Comparative analysis of centrally mediated and inflammatory pain experiences amongst patients diagnosed with rheumatoid arthritis: A multimethods study.

BACKGROUND: The identification of pain originating from distinct biological processes may lead to individualised pain treatment. In this study, we aimed to explore the pain experiences of patients with rheumatoid arthritis (RA), differentiating between those predominantly exhibiting features of peripheral inflammatory versus centrally mediated pain. METHODS: Through a multimethods approach we (i) quantitatively analysed the differences in pain descriptors between patients diagnosed with RA experiencing peripheral inflammatory and centrally mediated pain, utilising the Short Form-McGill Pain Questionnaire which includes the pain visual analogue scale (VAS) and (ii) qualitatively explored their subjective pain experiences grounded in the biopsychosocial model, commonly applied in chronic pain. RESULTS: Participants with centrally mediated pain reported higher pain scores on the VAS, used a wider range of pain descriptors, and a higher proportion selected each descriptor compared to those with inflammatory pain (p < .001). The qualitative analysis revealed the centrally mediated pain group's experiences were overwhelming and relentless, struggling to precisely articulate the nature of their pain. In contrast, individuals with inflammatory pain expressed their pain in more tangible terms and shared their adaptive and coping strategies. Importantly, both groups revealed the substantial psychological, functional and social impacts of their pain, highlighting the often 'invisible' and misunderstood nature of their symptoms. CONCLUSION: This study has gained a deeper insight into the pain experiences of patients living with RA, particularly in differentiating between centrally mediated and inflammatory types of pain, potentially facilitating a more individualised approach to pain treatment. PATIENT CONTRIBUTION: Patients actively participated in the study conception and design. This engagement includes collaboration with key stakeholders, such as members of the National Rheumatoid Arthritis Society and Patient Research Partners (PRPs), who provided continuous feedback and guidance throughout the research process. Specifically, the qualitative element was coproduced with two PRPs, who were involved in co-leading the focus groups and data analysis.

Human in vitro-induced IL-17A+ CD8+ T-cells exert pro-inflammatory effects on synovial fibroblasts.

IL-17A+ CD8+ T-cells, termed Tc17 cells, have been identified at sites of inflammation in several immune-mediated inflammatory diseases. However, the biological function of human IL-17A+ CD8+ T-cells is not well characterized, likely due in part to the relative scarcity of these cells. Here, we expanded IL-17A+ CD8+ T-cells from healthy donor PBMC or bulk CD8+ T-cell populations using an in vitro polarization protocol. We show that T-cell activation in the presence of IL-1ß and IL-23 significantly increased the frequencies of IL-17A+ CD8+ T-cells, which was not further enhanced by IL-6, IL-2, or anti-IFNγ mAb addition. In vitro-generated IL-17A+ CD8+ T-cells displayed a distinct type-17 profile compared with IL-17A- CD8+ T-cells, as defined by transcriptional signature (IL17A, IL17F, RORC, RORA, MAF, IL23R, CCR6), high surface expression of CCR6 and CD161, and polyfunctional production of IL-17A, IL-17F, IL-22, IFNγ, TNFα, and GM-CSF. A significant proportion of in vitro-induced IL-17A+ CD8+ T-cells expressed TCRVα7.2 and bound MR1 tetramers indicative of MAIT cells, indicating that our protocol expanded both conventional and unconventional IL-17A+ CD8+ T-cells. Using an IL-17A secretion assay, we sorted the in vitro-generated IL-17A+ CD8+ T-cells for functional analysis. Both conventional and unconventional IL-17A+ CD8+ T-cells were able to induce pro-inflammatory IL-6 and IL-8 production by synovial fibroblasts from patients with psoriatic arthritis, which was reduced upon addition of anti-TNFα and anti-IL-17A neutralizing antibodies. Collectively, these data demonstrate that human in vitro-generated IL-17A+ CD8+ T-cells are biologically functional and that their pro-inflammatory function can be targeted, at least in vitro, using existing immunotherapy.

Drivers of Inflammation in Psoriatic Arthritis: the Old and the New.

