Severe haematological involvement in children with systemic lupus erythematosus and clinical associations.

OBJECTIVES: To investigate the severe haematological involvement in children with SLE and assess its clinical associations, treatments, outcome and damage accrual. METHODS: The medical charts of children with SLE in whom haematological involvement was observed were reviewed. Severe haematological indices were defined as autoimmune haemolytic anaemia with a haemoglobin concentration < 8 g/dL, thrombocyte count < 30 000/µL, and neutrophil count < 500/µL. RESULTS: Among the 224 patients included, 102 (45.5%) displayed severe indices, predominantly at the initial involvement, and most frequently as severe anaemia in 54 (24.1%) and severe thrombocytopenia in 45 (20.1%). Disease activity did not differ according to the presence of severe disease indices. In addition, the presence of severe indices at initial involvement did not affect the damage accrual. However, a higher rate of damage (51.1% vs. 29.9%, p = 0.002) and steroid-induced damage (28.9% vs. 8.2%, p < 0.001) was evident in patients with flares of the haematological system. Regression analysis revealed that rituximab treatment during the initial episode (OR:4.5, p = 0.006) and the presence of anticardiolipin antibodies (OR:2.3, p = 0.014) significantly increases the odds for haematological system flare. However, severe indices at initial involvement did not increase the odds of a haematological flare. CONCLUSION: Severe haematological indices at onset are common but not related with disease outcomes. Prevention of flares is important to improve outcomes, and a more rigorous maintenance strategy would benefit most to children who display haematological indices refractory to conventional immunosuppressants and those with anti-cardiolipin antibodies.

Interleukin(IL)-1/IL-6-inhibitor-associated drug reaction with eosinophilia and systemic symptoms (DReSS) in systemic inflammatory illnesses.

BACKGROUND: After introducing interleukin(IL)-1/IL-6 inhibitors, some Still and Still-like patients developed unusual often fatal pulmonary disease. This complication was associated with scoring as DReSS (drug reaction with eosinophilia and systemic symptoms) implicating these inhibitors, although DReSS can be difficult to recognize in the setting of systemic inflammatory disease. OBJECTIVE: We sought to facilitate recognition of IL-1/IL-6 inhibitor-DReSS in systemic inflammatory illnesses (Still/Still-like) by looking at timing and reaction-associated features. We evaluated outcomes of stopping or not-stopping IL-1/IL-6-inhibitors after DReSS reaction began. METHODS: In an international study collaborating primarily with pediatric specialists, we characterized features of 89 drug-reaction cases versus 773 drug-exposed controls and compared outcomes of 52 cases stopping IL-1/IL-6-inhibitors to 37 cases not-stopping these drugs. RESULTS: Before reaction began, drug-reaction cases and controls were clinically comparable, except for younger disease onset age for reaction cases with pre-existing cardiothoracic comorbidities. After reaction began, increased rates of pulmonary complications and macrophage activation syndrome (MAS), differentiated drug-reaction cases from drug-tolerant controls (p=4.7x10-35; p=1.1x10-24, respectively). Initial DReSS feature was typically reported 2-8 weeks after initiating IL-1/IL-6-inhibition. In drug-reaction cases stopping versus not-stopping IL-1/IL-6-inhibitor treatment, reaction related features were indistinguishable, including pulmonary complication rates [75%(39/52] versus [76%(28/37)]. Those stopping subsequently required fewer medications for treatment of systemic inflammation, had decreased rates of MAS, and improved survival (p=0.005, multivariate regression). Resolution of pulmonary complications occurred in 67%(26/39) of drug-reaction cases who stopped and in none who continued inhibitors. CONCLUSIONS: In systemic inflammatory illnesses, recognition of IL-1/IL-6-inhibitor-associated reactions followed by avoidance of IL-1/IL-6-inhibitors significantly improved outcomes.

The HyperPed-COVID international registry: Impact of age of onset, disease presentation and geographical distribution on the final outcome of MIS-C.

