disease activity accounts for long-term efficacy of IL-1 blockers in pyogenic sterile arthritis pyoderma gangrenosum and severe acne syndrome.

OBJECTIVE: To provide a rationale for anti-IL-1 treatment in pyogenic sterile arthritis, pyoderma gangrenosum and acne (PAPA) by defining whether IL-1ß secretion is enhanced; requires NLRP3; and correlates with proline-serine-threonine phosphatase-interacting protein 1 mutations, disease activity and/or the clinical picture in PAPA. METHODS: Monocytes were isolated from 13 patients and 35 healthy donors and studied at baseline and following activation. Secretion pattern of IL-1ß, IL-1α, IL-1Ra, IL-6, IL-18 and TNF-α was assessed in supernatants by ELISA. The NLRP3 requirement for IL-1ß secretion was investigated by silencing technique in PAPA and healthy donor monocytes. Long-term follow-up (mean 26 months, range 4-38) was performed in five patients enrolled in an anti-IL-1 regimen. RESULTS: IL-1ß secretion in PAPA is increased, requires NLRP3 and correlates with disease activity. Patients with a history of osteoarticular flares release more IL-1ß, IL-6 and TNF-α compared with those with predominant cutaneous recurrences. Monocytes from patients in anti-IL-1 treatment dramatically reduced IL-1ß secretion after ex vivo activation, and long-term follow-up demonstrated decreased frequency of flares and normalization of acute phase reactants in all the patients. A straightforward correlation between genotype and IL-1ß signalling was not observed suggesting that factors other than mutation itself may play a role in regulating IL-1ß secretion and response to treatment in PAPA. CONCLUSION: PAPA patients with active lesions display increased NLRP3-mediated IL-1ß secretion, and long-term efficacy of IL-1 blockade was demonstrated. Even if other mechanisms related to the complex proline-serine-threonine phosphatase-interacting protein 1 protein networking might play additional roles, this study further supports the potential of IL-1 blockade as an effective therapeutic strategy in PAPA syndrome.

Dissecting the heterogeneity of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis.

OBJECTIVE: To seek insights into the heterogeneity of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA) through the analysis of a large patient sample collected in a multinational survey. METHODS: International pediatric rheumatologists and hemato-oncologists entered their patient data, collected retrospectively, in a Web-based database. The demographic, clinical, laboratory, histopathologic, therapeutic, and outcome data were analyzed in relation to (1) geographic location of caring hospital, (2) subspecialty of attending physician, (3) demonstration of hemophagocytosis, and (4) severity of clinical course. RESULTS: A total of 362 patients were included by 95 investigators from 33 countries. Demographic, clinical, laboratory, and histopathologic features were comparable among patients seen in diverse geographic areas or by different pediatric specialists. Patients seen in North America were given biologics more frequently. Patients entered by pediatric hemato-oncologists were treated more commonly with biologics and etoposide, whereas patients seen by pediatric rheumatologists more frequently received cyclosporine. Patients with demonstration of hemophagocytosis had shorter duration of sJIA at MAS onset, higher prevalence of hepatosplenomegaly, lower levels of platelets and fibrinogen, and were more frequently administered cyclosporine, intravenous immunoglobulin (IVIG), and etoposide. Patients with severe course were older, had longer duration of sJIA at MAS onset, had more full-blown clinical picture, and were more commonly given cyclosporine, IVIG, and etoposide. CONCLUSION: The clinical spectrum of MAS is comparable across patients seen in different geographic settings or by diverse pediatric subspecialists. There was a disparity in the therapeutic choices among physicians that underscores the need to establish uniform therapeutic protocols.

Female sex and oligoarthritis category are not risk factors for uveitis in Italian children with juvenile idiopathic arthritis.

