MDA5-autoimmunity and interstitial pneumonitis contemporaneous with the COVID-19 pandemic (MIP-C).

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5+-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. METHODS: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018 and December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5+-DM outbreak. FINDINGS: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. INTERPRETATION: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms. FUNDING: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

Risk of developing psoriatic arthritis in psoriasis cohorts with arthralgia: exploring the subclinical psoriatic arthritis stage.

OBJECTIVE: Subjects with subclinical psoriatic arthritis (PsA), defined as the presence of arthralgia in psoriasis (PsO), are at higher risk of PsA but scant real-world data exist. Our aims were to (1) estimate the probability of PsA development in subclinical PsA, (2) characterise subclinical PsA symptoms and (3) determine the clinical patterns at PsA diagnosis. METHODS: Patients with PsO, mainly subclinical PsA, were evaluated longitudinally in two European cohorts. The key outcome was new-onset PsA. Musculoskeletal symptoms including inflammatory and non-inflammatory symptoms before PsA diagnosis were collected. Occurrence of PsA was analysed with survival analysis and cumulative incidence functions (CIFs). RESULTS: 384 patients with PsO were included with a mean follow-up of 33.0 (±20.9) months. 311 of 384 (80.9%) had subclinical PsA with a PsA incidence rate of 7.7 per 100 patient-years. Subclinical PsA displayed a higher risk of PsA development compared with PsO (HR=11.7 (95% CI 1.57 to 86.7), p=0.016). The probability of new-onset PsA estimated by the CIF was 9.4% (95% CI 4.7% to 10.6%) at month 12 and 22.7% (95% CI 17.2% to 28.6%) at month 36. 58.9% of cases reported inflammatory symptoms in the months immediately prior to PsA diagnosis but prior non-inflammatory symptoms were evident in 83.9% prior to PsA diagnosis. Peripheral joint swelling was the predominant PsA presentation pattern (82.1%). CONCLUSIONS: The probability of PsA development among subclinical PsA was relatively high, emphasising the importance of emergent musculoskeletal symptoms when aiming for PsA prevention. Joint swelling was the dominant feature in new-onset PsA, likely reflecting clinical confidence in recognising joint swelling.

High prevalence of radiographic erosions in early, untreated PsA: results from the SpARRO cohort.

AIMS: To investigate the prevalence and distribution of bone erosions in an early psoriatic arthritis (PsA) population using conventional radiography (CR) and to explore the agreement between CR and ultrasound (US) detected bone erosions. METHODS: Newly diagnosed, treatment naïve PsA patients fulfilling the ClASsification for Psoriatic Arthritis (CASPAR) classification criteria of ≤5 years symptom duration were recruited as part of the Leeds Spondyloarthropathy Register for Research and Observation and underwent CR and US examination of hands and feet. RESULTS: Overall, 4655 hand and feet joints were assessed in 122 patients. CR erosions were detected in 24.6% (n=30) with lowest prevalence seen below 8 months of symptoms (17.5% vs 24.3%>24 months). The number of erosions was higher on CR (1.55% (63/4,655); US 1.04% (34/3,270)), with 5th metatarsophalangeal (MTP) joint being the most affected site in both CR (5.21% (11/211)) and US (7.14% (15/210)). Erosions in CR were more evenly distributed compared with US where three-quarters of the total number of bone erosions were detected in wrists, second metacarpophalangeal (MCP) and fifth MTP joints. Most joints had almost perfect prevalence-adjusted bias-adjusted kappa values ranging from 0.91 to 1. CONCLUSIONS: Erosions were seen in a quarter of patients with newly diagnosed, untreated PsA with a declining trend around the 8-month symptom duration cut-off. High levels of agreement between CR and US were seen with CR detecting more erosions. A focused US assessment of the wrist, second MCP and fifth MTP joints may be useful to detect bone erosions in early PsA.

The OMERACT whole-body MRI scoring system for inflammation in peripheral joints and entheses (WIPE) in spondyloarthritis - reference image atlas for the knee region.