OBJECTIVES: The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome. STUDY DESIGN: Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected. Five age groups (<1, 1-4, 5-11, 12-16, >16 years) and four geographic macro-areas, Western Europe, Central-Eastern Europe, Latin America, Asian-African resource-limited countries (LRC), were identified. RESULTS: Time to referral was significantly higher in LRC. Intensive anti-inflammatory treatment, including biologics, respiratory support and mechanic ventilation were more frequently used in older children and in European countries. The mortality rate was higher in very young children (<1 year), in older patients (>16 years of age) and in LRC. Multivariate analysis identified the residence in LRC, presence of severe cardiac involvement, renal hypertension, lymphopenia and non-use of heparin prophylaxis, as the factors most strongly associated with unfavorable outcomes. CONCLUSIONS: The stratification of patients by age and geographic macro-area provided insights into the clinical presentation, treatment and outcome of MIS-C. The mortality and sequelae rates exhibited a correlation with the age and geographical areas. Patients admitted and treated in LRC displayed more severe outcomes, possibly due to delays in hospital admission and limited access to biologic drugs and to intensive care facilities.

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.

Risk for cancer development in familial Mediterranean fever and associated predisposing factors: an ambidirectional cohort study from the international AIDA Network registries.

Objective: Inflammation has been associated with an increased risk for cancer development, while innate immune system activation could counteract the risk for malignancies. Familial Mediterranean fever (FMF) is a severe systemic inflammatory condition and also represents the archetype of innate immunity deregulation. Therefore, the aim of this study is to investigate the risk for cancer development in FMF. Methods: The risk ratio (RR) for malignancies was separately compared between FMF patients and fibromyalgia subjects, Still's disease patients and Behçet's disease patients. Clinical variables associated with cancer development in FMF patients were searched through binary logistic regression. Results: 580 FMF patients and 102 fibromyalgia subjects, 1012 Behçet's disease patients and 497 Still's disease patients were enrolled. The RR for the occurrence of malignant neoplasms was 0.26 (95% Confidence Interval [CI.] 0.10-0.73, p=0.006) in patients with FMF compared to fibromyalgia subjects; the RR for the occurrence of malignant cancer was 0.51 (95% CI. 0.23-1.16, p=0.10) in FMF compared to Still's disease and 0.60 (95% CI. 0.29-1.28, p=0.18) in FMF compared to Behçet's disease. At logistic regression, the risk of occurrence of malignant neoplasms in FMF patients was associated with the age at disease onset (ß1 = 0.039, 95% CI. 0.001-0.071, p=0.02), the age at the diagnosis (ß1 = 0.048, 95% CI. 0.039-0.085, p=0.006), the age at the enrolment (ß1 = 0.05, 95% CI. 0.007-0.068, p=0.01), the number of attacks per year (ß1 = 0.011, 95% CI. 0.001- 0.019, p=0.008), the use of biotechnological agents (ß1 = 1.77, 95% CI. 0.43-3.19, p=0.009), the use of anti-IL-1 agents (ß1 = 2.089, 95% CI. 0.7-3.5, p=0.002). Conclusions: The risk for cancer is reduced in Caucasic FMF patients; however, when malignant neoplasms occur, this is more frequent in FMF cases suffering from a severe disease phenotype and presenting a colchicine-resistant disease.

Further expanding the phenotype of anti-Ku antibody associated disease in children and adolescents.

