Autoinflammatory Research Articles

Updated genetic background of generalized pustular psoriasis as an autoinflammatory keratinization disease.

Generalized pustular psoriasis (GPP) is a severe autoinflammatory keratinization disease (AiKD) characterized by acute flares of widespread sterile pustules and high fever. GPP is potentially life-threatening. Recently clarified genetic predisposing factors for GPP suggest that the excessive activation of innate immune pathways in the skin, including of interleukin (IL)-1 and IL-36 signaling, plays a significant role in the GPP pathogenesis. IL36RN, CARD14, AP1S3, MPO, SERPINA3, BTN3A3, and MEFV have been identified as GPP-related genes. The pathogenesis of GPP provoked by variants in these seven genes is tightly associated with the excessive activation of innate immune pathways and the resulting autoinflammation in the skin. Various biologics, including inhibitors for the tumor necrosis factor, IL-17, and IL-23 pathways, are used as treatments for GPP. The new understanding of the genetic background of GPP, mentioned above, indicates that the genetic predisposing factors are predominantly related to the excessive activation of innate immunity and autoinflammation. In this context, inhibitors of inflammatory signaling, including of the IL-1 and IL-36 pathways, have been used in clinical practice and investigated as potential future therapies.

The knowledge and skills required for the onco-rheumatologist: Study of four-year consultation records of a high-volume cancer centre.

Onco-rheumatology, the intersection of oncology and rheumatology, is an emerging field requiring further definition. This study aimed to identify the knowledge and skills essential for rheumatologists in clinical oncology. We retrospectively reviewed consultations with the onco-rheumatology department of a high-volume tertiary cancer centre in Japan from January 2020 to December 2023. We analysed 417 consultations. The most common consultation (229, 55%) was related to immune checkpoint inhibitor-induced immune-related adverse events (irAEs). Of the 238 irAEs in 185 patients, 15% were rheumatic and 85% were non-rheumatic (e.g., hepatobiliary toxicities, colitis). Approximately 25% of non-endocrine irAEs were refractory/relapsing, requiring second-line therapy (e.g., mycophenolate mofetil, biologics, immunoglobulin). In addition to irAE consultations, 137 (33%) consultations were about possible rheumatic diseases. The final diagnosis often related to cancer treatment, such as granulocyte colony-stimulating factor-related aortitis (15 patients, 11%), olaparib-related erythema nodosum (10 patients, 7.3%), and surgical menopause-related arthralgia (10 patients, 7.3%). Five patients (3.6%) were diagnosed with autoinflammatory bone disease mimicking bone tumours. Onco-rheumatologists are expected to play a central role in the management of a wide range of irAEs, not limited to rheumatic irAEs. They must also manage rheumatologic manifestations during cancer treatment and rheumatic diseases that mimic tumours.

Recommendations for Transitioning Young People with Primary Immunodeficiency Disorders and Autoinflammatory Diseases to Adult Care

PurposeSignificant improvements in the prognosis for young patients with Primary Immunodeficiency Diseases (PID) and Autoinflammatory Disorders (AID), which together make up the majority of Inborn Errors of Immunity (IEI), have resulted in the need for optimisation of transition and transfer of care to adult services. Effective transition is crucial to improve health outcomes and treatment compliance among patients. Evaluations of existing transition programmes in European health centres identified the absence of disease-specific transition guidelines for PID and AID, as a challenge to the transition process. This research aimed to establish expert consensus statements for the transition of young patients with PID and AID to adult services.MethodsThis project used the Delphi method to establish mutual agreement for the proposed recommendations. A draft set of statements was developed following a literature review of existing transition programmes. Then the ERN RITA Transition Working Group convened to review the drafted recommendations and develop them into a survey. This survey was circulated among healthcare professionals to determine consensus using a five-point Likert scale, with the level of agreement set to 80% or greater. Statements that did not reach consensus were revised by the Working Group and recirculated among respondents.ResultsThe initial survey received 93 responses from 68 centres across 23 countries, while the following survey outlining revised recommendations received 66 responses. The respondents agreed upon recommendations detailing the structure and administration of transition programmes, collaborative working with social systems, and contraindications to transfer of care.ConclusionThis paper sets out a comprehensive set of recommendations to optimise transitional care for PID and AID.