OBJECTIVE: To develop a reference image atlas for the Outcome Measures in Rheumatology whole-body MRI scoring system for inflammation in peripheral joints and entheses (OMERACT MRI-WIPE) of the knee region. METHODS: Image examples of each pathology, location and grade, were collected and discussed at web-based, interactive meetings within the OMERACT MRI in Arthritis Working Group. Subsequently, reference images were selected by consensus. RESULTS: Reference images for each grade, pathology and location are depicted, along with definitions, reader rules and recommended MRI-sequences. CONCLUSION: The atlas guides scoring whole-body MRIs for inflammation in joints and entheses of the knee region according to MRI-WIPE methodology in clinical trials and cohorts.

Hip and pelvis region MRI reference image atlas for scoring inflammation in peripheral joints and entheses according to the OMERACT-MRI WIPE scoring system in patients with spondyloarthritis.

OBJECTIVE: To develop a reference image atlas for scoring the hip/pelvis region according to the OMERACT whole-body MRI scoring system for inflammation in peripheral joints and entheses (MRI-WIPE). METHODS: We collected image examples of each pathology, location and grade, discussed them at web-based, interactive meetings and, finally, selected reference images by consensus. RESULTS: Reference images for each grade and location of osteitis, synovitis and soft tissue inflammation are provided, as are definitions, reader rules and recommended MRI-sequences. CONCLUSION: A reference image atlas was created to guide scoring whole-body MRIs for arthritis and enthesitis in the hip/pelvis region in spondyloarthritis/psoriatic arthritis clinical trials and cohorts.

MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with the COVID-19 Pandemic (MIP-C).

Background: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5 + -DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 senses single-stranded RNA and is a key pattern recognition receptor for the SARS-CoV-2 virus. Methods: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018-December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5 + -DM outbreak. Results: Sixty new anti-MDA5+, but not other MSAs surged between 2020-2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. Few (8/60) had a prior history of COVID-19, whereas 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response. Conclusions: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.

EULAR points to consider for the definition of clinical and imaging features suspicious for progression from psoriasis to psoriatic arthritis.

BACKGROUND: The transition from psoriasis (PsO) to psoriatic arthritis (PsA) and the early diagnosis of PsA is of considerable scientific and clinical interest for the prevention and interception of PsA. OBJECTIVE: To formulate EULAR points to consider (PtC) for the development of data-driven guidance and consensus for clinical trials and clinical practice in the field of prevention or interception of PsA and for clinical management of people with PsO at risk for PsA development. METHODS: A multidisciplinary EULAR task force of 30 members from 13 European countries was established, and the EULAR standardised operating procedures for development for PtC were followed. Two systematic literature reviews were conducted to support the task force in formulating the PtC. Furthermore, the task force proposed nomenclature for the stages before PsA, through a nominal group process to be used in clinical trials. RESULTS: Nomenclature for the stages preceding PsA onset, 5 overarching principles and 10 PtC were formulated. Nomenclature was proposed for three stages towards PsA development, namely people with PsO at higher risk of PsA, subclinical PsA and clinical PsA. The latter stage was defined as PsO and associated synovitis and it could be used as an outcome measure for clinical trials evaluating the transition from PsO to PsA. The overarching principles address the nature of PsA at its onset and underline the importance of collaboration of rheumatologists and dermatologists for strategies for prevention/interception of PsA. The 10 PtC highlight arthralgia and imaging abnormalities as key elements of subclinical PsA that can be used as potential short-term predictors of PsA development and useful items to design clinical trials for PsA interception. Traditional risk factors for PsA development (ie, PsO severity, obesity and nail involvement) may represent more long-term disease predictors and be less robust for short-term trials concerning the transition from PsO to PsA. CONCLUSION: These PtC are helpful to define the clinical and imaging features of people with PsO suspicious to progress to PsA. This information will be helpful for identification of those who could benefit from a therapeutic intervention to attenuate, delay or prevent PsA development.

Characterisation of prodromal and very early psoriatic arthritis: a systematic literature review informing a EULAR taskforce.