Anti-Ku autoantibodies are associated with several autoimmune inflammatory diseases. We aimed to review our anti-Ku positive pediatric patients in this study. Four pediatric patients (all female) who had anti-Ku positivity were included (Patients 1-2-3 with idiopathic inflammatory myopathy (IIM); Patient 4 with chronic urticaria). Patient 1 (onset:10.5 years) had proximal muscle weakness, Raynaud phenomenon, sclerodactyly, hyperpigmentation, joint contracture, and tenosynovitis. The disease course was progressive despite treatment with corticosteroids, intravenous immunoglobulin (IVIG), plasma exchange, and 11 different immunosuppressive drugs. Patient 2 (onset:15 years) presented with proximal muscle weakness, fatigue, weight loss. She recovered normal muscle strength after treatment with corticosteroids, IVIG, methotrexate, cyclosporine A, mycophenolate mofetil. Patient 3 (onset:10 years) had juvenile dermatomyositis with proximal muscle weakness, Gottron's papules, and calcinosis. She also had anti-NXP2 positivity. Remission was achieved with corticosteroids, methotrexate, azathioprine, and infliximab. Muscle biopsy findings revealed a variable spectrum of necrosis, regeneration, perifascicular pattern, and inflammation. Patient 4 had only chronic urticaria (onset: 6.5 years). The striking features of this series were heterogeneity in clinical presentations including solely chronic urticaria and IIM; variable response to immunosuppressive treatments; and histopathology revealing a spectrum of necrosis, regeneration and inflammatory infiltration. Expanding the spectrum of anti-Ku positivity will allow better understanding of anti-Ku-associated phenotype clusters.

Polyarticular juvenile idiopathic arthritis has a distinct co-inhibitor receptor profile.

OBJECTIVES: Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease of childhood; the pathogenesis is associated with T cell activation. T cell activation can be counter-balanced by signals generated by inhibitory receptors (IRs) such as CTLA-4, PD-1, LAG-3, and TIM-3. Here, we identify the role of IRs in the pathogenesis of different JIA subtypes. METHODS: In total, we included 67 oligoarticular JIA, 12 IgM-RF negative polyarticular JIA, 17 enthesitis related arthritis, 11 systemic JIA patients and 10 healthy controls. We collected plasma (and synovial fluid) samples from the patients either at the onset or during a flare of their disease. We measured the soluble levels of co-IRs (IL-2Rα, 4-1BB, CD86, TGF-ß1, CTLA-4, PD-L1, PD-1, TIM-3, LAG- 3, Galectin-9) by cytometric bead array kits and their cellular expression (PD-1, CTLA-4, TIM-3, LAG-3) by flow cytometry. We compared the plasma levels and cellular expressions of different co-IRs within different JIA subgroups. RESULTS: The polyarticular-JIA group was different from the three other examined JIA subgroups, having higher levels of plasma sCTLA-4(p< 0.001), sPD-1(p< 0.05), and s4-1BB(p< 0.05) when compared with the other JIA subgroups and healthy controls. We analyzed the cellular surface expression of different co-IRs on the PBMCs of different JIA subtypes. Similar to plasma levels, both the percentage(p< 0.05) and the MFI (mean fluorescence intensity) (p< 0.01) of CTLA4 expression were higher in the poly-JIA subgroup. CONCLUSION: This is the first report studying the expression profile of different co-IRs in different subtypes of JIA. Polyarticular JIA patients had a different co-IR profile, having more CTLA-4, PD-1 and 4-1BB in their plasma than the other subtypes of JIA.

Transitioning from pediatric to adult-oriented healthcare in rheumatology: the pediatric side of the coin.

OBJECTIVES: The transition of adolescents and young adults (AYAs) from pediatric to adult-oriented healthcare may be affected by many factors, including the personal and cultural settings. We aimed to analyze the transition readiness and the factors affecting the transition success in rheumatology. METHODS: Patients older than 12 years were included in this prospective study. All filled out the Transition Readiness Assessment Questionnaire (TRAQ) 5.0. AYAs were phone-interviewed after their transfer to adult-oriented healthcare. Drug adherence was evaluated with 4-item Morisky Medication Adherence Scale (MMAS-4). AYAs rated their transitional care experience with visual analogue scale (VAS 0-10; 0, the worst; 10, the best). RESULTS: A total of 504 TRAQs were filled out by 406 patients (F/M = 1.5). The total TRAQ score was positively correlated with age and higher in the forms filled out by girls than boys (4.2 vs 4.0, respectively; p= 0.005). The transition was successful for 78 (83.9%) out of 93 patients transferred to adult-oriented healthcare. The VAS for the transition process was lower and the post-transfer MMAS-4 score was worse (8 vs 9, p= 0.030 and 3 vs 4, p= 0.020; respectively) in patients whose transition was not successful when compared with the successfully-transitioned ones. The best-performing TRAQ cut-off value was >4.0 for predicting transfer readiness in rheumatology. CONCLUSION: A TRAQ score of > 4 could be used while deciding about the transfer readiness of AYAs in rheumatology. Improving the AYAs' experience of the transition process and closely monitoring medication adherence during transition are essential for a successful transition.

