Rice bodies in children with rheumatic disorders: A case series and systematic literature review.

OBJECTIVES: Rice body (RB) formation is an uncommon inflammatory process seen in systemic disorders. In this study, we aimed to assess characteristic features of RBs in pediatric patients. METHOD: We retrospectively evaluated pediatric patients who underwent joint/extremity magnetic resonance imaging. A systematic literature review was conducted for articles including children with RBs. RESULTS: We found 24 patients (median age 6.1 years; F/M = 2.4) with RBs [23 with juvenile idiopathic arthritis (JIA) and one with arthralgia]. The most prevalent location for RBs was the knee joint (75%). RBs were most frequently seen as diffuse multiple millimetric structures. In three out of five patients with follow-up magnetic resonance imaging, resolution or regression of RBs was observed without surgical intervention. Our literature search identified 13 pediatric patients with RBs. Most (84.6%) had JIA, and the knee joint (71.4%) was the most commonly affected joint. Surgery was preferred in our 3 patients (12.5%) and 10 literature patients (83.3%) in the treatment. CONCLUSION: Our results showed that RBs were most commonly detected in the knee joint, and most cases were secondary to JIA. Although surgery is used as a treatment option, we observed that RBs can occasionally disappear during follow-up without surgical intervention.

Early-onset juvenile dermatomyositis: A tertiary referral center experience and review of the literature.

BACKGROUND/OBJECTIVES: The aim of our study is twofold: To evaluate the presentation, diagnosis, clinical course, and management of juvenile dermatomyositis (JDM) in children under three years of age, and to compare with older-onset patients. METHODS: Nine patients with early-onset, and 63 patients with older-onset JDM followed between December 2010 and April 2022 are included. We also reviewed the literature on early-onset JDM from the inceptions of the PubMed/MEDLINE and Scopus databases up to April 1st, 2022. RESULTS: Early-onset JDM patients were characterized by longer median diagnostic delay (p = 0.005), calcinosis (p = 0.006), anti-NXP2 antibody (p = 0.049). Diagnostic pathway included muscle biopsy (77.7% versus 50.8%). Muscle biopsy findings were more severe in the early-onset group (p<0.001). Although there was no difference in the partial and complete remission rates, the relapse rate was significantly higher in the early-onset group (p = 0.001), reflected to requirement of intravenous immunoglobulin (p = 0.001), cyclophosphamide (p = 0.011), and biological agents (p = 0.016). Literature search revealed 32 articles reporting 75 patients. The median diagnostic delay was 5 (1-30) months. Calcinosis was present in 29.5%. Twenty-three of the 44 patients (52.3%) had a muscle biopsy. Forty-one patients (64.1%) received second and third-line treatments. Complete remission was achieved in almost half of these patients (48.9%), but relapse was observed in 75%. The mortality rate was 10.2%. CONCLUSION: Diagnosis can be challenging and delayed in early-onset JDM patients. Compared to older-onset JDM patients, this group had higher relapse rate, more severe muscle biopsy findings, and received intensive immunosuppressive treatment.

Interstitial lung disease in autoinflammatory disease in childhood: A systematic review of the literature.

BACKGROUND/OBJECTIVES: The lung is one of the target organs in the systemic involvement of autoinflammatory disease (AID), and interstitial lung disease (ILD) is the primary phenotype of lung involvement in AID. In this review, we aimed to conduct a systematic review of the available literature to highlight ILD in AID. METHODS: We conducted a systematic literature search in PubMed/MEDLINE and Scopus from the inception of the databases to January 2022. References were first screened by title and then by abstract by two authors. Eighteen original papers were selected for full-text review. RESULTS: During the literature search, we identified 18 relevant articles describing 52 cases of AID and ILD. Of those, 44 patients had stimulator of interferon genes-associated vasculopathy with onset in infancy (SAVI), six had coatomer protein complex (COPA) syndrome, one had haploinsufficiency of A20, and one had mevalonate kinase deficiency. Pulmonary fibrosis, cyst formation, and ground glass areas were the most common findings in chest tomography of patients with COPA syndrome and SAVI. Janus kinase inhibitors were used to treat most of the patients with SAVI, which stabilized ILD. CONCLUSIONS: ILD should be considered carefully in children with AID, especially those with interferonopathy.