Cordycepin ameliorates autoimmunity by promoting STING degradation via autophagy pathway.

Stimulator of interferon response cGAMP interactor 1 (STING), a central hub protein of cyclic GMP-AMP synthase (cGAS)-STING signalling pathway, has a crucial role in regulating type I interferons (IFNs) production and response. Recent studies indicate that excessive activation of STING is strongly associated with autoimmune diseases, including systemic lupus erythematosus (SLE). Searching immunomodulators that negatively regulate STING might greatly contribute to the suppression of autoimmunity. The peripheral blood mononuclear cells (PBMCs) of SLE patients, Hela cells, L929 cells and bone marrow-derived macrophages (BMDMs) from mice were used as in vitro models. While, Trex1 KO mouse autoimmune disease model was used as in vivo model. After treatment with cordycepin, a nucleoside from Cordyceps mushrooms, type I IFNs production and response were determined by western blotting, real-time polymerase chain reaction (PCR), dual-luciferase assay, enzyme-linked immunosorbent assay (ELISA), haematoxylin-eosin staining and RNA-seq. Cordycepin inhibited type I IFNs production and response in human and murine systems following cGAS-STING signalling activation. Importantly, cordycepin markedly attenuates the autoinflammatory and autoimmune responses in Trex1 KO BMDMs and Trex1 KO mice. Furthermore, cordycepin effectively suppressed the production of type I IFNs and interferon-stimulated genes (ISGs) in the PBMCs of SLE patients. Mechanistically, cordycepin promoted STING degradation via autophagy pathway upon DNA stimulation. This study shows that cordycepin promotes STING autophagic degradation to alleviate autoimmunity upon DNA stimulation. Cordycepin might be a potential therapeutic candidate for alleviating aberrant type I IFNs in autoimmune and autoinflammatory diseases.

Современные представления о моногенных аутовоспалительных заболеваниях

Autoinflammatory diseases (AIDs) are a group of rare disorders characterized by recurrent episodes of inflammation with neither infectious nor autoimmune nor neoplastic trigger. The AIDs pathogenesis is based on mutations in genes that lead to uncontrolled and excessive production of proinflammatory cytokines. Authors represent current views on the pathogenesis, clinical manifestations, diagnosis and treatment of the most studied monogenic AIDs. New therapeutic approaches based on targeted blockade of key inflammatory mediators are described as well.

Генотип-фенотипическая характеристика детей с семейной средиземноморской лихорадкой (периодической болезнью) в регионе Российской Федерации

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) caused by mutations in the MEFV gene. The purpose of this research was to investigate clinical variability and potential genotypic and phenotypic correlations in children with clinically verified FMF and MEFV gene mutations in the City of Moscow, Russia. Materials and methods used: among 188 pediatric patients with suspected monogenic AIDs, MEFV gene mutations were identified in 9 through sequencing. In order to confirm the FMF diagnosis, patients were evaluated according to the modified Tel-Hashomer criteria and the Eurofever/PRINTO classification criteria. Results: clinical picture of FMF was characterized by the presence of periodic attacks of the disease lasting from 1 to 7 days accompanied by fever and increased acute phase reactants (observed in all patients), abdominal pain (in 8 children), peritonitis requiring diagnostic laparotomy (in a single child), chest pain (in 2 patients), pleurisy (in a single child), arthritis (in 7 children) and erysipeloid-like rash (in a single child). The pathogenic mutation M694V was identified in the MEFV gene in 8 out of 9 patients, this mutation was homozygous in 5 patients and heterozygous in 1, M680I mutation was detected on another allele in 2 children (compound heterozygous), and a mutation of unknown significance K695R was detected in a single child. No obvious clinical differences were found between homozygotes and heterozygotes as well as compound heterozygotes. Clinical response was achieved in 5 patients with colchicine monotherapy while canakinumab was prescribed to 4 patients due to ongoing attacks. Conclusion: the diagnosis involving the identification of MEFV gene mutations may allow the assessment of genotype-phenotype correlations in patients with FMF.

The role of PET/CT SCAN in addressing autoinflammatory diseases; A case report of a young man presenting with fever, splenomegaly and exanthem.