OBJECTIVE: To investigate the risk factors for chronic anterior uveitis in patients with juvenile idiopathic arthritis (JIA). METHODS: The clinical charts of patients followed between January 1987 and December 2011 were reviewed to establish whether they had uveitis. Inclusion criteria were a diagnosis of JIA and a disease category of persistent oligoarthritis, extended oligoarthritis, rheumatoid factor-negative polyarthritis, psoriatic arthritis, or undifferentiated arthritis. Risk factors included sex, age at arthritis onset, disease category, and antinuclear antibody (ANA) status. The association of risk factors with occurrence of uveitis was evaluated by survival analysis, with first episode of uveitis as the event of interest, and Cox regression analysis. RESULTS: Of a total of 1189 patients, 278 (23.4%) had uveitis a median of 1.1 years after onset of arthritis. There was no difference in the cumulative probability of developing uveitis between males and females and between patients belonging to different JIA categories, whereas uveitis was strongly associated with age at arthritis onset ≤ 3.5 years and positive ANA. Patients possessing the latter 2 factors in combination had a greater probability of having uveitis than patients who had either of them alone. CONCLUSION: In our patients, the risk of uveitis was related to younger age at onset of arthritis and presence of ANA, but not to female sex and disease category. This finding suggests that the patients who require the most intensive ophthalmologic screening are those who have early-onset JIA and are ANA-positive, regardless of their sex or disease subtype.

Development and initial validation of composite parent- and child-centered disease assessment indices for juvenile idiopathic arthritis.

OBJECTIVE: To develop and validate a parent-centered and a child-centered composite disease assessment index for juvenile idiopathic arthritis (JIA): the Juvenile Arthritis Parent Assessment Index (JAPAI) and the Juvenile Arthritis Child Assessment Index (JACAI), respectively. METHODS: The JAPAI and the JACAI include 4 measures: parent/child rating of overall well-being, pain, physical function, and health-related quality of life (HRQOL). Validation analyses were conducted on nearly 5,000 patients and included assessment of construct validity, discriminant validity, responsiveness to change, and reliability. Besides the 4-item version, a 3-item version of both indices, which did not include HRQOL, was tested. RESULTS: The JAPAI and the JACAI demonstrated good construct validity, yielding high correlations with the Juvenile Arthritis Disease Activity Score and moderate correlations with physician global rating and joint counts. Correlations obtained for the JAPAI and the JACAI and for the 4-item and the 3-item versions were comparable. Factorial analysis by principal component analysis showed that both indices are monodimensional. Both the JAPAI and JACAI discriminated well between different disease states and courses and between different levels of American College of Rheumatology Pediatric criteria in a clinical trial, and revealed fair responsiveness to clinical change. Internal consistency was satisfactory, with a Cronbach's alpha of >0.80 in all but 1 of the patient samples tested. CONCLUSION: The JAPAI and the JACAI were found to be valid instruments for assessment of disease status in JIA and suitable surrogates of physicians' evaluations. Both indices are potentially applicable in clinical practice, observational studies, and therapeutic trials.

Outcome and predicting factors of single and multiple intra-articular corticosteroid injections in children with juvenile idiopathic arthritis.

OBJECTIVES: To investigate the efficacy of IA CS (IAC) therapy in single and multiple joints in children with JIA and to seek for predictors of synovitis flare. METHODS: The clinical charts of patients who received their first IAC injection between January 2002 and December 2008 were reviewed. The CS used was triamcinolone hexacetonide for large joints and methylprednisolone acetate for small or difficult to access joints. Patients were stratified as follows: one joint injected; two joints injected; and three or more joints injected. Predictors included sex, age at disease onset, JIA category, age and disease duration, ANA status, iridocyclitis, general anaesthesia, number and type of injected joints, acute-phase reactants and concomitant MTX therapy. RESULTS: The cumulative probability of survival without synovitis flare for patients injected in one, two, or three or more joints was 70, 45 and 44%, respectively, at 1 year; 61, 32 and 30%, respectively, at 2 years; and 37, 22 and 19%, respectively, at 3 years. On Cox regression analysis, positive CRP, negative ANA and injection in the ankle were the strongest predictors for synovitis flare. The only significant side effect was skin hypopigmentation or s.c. atrophy, which occurred in <2% of patients. CONCLUSION: IAC therapy-induced sustained remission of synovitis in a substantial proportion of patients injected either in single or multiple joints, with a good safety profile. The risk of synovitis flare was higher in patients who had positive CRP, negative ANA and were injected in the ankle.