A treatment algorithm for familial Mediterranean fever patients with menstruation-associated attacks.

OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by febrile polyserositis attacks. Menstruation could be a trigger for attacks. We aimed to analyze the features of adolescent FMF patients with menstruation-associated attacks and propose a management algorithm. METHODS: All female FMF patients who had menarche and visited the Pediatric Rheumatology Unit between January-December 2022, were included into this study. Demographics, general characteristics, and the features of menstrual cycle and FMF attacks were noted. RESULTS: A total of 151 female FMF patients were included. Thirty-five (23.2%) had menstruation-associated attacks. Fever and arthritis were less frequent during the menstruation-associated attacks than the attacks not associated with menstruation in these patients (65.7% vs 88.6%, p= 0.01 and 2.9% vs 20%, p= 0.04; respectively). Patients with menstruation-associated FMF attacks were younger at symptom onset and diagnosis (2.5 vs 5 years, p= 0.004 and 4 vs 7 years, p= 0.01; respectively), had a higher rate of dysmenorrhea (74.3% vs 38.8%, p< 0.001, respectively) and higher pre- and post-menarche attack frequency (4 vs 2 and 10 vs 0, respectively; p< 0.001 for both) than patients whose attacks were not associated with menstruation. The interventions for menstruation-associated attacks included initiating colchicine, increasing the dose of colchicine, switching from coated to compressed colchicine tablets or anti-interleukin 1 drugs, and on-demand non-steroidal anti-inflammatory drugs, on-demand glucocorticoids, and on-demand anakinra. On-demand therapies were beneficial in controlling menstruation-associated attacks. CONCLUSIONS: This is the largest cohort of adolescent FMF patients with menstruation-associated attacks. Severe FMF may cause tendency to this association. On-demand therapies could be preferred in the management.

Detection of genetic mutations underlying early-onset systemic lupus erythematosus.

OBJECTIVE: We aimed to investigate the presence of monogenic causes of systemic lupus erythematosus (SLE) in our early-onset SLE patients. METHODS: Fifteen pediatric SLE cases who had early disease onset (≤6 years) were enrolled in this study. All patients fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria. Genomic DNA was used for whole exome sequencing (WES). Pathogenic variants were confirmed by Sanger sequencing. RESULTS: The median age at diagnosis of 15 early-onset SLE patients included in the study was 4 (2-6) years (F/M = 12/3). Significant gene mutations were detected in five of these patients (33.3%). Patients 1 and 2 with homozygous DNASE1L3 mutations [c.320+4_320+7del and G188 A (c.563 G>C) variants] had skin involvement and oral ulcers. One of them (patient 1) had arthritis and nephritis, and another (patient 2) had nonscarring alopecia and thrombocytopenia. They are currently clinically inactive but have positive serological findings. Patient 3 with homozygous pathogenic ACP5 mutation [G109 R (c.325 G>A) variant] had arthritis, nephritis, short stature, and skeletal dysplasia. Patient 4 with a heterozygote novel IFIH1 mutation [L809 F (c.2425 C>T) variant] had skin findings and leukopenia. Patient 5 with novel C1S variant [homozygous C147 W (c.441 C>G) variant] had marked skin findings, oral ulcers, nonscarring alopecia, pancytopenia, and low total hemolytic complement CH50 level. All patients have responded to the treatments and have low Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, on therapy. CONCLUSION: Genetic causes should be investigated in early-onset SLE, for better management and genetic counseling. On the other hand, multicenter studies may help to further define genotype-phenotype associations.

Drug-induced lupus erythematosus in childhood: Case-based review.