PURPOSE OF REVIEW: The recognition that IL-17 is produced by many lymphoid-like cells other than CD4+ T helper (Th17) cells raises the potential for new pathogenic pathways in IBD/psoriasis/SpA. We review recent knowledge concerning the role of unconventional and conventional lymphocytes expressing IL-17 in human PsA and axSpA. RECENT FINDINGS: Innate-like lymphoid cells, namely gamma delta (γδ) T-cells, invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells, together with innate lymphoid cells (ILCs) are found at sites of disease in PsA/SpA. These cells are often skewed to Type-17 profiles and may significantly contribute to IL-17 production. Non-IL-23 dependent IL-17 production pathways, utilising cytokines such as IL-7 and IL-9, also characterise these cells. Both conventional CD4 and CD8 lymphocytes show pathogenic phenotypes at sites of disease. A variety of innate-like lymphoid cells and conventional lymphocytes contribute towards IL-17-mediated pathology in PsA/SpA. The responses of these cells to non-conventional immune and non-immune stimuli may explain characteristic clinical features of these diseases and potential therapeutic mechanisms of therapies such as Jak inhibitors.

The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies.

Although the pathogenic mechanisms underlying axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) are not fully elucidated, several lines of evidence suggest that immune responses mediated by interleukin 17A (IL-17A) play a pivotal role in both diseases. This is best highlighted by the significant clinical efficacy shown with inhibitors of IL-17A in treating axSpA and PsA. Nevertheless, a number of knowledge gaps exist regarding the role of IL-17A in the pathophysiology of spondyloarthritis in man, including its cellular origin, its precise role in discrete disease processes such enthesitis, bone erosion, and bone formation, and the reasons for the discrepant responses to IL-17A inhibition observed in certain other spondyloarthritis manifestations. In this review, we focus on the latest data from studies investigating the role of IL-17A in ankylosing spondylitis (AS) and PsA that build on existing and emerging scientific knowledge in the field. Key remaining research questions are also highlighted to guide future research.

Best-practice Indicators in Psoriatic Disease Care.

OBJECTIVE: In 2016, members of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), in collaboration with KPMG LLP (UK), conducted a study to measure care in psoriatic arthritis (PsA). A key finding was that centers do not usually have processes in place to measure the effect of improved quality of care. Our objectives were to identify and select best-practice indicators to enable PsA caregivers to assess and monitor the outcomes of specific initiatives aimed at improving care in 4 focus areas: (1) shortening time to diagnosis; (2) improving multidisciplinary collaboration; (3) optimizing disease management; and (4) improving disease monitoring. METHODS: (1) Structured review of scientific and grey literature to obtain evidence for a long list of 100 potential indicators across the 4 focus areas; (2) survey expert rheumatologists and dermatologists to review the long list and identify the most meaningful and feasible indicators for use in day-to-day practice; (3) consensus discussion to identify a shortlist of indicators based on predefined selection criteria; (4) electronic group discussion to refine definitions of shortlisted indicators and targets; and (5) review of the shortlisted indicators at the annual GRAPPA meeting in July 2018 to ensure the indicators meet the preliminary criteria. RESULTS: The expert group arrived at a consensus with a shortlist of 8 best-practice indicators across 4 key focus areas aligned with the patient pathway. CONCLUSION: There were 8 evidence-based best-practice indicators and respective targets that were identified to enable the monitoring of quality of care and target improvements.

The SSB-positive/SSA-negative antibody profile is not associated with key phenotypic features of Sjögren's syndrome.

OBJECTIVE: To determine whether the Sjögren's syndrome B (SSB)-positive/Sjögren's syndrome A (SSA)-negative antibody profile is associated with key phenotypic features of SS. METHODS: Among registrants in the Sjögren's International Collaborative Clinical Alliance (SICCA) with possible or established SS, we compared anti-SSA/anti-SSB reactivity profiles against concurrent phenotypic features. We fitted logistic regression models to explore the association between anti-SSA/anti-SSB reactivity profile and each key SS phenotypic feature, controlling for potential confounders. RESULTS: Among 3297 participants, 2061 (63%) had negative anti-SSA/anti-SSB, 1162 (35%) had anti-SSA with or without anti-SSB, and 74 (2%) anti-SSB alone. Key SS phenotypic features were more prevalent and had measures indicative of greater disease activity in those participants with anti-SSA, either alone or with anti-SSB, than in those with anti-SSB alone or negative SSA/SSB serology. These between-group differences were highly significant and not explained by confounding by age, race/ethnicity or gender. Participants with anti-SSB alone were comparable to those with negative SSA/SSB serology in their association with these key phenotypic features. Among SICCA participants classified with SS on the basis of the American-European Consensus Group or American College of Rheumatology criteria, only 2% required the anti-SSB-alone test result to meet these criteria. CONCLUSIONS: The presence of anti-SSB, without anti-SSA antibodies, had no significant association with SS phenotypic features, relative to seronegative participants. The solitary presence of anti-SSB antibodies does not provide any more support than negative serology for the diagnosis of SS. This serological profile should thus be interpreted cautiously in clinical practice and potentially eliminated from future classification criteria.

