Phenotypic differences in disease expression across ethnic populations may hold the key to a better understanding of the pathophysiology of Behçet’s disease (BD), which has a wide geographical distribution and marked clinical variability between East Asian, Middle Eastern, and Western countries. In contrast to the predominance of vascular involvement in regions such as Turkey, intestinal involvement is more frequently observed in East Asian patients, particularly in Japan. Genome-wide association studies in inflammatory bowel disease (IBD), which shows clinical similarity to BD, have identified NOD2 and IL23R variants as major susceptibility loci in European populations. However, the relative absence of these IBD-related variants in East Asian populations, where intestinal BD is more prevalent, suggests the presence of alternative, BD-specific mechanisms driving gut involvement in different genetic backgrounds. Herein, we argue that this diversity in BD clinical expression may also reflect underlying differences in innate immune responses, particularly involving IL-1 signaling pathways. The striking prominence of MEFV variants (approximately 20% carrier frequency) in Turkish populations where vascular BD is more common, compared with their relative scarcity in East Asia, may offer important clues as to how population-specific genetic backgrounds shape distinct inflammatory phenotypes. In this article, we discuss these immunogenetic contrasts in relation to clinical heterogeneity, with a particular focus on the IL-1 pathway regulated by MEFV, to provide a more nuanced understanding of ethnic differences in BD pathogenesis and their implications for future therapeutic strategies.

BACKGROUND:Interleukin (IL)-17 inhibitors are effective in treating psoriatic disease, but paradoxical inflammatory reactions can occasionally occur. Palmoplantar pustular psoriasis (PPP) onset or flares have been rarely reported with anti-IL-17A but not dual IL-17A/F inhibition (bimekizumab). METHODS:Retrospective study: patients developing PPP while on anti-IL-17 were retrieved from hospital databases. RESULTS:Ten new PPP cases occurred during treatment with anti-IL-17: median age 46 years (range 33-59), females 40%. Six patients were obese, five smokers. Different IL-17 inhibitors were implicated, including secukinumab (n = 4), ixekizumab (n = 4), and for the first reported time bimekizumab (n = 2). PPP occurred after a median of 3 months (range 1-60) from anti-IL-17 initiation, earlier in those who did not respond in the primary disease domain (2 months, range 1-3) compared to responders (median 10 months, 1-60). Management of PPP included anti-IL-17 retention with topical agents, ciclosporin or colchicine, switching within class, or swapping to other mechanisms of action (IL-23, TNF, and JAK inhibition). Clinical benefit was reported with all approaches on available follow-up. CONCLUSIONS:PPP is rare during IL-17 inhibition but can occur under dual IL-17A/F inhibition. The underlying immunological mechanisms may involve neutrophil inflammation that independent from type-17 immune response.

OBJECTIVES:Identifying which patients with psoriasis (PsO) may develop PsA is a research priority. We have previously shown that elafin, along with IL-36γ, are excellent cutaneous biomarkers for PsO. The protease inhibitor elafin and its target protease, neutrophil elastase (NE), can be detected in both serum and epidermal samples. Our aims were to assess whether known PsO biomarkers are expressed differentially in patients affected by plaque PsO with and without PsA. METHODS:Protein expression of NE and elafin were analysed in matched epidermal samples and serum of PsO, PsA patients and healthy controls. Findings were validated in independent PsA and arthritis cohorts. RESULTS:The ratio between NE and elafin differed significantly between PsO and PsA patients. Expression of elafin was reduced in PsA samples as compared with plaque PsO patients. The ratio of NE to secretory leucocyte protease inhibitor was also increased in PsA as compared with PsO patients with no PsA, healthy controls and other arthritis patients. CONCLUSIONS:PsA patients show a reduced NE inhibitor expression in both the skin and blood compartment compared with those with plaque PsO only. This may suggest differences in the ability to regulated neutrophil activity in PsA patients.