BACKGROUND: Identifying subjects at risk of imminent psoriatic arthritis (PsA) would allow these subjects to participate in therapeutic interventions to delay or prevent PsA development. METHODS: A systematic literature review (SLR) was conducted in 2021 in Medline, Embase, PubMed, Central databases and international congress abstracts (PROSPERO CRD42022255102). All articles reporting the characteristics of patients transitioning from psoriasis (PsO) to PsA and from undifferentiated arthritis (UA) to PsA were included. Clinical and imaging characteristics were collated before PsA onset and at time of PsA diagnosis. RESULTS: Eighteen of 23 576 references evaluated for PsO/PsA transition were analysed; 14 were cohort studies, 2 case-control studies. Two SLRs were used to enrich the project but were not analysed per se. Of 7873 references focusing on UA to PsA, 3 studies were included. Meta-analysis was not possible due to excessive data heterogeneity. Patients with PsO who developed PsA often reported joint pain, joint tenderness and functional limitations. Arthralgia (PsO, n=669; incident PsA, n=99) was associated with subsequent PsA development. On imaging, subclinical enthesopathy (PsO=325; Incident PsA=39) appeared linked to later PsA development. At the time of PsA onset (incident PsA, N=214), peripheral arthritis, mainly oligo-arthritis (ie, the mean number of swollen joints ranged from 1.5 to 3.2), was the most frequent pattern of clinical presentation. CONCLUSIONS: Joint pain, arthralgia and entheseal involvement detected by imaging were frequent in individuals with PsO at risk for imminent PsA. Very early PsA was mainly oligoarticular. This review informed a EULAR taskforce on transition to PsA.

Association of circulating lymphocyte subsets with response to IL17i and TNFi in axial spondyloarthritis.

OBJECTIVES: Biologic disease-modifying anti-rheumatic drugs (b-DMARDs) have qualitatively improved the management of axial spondyloarthritis (axSpA), but up to 30-40% of patients do not respond. Although lymphocytes are clearly implicated in the pathology of SpA, circulating lymphocyte subsets (LS) dynamics has been poorly studied. The objective of this pilot study was to comprehensively analyse circulating LS abnormalities in axSpA, and to determine their potential association with response to b-DMARDs. METHODS: Sixty-nine patients with axSpA and 141 control subjects (HC) were included. The clinical features were measured at baseline, and additionally at 6 months in a subgroup of patients who received TNFi (n=36) or IL17i (n=26). Clinical response was defined as a 50% reduction of BASDAI or decrease in ASDAS of 1.1 point. CD4/CD8 T-cells, B-cells and NK-cells and their subsets were analysed by flow cytometry at inclusion. RESULTS: At baseline, alterations in LS were observed in axSpA with reduced/increased frequencies of 10/27 subsets (p<0.003 after correction) and trends for another 5. There was no association of response to bDMARDs with clinical data. Response to IL17i (61% cases) was associated with a higher frequency of NK-cells (p=0.003), trends for change in naïve/memory-CD8+T-cells (p<0.055) and increased expression of KIR3DL2 on Th17-cells (p=0.052). No LS was associated with response to TNFi (69% cases) although trends were observed (CD4+T-cells subsets, higher IL-6R on CD4+/CD8+T-cells). CONCLUSIONS: This pilot work demonstrated a dysregulation of LS in axSpA. The association observed between several LS and clinical response to IL17i (NK/CD8 subsets/Th17-KIR3DL2) was very different to that observed for TNFi (CD4/IL-6R).

Management of Dactylitis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: This literature review aimed to identify the most efficacious current interventions for dactylitis and provide up-to-date scientific evidence to support the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) recommendations on the management of psoriatic arthritis. METHODS: Original articles published from 2013 to 2020, registered in MEDLINE, Embase, and Cochrane Library, describing interventional trials and reporting dactylitis-related outcomes were included. The 20 members of the GRAPPA dactylitis group were divided into 9 subgroups according to treatment, and members of each group independently extracted data from articles/abstracts corresponding to their group by using a standardized data extraction form. RESULTS: Forty-nine publications were analyzed, representing 40 randomized clinical trials (RCTs) and including 16,752 patients. Dactylitis was assessed as a secondary outcome in 97.5% of these trials and more than 40% of RCTs did not employ a specific dactylitis measure or instrument. CONCLUSION: The emergence of agents with novel mechanisms of action in recent years, such as interleukin 17 (IL-17), IL-12/23, IL-23, and Janus kinase inhibitors, has significantly expanded the available treatment options for dactylitis. This article points out the lack of consensus regarding dactylitis assessment and the paucity of data concerning the effect of local steroid injections, nonsteroidal antiinflammatory drugs, and conventional disease-modifying antirheumatic drugs. Clinical trials evaluating the effect of these traditional and low-cost medications used to treat dactylitis should be encouraged.

