Evaluation of pediatric rheumatologists' approach to rituximab use: a questionnaire study.

Rituximab (RTX) is a chimeric monoclonal antibody that targets the CD20 antigen on B cells and is used in various autoimmune disorders. In this study, we aimed to measure the awareness of pediatric rheumatologists about the use of RTX through a survey. Between February and March 2023, a 42-question survey was sent via email to pediatric rheumatology specialists in Turkey. The participants were questioned for which diagnoses and system involvement they preferred to use RTX, which routine tests they performed, vaccination policy, and adverse events that occurred during or after infusion. Forty-one pediatric rheumatologists answered the survey. They prescribed RTX most frequently for systemic lupus erythematosus (87.8%) and ANCA-associated vasculitis (9.8%). Prior to the administration of RTX, 95% of clinicians checked renal and liver function tests, as well as immunoglobulin levels. The most frequently tested hepatitis markers before treatment were HBsAg and anti-HBs antibody (97.6%), while 85.4% of rheumatologists checked for anti-HCV. Clinicians (31.4%) reported that they postpone RTX infusion 2 weeks following an inactivated vaccine. Sixty-one percent of rheumatologists reported starting RTX treatment 1 month after live vaccines, while 26.8% waited 6 months. The most frequent adverse events were an allergic reaction during RTX infusion (65.9%), hypogammaglobulinemia (46.3%), and rash (36.6%). In the event of hypogammaglobulinemia after RTX treatment, physicians reported that they frequently (58.5%) continued RTX after intravenous immunoglobulin administration. CONCLUSIONS: RTX has become a common treatment option in pediatric rheumatology in recent years. Treatment management may vary between clinician such as vaccination and routine tests. WHAT IS KNOWN: • During the course of rituximab therapy, clinicians should be attentive to specific considerations in pre-treatment, during administration, and in post-treatment patient monitoring. WHAT IS NEW: • There are differences in practice among clinicians in the management of RTX therapy. These practice disparities have the potential to impact the optimal course of treatment. • This study highlights that standardized guidelines are needed for RTX treatment in pediatric rheumatology, particularly for vaccination policies and routine tests.

Thymic carcinoma presenting with overlap polyarthritis and myositis: A rare paraneoplastic syndrome in childhood.

Thymic tumors are very rare neoplasms in children and account for less than 1% of mediastinal tumors in pediatric patients. One-third of the pediatric patients present with symptoms related to the compression of the tumor mass on the surrounding anatomic structures, and paraneoplastic syndromes such as myasthenia gravis, pure red cell aplasia, acquired hypogammaglobulinemia, and connective tissue disorders, which rarely occur in children with thymic tumors. Herein, we report a case of thymic carcinoma mimicking the symptoms of a connective tissue disease with symmetrical polyarthritis accompanying myositis, fever, weight loss, and malaise in a 15-year-old male patient. To our knowledge, this is the first case pediatric thymic carcinoma accompany with severe polyarthritis and myopathy, thus we have reviewed the current literature regarding the cases of thymic malignancies coexisting with paraneoplastic syndromes in children.

How Safe Are Biological Agents in Pediatric Rheumatology?

OBJECTIVE: Biologic therapy has changed the prognosis of patients with rheumatologic disease. Despite all benefits of the biological agents, adverse events may occur due to their long-term use. The aim of this study is to analyze the adverse events observed in pediatric patients who received biological treatment. MATERIALS AND METHODS: This retrospective observational cohort study was conducted between January 2010 and January 2022. File records of 139 patients used biological agents for rheumatologic diseases in a pediatric rheumatology clinic were evaluated. Diagnosis, received treatment, the rationale for stopping treatment, requirement of tuberculosis prophylaxis, presence of an adverse event, and results were recorded. RESULTS: The most used biological therapy was etanercept (41.7%). Anakinra, adalimumab, canakinumab were used in 30.9%, 27.3%, 23.7% of patients, and the others in less than 10%. Totally 491 adverse events (97.9/100 patient-years) were encountered during the duration of biological treatment. The most often adverse event was recurrent upper respiratory tract infection in the patients (31.9/100 patient-years). Elevated aminotransferase levels (10.4/100 patient-years), abdominal pain (7/100 patient-years), and headache (5.2/100 patient-years) were among the other common side effects. Isoniazid (INH) prophylaxis was needed before biological treatment in 20.9% of the patients. Tuberculosis developed in none of the patients followed-up for latent tuberculosis, however, it developed in a patient while receiving etanercept due to noncompliance with his scheduled outpatient visits during etanercept treatment. CONCLUSION: The most commonly used biological treatments were TNFi and IL-antagonists, and the majority of side effects were infections and laboratory abnormalities. Although the rate of serious adverse events is quite low, close follow-up of patients receiving biological therapy is very important.

