Dennis Mcgonagle

University of Leeds

Background The Phase 3 QUASAR Induction Study (NCT04033445) was a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of guselkumab (GUS), an interleukin-23 p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC). Objectives To evaluate the early onset of symptom improvement. Meth...

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 I...

Background Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment. However, immune related adverse events are common and a persistent inflammatory arthritis (IA) can develop. Furthermore, 43% develop arthralgia, which may reflect subclinical inflammation in a proportion [1]. The imaging phenotype and pathoanatomy of this syndrome...

Background While Randomized Controlled Trials (RCTs) are the gold standard for efficacy, there is limited comparative data available for advanced therapies in psoriatic arthritis (PsA). Real-world (RW) evidence facilitates the comparison of a greater number of drugs, complementing RCTs. The P so R iatic Arthritis O bservational S tudy of P ers...

Background IL-23 is implicated in the pathogenesis of psoriasis (PsO), and myeloid cells that express FcγRI, known as CD64, have been identified as the primary cellular source of IL-23 in lesional PsO skin tissue.[1] The incidence and prevalence of psoriatic arthritis increases with the severity of PsO,[2] and joint disease activity is positively c...

Background The enthesis is a pivotal target tissue in spondyloarthritis (SpA), marked by inflammation in both the enthesis soft tissue (EST) and the contiguous anchoring peri-entheseal bone (PEB) [1]. The healthy human spinal enthesis harbors resident mesenchymal stem cells (MSCs), myeloid cells, innate immune cell populations, while notably lackin...

Background We recently reported that 2.7% of rheumatoid arthritis (RA) cases were polyrefractory (failure/tolerance of all b/tsDMARD classes). However, 40% of D2T-RA patients including polyrefractory RA (PFRA), lacked objective joint inflammation signs on ultrasound (US)- termed non-inflammatory refractory RA (NIRRA) whilst the remaining cases had...

Background Up to a third of psoriatic arthritis (PsA) patients fail their first biological/targeted synthetic disease modifying drug (b/tsDMARD) and likelihood of non-response (NR) is greater with each subsequent b/tsDMARD switch. This has substantial cost implications and impacts quality of life. Many factors contribute to NR, e.g. obesity and co-...

Background Enthesitis and dactylitis are hallmark manifestations of PsA and are reported in 35-50% and 40% of patients with PsA, respectively.[1-2] Patients with enthesitis have greater disease activity, erosive damage and poorer quality of life compared to patients without enthesitis. Similarly, dactylitis is associated with greater disease activi...

Background The optimal treatment strategy in Psoriatic Arthritis (PsA) is unknown despite the growing number of therapies available. Current European guidance on first line treatment recommends a step-up approach with methotrexate (MTX) or other conventional synthetic Disease Modifying Anti-Rheumatic Drugs (csDMARDs). The hypothesis underpinning th...

Background Despite available PsA treatments, a portion of PsA patients (pts) does not achieve improvements in PsA signs and symptoms according to the American College of Rheumatology (ACR) response criteria. Objectives Using data from the phase 3 DISCOVER-1 and DISCOVER-2 (D1/D2) studies in pts with active PsA, the purpose of this analysis was to...

Background Major depression is some of the numerous comorbidities associated with psoriasis (PsO) and psoriasis arthritis (PsA) [1]. Objectives Assessing the risk of developing depression in patients with pre-existing PsO treated with different treatment regimens; topical treatment, conventional disease-modifying anti-rheumatic drugs (cDMARDs), an...

Background Enthesitis and dactylitis are associated with greater disease activity and reduced quality of life. Results from the phase 3 randomized, placebo-controlled KEEPsAKE 1 and 2 studies ( NCT03675308 ; NCT03671148 ) of risankizumab in active PsA showed greater resolution of enthesitis and dactylitis with risankizumab 150 mg vs placebo at week...

Background Sustained minimal disease activity (MDA) is achieved by a minority of patients (pts) receiving biologics for psoriatic arthritis (PsA) [1]. Pt-reported MDA domains are less frequently achieved than physician-reported domains [2,3]. Here, we assessed MDA achievement in pts with PsA and inadequate response to 1–2 tumour necrosis factor inh...

Background The prevalence of nail disease in patients with psoriatic arthritis (PsA) ranges between 41% and 93% [1]. Psoriatic nail disease is intimately linked to adjacent distal interphalangeal joint (DIP) disease, and it is important to ascertain whether DIP-nail complex behaves differently under different biological therapies. Objectives The a...

Background Major adverse cardiovascular events (MACE) are some of the numerous comorbidities associated with psoriasis (PsO) and psoriasis arthritis (PsA). Previous studies addressed the contribution of sufficient anti-inflammatory therapy for PsO and PsA in decreasing MACE incidence [1,2]. Objectives Assessing the risk of developing MACE in patie...

