Tumor-necrosis factor α-rich environment alters type-I interferon response to viral stimuli in patients with juvenile idiopathic arthritis by altering myeloid dendritic cell phenotype.

The balance between the tumor-necrosis factor α (TNFα) and type-I interferon (T1IFN) pathways is crucial for proper immune function. Dysregulation of either pathway can contribute to autoimmune diseases development. Even though TNFα blockade has shown promising results in various autoimmune diseases, the effect on the balance between TNFα and T1IFN is elusive. We used targeted anti-TNFα therapies in juvenile idiopathic arthritis (JIA) as an experimental approach to study the cross-regulation between TNFα and type-I IFN. We found that TNFα-rich environment affected viral defense through the attenuation of T1IFN responses and affected the phenotype and distribution of myeloid dendritic cells, which are engaged in early viral infections. Anti-TNFα therapy normalized the observed deviations in JIA patients. We hypothesize that the inadequate immune response caused by a high TNFα environment could be projected to more frequent or lengthy viral infections and possibly play a role in the process of JIA disease development.

Power Doppler signal at the enthesis and bone erosions are the most discriminative OMERACT ultrasound lesions for SpA: results from the DEUS (Defining Enthesitis on Ultrasound in Spondyloarthritis) multicentre study.

OBJECTIVES: To assess, in spondyloarthritis (SpA), the discriminative value of the Outcome Measures in Rheumatology (OMERACT) ultrasound lesions of enthesitis and their associations with clinical features in this population. METHODS: In this multicentre study involving 20 rheumatology centres, clinical and ultrasound examinations of the lower limb large entheses were performed in 413 patients with SpA (axial SpA and psoriatic arthritis) and 282 disease controls (osteoarthritis and fibromyalgia). 'Active enthesitis' was defined as (1) power Doppler (PD) at the enthesis grade ≥1 plus entheseal thickening and/or hypoechoic areas, or (2) PD grade >1 (independent of the presence of entheseal thickening and/or hypoechoic areas). RESULTS: In the univariate analysis, all OMERACT lesions except enthesophytes/calcifications showed a significant association with SpA. PD (OR=8.77, 95% CI 4.40 to 19.20, p<0.001) and bone erosions (OR=4.75, 95% CI 2.43 to 10.10, p<0.001) retained this association in the multivariate analysis. Among the lower limb entheses, only the Achilles tendon was significantly associated with SpA (OR=1.93, 95% CI 1.30 to 2.88, p<0.001) in the multivariate analyses. Active enthesitis showed a significant association with SpA (OR=9.20, 95% CI 4.21 to 23.20, p<0.001), and unlike the individual OMERACT ultrasound lesions it was consistently associated with most clinical measures of SpA disease activity and severity in the regression analyses. CONCLUSIONS: This large multicentre study assessed the value of different ultrasound findings of enthesitis in SpA, identifying the most discriminative ultrasound lesions and entheseal sites for SpA. Ultrasound could differentiate between SpA-related enthesitis and other forms of entheseal pathology (ie, mechanical enthesitis), thus improving the assessment of entheseal involvement in SpA.

Faecal Bacteriome and Metabolome Profiles Associated with Decreased Mucosal Inflammatory Activity Upon Anti-TNF Therapy in Paediatric Crohn's Disease.