Adult-onset Still's disease (AOSD) is an uncommon autoinflammatory syndrome characterized by quotidian fever, arthritis, evanescent exanthem and splenomegaly. Lymphadenopathy is present in about a half of patients; it is usually symmetrical with the cervical area being most commonly involved. When constitutional symptoms are present, an extensive work-up should be performed in order to exclude hematological malignancies, such as lymphoma. A 38-year-old male is presented due to fatigue and high-grade fever that first appeared a month ago. He did also refer night sweats, arthralgias and an evanescent erythema on the trunk and anterior thigh area. Serology testing for bacteria and viruses as well as autoimmune rheumatic diseases was requested. Whole body computed tomography (CT) scan was ordered and displayed a marginal lymph node in the right hilum and smaller ones in the axillary region. Positron emission tomography/CT (PET/CT) with fluorine-18-fluoro-deoxy-glucose (18F-FDG) showed hypermetabolic lymph nodes, with the right upper internal jugular lymph node being the most dominant, as well as diffusely increased 18F-FDG uptake by bone marrow and spleen, posing in the differential diagnosis a neoplastic disease of the hematopoietic tissues. Further laboratory testing showed high ferritin levels. It was decided to procced with biopsy of the aforementioned hypermetabolic internal jugular lymph node and bone marrow. Histopathological examination did show hyperreactivity and no malignant cells neither in the lymph node nor in the bone marrow. Adult-onset Still's disease is a rare disorder and it is a diagnosis of exclusion. High-grade fever along with arthralgias, splenomegaly, high serum ferritin levels and the presence of exanthem should pose high in the differential the AOSD. In this case, PET/CT guided the anatomical location for lymph node biopsy in order to differentiate AOSD from lymphoma. The dissociated increased 18F-FDG uptake from the cervical and axillary lymph nodes is characteristic of AOSD.

25 Years of Biologics For The Treatment of Pediatric Rheumatic Diseases - Advances in Prognosis and Ongoing Challenges.

There are over 100 rheumatic diseases and approximately 300,000 children with a pediatric rheumatic disease (PRD) in the United States (U.S.). The most common PRDs are juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (cSLE), and juvenile dermatomyositis (JDM). Effective and safe medications are essential because there are generally no cures for these conditions. Etanercept was the first biologic therapy for the treatment of JIA, approved in 1999. Since then, other biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARD (tsDMARDs) blocking relevant immunological pathways have been approved for the treatment of JIA, resulting in a marked improvement of disease prognosis. Conversely, there is only one bDMARD that has been approved for cSLE, but none are approved for the treatment of JDM. Lack of approved therapeutic options, with established dosing regimens and known efficacy and safety, remains a central challenge in the treatment of all PRDs, including autoinflammatory diseases, and for complications of PRDs. This review provides an overview of bDMARD and tsDMARD treatments studied for the treatment of various subtypes of JIA, summarizes information from bDMARD studies in other pediatric rheumatic diseases, with a focus on pivotal trials that led to regulatory approvals and highlights improved outcomes in JIA with the use of these newer medications. Further, we outline barriers and challenges in the treatment of other PRDs. Lastly, we summarize the current regulatory landscape for bDMARD studies and medication approvals in PRDs.

Behçet's disease: incidence, prevalence, and real-word data on the use of biologic agents in Japan.

Behçet's disease (BD) is an autoinflammatory disease that can affect multiple organs, including the gastrointestinal tract. Conventional management comprises anti-inflammatory drugs such as glucocorticoids (GCs) and/or immunomodulators that alleviate symptoms. The introduction of biological agents that target tumor necrosis factorα (TNF-α) has improved disease management. The goal of this work was to analyze the current prevalence and incidence of total BD and gastrointestinal Behçet's disease (GIBD) in Japan, and examine treatment trends, especially regarding the use of TNF-α inhibitors (TNFαi). We performed a retrospective descriptive observational study in which BD and GIBD demographic trends, medical treatment patterns, and reported adverse events (AEs) were assessed among patients with data recorded between 2017 and 2021 in the Japan Medical Data Center Claims Database (now JMDC Inc.). Prevalence of BD and GIBD in Japan during the observation period increased at an annual rate of + 3% and + 4%, respectively, while incidence decreased by - 5% and - 2%, with a more prominent decline in confirmed GIBD cases (- 15%). Although GCs were the most common initial treatment administered, use of TNFαi for BD and GIBD management increased by + 5.6% and + 8.1%, respectively. Severe AEs (mainly pneumonia and GI-associated AEs) were reported in 40% of patients receiving TNFαi; however, a high retention rate (of up to 80%) was observed 3years after treatment initiation. The use of TNFαi for GIBD treatment has increased in Japan in recent years. Additional research is necessary to further evaluate TNFαi effectiveness in GIBD and other BD subtypes.