Interleukin-17A: a unique pathway in immune-mediated diseases: psoriasis, psoriatic arthritis and rheumatoid arthritis.

Experimental evidence points to the importance of the cytokine interleukin-17A (IL-17A) in the pathogenesis of several immunoinflammatory diseases including psoriasis, psoriatic arthritis and rheumatoid arthritis. Although a principal effector of T helper type 17 cells, IL-17A is produced by many other cell types including CD8(+) T cells and γδ T cells, and is found at high levels associated with mast cells and neutrophils at sites of skin and joint disease in humans. IL-17A up-regulates expression of numerous inflammation-related genes in target cells such as keratinocytes and fibroblasts, leading to increased production of chemokines, cytokines, antimicrobial peptides and other mediators that contribute to clinical disease features. Importantly, IL-17A must be considered within the context of the local microenvironment, because it acts synergistically or additively with other pro-inflammatory cytokines, including tumour necrosis factor. Several direct IL-17A inhibitors have shown promising activity in proof of concept and phase 2 clinical studies, thereby providing confirmation of experimental data supporting IL-17A in disease pathogenesis, although levels of response are not predicted by pre-clinical findings. IL-17A inhibitors produced rapid down-regulation of the psoriasis gene signature and high clinical response rates in patients with moderate-to-severe plaque psoriasis, consistent with an important role for IL-17A in psoriasis pathogenesis. Clinical response rates with IL-17A inhibitors in psoriatic arthritis and rheumatoid arthritis, however, were improved to a lesser degree compared with placebo, suggesting that IL-17A is either important in a subset of patients or plays a relatively minor role in inflammatory joint disease. Ongoing phase 3 clinical trials should provide further information on the role of IL-17A in these diseases.

Effects of golimumab, an anti-tumour necrosis factor-α human monoclonal antibody, on lipids and markers of inflammation.

OBJECTIVES: To assess the effect of golimumab, with or without methotrexate (MTX), on serum lipids and inflammatory markers of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) in two phase 3, randomised, placebo-controlled trials (GO-BEFORE and GO-FORWARD). METHODS: Patients in GO-BEFORE (n=637, MTX-naïve) and GO-FORWARD (n=444, MTX-inadequate response) were randomised to placebo+MTX, golimumab 100 mg+placebo, golimumab 50 mg+MTX, or golimumab 100 mg+MTX. Subcutaneous injections (placebo and golimumab) were given every 4 weeks. Patients with an insufficient response entered early escape at week 16 (GO-FORWARD) or 28 (GO-BEFORE). All placebo+MTX patients in GO-FORWARD crossed over to golimumab 50 mg+MTX at week 24. Changes from baseline to weeks 14 (GO-FORWARD) or 24 (GO-BEFORE), and 52 in serum lipid levels and inflammatory markers were assessed. RESULTS: At week 14 in the GO-FORWARD trial, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) increased in golimumab+MTX patients versus MTX-only patients (16.00 vs 2.00 (p<0.001); 3.00 vs 0.00 (p<0.05); 8.00 vs 4.00 (p<0.001); respectively); favourable changes in LDL subfractions were only observed in golimumab-treated patients. At week 24 in GO-BEFORE, TC and LDL increased, and LDL subfractions improved in the MTX-only and golimumab+MTX groups. Inflammatory markers of CVD risk improved significantly with golimumab+MTX versus placebo+MTX in both studies and were generally maintained through week 52. Atherogenic indices were generally stable. CONCLUSIONS: While TC and LDL levels increased mildly in RA patients receiving golimumab+MTX, atherogenic indices generally remained stable, favourable changes in LDL subfractions were observed, and inflammatory markers improved.

