Muscular polyarteritis nodosa (PAN), a disease that is predominantly confined to the skeletal muscle, has barely been described in adult literature and has been exceedingly rarely reported in children. The clinical presentation is non-specific, and the diagnosis is challenging and often delayed, requiring imaging evaluation and histopathological confirmation.[1] We aimed to describe the clinical presentation, complimentary workup, treatments given, and the outcome of this rare entity in a pediatric case series, underscoring the role of imaging evaluation in aiding the diagnosis. A search of medical databases in 4 pediatric rheumatology referral centers identified 4 patients diagnosed with muscular PAN between 2015 and 2023. Clinical presentation and laboratory workup data, including genetics, imaging, histopathology, detailed follow-up, and treatment outcomes, were collected retrospectively and prospectively. Diagnosis required meeting the EULAR/PRINTO/PRES childhood-PAN criteria, with no findings suggesting major extra-muscular, visceral involvement. Four pediatric patients (2 Females and 2 Males), aged 8.5 to 15 years at presentation, were enrolled. All presented with severe disabling muscular pain, ill appearance, arthralgia, preserved muscle power, normal muscle enzymes, and elevated inflammatory markers. Three of them also had a fever when presented. MRI of the limbs revealed hyperintense signaling and edema of the affected muscles in cases 1,2,4, whereas PET-CT done in cases 1,2,3 showed increased uptake in the involved muscles, indicating myositis. Case 1,2,4 had skin and muscle biopsies with features compatible with PAN, while case 3 had PAN-supportive skin biopsy. All had initial proper responses to corticosteroids and immunosuppressants (Methotrexate or Azathioprine), but 3 of them experienced recurrent relapses necessitating prolonged therapy. None of the patients have developed visceral involvement or evolved to systemic PAN. Pediatric practitioners should remain vigilant for the rare muscular-predominant PAN. Early recognition and diagnosis, aided by imaging tests such as MRI and occasionally PET-CT, along with histologic confirmation, are essential for prompt management and improved outcomes. [1.] Ganeshanandan LR. Semin Arthritis Rheum 2020;50(3):503-8.

In this review, I described the development of the healthcare system in Theresienstadt during the Holocaust, from the establishment of the camp in late 1941 through 1945. Despite the horrific conditions, the Jews established a highly organized and relatively efficient system that was able to deliver excellent medical care to those eligible to receive care. The major factors that enabled development of the system included the heroic efforts of the high-level providers, the trust of patients, a public health approach to prevent epidemics and the perceived propaganda value of a good healthcare system to the Nazi oppressor. There were many challenges, particularly an informal triage policy that largely excluded medical care from the elderly (above age 60 years), mentally ill, and disabled. There were often difficult relations between caregivers related to ageism, gender, and national origin of the providers. Despite these adversities and the eventual futility due to the murder of the vast majority of the inhabitants, the Jews in Theresienstadt clung to life and tried their best to conduct a civilized society, in a large part through the delivery of excellent medical care.

OBJECTIVES:To identify predictors of a severe clinical course of multisystem inflammatory syndrome in children (MIS-C), as defined by the need for inotropic support. METHODS:This retrospective study included patients diagnosed with MIS-C (according to the CDC definition) in nine Israeli and one US medical centre between July 2020 and March 2021. Univariate and multivariate regression models assessed odds ratio (OR) of demographic, clinical, laboratory and imaging variables during admission and hospitalization for severe disease. RESULTS:Of 100 patients, 61 (61%) were male; mean age 9.65 (4.48) years. Sixty-five patients were hypotensive, 44 required inotropic support. Eleven patients with MIS-C fulfilled Kawasaki disease diagnostic criteria; 87 had gastrointestinal symptoms on admission. Echocardiographic evaluation showed 10 patients with acute coronary ectasia or aneurysm, and 37 with left ventricular dysfunction. In a univariate model, left ventricular dysfunction was associated with severe disease [OR 4.178 (95% CI 1.760, 9.917)], while conjunctivitis [OR 0.403 (95% CI 0.173, 0.938)] and mucosal changes [OR 0.333 (95% CI 0.119, 0.931)] at admission were protective. Laboratory markers for a severe disease course were low values of haemoglobin, platelets, albumin and potassium; and high leukocytes, neutrophils, troponin and brain natriuretic peptide. In multivariate analysis, central nervous system involvement and fever >39.5°C were associated with severe disease. Mucosal involvement showed 6.2-fold lower risk for severe disease. Low haemoglobin and platelet count, and elevated C-reactive protein and troponin levels were identified as risk factors for severe disease. CONCLUSION:Key clinical and laboratory parameters of MIS-C were identified as risk factors for severe disease, predominantly during the disease course and not at the time of admission; and may prompt close monitoring, and earlier, more aggressive treatment decisions. Patients presenting with a Kawasaki-like phenotype were less likely to require inotropic support.