A new approach to clinical care of juvenile idiopathic arthritis: the Juvenile Arthritis Multidimensional Assessment Report.

OBJECTIVE: To develop and test a new multidimensional questionnaire for assessment of children with juvenile idiopathic arthritis (JIA) in standard clinical care. METHODS: The Juvenile Arthritis Multidimensional Assessment Report (JAMAR) includes 15 parent or patient-centered measures or items that assess well-being, pain, functional status, health-related quality of life, morning stiffness, disease activity, disease status and course, joint disease, extraarticular symptoms, side effects of medications, therapeutic compliance, and satisfaction with illness outcome. The JAMAR is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 7-18 years for use as a self-report. From March 2007 to September 2009, the questionnaire was completed by the parents of 618 children with JIA in 1814 visits and by 332 children in 749 visits. RESULTS: The JAMAR was found to be feasible and to possess face and content validity. All parents and children reported that the questionnaire was simple and easy to understand. Completion and scoring appeared to be quick, requiring < 15 minutes. There were very few missing data. Parents' proxy-reported and children's self-reported data were remarkably concordant. The JAMAR provided thorough information for the study patients about recent medical history and current health status. It performed similarly across different children's ages and characterized the level of disease activity and disability well. CONCLUSION: The development of the JAMAR introduces a new approach in pediatric rheumatology practice. This new questionnaire may help enhance the quality of care of children with JIA.

Antinuclear antibody-positive patients should be grouped as a separate category in the classification of juvenile idiopathic arthritis.

OBJECTIVE: We undertook this study to test the hypothesis that in the International League of Associations for Rheumatology (ILAR) classification of juvenile idiopathic arthritis (JIA), patients with similar characteristics can be classified into different categories. We sought to investigate whether antinuclear antibody (ANA)-positive patients having disease in the ILAR categories of oligoarthritis, rheumatoid factor-negative polyarthritis, psoriatic arthritis, and undifferentiated arthritis share homogeneous features and to compare these features with those of ANA-negative patients having the same categories of disease. METHODS: We identified JIA patients who had been followed up during a 22-year period. ANA positivity was defined as ≥2 positive results at a titer of ≥1:160. Demographic and clinical features were recorded retrospectively and compared between ANA-positive and ANA-negative patients. RESULTS: Of a total of 971 patients, 711 were ANA positive, 149 were ANA negative, and 111 had an indeterminate ANA status. Patients with indeterminate ANA status were excluded. ANA-positive patients in the different ILAR categories were similar in terms of age at disease presentation, female-to-male ratio, and frequency of asymmetric arthritis and iridocyclitis. Compared with ANA-positive patients, the ANA-negative group was older at disease presentation and had a lower prevalence of females, a lower frequency of iridocyclitis and asymmetric arthritis, a greater number of affected joints over time, and a different pattern of arthritis. The close relationship between the presence of ANAs and younger age at disease presentation, female predominance, asymmetric arthritis, development of iridocyclitis, lower number of affected joints over time, and lack of hip involvement was also confirmed by multivariate and multiple correspondence analysis. CONCLUSION: Our findings substantiate the hypothesis that ANA-positive patients classified into different JIA categories by current ILAR criteria constitute a homogeneous patient population.

Evaluation of 21-numbered circle and 10-centimeter horizontal line visual analog scales for physician and parent subjective ratings in juvenile idiopathic arthritis.