OBJECTIVES:Dual blockade of IL-4 and IL-13 in atopic dermatitis (AD) has been associated with activation of the IL-23/IL-17 axis, potentially leading to paradoxical psoriasis and PsA-like presentation. However, the specific cytokine responsible for these reactions remains unclear. We report a case series of PsA-like presentation following treatment with tralokinumab, an anti-IL-13 monoclonal antibody used for AD. METHODS:We identified four patients who developed a PsA-like presentation affecting the joints, entheses, and, in some instances, the skin, following tralokinumab initiation for AD. Clinical features, laboratory findings, imaging results and treatment outcomes were assessed. RESULTS:Among 139 patients treated with tralokinumab across two large UK referral centres, four developed new-onset PsA-like presentation with inflammatory arthritis and enthesitis that emerged after tralokinumab initiation. All four had previously failed dupilumab therapy. Skin biopsies and joint imaging confirmed PsA-like features. Symptoms began weeks to months after starting tralokinumab and resolved following treatment withdrawal or modification. CONCLUSION:To our knowledge, this is the first case series documenting arthritis and enthesitis associated with anti-IL-13 therapy, suggesting a potential pathogenetic role of IL-13 inhibition in the development of PsA-like presentation. These findings warrant further investigation.

OBJECTIVES:Venous thromboembolism (VTE), following Janus kinase inhibitors treatment (JAKi), is poorly understood in rheumatoid arthritis (RA). We investigated whether JAKi augmented immune cell-driven clotting or immunothrombosis in RA. METHODS:Peripheral blood leukocytes (PBLs) isolated from patients with RA and healthy controls were treated with various JAKi classes, before stimulation with Toll-like receptor (TLR)-4 (lipopolysaccharide [LPS]) or TLR3 (polyinosinic-polycytidylic acid-poly (I:C)) agonists. Conditioned supernatants were used in plasma turbidity assays to evaluate clot formation and lysis dynamics, while bulk RNA sequencing, enzyme-linked immunosorbent assay, and bead-based immunoassays were used to explore immunothrombosis mechanisms. RESULTS:Turbidity analyses showed that conditioned media from PBLs treated with LPS and tofacitinib significantly accelerated clot formation when compared to LPS alone, and this effect was tissue factor pathway dependent and accompanied by elevations in immunothrombotic cytokines, including tumour necrosis factor α, interleukin (IL)-1β, and IL-6. PBLs from patients with active RA exhibited significantly greater immunothrombotic potential compared to those with low disease activity, despite comparable baseline cytokine levels. RNA sequencing analysis revealed significant pathway enrichment in tofacitinib/LPS-treated PBLs, including activation of Nuclear Factor (NF)-κB pathways, increased tissue factor expression, and reduced levels of anticoagulant factors such as protein S. Pharmacological inhibition assays with 5 JAK therapies suggested that JAK1/tyrosine kinase 2-dependent effect underscored increased thrombosis but selective JAK3 inhibition did not reproduce the prothrombotic effects. Finally, patients with RA with JAK-associated pulmonary embolism showed interstitial changes compatible with immunothrombosis in 4/6 (67%). CONCLUSIONS:Immunothrombosis offers a novel explanation for JAKi-associated VTE in RA.

ObjectiveAlthough IL-17F is important in psoriasis, the rudimentary biology of IL-17F in the human enthesis remains undefined. We aimed to characterise IL-23-dependent and independent IL-17F production from entheseal innate and adaptive T cells and determine the impact of IL-17F on entheseal stromal function and mesenchymal stem cell (MSC) osteogenesis.MethodsAnti-CD3 and anti-CD28 activated human spinal entheseal T cells were immunophenotyped using multi-parameter flow cytometry and a 36-marker Cytometry by Time-Of-Flight (CyTOF) with cytokine profiling, including IL-17A, IL-17F, and TNF (n = 10). IL-17A, IL-17F, and TNF stimulation of entheseal MSC stromal function was evaluated using RNA-seq and by measuring CCL20 protein expression following stimulation with TNF in combination with IL-17A or IL-17F. The osteogenic effects of IL-17A and IL-17F on MSC differentiation were assessed.ResultsInducible IL-17A and IL-17F expression was predominantly from CD4 T cells and CD4+CD25+ T cells, with higher levels of IL-17F at 72 hr. IL-23 significantly increased IL-17F (p ≤ 0.0001) but not IL-17A. Either IL-17A or IL-17F in combination with TNF dramatically upregulated CCL20 protein expression and substantially changed entheseal stromal transcriptome, with differences in gene expression and pathway activation seen between IL-17A or IL-17F stimulation. However, entheseal MSC osteogenesis was not significantly changed.ConclusionsThere was differential induction of IL-17A and IL-17F from innate and adaptive entheseal T cells, with further significant IL-17F augmentation by IL-23, but not IL-17A. Furthermore, the synergistic effects of IL-17A or IL-17F and TNF on stromal function provide the basis for further enthesis IL-17F biology interrogation.