Choice and switch of biologic drugs in juvenile idiopathic arthritis.

BACKGROUND: In this study, we aimed to evaluate choices and changes of biologic drugs in juvenile idiopathic arthritis (JIA) patients according to disease subtypes. METHODS: We retrospectively analyzed JIA patients who received biologic treatment between January 2004 and July 2022. RESULTS: Of 294 JIA patients, 80 (27.2%) had systemic JIA, 68 (23.1%) had oligoarticular JIA, 61 (20.7%) had polyarticular JIA, 79 (26.9%) had enthesitis-associated arthritis (ERA), and six (2.1%) had psoriatic arthritis (PsA). Anakinra (n=66, 82.5%) was the most commonly preferred first line biologic in systemic JIA. Etanercept was the most frequently used biologic drug in patients with ERA (n=69, 87.3%), oligoarticular (n=37, 54.4%) and polyarticular JIA (n=43, 70.5%). Adalimumab was used as a first-line biologic drug in all PsA patients (n=6, 100%). One hundred-fourteen patients (38.8%) were switched to second-line and 29 (9.9%) to third-line biologic drugs. While the most common reason for switching to a second-line biologic was difficulty in usage of daily injections (n=37, 60.6%) in systemic JIA patients, it was an inadequate response to first biologics in non-systemic JIA patients (n=42, 79.2%). Side effects were detected in only seven patients (2.4%) during the follow-up. CONCLUSION: In this study, we revealed the biologic drug usage and switch strategies in our JIA patients. Good responses were obtained in most of our patients with a reliable profile. However, studies on larger patient groups are needed to clarify these results.

Treatment of childhood-onset Takayasu arteritis: switching between anti-TNF and anti-IL-6 agents.

OBJECTIVES: Biologics are new treatment alternatives in Takayasu arteritis (TA), although data in childhood are limited. The aim of this study was to share our experience in seven childhood-onset TA patients who received a TNF-α inhibitor (adalimumab) or an IL-6 receptor inhibitor (tocilizumab) and the effect of switching therapy. METHODS: We retrospectively evaluated the medical treatment records of seven patients with TA, followed between August 2005 and January 2021 at the Pediatric Rheumatology Department of Hacettepe University Faculty of Medicine. RESULTS: The median age of patients was 14 (IQR 4) years, and six were female. All of the patients had severe disease and high acute-phase reactants. The patients initially received only steroids or steroids+CYC. Prednisone was decreased, and biologic agents were started once the acute phase reactants decreased, and the Indian Takayasu Activity Score (ITAS) returned to normal. Initially, four patients received tocilizumab (TCZ) [median 25.5 (IQR 41) months] and three patients received adalimumab (ADA) [median 13 (IQR 31) months]. However, due to the progression of MR angiography findings or persistent elevation in acute-phase reactants, the biologic agents were switched from TCZ to ADA in four patients and from ADA to TCZ in three patients. The patients' median follow-up time after changing was 50 (IQR 77) months, and median ITAS was evaluated as '0' after 2 (IQR 4) months. CONCLUSIONS: In conclusion, both TNF-α and IL-6 inhibitors are effective alternatives in treating patients with childhood-onset TA. However, prospective randomized controlled trials are needed for the comparison of their effectiveness.

Probiotic use in the prophylaxis of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: a retrospective cohort study.