Chronic recurrent multifocal osteomyelitis in pediatric patients: A Chinese single center observational study and literature review.

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare autoinflammatory disorder that commonly poses diagnostic challenges due to its atypical symptomatology. This observational study aimed to investigate the clinical features, laboratory test results, imaging features, and treatment strategies for pediatric patients with CRMO. We retrospectively analyzed 7 pediatric patients with CRMO treated at the Department of Pediatric Orthopedics, First Affiliated Hospital of Guangzhou University of Chinese Medicine between January 2018 and February 2022. This study aimed to enhance current understanding of CRMO by exploring in-depth clinical data. The study cohort comprised 5 males and 2 females, aged 3 to 13 years. All patients experienced symptoms for a median duration of 6 months prior to hospitalization, at which point they presented with recurrent pain and various accompanying signs including hypothermia (14.28%), swelling (42.85%), localized skin warmth (42.85%), and plantar pustules (14.28%). The femurs (71.42%) and tibia (71.42%) were frequently affected. Radiographic and computed tomography scans revealed osteosclerosis and osteolytic lesions, while magnetic resonance imaging revealed bone marrow edema. Histological examination of bone biopsies from 4 patients revealed fibrous tissue hyperplasia and lymphocytic and neutrophilic infiltration, despite negative bacterial cultures. Laboratory test results were either normal or slightly elevated. Symptomatic improvement was observed in 6 patients (85.72%) treated with nonsteroidal anti-inflammatory drugs, while 1 patient (14.28%) resistant to nonsteroidal anti-inflammatory drugs responded well to tumor necrosis factor inhibitors. The clinical presentation of CRMO lacks specificity, with unexplained bone pain being the most common symptom. Precise diagnosis and timely intervention depend on a thorough magnetic resonance imaging evaluation for lesion detection, which facilitates CRMO diagnosis. This study offers valuable insights into the clinical manifestations, laboratory findings, imaging features, and treatment strategies of CRMO in pediatric patients.

Living with Pyoderma Gangrenosum: A Qualitative Study.

Pyoderma gangrenosum is a rare, autoinflammatory disorder characterized by rapidly progressive painful ulcers that are challenging to diagnose and treat. This qualitative study aimed to explore the experiences of patients living with pyoderma gangrenosum. Using an inductive qualitative approach, semi-structured interviews were completed with a purposive sample of 21 patients with pyoderma gangrenosum recruited from a public dermatology outpatient clinic in Melbourne, Australia. A reflexive thematic analysis was performed, yielding 5 themes: pain, physical challenges, social functioning and relationships, mental health, and treatment. The impact of pyoderma gangrenosum on quality of life was multifaceted and varied throughout disease progression, remission, and recurrence. Experiences of delayed diagnosis and misdiagnosis were common, causing distress and resulting in unnecessary treatments including surgery. Severe pain disrupted sleep and limited daily activities, eroding patients' sense of self-control and perpetuating depressed mood and anxiety. Management should include early specialist referral, providing information sheets for managing pain and wound care, and communicating disease expectations. In conclusion, this study has deepened understanding and given personal perspectives on what it is like to live with a condition poorly understood by many health professionals. Increased efforts should be made to increase clinician awareness regarding pyoderma gangrenosum to facilitate early diagnosis.

Clinical, Immunologic, and Genetic Characteristics in Patients with Syndrome of Undifferentiated Recurrent Fevers (SURF).