BACKGROUND: Drug-induced lupus erythematosus (DILE) is the development of lupus-like syndrome following a drug exposure. DILE has been reported less frequently among children than adults. METHODS: In this study, we present four children with DILE and similar published cases through a systematic literature review. RESULTS: We report four children (three girls and one boy) who developed DILE associated with the use of topiramate, doxycycline, etanercept, and ethosuximide. Three of them were positive for anti-histone antibodies. In all patients, the drug was discontinued and symptoms resolved completely. The literature review revealed 48 articles describing 61 children with DILE. In the evaluation of 65 patients (our 4 patients and 61 patients from the literature), the most frequently reported drugs associated with DILE were ethosuximide (n = 13) and minocycline (n = 12). Fever (n = 33), arthralgia (n = 31), rash (n = 30), and arthritis (n = 29) were the most common clinical manifestations. Antinuclear antibody (ANA) was positive in 93.5% of patients and anti-histone antibodies were detected in 72.2% of the patients. As for treatment, the responsible drug was discontinued in all patients, and corticosteroids were initiated in 53.3%. Improvement was achieved in 92.0% of patients. CONCLUSION: For children presenting with SLE features, proper drug history is crucial since DILE may be more frequent than anticipated. An association of the relevant drug with the symptoms, and resolution of symptoms on drug withdrawal provides evidence for the diagnosis of DILE.

Factors determining resistance to conventional disease-modifying anti-rheumatic drug treatment in oligoarticular juvenile idiopathic arthritis.

OBJECTIVE: Our study was designed to investigate the reasons for starting the conventional disease-modifying anti-rheumatic drugs (DMARDs) and the variables that impact the response to DMARD treatment in oligoarticular juvenile idiopathic arthritis (JIA) patients. METHODS: Oligoarticular JIA patients (n = 187) were categorized into two groups: Group A consisted of patients who achieved remission with DMARD, and Group B comprised those who did not respond to DMARD therapy. RESULTS: DMARDs were initiated for various reasons: 68 (36.4%) due to active disease despite nonsteroidal anti-inflammatory drugs (± intra-articular corticosteroid) treatment, 59 (31.6%) due to uveitis, 49 (26.2%) due to extended oligoarticular JIA, and 11 (5.9%) due to inflammatory bowel disease. One hundred twenty-three patients (65.8%) achieved remission with DMARDs (Group A), while 64 patients (34.2%) did not respond to DMARD therapy (Group B). In Group B, patients had higher C-reactive protein (CRP) levels as well as higher Juvenile Idiopathic Arthritis Disease Activity Scores-71 (JADAS-71) at diagnosis (both p < 0.001). Moreover, extended oligoarticular JIA subtype (p = 0.017) and involvement of small joints at diagnosis (p = 0.043) were more prevalent among these patients. Group A exhibited a higher frequency of antinuclear antibody positivity (p = 0.014). Elevated CRP levels (> 1.1 mg/dL) (OR 1.308, 95% CI 1.203-3.574; p < 0.001) and high JADAS-71 at diagnosis (> 15.8) (OR 1.659, 95% CI 1.179-2.941; p < 0.001) were associated with DMARD resistance. CONCLUSION: Elevated CRP and high JADAS-71 at diagnosis were the main factors associated with DMARD resistance in oligoarticular JIA. Prospective long-term studies may help verify the role of these factors associated with DMARD resistance in oligoarticular JIA. Key Points • Conventional DMARDs were most commonly started due to active disease despite NSAID (± intra-articular corticosteroids). • Remission was achieved with DMARD in 65.8% of oligoarticular JIA patients. • Elevated CRP and high JADAS-71 at diagnosis were associated with DMARD resistance.

Differentiating Multisystem Inflammatory Syndrome in Children from Kawasaki Disease During the Pandemic.