The disappointment stemming from IL-23 inhibition failure in axial spondyloarthritis has resulted in expert panels extrapolating these results to axial psoriatic arthritis, with recommendations against the use of IL-23 inhibitors in this setting. However, post-hoc analyses of clinical trials show clinical improvements in axial psoriatic arthritis following treatment with ustekinumab, guselkumab, and risankizumab. A growing body of real-world evidence also shows substantial amelioration of spinal pain, related outcome measures, and imaging-detected inflammation. Despite negative trials, IL-23 inhibition was associated with C-reactive protein reductions and some improvement in MRI scores in ankylosing spondylitis, indicating some modicum of potential benefit. Furthermore, inadequate response to biological therapies in axial spondyloarthritis was associated with absence of MRI-determined bone marrow oedema, whereas responses to secukinumab in axial spondyloarthritis were independent of bone marrow oedema, pointing to divergent pathophysiological processes. The growing recognition of clinical, microanatomical, and immunological differences between axial spondyloarthritis and axial psoriatic arthritis suggests differential IL-23 pathway dependence. This Personal View aims to provide a deeper examination of these distinctions as a basis to propose reconsidering the current moratorium on IL-23 inhibitors—particularly in phenotypes not linked to HLA-B27—and to potentially expand therapeutic options.

Takayasu arteritis, a granulomatosis vasculitis with a pathogenesis that is poorly defined but known to be associated with HLA-B*52, shares many features with other MHC-I-opathies. In addition to the shared clinical features of inflammatory bowel diseases, cutaneous inflammation, and HLA-B*52, is shared association of an IL12B single- nucleotide polymorphism encoding the common IL-12 and IL-23 p40 subunit, which might affect not only type 17 cytokine responses, but also IFNγ and TNF production—the cardinal type 1 cytokines in granuloma formation. Considering the translational context of responses to TNF inhibition in Takayasu arteritis, in this Personal View we propose Takayasu arteritis as a type 1 MHC-I-opathy. Additionally, type 1 and type 17 T-cell immune responses show immune plasticity, which connects the overlapping features of Takayasu arteritis and spondyloarthritis spectrum disorders, providing a basis for shared anti-TNF responses, and points to p40 and IFNγ cytokine antagonism and potential selective CD8 T-cell repertoire ablation.

OBJECTIVE:JAK inhibition (JAKi) is effective in seronegative spondyloarthropathy (SpA) spectrum disorders, but Tyk2 inhibition failed in SpA spectrum ulcerative colitis, and tofacitinib showed minimal benefit in Crohn disease, which highlights the complex role for JAK/STAT signaling in different inflammatory processes. In this study, we investigated whether JAKi might paradoxically activate entheseal innate immunity and aimed to identify the key regulatory cytokines involved in this process. METHODS:Spinal entheseal tissue was activated with Toll-like receptor (TLR) agonists, including TLR4 and interleukin-1 (IL-1) family proteins, and entheseal T cells were activated with anti-CD3/anti-CD28 with IL-23/IL-1β. JAKi via upadacitinib (JAK1/JAK2), deucravacitinib (Tyk2), and ritlecitinib (JAK3) inhibition was evaluated using multiplex cytokine assays, intracellular flow, and bulk RNA sequencing (RNAseq) and cytokine blocking or stimulation. RESULTS:Following interferon γ stimulation, JAK1 inhibition blocked STAT1 phosphorylation in entheseal cells and strongly blocked activated entheseal T cell tumor necrosis factor α (TNFα), IL-17A, and IL-17F production. The opposite effect was evident in entheseal myeloid cell with exaggerated TLR4 and other adjuvant-mediated cytokine production including IL-23 (~10-fold increase; P < 0.001) or TNFα (~10-fold increase; P < 0.0001). This myeloid effect was induced by upadacitinib and deucravacitinib but not ritlecitinib, suggesting IL-10R JAK1/Tyk2 signaling. Bulk RNAseq showed a multifaceted impact of JAKi on myeloid activation with strong M1 type monocyte polarization under TLR4 stimulation and JAK1 inhibition confirmed by flow cytometry. Direct IL-10 inhibition recapitulated inflammatory cytokine elevations and IL-10R agonist largely, but not completely, rescued this phenotype. CONCLUSION:These findings help explain the emergent efficacy of Tyk2 blockade in SpA spectrum-related arthritis that is not IL-10 dependent but indicates why such strategies may not be a panacea for SpA spectrum disorder-related intestinal inflammation.

