Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death.

TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.

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.

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.

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.

The difference of the inflammatory milieu in MIS-C and severe COVID-19.

BACKGROUND: Coronavirus disease 19 (COVID-19) may have a severe course in children. Multisystem inflammatory syndrome in children (MIS-C) is the post-COVID complication characterized by an exaggerated inflammation, observed in children. However, data on the underlying pathophysiology are sparse. We therefore aimed to assess the cytokine and chemokine profiles of children with MIS-C and compare these to life-threatening severe SARS-CoV-2 and healthy controls (HCs) to shed light on disease pathophysiology. METHODS: Samples of 31 children with MIS-C, 10 with severe/critical COVID-19 and 11 HCs were included. Cytokine and chemokine profiles were studied and compared in between groups. RESULTS: Most cytokines and chemokines related to IL-1 family and IFN-γ pathway (including IL-18 and MIG/CXCL9) and IL-17A were significantly higher in the MIS-C group when compared to the severe/critical COVID-19 group and HCs. IP-10/CXCL10 and IL-10 were higher in both MIS-C patients and severe/critical COVID-19 compared to HCs. CONCLUSION: Our results suggest that IL-1 and IFN-γ pathways play an important role in the pathophysiology of MIS-C. IMPACT: This study defines a pattern of distinctive immune responses in children with MIS-C and in patients with severe/critical COVID-19. As the COVID-19 pandemic continues, biomarkers to identify MIS-C risk are needed to guide our management that study results may shed light on it.

The challenges in diagnosing pediatric primary antiphospholipid syndrome.

Pediatric primary antiphospholipid syndrome (APS) is a very rare disease with significant distinctions from the APS in adults. Herein, we present our experience in the diagnosis and treatment of six pediatric primary APS patients, who met the updated Sapporo criteria for the APS diagnosis. One of them was also diagnosed as having probable catastrophic APS (CAPS) due to the involvement of three different organ systems simultaneously. Besides vascular involvement, four patients had thrombocytopenia, one had psychiatric disorder, and one had chorea and valvular heart disease. All patients received immunosuppressive treatment along with long-term anticoagulation therapy. Specific neurologic and hematologic manifestations that are not part of the classification criteria can be seen in children with primary APS. Therefore, using the adult criteria for diagnosing pediatric APS may result in missed or delayed diagnoses in children.

Impact of the COVID-19 pandemic on the frequency of the pediatric rheumatic diseases.

The impact of the COVID-19 pandemic, and implemented restrictions on the frequency of pediatric rheumatic diseases remain unknown, while they have probably prevented common infections in children. We present the effects of the COVID-19 on our pediatric rheumatology practice in a main referral center. We retrospectively reviewed the medical records of patients presenting to pediatric rheumatology department in 4 years before March 2020 and compared it to the pandemic year (March 2020-March 2021). Since there was an overall decrease in patient numbers, we calculated the percentage according to the total number of that year. A total of 32,333 patients were evaluated. The mean annual number of patients decreased by 42% during the COVID-19 pandemic. When follow-up visits (25,156) were excluded, there were 2818 new diagnoses of rheumatic diseases. In the pre-pandemic period, familial Mediterranean fever (FMF) (n = 695, 28.1%) was the most frequent, whereas in the pandemic period multisystem inflammatory syndrome in children (MIS-C) (n = 68, 19.2%) was the most common diagnosis. There were no significant differences in the percentages of juvenile idiopathic arthritis, autoimmune diseases, rare autoinflammatory diseases, and other vasculitides. However, there was a significant decrease in patients diagnosed with FMF, IgA vasculitis (IgAV), acute rheumatic fever (ARF), classic Kawasaki disease (KD), and macrophage activation syndrome (MAS) (all p < 0.05). During the pandemic year, the percentage of most common diseases did not differ. On the other hand, we suggest that the decreases in IgAV, KD (classic), and MAS, which parallels the decrease in ARF, confirm the role of infections in the pathogenesis for these diseases.

Clinical course of COVID-19 infection in paediatric familial Mediterranean fever patients.

OBJECTIVE: To evaluate the course of coronavirus-19 (COVID-19) infection in paediatric familial Mediterranean fever (FMF) patients and to investigate the risk factors for COVID-19 infection. METHODS: Medical records of 100 consecutive paediatric FMF patients and their COVID-19 infection status were evaluated. Age- and gender-matched control group consisted of 51 patients with positive results for severe acute respiratory syndrome coronavirus 2. RESULTS: Twenty-five of 100 paediatric FMF patients were detected to have COVID-19 infection. A history of contact with a COVID-19 case was present in ∼95% of patients in both the FMF and control groups with COVID-19 infection. Asymptomatic infection was detected in two patients in the paediatric FMF group (8.0%) and 17 patients in the control group (33.3%) (P = .017). Mild disease was observed in 23 paediatric FMF patients (92.0%) and 28 control patients (54.9%) (P = .001), whereas moderate disease was present in only 6 control patients (11.7%) (0 vs 11.7%, P = .074). Severe or critical disease was not observed in any patients. CONCLUSION: Paediatric FMF patients receiving colchicine had no moderate COVID-19 disease compared to the control group. We suggest that colchicine use may tune down the severity of the disease even if it does not prevent COVID-19 infection.