OBJECTIVE:To develop and externally validate a prediction model for new-onset chronic uveitis in children with juvenile idiopathic arthritis (JIA) for clinical application. METHODS:Data from the international Pharmachild registry were used to develop a multivariable Cox proportional hazards model. Predictors were selected by backward selection, and missing values were handled by multiple imputation. The model was subsequently validated and recalibrated in 2 inception cohorts: the UK Childhood Arthritis Prospective Study (CAPS) study and the German Inception Cohort of Newly diagnosed patients with juvenile idiopathic arthritis (ICON) study. Model performance was evaluated by calibration plots and C statistics for the 2-, 4-, and 7-year risk of uveitis. A diagram and digital risk calculator were created for use in clinical practice. RESULTS:A total of 5,393 patients were included for model development, and predictor variables were age at JIA onset (hazard ratio [HR] 0.83 [95% confidence interval (95% CI) 0.77-0.89]), ANA positivity (HR 1.59 [95% CI 1.06-2.38]), and International League of Associations for Rheumatology category of JIA (HR for oligoarthritis, psoriatic arthritis, and undifferentiated arthritis versus rheumatoid factor-negative polyarthritis 1.40 [95% CI 0.91-2.16]). Performance of the recalibrated prediction model in the validation cohorts was acceptable; calibration plots indicated good calibration and C statistics for the 7-year risk of uveitis (0.75 [95% CI 0.72-0.79] for the ICON cohort and 0.70 [95% CI 0.64-0.76] for the CAPS cohort). CONCLUSION:We present for the first time a validated prognostic tool for easily predicting chronic uveitis risk for individual JIA patients using common clinical parameters. This model could be used by clinicians to inform patients/parents and provide guidance in choice of uveitis screening frequency and arthritis drug therapy.

Spruance SL, Klock LE, Bailey A, Ward JR, Smith CB. Recurrent joint symptoms in children vaccinated with HPV-77DK12 rubella vaccine. J Pediatr 1972;80:413-7. Many viruses, including rubella, are associated with the development of arthritis, either from direct viral invasion or as an immune reactive arthropathy. The rubella vaccine is a live attenuated virus and was developed in the 1960s in response to epidemics resulting in birth defects among fetuses of women infected during the first trimester of pregnancy. The first successful strain developed was the HPV-77 strain, incubated in various animal cells such as dog kidney cells used in this paper. Joint adverse events were frequent after these vaccines (∼10%), usually lasting several weeks. The authors of this report contacted 225 patients who had developed joint symptoms following a vaccination campaign in Utah in 1970. They found 11 patients with persistent or recurrent episodes of joint symptoms 8 months after vaccination. All were between 2 and 10 years of age, and 6 were boys. The symptoms consisted of recurrent knee stiffness and pain. Episodes lasted 1-7 days, weekly to every 3 months. Those who were examined had clinical signs of arthritis. There were no predictors among those with joint symptoms who would develop persistent or recurrent symptoms, including the rubella titer. From our knowledge today, it is possible that some of these children, particularly the male ones, had the enthesitis-related form of juvenile idiopathic arthritis, often associated with HLAB27. The rubella vaccine strain used today is the RA 27/3 strain prepared in WI-38 human diploid cells. It is given together with measles, mumps, and varicella (MMRV) at much younger ages. It is very rare to observe joint adverse events following the MMRV vaccine and they are more likely to occur in adults than in children. The safety of coronavirus disease 2019 (COVID-19) vaccines often are intensely debated among the public; thus, it is important to remember that newer vaccines developed with modern technology are associated with fewer rheumatic immune adverse events than those reported by Spruance et al, which were associated with the initial types of the rubella vaccine developed more than 50 years ago.

Krieger I, Brough J. Raynaud's phenomenon in an infant. J Pediatr 1971;80:145-51. In a Clinical Pathologic Conference-style article, the authors describe a previously healthy 5-month-old female infant admitted with fever, macular and blotchy (probably livedo reticularis) rash, and irritability of several days' duration. Acute phase reactants were elevated. Her initial treatment included antibiotics. After a cold water emersion test that showed Raynaud-like color changes of the fingers, an alpha-adrenergic blocker was added. After discharge, the patient was described as being relatively well, until unfortunately at the age of 8 months she died of cardiocirculatory collapse. The autopsy revealed enlargement of the coronary arteries and their major epicardial branches. Histologic examination showed vasculitis involving small and medium-sized muscular arteries of all major visceral organs. The pathologic diagnosis was polyarteritis nodosa. We suggest that this infant may have suffered from Kawasaki disease and died as a consequence of coronary artery insufficiency. She was well for a few months, which is not the expected clinical course of disease in polyarteritis nodosa without immunosuppressive treatment. Raynaud phenomenon can be primary or secondary to diseases such as systemic lupus erythematosus, scleroderma, dermatomyositis, vasculitis, drugs (sympathomimetics, cocaine), and other conditions. In vasculitis and rheumatic diseases changes are often found in nailfold capillaries. Kawasaki disease was first described in 1967 in Japan; in the early 1970s, cardiac involvement became evident in postmortem examination and 1%-2% of patients were found to die suddenly from acute heart failure.1Yanagisawa M. Kobayashi N. Matsuya S. Myocardial infarction due to coronary thromboarteritis, following acute febrile mucocutaneous lymph node syndrome (MLNS) in an infant.Pediatrics. 1974; 54: 277-280Crossref PubMed Google Scholar Angiography and echocardiography were introduced for diagnosis and follow-up. Current guidelines strongly recommend that infants less than 6 months of age with unexplained fever for at least 1 week and elevated acute phase reactants undergo echocardiography even in the absence of other features of Kawasaki disease. Other possible diagnoses recently discovered are Mendelian genetic causes of vasculitis. These include deficiency of adenosine deaminase 2 and STING-associated vasculopathy with onset in infancy.