OBJECTIVE:Polymyalgia rheumatica (PMR) is an age-related inflammatory disease with shoulder/hip girdle involvement. Magnetic resonance imaging (MRI) reveals extracapsular/entheseal soft tissue involvement in both PMR and spondyloarthritis (SpA), with sacroiliac joint and perientheseal spinal bone marrow edema (BME) being characteristic of SpA. Therefore, some shared anatomic topography might be expected to result in similar clinical features. Herein, we describe the clinical and imaging features of SpA initially diagnosed as PMR. METHODS:Patients observed at Leeds Teaching Hospitals NHS Trust with a diagnosis of psoriatic arthritis (PsA) or axial SpA were screened to identify those initially diagnosed with PMR from 2002 to 2024. Only those patients who retrospectively fulfilled the 2012 EULAR/American College of Rheumatology classification criteria or the Bird et al criteria for PMR were included. Clinical data relevant to initial PMR diagnosis, imaging features, follow-up, and treatment data were collected, as well as radiographic or MRI features that established the final diagnosis. RESULTS:Thirty-one patients (median age 62 [interquartile range (IQR) 58-69] years; 17 women and 14 men) presenting with typical PMR shoulder/hip girdle pain were subsequently classified as having SpA spectrum disorders. The SpA diagnosis was made in 12 patients within three months of presentation and in 19 patients during the remaining follow-up period (median 3 [IQR 1-4] years). Four of 27 tested patients were HLA-B27 positive. BME on MRI was detected in the spine and/or sacroiliac joints in 20 of 25 patients (80%) who underwent imaging (sacroiliac joint: 17 patients [68%]; spine: 15 patients [60%]). Clinical resolution with C-reactive protein (CRP) level normalization occurred in 21 of 31 patients following initial glucocorticoid (GC) therapy, but 7 of these 21 initial responders experienced disease flares or elevations in CRP levels. Therapy-wise, disease-modifying antirheumatic drugs (DMARDs) were used in 21 of 31 patients: 8 received conventional synthetic DMARDs, and 11 received biologic agents (8 anti-tumor necrosis factor agents, 3 interleukin-17 inhibitors), whereas the remaining 10 patients were treated with ≤10 mg/day of GCs. CONCLUSION:Late-onset SpA with PMR clinical presentations is characterized by failure to respond to or taper GC therapy and is often identified by SpA-specific osteitis patterns on MRI. We propose that a PMR-SpA overlap may account for biologic therapy efficacy in steroid-refractory PMR.

BackgroundEczema and psoriasis are common diseases. Despite both showing active epidermal contribution to the inflammatory process, their molecular aetiology and pathological mechanisms are different.ObjectiveFurther molecular insight into these differences is therefore needed to enable effective future diagnostic and treatment strategies. The majority of our mechanistic and clinical understanding of psoriasis and eczema is derived from RNA, immunohistology and whole skin biopsy data.MethodsIn this study, non-invasive epidermal sampling of lesional, perilesional and non-lesional skin from diseased and healthy skin was used to perform an in depth proteomic analysis of epidermal proteins.ResultsOur findings confirmed the psoriasis-associated cytokine IL-36 gamma as an excellent protein biomarker for lesional psoriasis. However, ELISA and ROC curve analysis of 53 psoriasis and 42 eczema derived samples showed that the sensitivity and specificity were outperformed by elastase-specific protease inhibitor, elafin. Of note, elafin was also found upregulated in non-lesional psoriatic skin at non-predilection sites demonstrating inherent differences between the non-involved skin of healthy and psoriatic individuals. Mass spectrometry and ELISA analysis also demonstrated the upregulation of the anti-inflammatory molecule IL-37 in psoriatic perilesional but not lesional skin. The high expression of IL-37 surrounding psoriatic plaque may contribute to the sharp demarcation of inflammatory morphology changes observed in psoriasis. This finding was also specific for psoriasis and not seen in atopic dermatitis or autoimmune blistering perilesional skin. Our results confirm IL-36 gamma and add elafin as robust, hallmark molecules distinguishing psoriasis and eczema-associated inflammation even in patients under systemic treatment.ConclusionsOverall, these findings highlight the potential of epidermal non-invasive sampling and proteomic analysis to increase our diagnostic and pathophysiologic understanding of skin diseases. Moreover, the identification of molecular differences in healthy-looking skin between patients and healthy controls highlights potential disease susceptibility markers and proteins involved in the initial stages of disease. Epidermal sampling of lesional, perilesional and non-lesional skin from psoriasis and eczema patients as well as healthy skin was used to perform an in depth proteomic analysis. IL-36 gamma known to be expressed in lesional psoriasis skin was outperformed by the protease inhibitor Elafin as a disease-specific epidermal biomarker. Elafin is a robust marker presents across psoriasis subtypes and under systemic therapy as long as active lesions are present. Mass spectrometry and ELISA analysis also demonstrated the upregulation of the anti-inflammatory molecule IL-37 in psoriatic perilesional but not lesional skin. This anti-inflammatory activity at lesion border may contribute to the sharp demarcation seen in psoriatic plaques.image