BACKGROUND AND AIMS: Treatment with anti-tumour necrosis factor α antibodies [anti-TNF] changes the dysbiotic faecal bacteriome in Crohn's disease [CD]. However, it is not known whether these changes are due to decreasing mucosal inflammatory activity or whether similar bacteriome reactions might be observed in gut-healthy subjects. Therefore, we explored changes in the faecal bacteriome and metabolome upon anti-TNF administration [and therapeutic response] in children with CD and contrasted those to anti-TNF-treated children with juvenile idiopathic arthritis [JIA]. METHODS: Faecal samples collected longitudinally before and during anti-TNF therapy were analysed with regard to the bacteriome by massively parallel sequencing of the 16S rDNA [V4 region] and the faecal metabolome by 1H nuclear magnetic resonance imaging. The response to treatment by mucosal healing was assessed by the MINI index at 3 months after the treatment started. We also tested several representative gut bacterial strains for in vitro growth inhibition by infliximab. RESULTS: We analysed 530 stool samples from 121 children [CD 54, JIA 18, healthy 49]. Bacterial community composition changed on anti-TNF in CD: three members of the class Clostridia increased on anti-TNF, whereas the class Bacteroidia decreased. Among faecal metabolites, glucose and glycerol increased, whereas isoleucine and uracil decreased. Some of these changes differed by treatment response [mucosal healing] after anti-TNF. No significant changes in the bacteriome or metabolome were noted upon anti-TNF in JIA. Bacterial growth was not affected by infliximab in a disc diffusion test. CONCLUSIONS: Our findings suggest that gut mucosal healing is responsible for the bacteriome and metabolome changes observed in CD, rather than any general effect of anti-TNF.

Expanded population of low-density neutrophils in juvenile idiopathic arthritis.

Introduction: Juvenile idiopathic arthritis (JIA), a clinically variable disease characterized by autoimmune arthritis, affects children, and its immunopathology remains elusive. Alterations in neutrophil biology play an important role in this disease. In the present study, we aimed to explore the features of low-density neutrophils (LDNs) in patients with JIA. Methods: Gene expression of peripheral blood mononuclear cells (PBMCs) from children with distinct subtypes of JIA was analyzed by NanoString Immunology panel. Presence of LDNs was ascertained by flow cytometry and the release of neutrophil-associated products were analyzed by LUMINEX. Results: LDNs were detected in patients' peripheral blood mononuclear cells (PBMCs) after density gradient centrifugation. Transcriptomic analysis of JIA PBMCs revealed that genes related to neutrophil degranulation were markedly upregulated. The number of LDNs and level of their degranulation products increased in patients' PBMCs and correlated with serum calprotectin, but not with disease activity, sedimentation rate and C-reactive protein (CRP) levels. The phenotypes of LDNs varied from those of normal-density neutrophils and healthy donor LDNs. Phenotypical analysis revealed LDNs are immature and primed population with decreased suppressive capacity. A negative correlation between surface proteins CD62L, CD66b, and CD11b and the number of inflamed joints/JADAS was established. Conclusion: Our results describe LDNs as primed, degranulated, immature cells with impaired suppressive activities. This work thus contributes to the increasing body of evidence that LDNs in JIA are altered and their role in the disease immunopathogenesis and possible clinical associations should be investigated further.

Two phenotypes of chronic recurrent multifocal osteomyelitis with different patterns of bone involvement.

INTRODUCTION: Chronic Recurrent Multifocal Osteomyelitis (CRMO) is an autoinflammatory bone disorder with predominantly paediatric onset. Children present with multifocal osteolytic lesions accompanied by bone pain and soft tissue swelling. Patients often exhibit extraosseous co-morbidities such as psoriasis, inflammatory bowel disease, and arthritis. OBJECTIVES: Comparison of children with two different phenotypes of CRMO defined by presence or absence of extraosseous co-morbidities. METHODS: Children diagnosed with CRMO at the Motol University Hospital between 2010 and 2020 were retrospectively reviewed, and according to the absence or presence of extraosseous manifestations divided into two cohorts - bone limited CRMO and complex CRMO. The two groups were compared in terms of demographic data, age at disease onset, number and site of bone lesions, laboratory biomarker values, and need of escalation to a second-line therapy. RESULTS: Thirty-seven children (30 female, 7 male) with confirmed CRMO were included in the analysis. The mean age at disease onset was 10 years. All but 3 patients presented with multifocal disease. Twenty-three children (62%) had at least one extraosseous manifestation (13 sacroiliitis, 8 inflammatory bowel disease, 6 skin disease [acne, pustulosis, or psoriasis], 7 arthritis). Complex CRMO was associated with a significantly higher ESR rate (p = 0.0064) and CRP level (p = 0.018). The groups did not differ in number of foci or in age at disease onset. Bone lesion distribution differed between the two groups with significantly more frequent involvement of clavicle (p = 0.011) and pelvis (p = 0.038) in patients with complex CRMO. Children with complex CRMO more often needed escalation of therapy to DMARDs and biologic agents. CONCLUSION: Our data suggest that CRMO affecting solely the skeleton has milder course compared to complex CRMO with extraskeletal features. Further studies are needed to explore the clinical as well as the patient reported outcomes and promote individually tailored therapeutic strategies in both CRMO phenotypes.