Towards a standardized program of transitional care for adolescents with juvenile idiopathic arthritis for Turkey: a national survey study.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a prevalent childhood chronic arthritis, often persisting into adulthood. Effective transitional care becomes crucial as these patients transition from pediatric to adult healthcare systems. Despite the concept of transitional care being recognized, its real-world implementation remains inadequately explored. This study aims to evaluate the thoughts and practices of healthcare providers regarding transitional care for JIA patients. METHODS: A cross-sectional survey was conducted among pediatric and adult rheumatologists in Turkey. Based on the American Academy of Pediatrics' six core elements of transitional care, the survey included 86 questions. The respondents' demographic data, attitudes towards transitional care, and practical implementation were assessed. RESULTS: The survey included 48 rheumatologists, with 43.7% having a transition clinic. The main barriers to establishing transition programs were the absence of adult rheumatologists, lack of time, and financial constraints. Only 23.8% had a multidisciplinary team for transition care. Participants agreed on the importance of coordination and cooperation between pediatric and adult healthcare services. The timing of the transition process varied, with no consensus on when to initiate or complete it. Participants advocated for validated questionnaires adapted to local conditions to assess transition readiness. CONCLUSIONS: The study sheds light on the challenges and perspectives surrounding transitional care for JIA patients in Turkey. Despite recognized needs and intentions, practical implementation remains limited due to various barriers. Cultural factors and resource constraints affect the transition process. While acknowledging the existing shortcomings, the research serves as a ground for further efforts to improve transitional care and ensure better outcomes for JIA patients transitioning into adulthood.

Etanercept-associated episcleritis: a pediatric case report of a paradoxical adverse reaction and review of the literature.

Scleritis is an inflammation of the episcleral and scleral tissues, characterized by injection in both superficial and deep episcleral vessels. When only episcleral tissue is involved, it is referred to as episcleritis. Episcleritis is mainly idiopathic but may be secondary to an underlying rheumatologic disease. Despite being rare, drug-associated episcleritis and scleritis should also be included in the differential diagnosis. Tumor necrosis factor-alpha (TNF-α) inhibitors are generally well-tolerated, but etanercept, in particular, has the potential to cause paradoxical adverse reactions including ocular inflammations, such as uveitis, scleritis, and ocular myositis. Etanercept differs in its mechanism of action from other TNF-α inhibitors as it acts as a decoy receptor, and this may partly explain the more frequently reported etanercept-associated ocular inflammation. Etanercept may also be ineffective in preventing ocular inflammation. However, the dechallenge and rechallenge phenomena have proven there is a causative link between etanercept and new-onset ocular inflammation. We report a case of a 15-year-old boy with enthesitis-related arthritis and familial Mediterranean fever who presented with episcleritis and blepharitis while receiving etanercept treatment and subsequently showed dechallenge and rechallenge reactions. Therefore, physicians should also be aware that episcleritis should be considered a paradoxical adverse reaction to etanercept and can occur in pediatric patients. We also reviewed the English literature to provide an overview and evaluate intervention options.

Adhesive small-bowel obstruction as a challenging complication of familial Mediterranean fever: A case-based review.

Familial Mediterranean fever (FMF) is the most common inherited autoinflammatory disorder, characterized by recurrent and self-limiting episodes of fever and serosal inflammation. Recurrent serositis may rarely lead to the formation of adhesions in the peritoneum, which may result in mechanical bowel obstruction. The symptoms, such as abdominal pain and vomiting, may mimic typical FMF attacks, resulting in misdiagnosis and severe morbidity, including strangulation and intestinal necrosis. Physicians are generally aware of other complications associated with FMF but reports on peritoneal adhesions and intestinal obstruction in English-language literature are inadequate to increase clinicians' awareness. Therefore, it is crucial to meticulously evaluate FMF patients presenting with abdominal pain and ileus because these symptoms could be due to adhesive small-bowel obstruction (ASBO). Furthermore, patients presenting with ASBO without a history of abdominal surgery should also be thoroughly evaluated, especially as it could be an initial presentation for an autoinflammatory disease. Herein, we present a pediatric case of FMF with the M694V homozygous mutation, complicated by ASBO while under colchicine treatment. Additionally, we provide a comprehensive review of the available literature on ASBO in FMF.

Arterial Stiffness and Ambulatory Blood Pressure Measurements in Children With Familial Mediterranean Fever.