Plasma checkpoint protein levels and galectin-9 in juvenile systemic lupus erythematosus.

SLE is a disease of the adaptive immune system where T lymphocyte dysfunction has an important role as well. We assessed the plasma levels of checkpoint receptors expressed on T cells, along with Galectin-9 to reflect type-1 IFN activity and IL-2Rα in childhood SLE patients. Forty-nine children with SLE and15 healthy controls were included. SLEDAI scores were evaluated at the time of sampling. CD25 (IL-2Rα), 4-1BB, B7.2 (CD86), TGF-ß1, CTLA-4, PD-L1, PD-1, Tim-3, LAG- 3, Galectin-9 levels were studied by cytometric bead-based multiplex assay panel. Galectin-9 and PD-L1 were significantly higher in SLE patients. Other checkpoint proteins and IL-2Rα were also higher but did not reach statistical significance. There were significant correlations between SLEDAI and IL-2Rα, Galectin-9 and PDL1. There were three clinical clusters: Cluster 1 included patients with no major organ involvement, cluster 2 had predominantly haematological involvement(n=16) and cluster 3 (n=11) had predominantly renal involvement. Checkpoint proteins were not different among these three clusters. Our data supports that Galectin 9 and IL-2Rα are good markers for disease activity in childhood SLE. We need larger series to evaluate differences between disease clusters in SLE. We failed to show a significant correlation with checkpoint proteins and SLEDAI except for PDL1.

Performances of the "MS-score" And "HScore" in the diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis patients.

Macrophage activation syndrome (MAS) is a devastating complication of systemic JIA (sJIA), seen in approximately 10-25% of the sJIA patients. A number of criteria have been proposed to differentiate between activation of sJIA and MAS, including HScore and the recently proposed MS-score. This is the first study comparing the performances of MS-score and HScore for the diagnosis of MAS in sJIA patients. Systemic JIA patients followed at Hacettepe University Pediatric Rheumatology Unit were included in the study. Clinical features and laboratory findings at the time when the disease was most active or patients were diagnosed with MAS were recorded retrospectively. HScore and MS-score were calculated and the diagnostic performance for MAS was compared by receiver operating characteristic (ROC) curve analysis. Seventy-one sJIA patients were included (23 MAS, 48 activation). There was no difference in age of onset (median 4.7 vs. 5.0 years) and gender (73.9% vs. 54.2%) between patients who had MAS and sJIA activation. Median MS-score and HScore were higher in the MAS group. ROC curve analysis revealed that the HScore performed slightly better in diagnosing MAS, compared with the MS-score (AUC = 0.965 and 0.901 for HScore and MS-score respectively, P < 0.001). In our cohort, the optimal cut-off for the MS score was ≥ - 1.64 (sensitivity: 91.3%; specificity: 83.8%) and for the HScore it was ≥ 162.5 (sensitivity: 91.3%; specificity: 90.2%). HScore performed slightly better than MS-score for the diagnosis of MAS in our cohort.

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.

Biologics for immunoglobulin A vasculitis: targeting vasculitis or comorbid disease?

In this study, we aimed to evaluate the clinical features and treatments, including the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) in a large cohort of pediatric and adult immunoglobulin A vasculitis (IgAV). Since data on the use of bDMARDs in IgAV are very limited, we collated the reasons for use of bDMARDs during the disease course. Patients who were enrolled in the Hacettepe University Vasculitis Research Centre (HUVAC) registry were included. In this prospective database dating from 2014, there were 436 IgAV patients classified as IgAV according to Ankara 2008 and/or American College of Rheumatology 1990 criteria. 88 adults and 330 pediatric IgAV patients were included as the main study group. Concomitant spondyloarthritis (SpA) was observed only in adult patients (10% vs 0% in children, p < 0.001). IgAV relapse was more common in adults than in children (p: 0.017). Adult patients were mostly treated with corticosteroid (p < 0.001) and conventional synthetic disease-modifying anti-rheumatic drug treatment (< 0.001), while more than half of the pediatric patients were followed up without immunosuppressive treatment. Ten (11%) adult patients used biologics. Among them, two patients used rituximab due to IgAV disease activity, three used infliximab due to SpA, three used etanercept due to SpA (one patient had a pediatric onset enthesitis-related arthritis), and two used anakinra due to recurrent familial Mediterranean fever attacks. This is the first study evaluating the use of all bDMARDs for any reason in the IgAV cohorts in the literature. None of the pediatric patients used biologics. Our data suggest biologics are mainly used for comorbid inflammatory diseases over refractory vasculitis in adult IgAV.

Pulmonary Manifestations of Systemic Vasculitis in Children.

Vasculitides are defined according to the vessel size involved, and they tend to affect certain organ systems. Pulmonary involvement is rare in the common childhood vasculitides, such as Kawasaki disease, IgA vasculitis (Henoch Schonlein purpura). On the other hand, lung involvement is common in a rare pediatric vasculitis, granulomatosis with polyangiitis (GPA) (Wegener granulomatosis), where respiratory system findings are common. A criterion in the Ankara 2008 classification criteria for GPA is the presence of nodules, cavities, or fixed infiltrates. The adult data suggest that rituximab may be an alternative to cyclophosphamide in induction treatment.