Historically inflammation against self was considered autoimmune which stems back to the seminal observations by Ehrlich who described serum factors, now known to be autoantibodies produced by B lineage cells that mediate “horror autotoxicus”. The 20th century elucidation of B- and T-cell adaptive immune responses cemented the understanding of the key role of adaptive immune responses in mediating pathology against self. However, Mechnikov shared the Nobel Prize for the discovery of phagocytosis, the most rudimentary aspect of innate immunity. Fast forward some 100 years and an immunogenetic understanding of innate immunity led to the categorising of innate immunopathology under the umbrella term ‘auto inflammation’ and terminology such as “horror autoinflammaticus” to highlight the schism from the classical adaptive immune understanding of autoimmunity. These concepts lead to calls for a two-tiered classification of inflammation against self, but just as innate and adaptive immunity are functionally integrated, so is immunopathology in many settings and the concept of an autoimmune to autoinflammation continuum emerged with overlaps between both. Herein we describe several historically designated disorders of adaptive immunity where innate immunity is key, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) where the immunopathology phenotype is strongly linked to major histocompatibility complex (MHC) class II associations and responds to drugs that target T-cells. We also consider MHC-I-opathies including psoriasis and Behcet's disease(BD) that are increasingly viewed as archetype CD8 T-cell related disorders. We also briefly review the key role of barrier dysfunction in eczema and ulcerative colitis (UC) where innate tissue permeability barrier dysfunction and microbial dysbiosis contributes to prominent adaptive immune pathological mechanisms. We also highlight the emerging roles of intermediate populations of lymphocytes including gamma delta (γδ) and mucosal-associated invariant T (MAIT) cells that represent a blend of adaptive immune plasticity and innate immune rapid responders that may also determine site specific patterns of inflammation.