OBJECTIVE: We aimed to delineate the distinctive characteristics that aid in distinguishing between Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) with KD-like manifestations during the pandemic. MATERIALS AND METHODS: We evaluated KD patients and MIS-C patients with KD-like symptoms admitted during the pandemic (between January 2021 and December 2022). RESULTS: Thirty-three MIS-C patients and 15 KD patients were included. Kawasaki disease patients were younger than MIS-C patients (3.4 vs. 7.6 years). Rash (P = .044, 100% vs. 75.7%), oral mucosal changes (P = .044, 100% vs. 75.7%), and cervical lymphadenopathy (P = .001, 93.3% vs. 42.4%) were more common in KD. Multisystem inflammatory syndrome in children: patients had more hypotension (P = .002, 45.4% vs. 0), gastrointestinal (P .001, 72.7% vs. 13.3%), and respiratory symptoms (P = .044, 24.2% vs. 0). Multisystem inflammatory syndrome in children patients also had low lymphocyte and thrombocyte counts and elevated levels of d-dimer, ferritin, and cardiac parameters, unlike KD patients. Multisystem inflammatory syndrome in children patients exhibited a notable reduction in left ventricular systolic function in echocardiography. Another significant difference with regard to management was the anakinra treatment, which was prescribed for MIS-C patients. CONCLUSION: Although MIS-C patients might display a clinical resemblance to KD, several features could help differentiate between MIS-C and classical KD. Specific clinical (hypotension, gastrointestinal, and respiratory symptoms) and laboratory (low lymphocyte and thrombocyte counts with higher C-reactive protein, ferritin, d-dimer, and cardiac parameters) features are characteristic of MIS-C. In addition, divergence in management strategies is evident between the 2 diseases, as biologic drugs were more prevalently employed in MIS-C patients than in classical KD patients.

Treatment with Janus kinase inhibitors in juvenile dermatomyositis: A review of the literature.

BACKGROUND/OBJECTIVES: Janus kinase (JAK) inhibitors have been increasingly used in the treatment of juvenile dermatomyositis (JDM). This review aims to comprehensively analyze previous studies concerning the utilization of JAK inhibitors in JDM patients. METHODS: We conducted a thorough review of MEDLINE and Scopus databases, spanning from their inception to September 1st, 2023, to identify articles involving JDM patients treated with JAK inhibitors. RESULTS: Our literature search yielded 26 articles that encompassed 195 patients with JDM who received JAK inhibitors. The median (min-max) age of the patients was 4.9 (1-17) years (F/M:1.2). The most frequently used JAK inhibitor was tofacitinib (57.4 %), and improvement was achieved in 89.7 % of patients treated with tofacitinib. The improvement rate for ruxolitinib, which was the second most frequently used JAK inhibitor (27.2 %), was 69.2 %. For baricitinib (15.4 %), the improvement rate was 92.7 %. The most prevalent indication for JAK inhibitor use was resistant/recurrent skin involvement (34.7 %) followed by resistant/recurrent muscle involvement (28.6 %). Adverse events were reported in 72.1 % of the patients; an increase in infections (especially upper respiratory tract infections) was the most common side effect. CONCLUSION: Our findings suggest that JAK inhibitors may be a good therapeutic option, particularly in the management of refractory JDM cases with an acceptable safety profile. However, further controlled studies are essential to establish a higher level of evidence for the optimal use of JAK inhibitors in JDM treatment.

Rhupus syndrome in children: A multi-center retrospective cohort study and literature review.