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is an autoinflammatory recurrent fever syndrome that mainly affects children. Probiotics are currently used to prevent upper respiratory tract infections and flares of diseases associated with immune dysregulation. We aimed to evaluate the response to probiotic treatment in PFAPA patients. Patients with PFAPA syndrome who received probiotics and were followed between July 2019 and July 2021 were included in this retrospective study. Demographic and clinical features and response to probiotics were assessed. Twenty out of 111 children with PFAPA syndrome (F/M:1) were included. The median (min-max) ages at symptoms onset and diagnosis were 24 (3-72) and 51.5 (11-120) months, respectively. All 20 patients received probiotics during the disease course. The probiotic preparation they received included a combination of two lactobacilli as Lactobacillus plantarum HEAL9 (Lp HEAL9) and Lactobacillus paracasei 8700:2 (Lpa 8700:2). The median age at probiotic onset was 60 (33-192) months, while the duration of probiotic use was 4.5 (3-19) months. All patients except one experienced a decrease in attack frequency with probiotic use. After probiotic treatment, the median number of episodes during 3 months decreased from 3 to 1 (p < 0.001). Eight (40%) patients had no attacks during the 3 months after probiotic initiation. And, 5 (45%) of 11 patients who had ≥ 1 attacks on probiotics mentioned that the attack severity decreased significantly after probiotic initiation. Our results suggest that probiotic strains Lactobacillus plantarum HEAL9 and Lactobacillus paracasei 8700:2 could be beneficial in PFAPA patients by decreasing the attack frequency.

IgG4-related disease in pediatric patients: a single-center experience.

OBJECTIVE: Immunoglobulin G4-related disease (IgG4-RD) is a systemic, immune-mediated, and fibroinflammatory disease that can affect almost any organ system. We aimed to present our single-center experience of pediatric patients with IgG4-RD, a rare disease in children. METHODS: Pediatric patients diagnosed with IgG4-RD at the Hacettepe University between June 2014 and September 2020 were evaluated retrospectively. Patients with definite, probable, or possible diagnosis of IgG4-RD were included. RESULTS: A total of eight patients with a median age of 13.4 (IQR 9.5-15.0) years were included in the study. Clinical presentations were IgG4-related ophthalmic disease in six patients, IgG4-related lymphadenopathy in one patient, and IgG4-related sialadenitis and lymphadenopathy of several lymph nodes accompanied by pancreatitis, ulcerative colitis, and pulmonary manifestations in one patient. Elevated serum IgG4 was detected in three of eight patients (37.5%). The main histopathological feature was fibrosis and lymphoplasmacytic infiltrates. Corticosteroids were used as first-line treatment in almost all patients with or without steroid-sparing agents. Azathioprine, methotrexate and rituximab were used as steroid-sparing agents. Relapse occurred in two of seven patients. Radiotherapy was used as the last resort in one patient with severe orbital disease. CONCLUSION: IgG4 RD mainly presents with orbital manifestations in pediatric population but has wide phenotypic clinical variability. Although rare, early recognition and treatment are essential for a better outcome in these patients.

Differences and similarities of multisystem inflammatory syndrome in children, Kawasaki disease and macrophage activating syndrome due to systemic juvenile idiopathic arthritis: a comparative study.

To compare the clinical and laboratory findings of multisystem inflammatory syndrome in children (MIS-C), patients with Kawasaki disease (KD) and with macrophage activating syndrome due to systemic juvenile idiopathic arthritis (sJIA-MAS) on real-life data. Patients diagnosed with MIS-C, KD, and sJIA-MAS from 12 different centers in Turkey who were followed for at least 6 months were included in the study. Demographic, clinical, and laboratory findings of all patients were analyzed. A total of 154 MIS-C, 59 KD, and 31 sJIA-MAS patients were included. The median age of patients with MIS-C were higher than those with KD while lower than those with sJIA-MAS (8.2, 3, 12 years, respectively). Myalgia (39.6%), cardiac (50.6%), gastrointestinal (72.7%), and neurological (22.1%) involvements were more common in patients with MIS-C compared to others. MIS-C patients had lower levels of lymphocyte (950 vs 1700 cells/µl) and thrombocyte (173,000 vs 355,000 cells/µl) counts and higher pro-BNP (1108 vs 55 pg/ml) levels than KD. Ferritin levels were higher in patients with MIS-C compared to patients with KD while they were lower than patients with sJIA-MAS (440, 170, 10,442 ng/ml, respectively). Patients with MIS-C had a shorter duration of hospitalization than sJIA-MAS (p = 0.02) while they required intensive care unit admission more frequently (55 vs 8 patients, p < 0.001). The median MAS/sJIA score of MIS-C patients was - 1.64 (- 5.23 to 9.68) and the median MAS/sJIA score of sJIA-MAS patients was -2.81 ([- 3.79] to [- 1.27]). MIS-C patients displayed certain differences in clinical and laboratory features when compared to KD and sJIA-MAS. Definition of the differences and similarities between MIS-C and the other intense inflammatory syndromes of childhood such as KD and MAS will help the clinicians while making timely diagnosis.