OBJECTIVE: To evaluate the measurement properties of 21-numbered circle visual analog scales (VAS) and traditional 10-cm horizontal line VAS for physician and parent subjective ratings in children with juvenile idiopathic arthritis (JIA). METHODS: We studied 2 patient samples in whom physician global rating of overall disease activity, parent global rating of the child's overall well-being, and parent rating of intensity of child's pain were performed using traditional 10-cm horizontal line VAS (n = 397) or 21-numbered circle VAS (n = 471). The measurement performances of the 2 VAS formats were examined by assessing construct validity, score distribution, responsiveness to change over time, and minimal clinically important difference (MCID). RESULTS: Most Spearman correlations with other JIA outcome measures yielded by 21-numbered circle VAS were greater than those obtained with 10-cm horizontal line VAS, revealing that the circle VAS format has better construct validity. Ceiling effects (i.e., score = 0) for physician and parent global ratings were 43.7% and 32.9%, respectively, on 21-numbered circle VAS, and 31.6% and 35.3%, respectively, on 10-cm horizontal line VAS. Responsiveness of 21-numbered circle VAS was good (standardized response mean > 0.8) or moderate (standardized response mean > 0.6) among patients classified as improved or worsened, respectively, by the physician or the parent. Overall, MCID values for 21-numbered circle VAS tended to be greater for worsening than for improvement. CONCLUSION: The 21-numbered circle VAS are a suitable alternative to the 10-cm horizontal line VAS and may facilitate incorporation of physician and parent subjective ratings in standard clinical practice.

A new short and simple health-related quality of life measurement for paediatric rheumatic diseases: initial validation in juvenile idiopathic arthritis.

OBJECTIVE: To develop and validate a new short and simple measure of health-related quality of life (HRQL) in children with juvenile idiopathic arthritis (JIA). METHODS: The Paediatric Rheumatology Quality of Life Scale (PRQL) is a 10-item questionnaire that explores HRQL in two domains: physical health (PhH) and psychosocial health (PsH). Validation of the parent proxy report and child self-report versions of the instrument was accomplished by evaluating 472 JIA patients and approximately 800 healthy children. Validation analyses included assessment of feasibility, face and content validity; construct and discriminative ability; internal structure and consistency; test-retest reliability; responsiveness to clinical change; and minimal clinically important difference. RESULTS: The PRQL was found to be feasible and to possess both face and content validity. The PRQL score correlated in the predicted range with most of the other JIA outcome measures, thereby demonstrating good construct validity, and discriminated well between different levels of disease severity. Assessment of internal structure (factor analysis) revealed that the PhH and PsH subscales identify two unambiguously separated domains. The internal consistency (Cronbach's alpha) was 0.86. The intraclass correlation coefficient for test-retest reliability was 0.91. The PRQL revealed fair responsiveness, with a standardized response mean of 0.67 in improved patients. Overall, the PRQL appeared to be more able to capture physical HRQL than psychosocial HRQL. CONCLUSION: The PRQL was found to possess good measurement properties and is, therefore, a valid instrument for the assessment of HRQL in children with JIA. This tool is primarily proposed for use in standard clinical care.

Physicians' and parents' ratings of inactive disease are frequently discordant in juvenile idiopathic arthritis.

OBJECTIVE: To investigate discrepancies between physicians' and parents' ratings of inactive disease in children with juvenile idiopathic arthritis (JIA) and the determinants of the discrepancy. METHODS: Study data were obtained from the clinical database generated at the study unit. Each patient visit included a standardized assessment of JIA outcome measures. One visit for each patient was selected for analysis. Three definitions of inactive disease were applied to the data: a physician-based definition (physician global assessment = 0); a parent-based definition (parent global assessment = 0); and a formal definition, based on fulfillment of newly developed criteria for inactive disease in JIA. RESULTS: Of 1237 visits made by 537 patients that included both physician and parent global assessments, 265 fulfilled the physician-based definition and/or the parent-based definition of inactive disease. Concordance between physicians and parents in rating the disease as inactive was seen in 40% of the visits, whereas in 60% of visits the 2 assessments were discordant. Parents tended to disagree with physicians in rating the disease as inactive if the child had pain or functional impairment, whereas physicians tended to disagree with parents in the presence of active joint symptoms. Only 2/3 of the 79 visits that fulfilled the formal definition of inactive disease also met the parent-based definition of inactive disease. CONCLUSION: We found frequent discordance between physicians' and parents' ratings of inactive disease in children with JIA, which suggests that the parent's rating of a child's disease activity should be considered for inclusion in the definition of clinical remission for JIA.