SARS-CoV-2-specific humoral and cellular immune responses to BNT162b2 vaccine in Fibrodysplasia ossificans progressiva patients.

Introduction: Fibrodysplasia ossificans progressiva (FOP) is characterized by progressive heterotopic ossification triggered by various conditions, such as trauma, infection, including COVID-19 infection, and vaccination. Although SARS-CoV-2 vaccinations prevent poor outcomes in the general population, there is limited evidence on safety, immunogenicity, and efficacy of SARS-CoV-2 vaccines for inpatients with FOP. Methods: A case series of two patients with FOP focused on humoral, cellular post-vaccination response, and the incidence of adverse events after administration of the BNT162b2 vaccine (Comirnaty). Results: Injection site reactions, fever, myalgia, and fatigue were the most common adverse events (AE). Neither severe AE (SAE), nor disease flare-ups were observed. No differences between patients with FOP and healthy controls were observed in humoral and cellular responses. Conclusions: The BNT162b2 vaccine induced high humoral and cellular response levels in patients with FOP. Vaccination was not associated with SAE or disease relapse. The AEs spectrum was comparable to that of the general population.

Immunomodulation of neutrophils and platelets by TNF blockage in patients with juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is a multifactorial autoimmune disease mediated by both adaptive and innate immunity. The role of neutrophils in the pathogenesis of autoimmune diseases is well-established; however, in JIA they are still markedly understudied. Here, we explored the neutrophil features and role of platelet-neutrophil aggregates in JIA patients and assessed the effect of TNF inhibitor (TNFi) therapy. We provide evidence of dysbalanced neutrophil subsets in JIA patients, with a shift towards immature and suppressive subpopulations that lack the cell-adhesion molecules. Correspondingly, patient sera contained high amounts of neutrophil- and platelet-related products. Transcriptomic analysis revealed neutrophil degranulation as the most affected process by TNFi therapy, which was mirrored by the decrease in degranulation products in the patient sera. Toll-like receptors -4, -7, and - 8 signaling pathways are particularly hyperresponsive in patients, but are strongly suppressed by TNFi. Overall, our study demonstrates augmented neutrophil and platelet responses in JIA patients.

Immunogenicity and safety of the booster BNT162b2 vaccine in patients with axial spondyloarthritis treated with biological disease-modifying drugs.