Wind of Change in the Treatment of Childhood-Onset Takayasu Arteritis: a Systematic Review.

PURPOSE OF REVIEW: We lack evidence-based data for the treatment of childhood-onset Takayasu arteritis (c-TA) since it is a rare disease in children. In this systematic literature review, we aimed to evaluate the treatment choices in c-TA patients and integrate our experience for the treatment of our patients in the recent years/in the biologic era. RECENT FINDINGS: We reviewed 24 articles addressing treatments of 413 c-TA patients. Steroids were given to 352 patients (85.2%) as the main immunosuppressive therapy. Other immunosuppressive agents included methotrexate (37.3%), cyclophosphamide (24.5%), azathioprine (16.9%), and mycophenolate mofetil (7.9%). Besides, various biological agents were used, including tumor necrosis factor-alpha inhibitors in 70 of 107 c-TA patients (65.4%) and interleukin-6 inhibitors in 33 of them (30.8%). Biologics are increasingly used in our center as well. Even in severe patients, CYC is switched to either anti-TNF or antiIL6 once disease control is achieved. Recently, in addition to conventional immunosuppressants, biologics are increasingly used in c-TA. We have revised our treatment protocol to start with 1-3 doses of high-dose steroids and CYC, in a child with TA with types III-V involvement and high acute phase reactants; once clinical features subside and CRP normalizes, biologics should be started to replace CYC while decreasing the steroid dose.

Systematic review of childhood-onset polyarteritis nodosa and DADA2.

BACKGROUND: Diagnosis of childhood polyarteritis nodosa (PAN) has become challenging after the definition of deficiency of adenosine deaminase 2 (DADA2). We aimed to define the differential features of pediatric PAN and DADA2 patients in our center and in the literature. METHODS: The charts of pediatric PAN and DADA2 patients followed at the Pediatric Rheumatology Unit of Hacettepe University between 2010-2020 were analyzed. A systematic literature review was conducted for articles regarding pediatric PAN or DADA2. RESULTS: Thirty-four pediatric PAN and 18 pediatric DADA2 patients were included. The age at onset was younger, parental consanguinity, livedo reticularis, neurologic involvement (especially strokes), lymphopenia, and hypogammaglobulinemia were more frequent, while thrombocytosis and panniculitis were less frequent in DADA2 patients. The primary treatment was anti-tumor necrosis factor (anti-TNF) in DADA2. For induction treatment, all systemic PAN patients received corticosteroids, and cyclophosphamide (n=11) or mycophenolate mofetil (MMF) (n = 3). Cyclophosphamide was replaced with MMF in nine once remission was confirmed with PVAS. In the literature, 28 articles describing 613 pediatric PAN patients and 26 articles describing 207 pediatric DADA2 patients were identified. Neurologic, gastrointestinal, and cardiac involvements were more frequent in DADA2, while constitutional symptoms and testis involvement were more common in PAN. CONCLUSION: In a child with PAN-like phenotype, DADA2 should be considered in the presence of young age at disease onset, parental consanguinity, strokes, lymphopenia, and lack of thrombocytosis during active disease. Anti-TNF treatment is indicated for vasculitic DADA2. Cyclophosphamide could be switched to MMF when remission is confirmed with PVAS in severe PAN.

Multisystem inflammatory syndrome in children during the COVID-19 pandemic in Turkey: first report from the Eastern Mediterranean.

