Evaluation of childhood malignancies presenting with musculoskeletal manifestations from two different divisions: a multicenter study.

BACKGROUND: The aim of the study was to evaluate the approaches of pediatric rheumatologists and pediatric hematologists to patients with similar musculoskeletal (MSK) complaints and to highlight the differences that general pediatricians should consider when referring patients to these specialties. METHODS: This is a cross-sectional study involving the patients who applied to pediatric rheumatology centers with MSK complaints and were diagnosed with malignancy, as well as patients who were followed up in pediatric hematology centers with a malignancy diagnosis, and had MSK complaints at the time of admission. RESULTS: A total of 142 patients were enrolled in the study. Of these patients, 83 (58.4%) applied to pediatric rheumatology centers, and 59 (41.6%) applied to pediatric hematology centers. Acute lymphoblastic leukemia (ALL) was the most common diagnosis among the patients who applied to both centers, with 80 cases (56.3%). The median age of diagnosis was 87 (interquartile range, IQR: 48-140) months. The most common preliminary diagnosis in pediatric rheumatology centers was juvenile idiopathic arthritis (JIA), with 37 cases (44.5%). MSK involvement was mainly seen as arthralgia, and bone pain. While arthralgia (92.7%) was the most common complaint in rheumatology centers, bone pain (88.1%) was more common in hematology centers. The most frequently involved joints were the knee (62.9%), ankle (25.9%), hip (25%), and wrist (14%). The most common laboratory abnormalities were high lactate dehydrogenase (LDH), high C-reactive protein (CRP), anemia, and high erythrocyte sedimentation rate (ESR). Thrombocytopenia, neutropenia, and high LDH were statistically significantly more frequent in patients admitted to hematology centers than in patients admitted to rheumatology centers (p < 0.001, p=0.014, p=0.028, respectively). Patients who applied to rheumatology clinics were found to have statistically significantly higher CRP levels (p=0.032). CONCLUSIONS: Malignancies may present with only MSK system complaints in childhood. Therefore, malignancies should be included in the differential diagnosis of patients presenting with MSK complaints.

C-terminal variants in CDC42 drive type I interferon-dependent autoinflammation in NOCARH syndrome reversible by ruxolitinib.

C-terminal variants in CDC42 encoding cell division control protein 42 homolog underlie neonatal-onset cytopenia, autoinflammation, rash, and hemophagocytic lymphohistiocytosis (NOCARH). Pyrin inflammasome hyperactivation has been shown to contribute to disease pathophysiology. However, mortality of NOCARH patients remains high despite inflammasome-focused treatments. Here, we demonstrate in four NOCARH patients from three families that cell-intrinsic activation of type I interferon (IFN) is a previously unrecognized driver of autoinflammation in NOCARH. Our data show that aberrant innate immune activation is caused by sensing of cytosolic nucleic acids released from mitochondria, which exhibit disturbances in integrity and dynamics due to CDC42 dysfunction. In one of our patients, treatment with the Janus kinase inhibitor ruxolitinib led to complete remission, indicating that inhibition of type I IFN signaling may have an important role in the management of autoinflammation in patients with NOCARH.

Unexpected condition in a rare disease: encephalopathy in early-onset sarcoidosis.

BACKGROUND: Granulomatous autoinflammatory diseases are monogenic syndromes caused by mutations in the region encoding the nucleotide-binding domain of the nucleotide-binding oligomerization domain-containing 2 gene. Blau syndrome and early-onset sarcoidosis are familial and sporadic forms of the same disease and are very rare. Many organ systems may be involved; however, neurologic involvement is infrequent. We reported a case of encephalitis in a 12-year-old girl followed with a diagnosis of early-onset sarcoidosis. CASE: The patient was diagnosed with juvenile idiopathic arthritis at 3 years of age. We considered druginduced sarcoidosis at 6 years of age with granulomatous inflammation of liver and kidney. Small joint involvement and camptodactyly developed during follow-up. M315T mutation was detected in the NOD2 gene supporting the diagnosis of early-onset sarcoidosis. The patient suffered from encephalopathy when she was under methotrexate, infliximab, and systemic steroid treatment at 12 years of age. Cerebrospinal fluid limbic encephalitis antibody panel was negative. CONCLUSION: Encephalopathy is not common in Blau syndrome and early-onset sarcoidosis. The cause of encephalopathy in our patient was interpreted as autoimmune encephalitis.