A Large Cluster of New Onset Autoimmune Myositis in the Yorkshire Region Following SARS-CoV-2 Vaccination.

BACKGROUND: The novel SARS-CoV-2 vaccines partially exploit intrinsic DNA or RNA adjuvanticity, with dysregulation in the metabolism of both these nucleic acids independently linked to triggering experimental autoimmune diseases, including lupus and myositis. METHODS: Herein, we present 15 new onset autoimmune myositis temporally associated with SARS-CoV-2 RNA or DNA-based vaccines that occurred between February 2021 and April 2022. Musculoskeletal, pulmonary, cutaneous and cardiac manifestations, laboratory and imaging data were collected. RESULTS: In total, 15 cases of new onset myositis (11 polymyositis/necrotizing/overlap myositis; 4 dermatomyositis) were identified in the Yorkshire region of approximately 5.6 million people, between February 2021 and April 2022 (10 females/5 men; mean age was 66.1 years; range 37-83). New onset disease occurred after first vaccination (5 cases), second vaccination (7 cases) or after the third dose (3 cases), which was often a different vaccine. Of the cases, 6 had systemic complications including skin (3 cases), lung (3 cases), heart (2 cases) and 10/15 had myositis associated autoantibodies. All but 1 case had good therapy responses. Adverse event following immunization (AEFI) could not be explained based on the underlying disease/co-morbidities. CONCLUSION: Compared with our usual regional Rheumatology clinical experience, a surprisingly large number of new onset myositis cases presented during the period of observation. Given that antigen release inevitably follows muscle injury and given the role of nucleic acid adjuvanticity in autoimmunity and muscle disease, further longitudinal studies are required to explore potential links between novel coronavirus vaccines and myositis in comparison with more traditional vaccine methods.

COVID-19 Vasculitis and vasculopathy-Distinct immunopathology emerging from the close juxtaposition of Type II Pneumocytes and Pulmonary Endothelial Cells.

The SARS-CoV-2 virus ACE-2 receptor utilization for cellular entry and the defined ACE-2 receptor role in cardiovascular medicine hinted at dysregulated endothelial function or even direct viral endotheliitis as the key driver of severe COVID-19 vascular immunopathology including reports of vasculitis. In this article, we critically review COVID-19 immunopathology from the vasculitis perspective and highlight the non-infectious nature of vascular endothelial involvement in severe COVID-19. Whilst COVID-19 lung disease pathological changes included juxta-capillary and vascular macrophage and lymphocytic infiltration typical of vasculitis, we review the evidence reflecting that such "vasculitis" reflects an extension of pneumonic inflammatory pathology to encompass these thin-walled vessels. Definitive, extrapulmonary clinically discernible vasculitis including cutaneous and cardiac vasculitis also emerged- namely a dysregulated interferon expression or "COVID toes" and an ill-defined systemic Kawasaki-like disease. These two latter genuine vasculitis pathologies were not associated with severe COVID-19 pneumonia. This was distinct from cutaneous vasculitis in severe COVID-19 that demonstrated pauci-immune infiltrates and prominent immunothrombosis that appears to represent a novel immunothrombotic vasculitis mimic contributed to by RNAaemia or potentially diffuse pulmonary venous tree thrombosis with systemic embolization with small arteriolar territory occlusion, although the latter remains unproven. Herein, we also performed a systematic literature review of COVID-19 vasculitis and reports of post-SARS-CoV-2 vaccination related vasculitis with respect to the commonly classified pre-COVID vasculitis groupings. Across the vasculitis spectrum, we noted that Goodpasture's syndrome was rarely linked to natural SARS-CoV-2 infection but not vaccines. Both the genuine vasculitis in the COVID-19 era and the proposed vasculitis mimic should advance the understanding of both pulmonary and systemic vascular immunopathology.

2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19.

OBJECTIVES: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19. METHODS: According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting. RESULTS: We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy CONCLUSIONS: Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19.

The Digital Way to Intercept Psoriatic Arthritis.