Syndrome of Undifferentiated Recurrent Fevers (SURF) is characterized by recurrent fevers and autoinflammation without a confirmed molecular diagnosis of a Hereditary Recurrent Fever syndrome (HRF), and not fulfilling criteria for Periodic Fever, Adenitis, Pharyngitis, Aphthous stomatitis syndrome (PFAPA). The goal of this study was to characterize clinical features of SURF patients compared to PFAPA, and to analyze their cytokine signature, genetic variations, and responses to treatment. We enrolled 46 patients followed at Cincinnati Children's Hospital Medical Center. Baseline data and inflammatory cytokines were collected at enrollment, and their clinical course was followed. Cytokine analysis was performed using a cytokine multiplex assay. Many patients had specific or whole exome genetic testing. The prevalence of rash and arthralgias were higher in SURF compared to PFAPA. Pharyngitis and adenopathy were less frequent. A subset of SURF patients clustered together with elevated pro-inflammatory cytokines and more frequently required biologic therapy. Focused analysis of WES data revealed that variants of unknown clinical significance (VUCS) were frequently identified in genes implicated in B cell development, immunodeficiencies, and inflammatory bowel disease risk. Treatments for SURF patients commonly included on-demand steroids, colchicine, and anti-IL1 therapy. Our findings suggest SURF is a heterogeneous group but has distinct clinical and immunologic features from disorders like PFAPA. Patients have frequent VUCS, which may have relevance to disease pathogenesis. A subset of patients showed more inflammation and increased need for biologic use. Further research is necessary to define whether there exist distinct SURF endotypes and to better predict treatment outcomes.

Emerging concepts and treatments in autoinflammatory interferonopathies and monogenic systemic lupus erythematosus.

Over the past two decades, the number of genetically defined autoinflammatory interferonopathies has steadily increased. Aicardi-Goutières syndrome and proteasome-associated autoinflammatory syndromes (PRAAS, also known as CANDLE) are caused by genetic defects that impair homeostatic intracellular nucleic acid and protein processing respectively. Research into these genetic defects revealed intracellular sensors that activate type I interferon production. In SAVI and COPA syndrome, genetic defects that cause chronic activation of the dinucleotide sensor stimulator of interferon genes (STING) share features of lung inflammation and fibrosis; and selected mutations that amplify interferon-α/β receptor signalling cause central nervous system manifestations resembling Aicardi-Goutières syndrome. Research into the monogenic causes of childhood-onset systemic lupus erythematosus (SLE) demonstrates the pathogenic role of autoantibodies to particle-bound extracellular nucleic acids that distinguishes monogenic SLE from the autoinflammatory interferonopathies. This Review introduces a classification for autoinflammatory interferonopathies and discusses the divergent and shared pathomechanisms of interferon production and signalling in these diseases. Early success with drugs that block type I interferon signalling, new insights into the roles of cytoplasmic DNA or RNA sensors, pathways in type I interferon production and organ-specific pathology of the autoinflammatory interferonopathies and monogenic SLE, reveal novel drug targets that could personalize treatment approaches.

Autoinflammatory diseases. Part 1: concept, classification, immunobiology, diagnosis

Autoinflammatory diseases. Part 1: concept, classification, immunobiology, diagnosis

Optimizing Gout Treatment: A Comprehensive Review of Current and Emerging Uricosurics

Gout is the most common inflammatory arthritis, affecting approximately 5.1% of adults in the United States (US) population. Gout is a metabolic and autoinflammatory disease. Elevated uric acid pools lead to the precipitation of monosodium urate (MSU) crystals in and around joints, as well as other tissues, and the subsequent autoinflammatory response. Since elevated serum urate (SU) levels (hyperuricemia) correspond with gout severity, urate-lowering therapies (ULTs) are the cornerstone of gout treatment.ULTs include xanthine oxidoreductase inhibitors, uricosurics, less commonly used in the US but widely used in Europe and Asia, including benzbromarone, dotinurad, and probenecid (the only US Food and Drug Administration (FDA) approved uricosuric in the US), and uricases, including rasburicase and pegloticase (available only in the US).Over 90% of the daily load of uric acid filtered by the kidneys is reabsorbed through renal transporters. These urate transporters include uric acid transporter 1 (URAT1), glucose transporter 9, and organic anion transporters 1, 3, and 4 (OAT1, OAT3, OAT4). They are the target of approved and in-the-pipeline uricosurics.Any drug that increases renal excretion of uric acid, independently of the mechanism through which it exerts its effect, may be considered a uricosuric drug. This review discusses drugs that increase renal excretion of uric acid, either approved or in development, as well as off-label drugs with uricosuric properties.

The first proteomics analysis of tonsils in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA).

Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a recurrent fever syndrome. The exact etiopathogenesis of PFAPA syndrome remains unknown. Biological fluids or tissues may provide disease-specific biomarkers that may help clinicians to find new pathogenic pathways. Tonsil tissues of seven patients with PFAPA were collected during the tonsillectomy. Seven patients who underwent tonsillectomy for reasons other than chronic tonsillitis were enrolled as a control group. The nHPLC LC-MS/MS system was used for protein identification and label-free quantification. Bioinformatics analysis was carried out using the UniProt accession numbers of the identified proteins. Proteomics analysis revealed to identity of proteins of which at least 23 were up and 57 were downregulated. Bioinformatics analysis of differentially regulated proteins by STRING indicated that protein folding and clearance machinery were interrupted in PFAPA patients compared to the controls. The affected pathways underlined the importance of the mitochondrial electron transport chain and ATP biosynthesis process. Although it is not clear that changes in tonsil protein expression whether directly related to pathogenesis or simply result of chronic inflammation, the identification of tonsil biomarkers for PFAPA may provide clinicians an opportunity to understand disease pathogenesis or develop new molecular targets for treatments. Proteomics analyses of tonsils revealed the identity of 80 proteins of which at least 23 were up and 57 were downregulated. Bioinformatics analysis underlined the importance of mitochondrial ETC and regulation of ATP biosynthetic process. This is the first study evaluating the proteomics of the tonsils of PFAPA patients. The identification of tonsil biomarkers for PFAPA may provide clinicians an opportunity to understand disease pathogenesis or develop new molecular targets for treatments.

Relationships between emotional state, sleep disturbance and health-related quality of life in patients with axial spondyloarthritis.

Axial spondyloarthritis (ax-SpA) is an autoinflammatory disease affecting multiple organs. While emphasizing the treatment of chronic diseases, it has been found that the prevalence of mental disorders and insomnia in patients is also increasing. We investigated mood status, sleep quality and the health-related quality of life (HRQoL) in these patients. A total of 94 pairs ax-SpA patients and age- and sex-matched healthy controls were included in this cross-sectional study. Demographic and clinical data were collected. We assessed the disease activity by the Ankylosing Spondylitis Disease Activity Score, including C-reactive protein (ASDAS-CRP), the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Bath Ankylosing Spondylitis Functional Index (BASFI). The Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI) and the Medical Outcomes Survey Sheet Form-36 (SF-36) were used to evaluate mood status and quality of sleep and life, respectively. We evaluated the factors related to anxiety and depression scores, sleep disturbance scores and quality of life scores, and the predictors of anxiety, depression and sleep disturbance were analyzed. Forty-five active patients and forty-nine relieved patients were enrolled. We found that the median HADS anxiety (HADS-A), depression (HADS-D) subscale scores and PSQI score were significantly higher in active ax-SpA than in inactive patients, and were significantly higher than those in controls (HADS-A 9 vs. 5 vs. 3, p < 0.001; HADS-D 8 vs. 5 vs. 3, p < 0.001; PSQI 10 vs. 6 vs. 3, p < 0.001). Moreover, the HADS-A scores were positively correlated to positive HLA-B27 (p = 0.042), pain (p = 0.002) and the BASFI score (p = 0.012), HADS-D scores were positively correlate to disease course (p < 0.001) and PSQI scores were significantly positively correlated to the BASFI score (p = 0.009). Logistic regression analysis showed that BASFI was a risk factor for anxiety, age was a protective factor for depression and disease course was a risk factor for depression. The optimal cut-off value of BASFI in predicting anxiety was 1.55 with an area under the curve value of 0.8488 (p < 0.001), and the optimal cut-off value of age and the course of the disease in predicting depression was 50.5years old with an area under the curve value of 0.62 (p = 0.0482) and 54months with an area under the curve value of 0.7988 (p < 0.001). In addition, disease activity was negatively correlated with SF-36 dimensions, and anxiety, depression and sleep disturbance in ax-SpA patients also had significant negative effects on HRQoL (p < 0.05). Patients with active ax-SpA tend to be more anxious, depressed and sleep disturbed, and have worse HRQoL than patients in remission. Patients with ax-SpA are more likely to be anxious with worse spinal function, more likely to be depressed with younger age and longer course of disease. Therefore, the assessment of mental health, sleep and HRQoL should also be included in the long-term management of patients with ax-SpA. Key Points • Active ax-SpA patients tend to have more anxiety, depression, sleep disturbances and worse HRQoL compared with patients in remission • The optimal cut-off value of BASFI in predicting anxiety was 1.55, the age and the course of the disease in predicting depression was 50.5years old and 54months.