Background: Cytokines including IL-17A, IL-17F and TNFα are thought to be central to spondyloarthropathy (SpA) and psoriasis immunopathology. Although IL-17A and IL-17F show strong structural homology and overlapping functions, the combined blockade of IL-17A and IL-17F is more effective in psoriasis. IL-23 is thought to be a critical regulator of IL-17 in a subset of T-helper cells. Our previous work demonstrates both IL-23 dependent and independent IL-17A and IL-17F production. In this study we sought to determine the pathways involved in production of IL-17 at site of disease. Enthesitis is the cardinal process in Spa, however, even the most rudimentary biology of IL-17F at the human enthesis remains undefined. Objectives: The aim of the study was to characterise the IL-23 dependent and independent production of IL-17F at the normal enthesis from innate and adaptive T-cells. To determine impact of IL-17F on stromal function including chemokine production and in vitro spine entheseal mesenchymal stem cell (MSC) osteogenesis. Methods: Spinal enthesis samples were collected from spinal decompression/scoliosis correction surgery. Immune cell populations were isolated by mechanical digest followed by red cell lysis. T-cells were stimulated with plate bound anti-CD3 (100ng/ml) and soluble anti-CD28 (100ng/ml) for 72hrs in RPMI media with GolgiPlug addition prior to intracellular staining of IL-17A and IL-17F. Samples were analysed either by flow cytometry or CyTOF analysis using a 36-marker in-depth immune cell phenotyping CyTOF panel (n=5). Similar stimulations with/without IL-23 (50ng/ml) were undertaken and a multiplex bead immunoassay measured inflammatory cytokine production (n=4). Mesenchymal stem cells (MSCs) were isolated from entheseal soft tissue and bone using a collagenase digest and placed in an osteogenic differentiation system in the presence of IL-17A (50ng/ml), IL-17F (50ng/ml) or both (n=5). The effects on osteogenesis were evaluated by alkaline phosphatase and calcium levels along with a 48-gene panel. Results: Following aCD3/aCD28 stimulation both conventional flow and CyTOF demonstrated the inducible expression of both IL-17A and IL-17F by innate and adaptive T cells predominantly from the CD4 T-cells and γδ T-cells. After 72hrs of T-cell activation, there are higher levels of IL-17F than IL-17A at the enthesis. Addition of IL-23 to aCD3/aCD28 stimulated cells enhanced IL-17A/F production but IL-23 was unable to stimulate expression alone. Culture expanded entheseal MSCs exposed to IL-17A and IL-17F or both, showed IL-17A and IL-17F marginally increased alkaline phosphatase but was not associated with significant changes in MSC osteogenesis or osteogenic transcripts such as RUNX, BGLAP or RANKL. With respect to enthesis stromal function, IL-17A or IL-17F in combination with TNF dramatically upregulated CCL-20. However, IL-17A and IL-17F together show no additive effects. Conclusion: This is the first functional study of IL-17F immunobiology of the human enthesis. Akin to the normal skin the normal enthesis has innate and adaptive T-cells capable of induced IL-17F expression in addition to IL-17A. Addition of IL-23 to activated T-cells enhanced IL-17F but IL-23 driven production of IL-17F expression was not observed. We noted the synergistic effects of IL-17F with TNF on stromal function but not on MSC osteogenesis activity from entheseal derived cells. REFERENCES: NIL. Acknowledgements: This work is funded in collaboration with UCB Pharma who provided support and access for CyTOF work. Disclosure of Interests: Nicole McDermott: None declared, Mark Harland: None declared, Chi Wong: None declared, Ala Altaie: None declared, Tom Macleod: None declared, Charlie Bridgewood: None declared, Peter Loughenbury: None declared, Robert Dunsmuir: None declared, Almas Khan: None declared, Abhay S Rao: None declared, Vishal Borse: None declared, Avneet Manghera UCB, Stevan Shaw UCB, Dennis McGonagle UCB, Abbvie, BMS, Janssen Pharmaceuticals.

Objective Obesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of such therapy in viral pneumonia is not well understood. We evaluated the impact of obesity and age on survival following baricitinib therapy for severe COVID-19.Methods A post hoc analysis of the COV-BARRIER multicentre double-blind randomised study of baricitinib versus placebo (PBO) with an assessment of 28-day mortality was performed. All-cause mortality by day 28 was evaluated in a Cox regression analysis (adjusted to age) in three different groups according to body mass index (BMI) (<25 kg/m2, 25–30 kg/m2 and >30 kg/m2) and age <65 years and ≥65 years.Results In the high BMI group (>25 kg/m2), baricitinib therapy showed a significant survival advantage compared with PBO (incidence rate ratio (IRR) for mortality by day 28 0.53 (95% CI 0.32 to 0.87)) and 0.66 (95% CI 0.46 to 0.94) for the respective <65 years and ≥65 years, respectively. The 28-day all-cause-mortality rates for BMI over 30 were 5.62% for baricitinib and 9.22% for PBO (HR=0.6, p<0.05). For BMI under 25 kg/m2, irrespective of age, baricitinib therapy conferred no survival advantage (IRR of 1.89 (95% CI 0.49 to 7.28) and 0.95 (95% CI 0.46 to 1.99) for <65 years and ≥65 years, respectively) ((mortality 6.6% baricitinib vs 8.1 in PBO), p>0.05).Conclusion The efficacy of baricitinib in COVID-19 pneumonia is linked to obesity suggesting that immunomodulatory therapy benefit is associated with obesity-associated inflammation.