Psoriasis (PsO) and Psoriatic Arthritis (PsA) are chronic, immune-mediated diseases that share common etiopathogenetic pathways. Up to 30% of PsO patient may later develop PsA. In nearly 75% of cases, skin psoriatic lesions precede arthritic symptoms, typically 10 years prior to the onset of joint symptoms, while PsO diagnosis occurring after the onset of arthritis is described only in 15% of cases. Therefore, skin involvement offers to the rheumatologist a unique opportunity to study PsA in a very early phase, having a cohort of psoriatic "risk patients" that may develop the disease and may benefit from preventive treatment. Progression from PsO to PsA is often characterized by non-specific musculoskeletal symptoms, subclinical synovio-entheseal inflammation, and occasionally asymptomatic digital swelling such as painless toe dactylitis, that frequently go unnoticed, leading to diagnostic delay. The early diagnosis of PsA is crucial for initiating a treatment prior the development of significant and permanent joint damage. With the ongoing development of pharmacological treatments, early interception of PsA has become a priority, but many obstacles have been reported in daily routine. The introduction of digital technology in rheumatology may fill the gap in the physician-patient relationship, allowing more targeted monitoring of PsO patients. Digital technology includes telemedicine, virtual visits, electronic health record, wearable technology, mobile health, artificial intelligence, and machine learning. Overall, this digital revolution could lead to earlier PsA diagnosis, improved follow-up and disease control as well as maximizing the referral capacity of rheumatic centers.

Immunomodulatory therapies for the treatment of SARS-CoV-2 infection: an update of the systematic literature review to inform EULAR points to consider.

OBJECTIVE: To update the EULAR 2020 systematic literature review (SLR) on efficacy and safety of immunomodulatory agents in SARS-CoV-2 infection. METHODS: As part of a EULAR taskforce, a systematic literature search update was conducted from 11 December 2020 to 14 July 2021. Two reviewers independently identified eligible studies and extracted data on efficacy and safety of immunomodulatory agents used therapeutically in SARS-CoV-2 infection at any stage of disease. The risk of bias (RoB) was assessed with validated tools. RESULTS: Of the 26 959 records, 520 articles were eligible for inclusion. Studies were mainly at high or unclear RoB. New randomised controlled trials (RCTs) on tocilizumab clarified its benefit in patients with severe and critical COVID-19, mainly if associated with glucocorticoids. There are emergent data on the usefulness of baricitinib and tofacitinib in severe COVID-19. Other therapeutic strategies such as the use of convalescent plasma and anti-SARS-CoV-2 monoclonal antibodies showed efficacy in subjects not mounting normal anti-SARS-CoV-2 antibody responses. CONCLUSION: This new SLR confirms that some immunomodulators (tocilizumab and JAK inhibitors) have a role for treating severe and critical COVID-19. Although better evidence is available compared with the previous SLR, the need of RCT with combination therapy (glucocorticoids+anti-cytokines) versus monotherapy with glucocorticoids still remains alongside the need for standardisation of inclusion criteria and outcomes to ultimately improve the care and prognosis of affected people. This SLR informed the 2021 update of the EULAR points to consider on the use of immunomodulatory therapies in COVID-19.

Psoriatic Dactylitis: Current Perspectives and New Insights in Ultrasonography and Magnetic Resonance Imaging.

Dactylitis, one of the most typical features of psoriatic arthritis (PsA), is the diffuse swelling of the digits and is determined by the involvement of different anatomic structures, including: the subcutaneous fibrous tissue "accessory pulley" system; flexor tendons, with their related structures; the articular synovium; the small enthesis of the hands. Dactylitis is currently considered both a marker of disease activity and severe prognosis and its importance in PsA is emphasized by the inclusion in the classification criteria of PsA. This review focuses on the role of imaging in the management of PsA patients with dactylitis in clinical practice and in a research setting. Furthermore, imaging could be a valuable tool to assist in unravelling some of the underlying mechanisms of the onset and chronicization of dactylitis in PsA patients.

Arthritis and enthesitis in the hip and pelvis region in spondyloarthritis - OMERACT validation of two whole-body MRI methods.