Background: Vaccination confers relatively short-term protection against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), indicating the need for booster doses. Immunocompromised individuals, including those with immune-mediated inflammatory diseases (IMIDs), may have pronounced immune response waning. Vaccine-boosted humoral and T-cell responses minimize poor coronavirus disease 19 (COVID-19) outcome without increasing adverse events (AE). There is limited evidence of third-dose vaccination in axial spondyloarthritis (AxSpA) patients. We investigated immune-response persistence after primary vaccination and immunogenicity and safety after the BNT162b2 booster vaccination. Methods: This prospective observational study enrolled an AxSpA cohort treated with interleukin-17 (IL-17) and tumor necrosis factor-alpha (TNFα) inhibitors. Serum SARS-CoV-2-specific and virus-neutralizing antibodies for humoral response and flow cytometric detection of intracellular cytokines following SARS-CoV-2-specific peptide-based stimulation for T-cell immune responses were assessed, and safety was evaluated via a clinical questionnaire. Results: Fifteen male AxSpA patients treated with TNFα (73·3%) or IL-17 (26·7%) inhibitors were enrolled and had humoral response persistence at 6 months: 905·6 ( ± 186·1 SD) and 409·1 ( ± 335·7) U/mL. Specific antibody concentrations further increased after booster vaccination to 989·7 ( ± 12·62) and 1000 U/mL and T-cell responders from 53·3% to 80%, with no differences between AxSpA (including "vaccination only" and "hybrid immunity" subgroups) and healthy control (HC) cohorts. No severe AE occurred; the AE spectrum was comparable to that of the general population. Conclusion: Immune-response persistence after primary vaccination and immunogenicity after booster vaccination were unaffected by anti-IL17 or anti-TNFα therapy with similar AE as in the general population.

Increased histone citrullination in juvenile idiopathic arthritis.

Objective: Posttranslational modifications (PTMs) of proteins are crucial for regulating various biological processes. However, protein alteration via PTMs, and consequently, the creation of new epitopes, can induce abnormal autoimmune responses in predisposed individuals. Immunopathogenesis of several rheumatic diseases, including the most common childhood form, juvenile idiopathic arthritis (JIA), is associated with the generation of autoantibodies against such modified proteins. Dysregulated generation of neutrophil extracellular traps (NETs) can be a source of post-translationally altered proteins. Thus, we investigated the role of PTMs and the presence of NET-associated markers in JIA patients. Methods: We recruited 30 pediatric patients with JIA (20 with active disease and 10 in remission) and 30 healthy donors. The serum concentrations of citrullinated histone H3 (citH3), peptidyl arginine deiminases (PADs), and NET-related products were detected using ELISA, and the number of citH3+ neutrophils was assessed using flow cytometry. Results: The serum levels of citH3 and PADs were higher in active as well as in remission JIA patients than in healthy donors. Similarly, the number of citH3+ neutrophils was higher in the peripheral blood of patients with JIA, implying an enhanced process of NETosis. This was effectively reflected by elevated serum levels of NET-associated products, such as neutrophil elastase, LL37, and cell-free DNA-histone complexes. Additionally, 16.7% of active JIA patients were seropositive for carbamylated autoantibodies, the levels of which declined sharply after initiation of anti-TNFα therapy. Conclusion: Collectively, our data suggest that the accelerated process of NETosis and PTMs in JIA may result in the generation of anti-citrullinated/carbamylated autoantibodies against various epitopes later in life, which could be prevented by effectively regulating inflammation using immune therapy.

Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines.

Dendritic cells (DCs) have received considerable attention as potential targets for the development of novel cancer immunotherapies. However, the clinical efficacy of DC-based vaccines remains suboptimal, largely reflecting local and systemic immunosuppression at baseline. An autologous DC-based vaccine (DCVAC) has recently been shown to improve progression-free survival and overall survival in randomized clinical trials enrolling patients with lung cancer (SLU01, NCT02470468) or ovarian carcinoma (SOV01, NCT02107937), but not metastatic castration-resistant prostate cancer (SP005, NCT02111577), despite a good safety profile across all cohorts. We performed biomolecular and cytofluorometric analyses on peripheral blood samples collected prior to immunotherapy from 1000 patients enrolled in these trials, with the objective of identifying immunological biomarkers that may improve the clinical management of DCVAC-treated patients. Gene signatures reflecting adaptive immunity and T cell activation were associated with favorable disease outcomes and responses to DCVAC in patients with prostate and lung cancer, but not ovarian carcinoma. By contrast, the clinical benefits of DCVAC were more pronounced among patients with ovarian carcinoma exhibiting reduced expression of T cell-associated genes, especially those linked to TH2-like signature and immunosuppressive regulatory T (TREG) cells. Clinical responses to DCVAC were accompanied by signs of antitumor immunity in the peripheral blood. Our findings suggest that circulating signatures of antitumor immunity may provide a useful tool for monitoring the potency of autologous DC-based immunotherapy.