Migraine-like headache due to frontal osteitis and meningitis in a delayed diagnosis of SAPHO syndrome: A case report and literature review

Synovitis, acne, pustulosis, hyperostosis, and osteomyelitis (SAPHO) syndrome is a rare polygenic autoinflammatory disorder that is associated with headaches of different etiological origins. Herein we report the case of a patient with SAPHO syndrome and provide a literature review. The patient was a 64-year-old female who complained of a recurrent headache, which had persisted for several years, and diffuse arthralgias. A computed tomography-angiogram demonstrated the narrowing of the left carotid canal. The patient had an erythrocyte sedimentation rate of 19 mm/s, and her cerebrospinal fluid contained 20 leukocytes/&amp;mu;L (13 mononuclear) and 0.43 g/L of proteins. Bone scintigraphy showed radiotracer uptake in the frontal bones and spine. The patient&amp;rsquo;s son had previously been diagnosed with SAPHO syndrome; therefore, the possibility of a disorder in the same spectrum was considered. Corticotherapy followed by sulphasalazine resolved the symptoms. This case illustrates an atypical cranial and meningeal involvement of the SAPHO autoinflammatory process. Our findings underscore the importance of considering immune-mediated disorders in the differential diagnosis of headaches.

Long-Term Symptoms in Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome After Tonsillectomy

To investigate the initial and long-term clinical course of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome after tonsillectomy regarding fever episodes and non-febrile PFAPA-related symptoms. An observational cohort study with retrospective and cross-sectional data based on 86 of 101 patients who underwent tonsillectomy for PFAPA between January 2006 and March 2020 from a cohort of 336 patients diagnosed with PFAPA as children. Data were collected by structured telephone interviews and review of medical records. Parents were interviewed regarding initial response to tonsillectomy and the clinical course following tonsillectomy. Patients, if ≥18 years old, or parents, if patients were younger, were interviewed regarding symptoms present at the time of this long-term follow-up study. Six months after tonsillectomy, 45 of 86 (54%) participants had no symptoms of PFAPA, 19 (22%) had only non-febrile PFAPA-related symptoms, 17 (20%) had ongoing but fewer or milder fever episodes, 1 (1%) had ongoing febrile episodes without improvement, and 4 (5%) had missing data because parents were unavailable. In 10 of 45 patients with initial remission, fever episodes reappeared 0.5-4.5 years after tonsillectomy. At long-term follow-up (median 8.8 years [range 2.8-16.1 years] after tonsillectomy), 54 of 86 (63%) had no symptoms of PFAPA, 15 (17%) had febrile episodes, generally with longer intervals between flares than before tonsillectomy, and 17 (20%) had non-febrile PFAPA-related symptoms. While PFAPA symptoms resolve or are milder post-tonsillectomy among most of the patients, the long-term outcomes showing residual symptoms among a substantial minority should be considered when evaluating tonsillectomy as a treatment option for PFAPA. Increased awareness of persistent symptoms after tonsillectomy may improve understanding and healthcare for these patients.

A strategy to design protein-based antagonists against type I cytokine receptors.

Excessive cytokine signaling resulting from dysregulation of a cytokine or its receptor can be a main driver of cancer, autoimmune, or hematopoietic disorders. Here, we leverage protein design to create tailored cytokine receptor blockers with idealized properties. Specifically, we aimed to tackle the granulocyte-colony stimulating factor receptor (G-CSFR), a mediator of different types of leukemia and autoinflammatory diseases. By modifying designed G-CSFR binders, we engineered hyper-stable proteins that function as nanomolar signaling antagonists. X-ray crystallography showed atomic-level agreement with the experimental structure of an exemplary design. Furthermore, the most potent design blocks G-CSFR in acute myeloid leukemia cells and primary human hematopoietic stem cells. Thus, the resulting designs can be used for inhibiting or homing to G-CSFR-expressing cells. Our results also demonstrate that similarly designed cytokine mimics can be used to derive antagonists to tackle other type I cytokine receptors.