Familial Mediterranean fever (FMF) is an autoinflammatory disease which may cause endothelial dysfunction and arterial stiffness. In this study, we evaluated patients with FMF in terms of arterial stiffness indicators and investigated whether there was any difference according to colchicine response. This is a single-center, prospective, case-control study conducted on pediatric patients with FMF. Patients were categorized into 2 groups: patients on colchicine monotherapy (group 1) and patients who used anti-interleukin-1 (IL-1) plus colchicine (group 2). Patient age, mutations in the MEFV gene, overall duration of treatments, and general characteristics of symptoms were recorded. Laboratory values in an attack-free period were noted. Pulse wave velocity (PWV) was measured in all patients. Erythrocyte sedimentation rate and C-reactive protein, nocturnal hypertension, and PWV were higher in group 2. Arterial stiffness develops due to subclinical inflammation in patients with FMF. It is more pronounced in colchicine-resistant patients.

A possibly new autoinflammatory disease due to compound heterozygous phosphomevalonate kinase gene mutation.

BACKGROUND: Mevalonate kinase (MVK) plays a role in cholesterol and non-sterol isoprenoid biosynthesis and its deficiency-related diseases are caused by bi-allelic pathogenic mutations in the MVK gene, (MVK), which leads to rare hereditary autoinflammatory diseases. The disease may manifest different clinical phenotypes depending on the degree of the deficiency in the enzyme activity. The complete deficiency of the enzyme activity results in the severe metabolic disease called mevalonic aciduria, while a partial deficiency results in a broad spectrum of clinical presentations called hyper-immunoglobulin D syndrome (HIDS). Serum immunoglobulin (Ig) D and urine mevalonic acid levels may be increased during inflammatory attacks of HIDS. CASE PRESENTATION: Herein, for the first time in the literature, we present a 6-year-old male patient who suffered from recurrent episodes of fever, polyarthritis, skin rash, diarrhea, abdominal pain, and inflammatory bowel disease-like manifestations with elevated levels of serum IgD, and urine mevalonic acid. Eventually we detected compound heterozygous mutations in the phosphomevalonate kinase (PMVK) gene coding the second enzyme after mevalonate kinase in the mevalonate pathway. CONCLUSION: For patients presenting with HIDS-like findings, disease exacerbations and persistent chronic inflammation, and having high urinary mevalonic acid and serum IgD levels, raising suspicion in terms of MVK deficiency (MVKD), it is recommended to study all mevalonate pathway enzymes, even if there is no mutation in the MVK gene. It should be kept in mind that novel mutations might be seen such as PMVK gene.

Recurrent macrophage activation syndrome due to hyperimmunoglobulin D syndrome: a case-based review.

Hyperimmunoglobulin D syndrome (HIDS) is a hereditary autoinflammatory disease characterized by recurrent inflammatory attacks with fever, abdominal pain, lymphadenopathy, aphthous stomatitis, and skin lesions. There are few reports on HIDS patients complicated with macrophage activation syndrome (MAS); however, to our knowledge, there is no case of HIDS with recurrent MAS attacks. We report two pediatric patients initially diagnosed as Kawasaki disease and systemic juvenile idiopathic arthritis presented with recurrent MAS episodes with prolonged fever, skin rash, hepatosplenomegaly, cervical lymphadenopathy, aphthous stomatitis, headache, pancytopenia, hyperferritinemia, and hypofibrinogenemia, finally diagnosed as HIDS with a documented homozygous MVK gene mutation. This is the first report on recurrent MAS attacks due to HIDS in pediatric patients who were successful treated with corticosteroids and anti-IL-1 therapies. Thus, clinicians should be vigilantly investigated signs of autoinflammatory diseases in patients with recurrent MAS attacks during their disease course, and HIDS should be considered an underlying disease for triggering recurrent MAS attacks. We have also reviewed the current literature regarding HIDS cases complicated with a MAS attack and summarized their demographic, treatment, and outcome characteristics. Key points • Hyperimmunoglobulin D syndrome should be considered in differential diagnosis in patients who experienced recurrent macrophage activation syndrome attacks.

Chest pain in children with familial Mediterranean fever.

BACKGROUND: Familial Mediterranean fever (FMF) is the most common and autosomal recessive inherited autoinflammatory disease. The most common signs and symptoms are fever, abdominal pain, chest pain, and arthritis. The aim of this study was to describe the clinical, laboratory and genetic differences between pediatric FMF patients with and without chest pain. METHODS: Between January 2006 and January 2022, 1134 patients with FMF were analyzed retrospectively. Patients were divided into two groups including those with and without recurrent chest pain. These groups were compared in demographic, clinical, treatment, and MEFV gene analyses. RESULTS: A hundred and sixty-two (14.3%) patients had recurrent chest pain. In patients with recurrent chest pain, the age of onset of symptoms was younger (p=0.003), and the family history of FMF was higher (p=0.002). Patients with chest pain had a higher annual attack frequency (p < 0.001), a longer attack duration (p < 0.001), and higher Pras disease activity scores (p < 0.001). The colchicine dose used in the treatment was higher in FMF patients with chest pain (p=0.005), and anti-IL-1treatment was higher (p < 0.001). M694V homozygous mutation was found more frequently (p=0.001), whereas M694V/V726A mutation was found less frequently in patients with recurrent chest pain (p=0.017). CONCLUSIONS: Patients with recurrent chest pain seem to have early onset symptoms, often are more likely to have family history, and have a higher disease severity. In addition, the presence of homozygous M694V mutation is more common in patients with chest pain.