Current treatment options for monogenic periodic fever syndromes - the role of interleukin 1 inhibitors.

Monogenic periodic fever syndromes are heterogeneous group of autoinflammatory diseases including distinct syndromes, such as cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor alpha receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). Individual diseases differ in pathogenesis, clinical manifestations, and severity. However, cytokines from the interleukin 1 (IL-1) family play a key role in all of them. Inhibition of these cytokines, especially IL-1, thus plays a crucial role in their treatment. At present, we have a wide range of drugs that differ in structure, mechanism of action, efficacy, and spectrum of side effects. The most available are anakinra, canakinumab and rilonacept. Moreover, several clinical trials are currently underway with other very promising drugs, such as gevokizumab, tadekinig alfa or tranilast. In the following review, we provide a new perspective on the efficacy and safety of IL-1 inhibitors that have provided the novel results coming from recently published clinical trials.

Delayed treatment with a tumor necrosis factor alpha blocker associated with worse outcomes in patients with spondyloarthritis: data from the Czech National Registry ATTRA.

Introduction: The administration of biologic disease-modifying antirheumatic drugs, including tumor necrosis factor (TNF)-α inhibitors, is observed to interfere with the disease activity and progression. In this study, we aimed to assess the effectiveness and response predictors of adalimumab (ADA), a TNF-α blocker, in patients with axial spondyloarthritis (AxSpA). Methods: This study was a historical prospective, registry-based observational study on patients with AxSpA treated with first-line ADA after conventional drug failure. For evaluation and comparison, patients were divided into three groups according to the number of years from AxSpA diagnosis to initiation of ADA treatment: (A) <5 years, (B) 5-10 years, and (C) >10 years. The assessment instruments ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis activity index (BASDAI), Bath ankylosing spondylitis functional index (BASFI), health assessment questionnaire (HAQ), Short Form 36 questionnaire (SF-36), and EuroQoL 5 dimension questionnaire (EQ-5D) were regularly administered for up to 24 months of follow-up. Results: This study included 1043 patients with AxSpA (9.2% with non-radiographic AxSpA, 68.9% men). By month 6, a significantly higher proportion of patients with ASDAS remission (<1.3) was achieved upon earlier intervention in group A (30.1%) and B (32.9%) than in the late intervention group C (22.6%) (p ⩽ 0.05). At month 6, lower age and better BASFI at treatment initiation were identified as the strongest predictors of ASDAS remission in both univariable [odds ratio (OR): 0.956, p ⩽ 0.001; OR: 0.834, p ⩽ 0.001, respectively] and multivariable analyses (OR: 0.963, p ⩽ 0.001; OR: 0.859, p ⩽ 0.001, respectively). Earlier intervention also led to improvement in most patient-reported outcomes (PROs) based on HAQ, SF-36, and EQ-5D. Conclusion: Results from the ATTRA registry concur with previous clinical trials that supported efficacy of TNF-α blockers and showed better treatment outcomes with early interventions, including reduction of disease activity and improvement in PROs. We identified age and BASFI as the main factors influencing treatment effectiveness.

Reliability assessment of ultrasound muscle echogenicity in patients with rheumatic diseases: Results of a multicenter international web-based study.