The influence of carrying MEFV gene variants on juvenile systemic lupus erythematosus.

Juvenile-onset systemic lupus erythematosus (jSLE) patients typically have a more severe disease course than adults with SLE. We aimed to assess the prevalence and disease course of jSLE patients carrying MEFV variants. MEFV variant analyses were performed in 44 jSLE patients and effect of these variants on disease severity and course was analyzed by SLEDAI score and SLICC/ACR index. Ten of the patients (22.7%) had a MEFV variant. The median (min-max) SLEDAI score and SLICC/ACR index were 2(0-13) and 0(0-3), respectively. Median age at disease onset, disease duration, SLICC/ACR indexes, SLEDAI scores, clinical and laboratory findings of the patients were comparable in carriers of variants and non-carriers. Nineteen patients (43.2%) had biopsy-proven lupus nephritis and four of these patients had MEFV variants. There was no significant difference between patients with and without MEFV carriers in terms of lupus nephritis. Even though not significant statistically, renal involvement was milder in MEFV carriers than non-carriers. The presence of MEFV variants does not increase the overall susceptibility to jSLE in our cohort, while larger number of patients is required to display the protective role of MEFV variants in jSLE.

Evaluation of factors affecting the duration of disease-modifying anti-rheumatic drugs application in patients with enthesitis-related arthritis.

OBJECTIVE: Treatments for enthesitis-related arthritis (ERA) consist of a mono- or combination therapy with non-steroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs (DMARDs), and biological agents, and they are primarily based on adult studies and studies on other forms of juvenile idiopathic arthritis, depending on whether there is axial or peripheral involvement. We use DMARDs frequently in our daily practice, even in patients with axial involvement. The main reason for this is that the health insurance system in Turkey does not allow the use of Tumor Negrosis Factor (TNF) blockers as the first line of treatment. The aim of this study is to evaluate the factors affecting the duration of DMARDs application in patients with ERA. METHODS: Fifty-two patients with ERA were accepted in this retrospective cohort study. These patients did not have an inflammatory bowel disease, reactive arthritis or undifferentiated arthritis, psoriasis, and familial Mediterranean fever. Demographic characteristics, medical history, the initial and follow-up physical examination, initial Juvenile Spondyloarthritis Disease Activity Index (JSpADA), initial laboratory tests, radiographic tests, Juvenile Arthritis Damage Index-articulary (JADI-A) and extra-articulary (JADI-E) on the last admission, and data on medical treatments were recorded from the registered data. The univariate Cox proportional hazards regression analyses was used to determine factors affecting the non-response time of ERA patients to DMARDs before the biological treatment was started. RESULTS: Twenty-seven patients (52%) achieved remission with DMARDs, while 25 (48%) patients did not. The age at diagnosis (HR=1.12; p=0.247); gender (HR=2.53; p=0.210); family history of ankylosing spondylitis (HR=1.17; p=0.730); inflammatory back pain (HR=0.57; p=0.175); the shoulder (HR=0.75 p=0.706), hip (HR=0.45; p=0.129), and small-joint involvement (HR=1.53; p=0.439); sacroiliitis with physical examination (HR=0.90; p=0.814) and magnetic resonance imaging (MRI) (HR=2.84; p=0.110); enthesitis (HR=0.83; p=0.670); presence of uveitis (HR=2.04; p=0.342); presence of HLA-B27 (HR=1.39; p=0.524); initial high acute phase reactants levels(HR=1.89; p=0.183); initial JSpADA score (HR=0.98; p=0.944); and last JADI-A (HR=1.41; p=0.060) score did not affect the duration of DMARDs treatment before switching to biological treatments. CONCLUSION: In our study, the absence of factors affecting the duration of DMARDs application in patients with ERA showed that DMARDs may still be applied as the first line of treatment.