Predictors of persistent inflammation in children with familial Mediterranean fever.

OBJECTIVES: Persistent inflammation is an insidious feature of familial Mediterranean fever (FMF) that may cause chronic complications. This study aimed to investigate the predictors of persistent inflammation in children with FMF. METHODS: The medical charts of 1077 paediatric FMF patients were retrospectively collected. The patients were divided into two groups: with and without subclinical inflammation. RESULTS: A total of 133 (12%) patients had persistent inflammation. M694V homozygosity, colchicine resistance, positive family history for FMF, erysipelas-like erythema, leg pain, arthritis, chest pain, inflammatory comorbidities, early disease onset, high PRAS score, and long attack duration were established as independent predictors of persistent inflammation (P < .001, P < .001, P < .001, P < .001, P = 0.006, P < .001, P < .001, P = .014, P < .001, P < .001, and P < .001, respectively). However, gender, abdominal pain, fever, and attack frequency were not found to be independent risk factors for predicting persistent inflammation (P = .412, P = .531, P = .451, and P = .693, respectively). CONCLUSIONS: M694V homozygosity, colchicine resistance, positive family history, erysipelas-like erythema, leg pain, arthritis, chest pain, inflammatory comorbidities, early disease onset, high activity score, and long attack duration may be predictors of persistent inflammation in FMF. These predictors may help clinicians suspect the occurrence of subclinical inflammation and should aid in better disease management in FMF.

Paroxysmal Amnesia Attacks due to Hashimoto's Encephalopathy.

Hashimoto's encephalopathy is a rare disease which is thought to be autoimmune and steroid responsive. The syndrome is characterized by cognitive impairment, encephalopathy, psychiatric symptoms, and seizures associated with increased level of anti-thyroid antibodies. The exact pathophysiology underlying cerebral involvement is still lesser known. Although symptoms suggest a nonlesional encephalopathy in most of the cases, sometimes the clinical appearance can be subtle and may not respond to immunosuppressants or immunomodulatory agents. Here we report a case who presented with drowsiness and amnestic complaints associated with paroxysmal electroencephalography (EEG) abnormalities which could be treated only with an antiepileptic drug.

Eyelid myoclonia seizures in adults: An alternate look at the syndrome paradox.

OBJECTIVES: Eyelid myoclonia (EM), without or with absences (EMA), is induced by eye closure (ECL)-associated generalized paroxysms of polyspikes and waves. Although considered as an epileptic syndrome, it has been listed as a type of seizure in the recent epilepsy classifications, perhaps because of its clinical heterogeneity. In this study, we aimed to specifically study the clinical and electroencephalogram (EEG) features and the prognosis of long-term followed-up adult patients with EMs and to determine common points between EMAs, idiopathic generalized epilepsies (IGEs), and symptomatic epilepsies. METHODS: Between 1996 and November 2011, 61 adult patients with EMs with or without absences and bilateral EEG paroxysms were retrospectively enrolled in the study and followed up for 1-34 years (mean: 5.8 years). RESULTS: According to patient history, seizure semiology, and EEG findings, we classified the patients having EM seizures into three main groups. In group 1 (n=31), all patients had prominent EMs with or without absences associated with upward rolling of eyeballs. The second group included 20 patients with EM seizures associated with generalized tonic-clonic seizures (GTCSs) and/or massive myoclonias. The third group of 7 patients had varying diagnosis of symptomatic epilepsies. In the first group with pure EMA, the diagnosis was more delayed than in the other groups (p=0.01). In the group with pure EMA, EMs continued in adulthood (p=0.00), and only 24% of patients were seizure-free, which was considered poor prognosis. On EEG, occipital (n=3) and frontal (n=4) focal discharges were found in the group with pure EMA. Interestingly, 2 patients with symptomatic epilepsy with frontal lesions also had EM seizures. CONCLUSION: The patients with pure EMA have many similarities to patients with IGEs. We also demonstrated that EMs could be seen as a seizure type in symptomatic epilepsies. Eyelid myoclonia with absences meets the criteria for an epileptic syndrome with the early onset and long duration of seizures, special seizure type, specific EEG findings, possibility of cognitive impairment, precipitating modalities, photosensitivity, and presence of family history, suggesting a strong genetic background.