Objectives: To investigate the inter/intra-reliability of ultrasound (US) muscle echogenicity in patients with rheumatic diseases. Methods: Forty-two rheumatologists and 2 radiologists from 13 countries were asked to assess US muscle echogenicity of quadriceps muscle in 80 static images and 20 clips from 64 patients with different rheumatic diseases and 8 healthy subjects. Two visual scales were evaluated, a visual semi-quantitative scale (0-3) and a continuous quantitative measurement ("VAS echogenicity," 0-100). The same assessment was repeated to calculate intra-observer reliability. US muscle echogenicity was also calculated by an independent research assistant using a software for the analysis of scientific images (ImageJ). Inter and intra reliabilities were assessed by means of prevalence-adjusted bias-adjusted Kappa (PABAK), intraclass correlation coefficient (ICC) and correlations through Kendall's Tau and Pearson's Rho coefficients. Results: The semi-quantitative scale showed a moderate inter-reliability [PABAK = 0.58 (0.57-0.59)] and a substantial intra-reliability [PABAK = 0.71 (0.68-0.73)]. The lowest inter and intra-reliability results were obtained for the intermediate grades (i.e., grade 1 and 2) of the semi-quantitative scale. "VAS echogenicity" showed a high reliability both in the inter-observer [ICC = 0.80 (0.75-0.85)] and intra-observer [ICC = 0.88 (0.88-0.89)] evaluations. A substantial association was found between the participants assessment of the semi-quantitative scale and "VAS echogenicity" [ICC = 0.52 (0.50-0.54)]. The correlation between these two visual scales and ImageJ analysis was high (tau = 0.76 and rho = 0.89, respectively). Conclusion: The results of this large, multicenter study highlighted the overall good inter and intra-reliability of the US assessment of muscle echogenicity in patients with different rheumatic diseases.

Clinical effectiveness and safety of intra-articular injection of HYALGO in the management of knee osteoarthritis symptoms: A multicenter prospective study.

BACKGROUND: The reduced concentration of hyaluronic acid in the synovial fluid, leading to impairment of joint function and painful symptomatology during knee osteoarthritis (OA), can be restored by using injectable formulations of hyaluronic acid (HA) and chondroitin sulfate (CS), variable for relative composition, HA/CS molecular modifications, and injection protocols. The present study aims to assess the safety and performance of the intra-articular (IA) viscosupplementing agent HYALGO, a formulation combining 40 mg/mL HA (>1700 kDa) and 40 mg/mL CS, in the treatment of patients suffering from knee OA. METHODS: 74 patients affected by knee lesions classified as grade II and III according to Kellgren and Lawrence classification were prospectively recruited and treated with three HYALGO injections (2 mL) given one week apart. Visual analogue scale (VAS) pain changes were monitored at each injection and over-time at 6, 14, and 26 weeks of follow-up. Secondary endpoints were: Western Ontario McMaster University Osteoarthritis index (WOMAC), Patient's Global Assessment (PGA) score, Clinical Observer Global Assessment (COGA) score, Outcome Measures in Rheumatology Committee (OMERACT) and Osteoarthritis Research Society International (OARSI) responders rates. Patients were also assessed for changes in their ultrasound joint scores according to the criteria of the OMERACT US Task Force Group. RESULTS: Pain reduction was statistically significant starting from the first IA injection. Mean pain reduction from baseline to week 26 was -90.6%. At 26 weeks, WOMAC Pain was reduced by -62.7%, WOMAC Stiffness by -47.2%, WOMAC Physical Function by -54.1%; Total WOMAC by -53.8%. The VAS PGA change from baseline was -48.0 [mm] and VAS COGA -41.0 [mm]. Responders at week 26 were 78.4%. Ultrasound parameters (joint effusion, synovial thickness, and popliteal cysts) improved or remained stable from baseline to week 6. CONCLUSIONS: Three injections of HYALGO were safe and effective to manage symptomatic knee OA, with a beneficial effect that increased progressively over time, peaking 6 months after injection.

Interleukin-1 Blockade in Polygenic Autoinflammatory Disorders: Where Are We now?