OBJECTIVE: We aimed to describe the typical clinical and laboratory features and treatment of children diagnosed with multisystem inflammatory syndrome in children (MIS-C) and to understand the differences as compared to severe/critical pediatric cases with COVID-19 in an eastern Mediterranean country. METHODS: Children (aged <18 years) who diagnosed with MIS-C and severe/critical pediatric cases with COVID-19 and were admitted to hospital between March 26 and November 3, 2020 were enrolled in the study. RESULTS: A total of 52 patients, 22 patients diagnosed with COVID-19 with severe/critical disease course and 30 patients diagnosed with MIS-C, were included in the study. Although severe COVID-19 cases and cases with MIS-C share many clinical and laboratory features, MIS-C cases had longer fever duration and higher rate of the existence of rash, conjunctival injection, peripheral edema, abdominal pain, altered mental status, and myalgia than in severe cases (p<0.001 for each). Of all, 53.3% of MIS-C cases had the evidence of myocardial involvement as compared to severe cases (27.2%). Additionally, C-reactive protein (CRP) and white blood cell (WBC) are the independent predictors for the diagnosis of MIS-C, particularly in the existence of conjunctival injection and rash. Corticosteroids, intravenous immunoglobulin (IVIG), and biologic immunomodulatory treatments were mainly used in MIS-C cases rather than cases with severe disease course. There were only three deaths among 52 patients, one of whom had Burkitt lymphoma and the two cases with severe COVID-19 of late referral. CONCLUSION: Differences between clinical presentations, acute phase responses, organ involvements, and management strategies indicate that MIS-C might be a distinct immunopathogenic disease as compared to pediatric COVID-19. Conjunctival injection and higher CRP and low WBC count are reliable diagnostic parameters for MIS-C cases. Key Points • MIS-C cases had longer fever duration and higher rate of the existence of rash, conjunctival injection, peripheral edema, abdominal pain, altered mental status, and myalgia than in severe/critical pediatric cases with COVID-19. • Higher CRP and low total WBC count are the independent predictors for the diagnosis of MIS-C. • MIS-C might be a distinct immunopathogenic disease as compared to pediatric COVID-19.

Children With Behçet Disease-associated Thrombosis: A Single-Center Experience.

Behçet disease (BD) is a systemic vasculitis that can be complicated with thrombosis, which is an important cause of mortality and morbidity. The course of BD is more severe, and the diagnosis is usually delayed. In children, thrombosis associated with BD is very rare. In this study, we aimed to evaluate the characteristics of children with BD complicated with thrombosis. Forty-six patients with BD who were followed-up at a pediatric rheumatology department between January 2012 and September 2019 were evaluated retrospectively. Thrombosis was detected in 10 patients (21.7%), and it was the first sign of BD in 7 patients. Four patients had cerebral sinus venous thrombosis, 4 patients had deep-vein thrombosis, 1 patient had renal vein thrombosis, 1 had pulmonary artery thrombosis, and 1 had intracardiac thrombosis. None of the patients had arterial thrombosis. All patients had received anticoagulant therapy with immunosuppressive treatment. Any complication due to anticoagulant therapy was not detected. One patient had recurrent thrombosis, and none of the patients died during follow-up. Vasculitic diseases such as BD may cause a predisposition to thrombosis, and thrombosis might be the first sign of BD. Therefore, in children presenting with unprovoked thrombosis, BD should also be investigated.

C3 glomerulopathy in NLRP12-related autoinflammatory disorder: case-based review.

Autoinflammatory diseases (AIDs) are a recently described group of conditions caused by mutations in multiple genes that code for proteins of the innate immune system. Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory diseases comprising three clinically overlapping disorders: familial cold urticarial syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). CAPS have been associated with gain-of-function variations in NLRP3 (NOD-like receptor family, pyrin containing domain-3). However, a new class of autoinflammatory disease resembling FCAS or MWS has been described in patients with NLRP12 mutations. Here, we report a 6-year-old boy diagnosed with AID who developed an unexpected C3 glomerulopathy during attacks and carried a novel variation in NLRP12. Following treatment with IL (interleukin) 1 targeting agents, all symptoms and inflammation resolved. This is the first case in the literature affected by both autoinflammatory disease and C3 glomerulopathy.