Background Upadacitinib is effective in spondyloarthritis (SpA) associated arthropathy and is licensed for ankylosing spondylitis and psoriatic arthritis. Collectively SpA is linked to enthesitis with both myeloid lineage and T-lineage cells contributing to the IL-23/IL-17 and TNF axes that underscore disease. Objectives To investigate the effect of upadacitinib on an in vitro human enthesis model by focusing separately on the IL-23/IL-17 axis component myeloid and T-cells to better elucidate mechanisms of action in vivo. Methods Normal spinous process enthesis (n=26) was obtained from patients undergoing spinal decompression or surgery for scoliosis correction as previously described [1]. Enthesis cells were subsequently isolated by mechanical digestion. Entheseal myeloid cells were stimulated with LPS with and without upadacitinib. IL-23, TNFα and other proinflammatory cytokines in the supernatants were quantified using ELISA. IL-23 levels were measured after myeloid cell stimulation with LPS in the presence of upadacitinib and IL-10. IL-23 levels were also measured after stimulation with LPS in the presence of an IL-10Rα blocking antibody. Entheseal cells were stimulated with anti-CD3 with or without LPS, Th17-driving cytokines (IL-23 and IL-1β) and upadacitinib. Supernatants were measured by ELISA and cytokine-positive cell populations assessed by intracellular flow cytometry. Results Unexpectedly, upadacitinib significantly increased myeloid cell secretion of IL-23, TNFα and other proinflammatory cytokines after stimulation with LPS (Figure 1) (LPS = 51.2 pg/ml vs LPS + 1 µM Upa = 1048 pg/ml IL-23, n= 11). Addition of recombinant IL-10 attenuated such IL-23. Blockade of the IL-10 receptor with a blocking antibody increased IL-23 secretion from myeloid cells after stimulation with LPS (100 ng/ml IL-10 = 2.79 mean fold increase in IL-23, n=5). Despite this effect, upadacitinib strongly blocked TNFα and IL-17 from Th17 and Tc17 entheseal derived cells stimulated with exogenous IL-23 (138.19 pg/ml vs 14.2 pg/ml IL-17A after addition of 1 µM Upa to Th17 driving conditions, n = 5). Furthermore, addition of upadacitinib to LPS + anti-CD3 activated entheseal cells strongly downregulated T-cell derived IL-17 and TNFα despite a simultaneous increase in myeloid IL-23. Conclusion LPS activated myeloid cells, predominantly monocyte lineage further increase key cytokines IL-23 and TNFα post upadacitinib. This involves IL-10 pathway inhibition. However, in this system T-cell derived cytokine production is completely blocked despite elevation of myeloid IL-23 and TNFα. These unexpected findings highlight the pivotal role of T-cell derived cytokines in SpA given the known efficacy of JAK inhibition and these findings merit consideration in other domains such as intestinal inflammation that may have a greater innate immune driven component. Reference [1]Bridgewood, C., et al., Identification of myeloid cells in the human enthesis as the main source of local IL-23 production. Annals of the rheumatic diseases, 2019. 78(7): p. 929-933. Acknowledgements The study is funded by an Abbvie research grant. Disclosure of Interests Sami Giryes: None declared, Tom Macleod: None declared, Chi Wong: None declared, Mark Harland: None declared, Nicole McDermott: None declared, Charlie Bridgewood: None declared, Abhay S Rao: None declared, Almas Khan: None declared, Peter Loughenbury: None declared, Dennis McGonagle Grant/research support from: The study is funded by an Abbvie research grant.

Neutrophilic inflammation is a pervasive characteristic common to spondyloarthropathies and related disorders. This inflammation manifests as Munro's microabscesses of the skin and osteoarticular neutrophilic inflammation in patients with psoriatic arthritis, intestinal crypt abscesses in patients with inflammatory bowel disease, ocular hypopyon in anterior uveitis, and neutrophilic macroscopic and microscopic inflammation in patients with Behçet's disease. Strong MHC class I associations are seen in these diseases, which represent so-called MHC-I-opathies, and these associations indicate an involvement of CD8 T-cell immunopathology that is not yet well understood. In this Personal View, we highlight emerging data suggesting that the T-cell-neutrophil axis involves both a T-cell-mediated and interleukin (IL)-17-mediated (type 17) recruitment and activation of neutrophils, and also a sequestration of activated neutrophils at disease sites that might directly amplify type 17 T-cell responses. This amplification likely involves neutrophilic production of IL-23 and proteases as well as other feedback mechanisms that could be regulated by local microbiota, pathogens, or tissue damage. This crosstalk between innate and adaptive immunity offers a novel explanation for how bacterial and fungal microbes at barrier sites could innately control type 17 T-cell development, with the aim of restoring tissue homoeostasis, and could potentially explain features of clinical disease and treatment response, such as the fast-onset action of the IL-23 pathway blockade in certain patients. This axis could be crucial to understanding non-response to IL-23 inhibitors among patients with ankylosing spondylitis, as the axial skeleton is a site rich in neutrophils and a site of haematopoiesis with myelopoiesis in adults.