Polygenic autoinflammatory diseases (AIDs), such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease, Kawasaki disease, idiopathic recurrent pericarditis (IRP), Behçet's Syndrome, Crystal-induced arthropatihes such as gout or Calcium pyrophosphate deposition disease are characterized by the overexpression of inflammasome-associated genes, leading to a dysregulation of the innate immune response. The IL-1 cytokine family (IL-1α, IL-1ß, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36ß, IL-36g, IL-38, IL-33) was defined to be principally responsible for the inflammatory nature of polygenic AIDs. Several clinical trials were initiated, and IL-1 blockade has been proven to cause a rapid reduction of clinical symptoms and normalization of laboratory parameters in the majority of cases. Randomized, placebo-controlled, clinical trials, together with registry-based clinical trials and open-label, retrospective and prospective observational studies, supported the efficacy and safety of IL-1 inhibitors in the treatment of polygenic AIDs. Most of the current data are focused on the therapeutic use of anakinra, an IL-1 receptor antagonist, canakinumab, an anti-IL-1ß monoclonal antibody, and rilonacept, a soluble decoy receptor. However, other promising agents, such as gevokizumab, IL-1ß blocking monoclonal antibody, tadekinig alfa, a human recombinant IL-18-binding protein, and tranilast, an analog of a tryptophan metabolite, are currently being tested. Anakinra, canakinumab and rilonacept caused impressive improvements in both systemic and musculoskeletal symptoms. Furthermore, the anti-IL-1 therapy allowed corticosteroid tapering and, in some cases, even withdrawal. This article reviews the current IL-1 inhibitors and the results of all clinical trials in which they have been tested for the management of broad spectrum of polygenic AIDs.

IL-1 Inhibitors in the Treatment of Monogenic Periodic Fever Syndromes: From the Past to the Future Perspectives.

Autoinflammatory diseases (AIDs) represent a rare and heterogeneous group of disorders characterized by recurrent episodes of inflammation and a broad range of clinical manifestations. The most common symptoms involve recurrent fevers, musculoskeletal symptoms, and serositis; however, AIDs can also lead to life-threatening complications, such as macrophage activation syndrome (MAS) and systemic AA amyloidosis. Typical monogenic periodic fever syndromes include cryopyrin-associated periodic fever syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). However, a number of other clinical entities, such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease (AOSD), Kawasaki disease (KD) and idiopathic recurrent pericarditis (IRP), display similar phenotypical and immunological features to AIDs. All these diseases are pathophysiologicaly characterized by dysregulation of the innate immune system and the central pathogenic role is attributed to the IL-1 cytokine family (IL-1α, IL-1ß, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36ß, IL-36g, IL-38, and IL-33). Therefore, reasonable therapeutic approaches aim to inhibit these cytokines and their pathways. To date, several anti-IL-1 therapies have evolved. Each drug differs in structure, mechanism of action, efficacy for the treatment of selected diseases, and side effects. Most of the available data regarding the efficacy and safety of IL-1 inhibitors are related to anakinra, canakinumab, and rilonacept. Other promising therapeutics, such as gevokizumab, tadekinig alfa, and tranilast are currently undergoing clinical trials. In this review, we provide sophisticated and up-to-date insight into the therapeutic uses of different IL-1 inhibitors in monogenic periodic fever syndromes.

The identification and management of interstitial lung disease in systemic sclerosis: evidence-based European consensus statements.