OBJECTIVE: In this study, we aimed to evaluate the characteristics of pediatric rhupus patients including all the related series in the literature. METHODS: Thirty pediatric patients with rhupus syndrome from 12 different centers in Turkey were included in this study. The literature was also reviewed for pediatric patients with rhupus syndrome. RESULTS: The most prominent phenotype of these 30 patients was juvenile idiopathic arthritis (JIA) (60%) at the disease onset and SLE (73.3%) at the last visit. Major SLE-related organ involvements were skin (80%), hematological system (53.3%), and kidney (23.3%). Arthritis was polyarticular (73.3%), asymmetric (66.7%), and erosive (53.3%) in most patients. Hydroxychloroquine (100%), glucocorticoids (86.7%), and mycophenolate mofetil (46.7%) were mostly used for SLE, while glucocorticoids (76.6%), methotrexate (73.3%), and nonsteroidal anti-inflammatory drugs (NSAIDs) (57.6%) were mainly preferred for JIA. Our literature search revealed 20 pediatric patients with rhupus syndrome (75% were RF positive). The most prominent phenotype was JIA (91.7%) at the disease onset and SLE (63.6%) at the last visit. Major SLE-related organ involvements were skin (66.7%), hematological system (58.3%), and kidney (58.3%). Arthritis was polyarticular (77.8%), asymmetric (63.6%), and erosive (83.3%) in most patients. Glucocorticoid (100%), hydroxychloroquine (76.9%), and azathioprine (46.2%) were mostly used for SLE, while methotrexate (76.9%) and NSAIDs (46.2%) were mainly preferred for the JIA phenotype. CONCLUSION: Our study is the largest cohort in the literature evaluating pediatric rhupus cases. Most of the pediatric patients had polyarticular, asymmetric, and erosive arthritis, as well as organ involvements associated with SLE, including the skin, hematological system, and kidney.

Is it possible to predict a disease course prone to macrophage activation syndrome at systemic juvenile idiopathic arthritis diagnosis?

OBJECTIVES: Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile idiopathic arthritis (SJIA). We aimed to compare the characteristics of SJIA patients who developed MAS in the disease course to those who never experienced MAS. METHODS: Patients with SJIA were included. The features of the patients at the time of SJIA diagnosis were compared. Multivariate logistic regression and ROC analyses were used while evaluating factors associated with MAS. RESULTS: Overall, 126 SJIA patients (M/F:1.17) were included. Eighty-six (68.2%) never had MAS. At the time of SJIA diagnosis, age was younger; the duration of fever was longer; rash, hepatomegaly, and splenomegaly were more frequent and arthralgia/arthritis was less common among patients who had MAS in the follow-up than those who never had MAS. Also, white blood cell, neutrophil, and platelet counts and fibrinogen were lower, while transaminases, lactate dehydrogenase, triglyceride (TG), and ferritin levels were higher among patients with MAS than those without MAS. The multivariate regression analysis disclosed age at symptom onset, duration of fever, platelet count, TG and ferritin levels as independent MAS predictors. For ferritin level/platelet count (F/P) ratio at the time of SJIA diagnosis, a threshold of ≥1.1 performed best to predict a MAS-prone disease course with a sensitivity of 90% and a specificity of 82.6%. CONCLUSION: The F/P ratio at the time of SJIA diagnosis may be a promising biomarker to predict MAS-prone disease course in SJIA. Determining MAS-prone patients at the time of SJIA diagnosis could assist physicians while tailoring SJIA treatment individually. Key points • Systemic juvenile idiopathic arthritis (SJIA) patients with macrophage activation syndrome (MAS) differ from SJIA patients who never have MAS, at the time of SJIA diagnosis. • It could be possible to predict a MAS-prone disease course at the time of SJIA diagnosis. • The ferritin/platelet ratio is a promising biomarker for predicting MAS-prone SJIA disease course.

Biologic drugs in the treatment of juvenile dermatomyositis: a literature review.

There is no clear consensus in the literature regarding the choice of biologic therapies and efficacy in juvenile dermatomyositis (JDM). In this review, we aimed to examine previous studies regarding biologic drug use in JDM patients. We screened MEDLINE and Scopus for articles involving JDM patients treated with biologic drugs. We identified 74 articles describing 495 JDM patients treated with biologic drugs (538 biologic treatments) during our literature search. The median (min-max) age of these patients was 9.8 (1-17) years (F/M:1.8). The most frequently used biologic drugs were rituximab (RTX, 50%) and tumor necrosis factor (TNF) inhibitors (34.8%). In a few cases, abatacept (4.3%), anti-interleukin-1 agents (0.9%), tocilizumab (0.9%), bortezomib (0.4%), ustekinumab (0.2%), eculizumab (0.2%), and golimumab (0.2%) were used. RTX was most frequently preferred in patients with severe skin involvement (46.3%). Improvement with RTX was obtained in 60.1% of RTX treatments. Infliximab was most frequently preferred in calcinosis (43.3%), while adalimumab in skin involvement (50%) and etanercept in resistant/recurrent diseases (80%). Improvement was achieved in 44.4% of anti-TNF treatments. Adverse events were observed in 46.8% (58/124) of all treatments. Our results suggest that biologic agents may be a promising alternative for the treatment of particularly resistant JDM cases. Controlled studies are required to provide higher level of evidence for the timing of biologic use in JDM treatment. Key Points • There is no consensus on the choice and efficacy of biologic therapies in JDM. • RTX and TNF inhibitors are the most commonly used biologic drugs. • Biologics were especially preferred in severe skin involvement, calcinosis, and resistant diseases.