OBJECTIVE: To validate reliability, correlation and responsiveness of two whole-body MRI scores for the hip/pelvis region in spondyloarthritis. METHODS: Assessment of hip/pelvis inflammation in 4 multi-reader exercises using the OMERACT MRI Whole-body score for Inflammation in Peripheral joints and Entheses (MRI-WIPE) and Hip Inflammation Magnetic Resonance Imaging Scoring System (HIMRISS). RESULTS: In exercises 3-4 (11/20 cases, respectively; 9 readers) reliability was mostly good for the 3 best calibrated readers. Median pairwise single-measure ICC for status were 0.58-0.65 (WIPE-osteitis), 0.10-0.88 (HIMRISS-osteitis) and for status/change 0.38-0.72/0.52-0.60 (WIPE-synovitis/effusion) and 0.68-0.89/0.78-0.85 (HIMRISS-synovitis/effusion). SRM was 1.23 for WIPE-osteitis, while lower for WIPE-synovitis/effusion and HIMRISS. CONCLUSION: MRI-WIPE and HIMRISS may after further validation be useful in future spondyloarthritis trials.

Joint and entheseal inflammation in the knee region in spondyloarthritis - reliability and responsiveness of two OMERACT whole-body MRI scores.

OBJECTIVE: To perform region-based development of whole-body MRI through validation of knee region scoring systems in spondyloarthritis (SpA). METHODS: Assessment of knee inflammatory pathologies using 2 systems, OMERACT MRI Whole-body score for Inflammation in Peripheral joints and Entheses (MRI-WIPE) and Knee Inflammation MRI Scoring System (KIMRISS), in 4 iterative multi-reader exercises. RESULTS: In the final exercise, reliability was mostly good for readers with highest agreement in previous exercise. Median pairwise single-measure ICCs for osteitis and synovitis/effusion status/change were 0.71/0.48 (WIPE-osteitis), 0.48/0.77 (WIPE-synovitis/effusion), 0.59/0.91 (KIMRISS-osteitis) and 0.92/0.97 (KIMRISS-synovitis/effusion). SRMs were 0.74 (WIPE-synovitis/effusion) and 0.78 (KIMRISS-synovitis/effusion). CONCLUSION: MRI-WIPE and KIMRISS may both be useful in SpA whole-body evaluation studies.

Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection.

Herein, we consider venous immunothrombotic mechanisms in SARS-CoV-2 infection and anti-SARS-CoV-2 DNA vaccination. Primary SARS-CoV-2 infection with systemic viral RNA release (RNAaemia) contributes to innate immune coagulation cascade activation, with both pulmonary and systemic immunothrombosis - including venous territory strokes. However, anti-SARS-CoV-2 adenoviral-vectored-DNA vaccines -initially shown for the ChAdOx1 vaccine-may rarely exhibit autoimmunity with autoantibodies to Platelet Factor-4 (PF4) that is termed Vaccine-Induced Thrombotic Thrombocytopenia (VITT), an entity pathophysiologically similar to Heparin-Induced Thrombocytopenia (HIT). The PF4 autoantigen is a polyanion molecule capable of independent interactions with negatively charged bacterial cellular wall, heparin and DNA molecules, thus linking intravascular innate immunity to both bacterial cell walls and pathogen-derived DNA. Crucially, negatively charged extracellular DNA is a powerful adjuvant that can break tolerance to positively charged nuclear histone proteins in many experimental autoimmunity settings, including SLE and scleroderma. Analogous to DNA-histone interactons, positively charged PF4-DNA complexes stimulate strong interferon responses via Toll-Like Receptor (TLR) 9 engagement. A chain of events following intramuscular adenoviral-vectored-DNA vaccine inoculation including microvascular damage; microbleeding and platelet activation with PF4 release, adenovirus cargo dispersement with DNA-PF4 engagement may rarely break immune tolerance, leading to rare PF4-directed autoimmunity. The VITT cavernous sinus cerebral and intestinal venous territory immunothrombosis proclivity may pertain to venous drainage of shared microbiotal-rich areas of the nose and in intestines that initiates local endovascular venous immunity by PF4/microbiotal engagement with PF4 autoantibody driven immunothrombosis reminiscent of HIT. According to the proposed model, any adenovirus-vectored-DNA vaccine could drive autoimmune VITT in susceptible individuals and alternative mechanism based on molecular mimicry, vaccine protein contaminants, adenovirus vector proteins, EDTA buffers or immunity against the viral spike protein are secondary factors. Hence, electrochemical DNA-PF4 interactions and PF4-heparin interactions, but at different locations, represent the common denominator in HIT and VITT related autoimmune-mediated thrombosis.