BACKGROUND: Systemic sclerosis-associated interstitial lung disease (ILD) carries a high mortality risk; expert guidance is required to aid early recognition and treatment. We aimed to develop the first expert consensus and define an algorithm for the identification and management of the condition through application of well established methods. METHODS: Evidence-based consensus statements for systemic sclerosis-associated ILD management were established for six domains (ie, risk factors, screening, diagnosis and severity assessment, treatment initiation and options, disease progression, and treatment escalation) using a modified Delphi process based on a systematic literature analysis. A panel of 27 Europe-based pulmonologists, rheumatologists, and internists with expertise in systemic sclerosis-associated ILD participated in three rounds of online surveys, a face-to-face discussion, and a WebEx meeting, followed by two supplemental Delphi rounds, to establish consensus and define a management algorithm. Consensus was considered achieved if at least 80% of panellists indicated agreement or disagreement. FINDINGS: Between July 1, 2018, and Aug 27, 2019, consensus agreement was reached for 52 primary statements and six supplemental statements across six domains of management, and an algorithm was defined for clinical practice use. The agreed statements most important for clinical use included: all patients with systemic sclerosis should be screened for systemic sclerosis-associated ILD using high-resolution CT; high-resolution CT is the primary tool for diagnosing ILD in systemic sclerosis; pulmonary function tests support screening and diagnosis; systemic sclerosis-associated ILD severity should be measured with more than one indicator; it is appropriate to treat all severe cases; no pharmacological treatment is an option for some patients; follow-up assessments enable identification of disease progression; progression pace, alongside disease severity, drives decisions to escalate treatment. INTERPRETATION: Through a robust modified Delphi process developed by a diverse panel of experts, the first evidence-based consensus statements were established on guidance for the identification and medical management of systemic sclerosis-associated ILD. FUNDING: An unrestricted grant from Boehringer Ingelheim International.

Prevalence and distribution of cartilage damage at the metacarpal head level in rheumatoid arthritis and osteoarthritis: an ultrasound study.

OBJECTIVES: To determine the prevalence and distribution of US-detected qualitative cartilage damage at metacarpal heads of patients with RA and hand OA. METHODS: Fifty-two RA patients and 34 patients with hand OA were enrolled. US examination of the metacarpal head cartilage from the II to V finger of both hands was performed. A total of 414 MCP joints in RA and 266 MCP joints in OA patients were scanned with a linear probe up to 22 MHz. Qualitative assessments using a previously described scoring system for cartilage damage were performed. The prevalence and distribution of cartilage damage were analysed. Multivariate regression analysis was used to determine the predictive value of age, gender, BMI, disease duration and the presence of RF and anti-CCP antibodies for US-detected cartilage damage. RESULTS: The metacarpal head cartilage was positive for cartilage damage in 35.7% (148/414) of MCP joints in RA and in 43.6% (116/266) of MCP joints in OA patients. In RA, the hyaline cartilage of the II and III metacarpal heads (bilaterally) was the most frequently affected. In OA, cartilage damage was more homogeneously distributed in all MCP joints. Multivariate regression analysis showed that age and disease duration, but not gender, BMI or autoantibody status, were independent predictors of US-detected cartilage damage in RA. CONCLUSION: Cartilage damage was found in more than one-third of the MCP joints in both RA and OA patients, and in RA patients, the II and III MCP joints were the most damaged.

Bronchial Asthma and Bronchial Hyperresponsiveness and Their Characteristics in Patients with Common Variable Immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is one of the most frequent primary immunodeficiencies and is characterized by disturbed immunoglobulin production and dysregulation of the immune system. Results of previous studies suggest a higher prevalence of bronchial asthma (BA) in CVID patients than in the general population. We initiated this study to evaluate lung functions and identify risk factors for BA and bronchial hyperresponsiveness (BHR) in patients with CVID. METHODS: Twenty-three patients with CVID were included in this study. In all of them, spirometry and a metacholine bronchoprovocation test were performed. We also investigated the role of atopy, eosinophilic inflammation, and potential risk factors such as gender, age, or immunoglobulin levels at the time of diagnosis. RESULTS: BHR was confirmed in 12 patients (52%), all of whom had normal FEV1 and FEV1/FVC. However, BHR-positive patients had significantly decreased MEF25. BHR-positive patients had also more symptoms related to bronchial obstruction, with 8 of them (35%) being suspected of having BA at the end of the study. A higher prevalence of BHR was found in females, with a relative risk of 2.89. CONCLUSIONS: An increased prevalence of BHR and BA was detected in CVID patients compared to the general population. BA may develop despite the disturbed immunoglobulin production, and the majority of patients display nonatopic and noneosinophilic properties. These results suggest a limited role of atopy and eosinophilic inflammation in the pathogenesis of BA in CVID patients.