Background Melanoma differentiation-associated protein 5 (MDA5) is an intracellular detector of viral RNA. It is considered that viral infections are involved in the aetiology of autoimmune diseases, including autoimmune myositis. Previously we reported on a post-COVID-19 pandemic cluster of myositis occurring in the Yorkshire region (De Marco, 202...

Background The association between chronic inflammatory conditions and cardiovascular disease is well established. Considering Familial-Mediterranean-Fever (FMF), few studies exist investigating the risk of ischemic heart disease, and none address the risk of stroke. Objectives To evaluate the incidence and risk for stroke in FMF patients compared...

Background Psoriasis (PsO) is an inflammatory skin disorder with an estimated worldwide prevalence of 2–4% [1]. Psoriatic arthritis (PsA) is highly associated with higher severity of PsO, present in up to 30% of patients and 0.3–1.0% of the global population and PsA typically develops after PsO [1,2]. There are some contradictory studies in relatio...

Background Monoclonal antibodies targeting the interleukin (IL)-23p19 subunit are effective in the treatment of psoriatic disease but have different molecular attributes that may translate to differences in clinical efficacy. Within this class, guselkumab (GUS) is a fully human IgG1 monoclonal antibody with a native Fc region, while risankizumab (R...

Background Guselkumab (GUS), an IL-23p19 inhibitor, has demonstrated efficacy in psoriatic arthritis (PsA) across key Group for Research and Assessment of Psoriasis (PsO) and Psoriatic Arthritis (GRAPPA)-recommended domains [1,2]. Skin disease and enthesitis have been identified as disease manifestations with earlier response times than others [3]....

Background Given the chronic, long-term nature of psoriatic arthritis (PsA), sustaining high levels of disease control with treatment is important. Assessing the maintenance of response in patients (pts) that achieve treatment targets is of interest, particularly as pts can experience loss of response with long-term therapy [1]. Bimekizumab (BKZ),...

Background The combination treatment of golimumab (GOL), a tumor necrosis factor-alpha (TNFα) antagonist, and guselkumab (GUS), an interleukin (IL)-23 inhibitor was shown to induce higher rates of clinical remission, endoscopic improvement, and histologic remission than each monotherapy in a randomized phase 2 induction study in TNFα-naïve patients...

Background The IL-17/IL-23 pathway has been implicated in many inflammatory diseases such as ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease and psoriasis, and has led to the development of several IL-17 inhibitors. The enthesis is connective tissue where the tendon or ligament attaches to the bone. Enthesitis is the cardina...

Objective To compare magnetic resonance imaging (MRI)–detected structural abnormalities in patients with symptomatic midfoot osteoarthritis (OA), patients with persistent midfoot pain, and asymptomatic controls, and to explore the association between MRI features, pain, and foot‐related disability. Methods One hundred seven adults consisting of 50...

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...

Background Guselkumab (GUS), a selective inhibitor of IL-23, significantly improved the diverse manifestations of active psoriatic arthritis (PsA), including dactylitis and enthesitis, in DISCOVER (D)-1 & 2 trials of patients (pts) with active PsA 1,2 , with maintenance of response rates through 1 year (yr). 3,4 Dactylitis and enthesitis, extra-art...

Background The transition from psoriasis (PsO) to psoriatic arthritis (PsA) is a focus of considerable scientific interest: is it possible to target pre-PsA and very early PsA, in particular for physiopathology and drug studies? Recently, a EULAR taskforce has been set up in this area (1). Objectives To characterize the prodromal and the very earl...

Background Pain in patients (pts) with psoriatic arthritis (PsA) has multifaceted origins; sustained improvement is difficult to achieve. ¹ Guselkumab (GUS), a fully human monoclonal antibody that selectively inhibits IL-23, is effective in treating multiple domains of PsA including joint, skin, and entheseal symptoms, and also elicits long-lasting...

Background Enthesitis or inflammation of the tendon/ligament anchorage points is the cardinal lesion in spondyloarthritis (SpA)[1]. Several key mediators have been shown to have a role in SpA including TNFα, IL-23, IL-17A and IL-17F [1]. There is a need for new therapeutic agents to treat SpA as current therapeutics fail to adequately target all it...

The skin barrier would not function without IL-1 family members, but their physiological role in the immunological aspects of skin barrier function are often overlooked. This review summarises the role of IL-1 family cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37 and IL-38) in the skin. We focus on novel aspec...

Objective To characterise the impact of dactylitis in disease-modifying antirheumatic drug (DMARD)-naive early psoriatic arthritis (PsA). Methods Patients with early PsA meeting the classification criteria for PsA (CASPAR) were recruited. Clinical outcomes were recorded, and ultrasonography was conducted to assess grey scale (GS) and power Doppler...