Berardinelli JL, Hyman CJ, Campbell EE, Fireman P. Presence of rheumatoid factor in ten children with isolated rheumatoid-like nodules. J Pediatr 1972;81:751-7. The authors described 10 children with rheumatoid-like nodules (also called pseudorheumatoid). As in rheumatoid nodules, pathology findings included a zone of central necrosis surrounded by palisading connective tissue (eg, fibroblast) cells with giant cells, enveloped by a layer of granulation tissue. Nine of the children developed rheumatoid factors (RF) within 2-16 years in at least 1 of the following techniques: sheep red cell agglutination, latex fixation, euglobulin extraction, or euglobulin inhibition of high-titer rheumatoid sera. The authors concluded that isolated rheumatoid-like nodules in children should be considered as part of the spectrum of juvenile idiopathic (rheumatoid) arthritis (JIA). However, none of the children in this series developed arthritis. Furthermore, these findings are opposed to other studies quoted by the authors before the current study and to many studies since, in which the finding of isolated rheumatoid-like nodules is not associated with the development of arthritis. One of the explanations is that methods used to measure IgM RF have changed since 1972. From the use of agglutination of sheep red blood cells with serum from patients (Rose–Waller test) and the latex particles, as used in this study, modern-day measurements use the more-reliable enzyme-linked immunosorbent assay or laser nephelometry/turbidimetry techniques. The latter measures the effect of particles on light intensity or light scattering. In general, rheumatoid nodules can be found in children with the RF-positive subclass of JIA, who comprise about 5%-10% of children with JIA. The nodules appear often in patients with severe disease and can be exacerbated by treatment with methotrexate and leflunomide. However, only a minority of children with positive RF have JIA. RF is found more commonly in infections or other chronic inflammatory diseases and even among healthy individuals. In many children, these nodules represent deep granuloma annulare. Pathology can often distinguish granuloma annulare from rheumatoid nodules by the finding of mucin deposits in the former. Therefore, we believe there is no need to measure RF in children with isolated rheumatoid-like nodules and no signs of arthritis. Unlike the suggestions of these authors, finding a RF does not predict the development of JIA.

Schaller J. Arthritis as a presenting manifestation of malignancy in children. J Pediatr 1972;81:793-7. In 1972, Schaller published a case series of 13 children who presented for rheumatologic evaluation of inflammatory arthritis-like symptoms but were later found to have malignancy. Her article showcased how malignancies and rheumatologic conditions like juvenile idiopathic arthritis can present similarly and how difficult it can be to differentiate between the two. In the article, 10 of the children had acute lymphoblastic leukemia (ALL), but the cases also included rarer malignancies. Most of the patients presented with oligoarticular pain, swelling, and/or limited range of motion of the large joints, but some had polyarticular involvement. Seven of the patients with ALL presented with abnormal blood counts, 8 had elevated inflammatory markers, and 2 patients had positive rheumatoid factor. A minority of the patients had radiographic findings concerning for leukemia at presentation, but others had nonspecific changes, and 1 case had bony erosions of the sacroiliac joints. Eight of the patients were diagnosed correctly with leukemia shortly after initial evaluation, but others had nondiagnostic initial workups or were treated as having rheumatologic disease for a few months before the correct diagnosis was established. In the 10 patients with ALL, the most helpful distinguishing features were severe joint pain and hematologic abnormalities. These cases emphasized the importance of maintaining a high suspicion for malignancy in the differential of inflammatory arthritis; this lesson still holds true today. Brix et al recently published a cross-sectional retrospective study comparing clinical manifestations and laboratory results of 26 children with ALL and arthritis vs 485 children with juvenile idiopathic arthritis and similarly concluded that distinction on clinical grounds was difficult; in this study, neutropenia and thrombocytopenia had the greatest ORs for identifying malignancy.1Brix N. Rosthøj S. Glerup M. Hasle H. Herlin T. Identifying acute lymphoblastic leukemia mimicking juvenile idiopathic arthritis in children.PLoS One. 2020; 15: e0237530https://doi.org/10.1371/journal.pone.0237530Crossref PubMed Scopus (5) Google Scholar Schaller's article is still relevant because, 50 years later, medicine has yet to develop tests that reliably differentiate between inflammatory arthritis and arthritis as initial presentation of malignancy. Blood counts, inflammatory markers, autoantibodies, and imaging studies, although helpful, are only supportive information, and the decision to pursue further evaluation still relies on the judicious clinical discernment of physicians. Research into biomarkers for the diagnosis of rheumatologic diseases is ongoing; in the meantime, a high index of suspicion is still needed to identify atypical presentations of malignancy and successfully treat these patients.