A score for predicting colchicine resistance at the time of diagnosis in familial Mediterranean fever: data from the TURPAID registry.

OBJECTIVES: Colchicine forms the mainstay of treatment in FMF. Approximately 5-10% of FMF patients are colchicine resistant and require anti-IL-1 drugs. We aimed to compare the characteristics of colchicine-resistant and colchicine-responsive patients and to develop a score for predicting colchicine resistance at the time of FMF diagnosis. METHODS: FMF patients (0-18 years) enrolled in the Turkish Paediatric Autoinflammatory Diseases (TURPAID) registry were included. The predictive score for colchicine resistance was developed by using univariate/multivariate regression and receiver operating characteristics analyses. RESULTS: A total of 3445 FMF patients [256 (7.4%) colchicine-resistant and 3189 colchicine-responsive) were included (female:male ratio 1.02; median age at diagnosis 67.4 months). Colchicine-resistant patients had longer, more frequent attacks and were younger at symptom onset and diagnosis (P < 0.05). Fever, erysipelas-like erythema, arthralgia, arthritis, myalgia, abdominal pain, diarrhoea, chest pain, comorbidities, parental consanguinity and homozygosity/compound heterozygosity for exon 10 MEFV mutations were significantly more prevalent among colchicine-resistant than colchicine-responsive patients (P < 0.05). Multivariate logistic regression analysis in the training cohort (n = 2684) showed that age at symptom onset, attack frequency, arthritis, chest pain and having two exon 10 mutations were the strongest predictors of colchicine resistance. The score including these items had a sensitivity of 81.3% and a specificity of 49.1%. In the validation cohort (n = 671), its sensitivity was 93.5% and specificity was 53.8%. CONCLUSION: We developed a clinician-friendly and practical predictive score that could help us identify FMF patients with a greater risk of colchicine resistance and tailor disease management individually at the time of diagnosis.

Subclinical enthesitis in enthesitis-related arthritis and sacroiliitis associated with familial Mediterranean fever.

OBJECTIVES: In our study, we investigated the presence of subclinical enthesitis by ultrasonography (US) in asymptomatic patients with enthesitis-related arthritis (ERA) and sacroiliitis associated with familial Mediterranean fever (FMF). METHODS: A total of 50 patients, including 35 patients with ERA and 15 with sacroiliitis associated with FMF, were included in the study. All patients were evaluated with US by a paediatric radiologist. Enthesis of seven tendons (common extensor and flexor tendons, quadriceps tendon, proximal and distal patellar tendon, Achilles tendon, and plantar fascia) was examined on both sides. RESULTS: Subclinical enthesitis was detected in 10 ERA (28.5%) and three FMF (20%) patients. Enthesitis was radiologically diagnosed in 16 (2.3%) out of 700 evaluated entheseal sites. The most frequent sites of enthesitis were Achilles (37.5%) and quadriceps (31.3%) tendons. All patients were in clinical remission and had no active complaints, and acute phase reactants were within normal limits. Therefore, the patients were followed up without treatment change. However, disease flare-up was observed in three of these patients (23.1%) during the follow-up, and their treatments were intensified. CONCLUSIONS: Our results showed that the US can be particularly helpful in detecting subclinical enthesitis and predicting disease flare-ups.