Introduction L’enthésite est une manifestation précoce du rhumatisme psoriasique associée à une activité importante de la maladie [1]. L’étude face-face en double aveugle EXCEED a montré une efficacité comparable au niveau articulaire et sur la résolution des enthésites des traitements par sécukinumab (SEC) et adalimumab (ADA) à la semaine (S) 52 [...

Introduction La place centrale de l’IL-17A dans la physiopathologie de la spondyloarthrite axiale (AxSpA) a été confirmée par le succès des anti-IL-17A. Cependant, la nature des populations cellulaires produisant cette importante cytokine pro-inflammatoire reste mal définie. Nous avons donc caractérisé les principales populations cellulaires produc...

Introduction Les formes sévères de COVID-19 comportent à une hyperinflammation systémique intense ; ce qui a justifié des essais thérapeutiques avec des immunomodulateurs régulièrement utilisés chez les patients atteints de maladies systémiques auto-immunes ou inflammatoires Depuis février 2021 où les premières recommandations EULAR sur l’utilisati...

Many inflammatory skin diseases exhibit a chronic course with unsatisfactory long-term outcomes. Insights into early intervention approaches in other autoimmune contexts could improve the trajectory of lifelong diseases in terms of sustained remission or minimal disease activity, reduced requirement for therapy and medical resource use, and improve...

Objective: Dupilumab (Dupixent®) is a monoclonal antibody that inhibits IL-4 and IL-13 signaling used for the treatment of allergic diseases. Whilst biologic therapy is traditionally regarded as immunosuppressive and capable to increase the infectious risk, Dupilumab does not display these characteristics and may be even protective in certain case...

The application of biologics in clinical practice allows immunological observations under real-life conditions. In a new article in the Journal of Investigative Dermatology, Bakker et al. (2021) use deep immune cell phenotyping to demonstrate how dupilumab acts in a targeted fashion on skin-homing T cells, the driver cells of atopic dermatitis.

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...

Background Enthesitis is a key musculoskeletal manifestation of psoriatic arthritis (PsA). EULAR guidelines recommend biologics for patients with enthesitis and an inadequate response to or intolerance of nonsteroidal anti-inflammatory drugs, although no guidance on specific biologics is offered. In the EXCEED head-to-head, double-blind study ( NCT...

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, a deleterious aberrant non-effective host immune response plays an important role especially in severe forms of COVID-19. There is intense investigation to explore the utility of immuno...

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is a global health problem. Beside the specific pathogenic effect of SARS-CoV-2, incompletely understood deleterious and aberrant host immune responses play critical roles in severe disease. Rheumatologists have the best experience of studying and treating these co...

Objectives: We theorized that myelodysplastic syndrome (MDS) with somatic mutations and karyotype abnormalities are associated with autoinflammation, and that the presence of autoinflammatory disease affected prognosis in MDS. Methods: One hundred thirty-four MDS patients were assessed for the prevalence of autoinflammatory complications and its li...

Osteoarthritis (OA) is the most common musculoskeletal disorder. Although joint replacement remains the standard of care for knee OA patients, knee joint distraction (KJD), which works by temporarily off-loading the joint for 6–8 weeks, is becoming a novel joint-sparing alternative for younger OA sufferers. The biological mechanisms behind KJD stru...

Osteoarthritis (OA), the most common joint disorder, is characterised by progressive structural changes in both the cartilage and the underlying subchondral bone. In late disease stages, subchondral bone sclerosis has been linked to heightened osteogenic commitment of bone marrow stromal cells (BMSCs). This study utilised cell sorting and immunohis...

Background: In the absence of definitive anti-viral therapy, there is considerable interest in mitigating against severe inflammatory reactions in coronavirus disease-2019 (COVID-19) pneumonia to improve survival. These reactions are sometimes termed cytokine storm. PDE4 inhibitors (PDE4i) have anti-inflammatory properties with approved indication...

Background Synovial fluid contains resident mesenchymal stem cells (SF-MSCs) that are derived from the synovial membrane and may interact with superficial cartilage injury sites. We previously reported on a novel methodology for increasing the number of MSCs in the knee joints using synovial brushing combined with platelet lysate (PL) as a chondrog...

Background Fat formation in the bone adjacent to the enthesis is an important but poorly characterised intermediate stage in new bone formation that occurs in the spine in AS. We and others have previously reported that IL-17A can increase mesenchymal stem cell (MSC) mediated osteogenesis in normal and AS spinal tissue (1, 2). Objectives Herein we...

Background Monoclonal gammopathy of undetermined significance (MGUS) is considered to be a premalignant condition with on average of 1% annual risk of progression to multiple myeloma or other lymphoproliferative disorders [1]. Numerous studies have highlighted a common feature of autoimmune inflammatory diseases is non-specific hypergammaglobulinae...