Hemorragia pulmonar, una complicación poco frecuente en una niña con púrpura de Schonlein-Henoch / Pulmonary hemorrhage, a rare complication in a girl with Henoch-Schonlein purpura

La púrpura de Schonlein-Henoch (PSH) es la vasculitis más frecuente en los niños. Los procesos vasculíticos pueden afectar el pulmón. Si bien la hemorragia alveolar difusa puede considerarse una de las manifestaciones de la PSH, no es un cuadro frecuente. En este artículo presentamos el caso de una niña de 10 años con nefritis por PSH que sufrió hemorragia pulmonar. La paciente recibió un tratamiento satisfactorio con metilprednisolona intravenosa. La revisión de las publicaciones reveló que la edad temprana puede influir de manera positiva en el pronóstico, y que los inmunosupresores y el tratamiento complementario son fundamentales.

Henoch-Schonlein purpura (HSP) is the most common vasculitis in children. Vasculitic processes can involve the lung. Although diffuse alveolar hemorrhage may be seen as one of the manifestation of HSP, it is not a frequent presentation. Here we reported the case of a 10-year-old girl with HSP nephritis who developed pulmonary hemorrhage. The patient was treated successfully with intravenous methylprednisolone. A review of the literature revealed that young age may be a good prognostic sign and that immunosuppressive drugs and supportive management are essential in the treatment.

Atypical presentation of multicentric Castleman disease in a pediatric patient: pleural and pericardial effusion.

UNLABELLED: Castleman disease (CD) is a rare poorly understood lymphoproliferative disorder. Pediatric onset CD has been reported before. However, most of them have benign unicentric pattern. Multicentric CD (MCD) is quite rare in children. Herein, we report a 13-year-old adolescent boy with MCD of the hyaline vascular variant presenting with pleural and pericardial effusion, which is an uncommon presentation. CONCLUSION: MCD should be considered in the differential diagnosis of pleural and/or pericardial effusion with unexplained lymph nodes in children. What is Known •Pediatric Castleman disease (CD) most commonly occurs in the unicentric form, which typically is asymptomatic and cured by lymph node excision. •The diagnosis of MCD can be difficult owing to the heterogeneity of presentation and potential for nonspecific multisystem involvement. What is New •A 13-year-old adolescent boy was diagnosed with MCD of the hyaline vascular variant presenting with pleural and pericardial effusion, which is an uncommon presentation. •In a pediatric patient with fever, pleural-pericardial effusion and multiple lymph nodes, MCD should be considered in differantial diagnosis.

Hemophagocytic lymphohistiocytosis secondary to Varicella zoster infection in a child with Henoch-Schönlein purpura.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal, hyper-inflammatory syndrome that is characterized by untimely activation of macrophages, and manifests as cytopenia, organ dysfunction, and coagulopathy. Secondary HLH can be associated with infection, drugs, malignancy, and transplantation, and is mostly triggered by infection. Herein, we report the case of a patient with Henoch-Schönlein purpura (HSP) who developed severe HLH secondary to Varicella zoster infection.

A rare metabolic complication of acute lymphoblastic leukemia in childhood: lactic acidosis.

A 13-year-old boy presented with nausea, fatigue, weight loss, and bone pain for two months. Complete blood count and serum renal and liver function tests were all normal. Blood gas analysis revealed severe metabolic acidosis with high anion gap. Lactate level was 61.2 mmol/L. Abdominal ultrasonography yielded bilateral nephromegaly and hepatomegaly with increased echogenicity. Peripheral blood smear revealed 2% blasts. Bone marrow aspiration showed 'Common ALL Antigen'-negative acute lymphoblastic leukemia by flow cytometric analysis. Metabolic acidosis dissolved as soon as chemotherapy was begun. Lactic acidosis at the presentation of acute lymphoblastic leukemia--especially with low tumor burden--is a very rare and almost always fatal complication. Our patient is still alive and in remission, which is a point of interest in this child.