Background It is well known that viral infections may trigger psoriatic arthritis (PsA), a disease that typically has extensive pre-clinical entheseal abnormalites. Skin resident plasmacytoid dendritic cells (pDCs) produce IFNα that contribute to T cell expansion and the development of experimental psoriasis [1, 2]. IFN pathway SNPs have been repor...

Background Ultrasound (US) is an imaging adjunct to clinical joint examination adding sensitivity and objectivity to the assessment of inflammation. Previous studies in PsA have shown disparity between ultrasound and clinical findings with significant subclinical joint inflammation. A clinical challenge in PsA is to interpret tender joints (TJ) tha...

Background We previously reported that ANA-negative cases with systemic sclerosis (SSc) and concomitant cancer had a worse survival than ANA-positive cases with associated cancer possibly suggesting that humoral mediated autoimmunity conferred a survival advantage (1). Dermatomyositis (DM) and polymyositis (PM) are two immune-mediated myopathies as...

Background IL-4 and IL-13 are related Th2 cytokines, with documented roles in allergic inflammation such as atopic dermatitis (AD). Psoriatic Arthritis (PsA) is typically thought to be a result of Th1/Th17 driven response, and blockage of this pathway (IL-23, IL-17 and TNF) has proven successful. Despite this, there is a strong genetic risk associa...

Background We have previously reported that the normal spinal enthesis has populations of conventional T-cells including CD4+ & CD8+ T-cells that could be induced to produce IL-17A and TNF following anti-CD3/CD28 stimulation. The biology of such cells in health including their normal function and antigen reactivity is completely unknown. The purpos...

Background Enthesitis, defined as inflammation of anchorage points of tendons, ligaments and joint capsules to bones, is now understood to be the cardinal pathogenic lesion in spondyloarhtopathies (SpA). Evidence from genetic studies, animal models, and therapeutic studies firmly implicates the IL-23/IL-17 axis in the pathogenesis of SpA. We have r...

Background Dactylitis is a hallmark feature of Psoriatic arthritis (PsA) and Spondyloarthritis (SpA) defined as a uniform swelling of a digit (“sausage digit”). Dactylitis is associated with radiographic damage in chronic PsA. However, there are a paucity of data on the significance of dactylitis and its potential impact in disease burden in early...

Background A higher prevalence of ischemic heart disease (IHD) in patients with systemic sclerosis (SSc) was reported. However, contrasting findings were published concerning the role of SSc-related autoantibodies in IHD risk which remains controversial. Objectives The current study explored the link between SSc and IHD, impact of putative links o...

Background Guselkumab (GUS), a novel monoclonal antibody that specifically binds to the p19-subunit of IL-23, demonstrated efficacy in the Ph 3 DISCOVER-1 (D1) & DISCOVER-2 (D2) trials of pts with active psoriatic arthritis (PsA). 1,2 Dactylitis & enthesitis, key PsA clinical manifestations, can be difficult to treat and may portend more significan...

Background: The biological mechanisms that contribute to atrophic long bone non-union are poorly understood. Multipotential mesenchymal stromal cells (MSCs) are key contributors to bone formation and are recognised as important mediators of blood vessel formation. This study examines the role of MSCs in tissue formation at the site of atrophic non...

Background & Aim Synovial fluid contains resident mesenchymal stem cells (SF-MSCs) that are derived from the synovial membrane and may interact with superficial cartilage injury sites . We previously reported novel methodology for increasing the number of MSC in knee joints using synovial brushing and of platelet lysate (PL) as chondrogenic inducer...

Objective Type I interferon (IFN) responses are broadly associated with autoimmune diseases, including systemic lupus erythematosus (SLE). Given the cardinal role of autoantibodies in SLE, this study was undertaken to investigate whether the findings of a B cell–specific IFN assay correlate with SLE activity. Methods B cells and peripheral blood m...

Meteorin-like(IL-41), is a novel cytokine that is thought to be immunoregulatory and is highly expressed in psoriatic skin. We investigated IL-41 protein expression in synovial tissue in RA(Rheumatoid Arthritis), PsA(Psoriatic Arthritis) and OA(Osteoarthritis) patients and evaluated IL-41 production from healthy enthesis samples, as the enthesis re...

Objectives: To develop evidence-based recommendations on the use of MRI in the diagnosis of axial SpA (axSpA). Methods: A working group comprising nine rheumatologists and nine musculoskeletal radiologists with an interest in axSpA was established, with support from the British Society of Spondyloarthritis (BRITSpA). Two meetings were held. In t...

Osteoarthritis (OA) is the most common degenerative joint disorder. Multipotential stromal cells (MSCs) have a crucial role in joint repair, but how OA severity affects their characteristics remains unknown. Knee OA provides a good model to study this, as osteochondral damage is commonly more severe in the medial weight-bearing compartment compared...