Interaction with activated monocytes enhances cytokine expression and suppressive activity of human CD4+CD45ro+CD25+CD127(low) regulatory T cells.

OBJECTIVE: Despite the high frequency of CD4+ T cells with a regulatory phenotype (CD25+CD127(low) FoxP3+) in the joints of patients with rheumatoid arthritis (RA), inflammation persists. One possible explanation is that human Treg cells are converted into proinflammatory interleukin-17 (IL-17)-producing cells by inflammatory mediators and thereby lose their suppressive function. The aim of this study was to investigate whether activated monocytes, which are potent producers of inflammatory cytokines and are abundantly present in the rheumatic joint, induce proinflammatory cytokine expression in human Treg cells and impair their regulatory function. METHODS: The presence and phenotype of CD4+CD45RO+CD25+CD127(low) T cells (memory Treg cells) and CD14+ monocytes in the peripheral blood (PB) and synovial fluid (SF) of patients with RA were investigated by flow cytometry. Memory Treg cells obtained from healthy control subjects underwent fluorescence-activated cell sorting and then were cocultured with autologous activated monocytes and stimulated with anti-CD3 monoclonal antibodies. Intracellular cytokine expression, phenotype, and function of cells were determined by flow cytometry, enzyme-linked immunosorbent assay, and proliferation assays. RESULTS: In patients with RA, the frequencies of CD4+CD45RO+CD25+CD127(low) Treg cells and activated CD14+ monocytes were higher in SF compared with PB. In vitro-activated monocytes induced an increase in the percentage of IL-17-positive, interferon-γ (IFNγ)-positive, and tumor necrosis factor α (TNFα)-positive Treg cells as well as IL-10-positive Treg cells. The observed increase in IL-17-positive and IFNγ-positive Treg cells was driven by monocyte-derived IL-1ß, IL-6, and TNFα and was mediated by both CD14+CD16- and CD14+CD16+ monocyte subsets. Despite enhanced cytokine expression, cells maintained their CD25+FoxP3+CD39+ Treg cell phenotype and showed an enhanced capacity to suppress T cell proliferation and IL-17 production. CONCLUSION: Treg cells exposed to a proinflammatory environment show increased cytokine expression as well as enhanced suppressive activity.

A randomised controlled trial of the effect of intra-articular lidocaine on pain scores in inflammatory arthritis.

ABSTRACT: Chronic pain in inflammatory arthritis (IA) reflects a complex interplay between active disease in a peripheral joint and central pronociceptive mechanisms. Because intra-articular lidocaine may be used to abolish joint-specific peripheral input to the central nervous system, we aimed to validate its use as a clinical tool to identify those patients with IA whose pain likely incorporates centrally mediated mechanisms. We began by investigating whether there was a placebo response of intra-articular injection in patients with IA 1:1 randomised to receive intra-articular lidocaine or control (0.9% saline). After, in a larger patient cohort not randomized to placebo vs lidocaine groups, we tested whether patients with IA could be stratified into 2 cohorts based on their response to intra-articular lidocaine according to markers of centrally mediated pain. To this end, we evaluated postlidocaine pain numerical rating scale (NRS) scores alongside baseline painDETECT, fibromyalgia criteria fulfillment, and quantitative sensory testing outcomes. Numerical rating scale scores were collected at baseline and 3-, 5-, and 10-minutes postinjection. Firstly, the placebo effect of intra-articular injection was low: compared to baseline, the mean pain NRS score 5-minutes postinjection was reduced by 3.5 points in the lidocaine group vs 1.2 points in the control group. Secondly, postlidocaine NRS scores were significantly higher in those with a high (>18) baseline painDETECT score, fibromyalgia, and low-pressure pain threshold at the trapezius (P = 0.002, P = 0.001, P = 0.005, respectively). Persistent high pain after intra-articular lidocaine injection could be used as an indicator of pronociceptive mechanisms that are centrally mediated, informing centrally targeted analgesic strategies.

Pain sensitisation and joint inflammation in patients with active rheumatoid arthritis.

INTRODUCTION: Despite better therapies and strategies, many people with rheumatoid arthritis (RA) have persistent pain, often from abnormal pain processing, now termed nociplastic pain. However, RA patients with fibromyalgia (FM), a central nociplastic pain syndrome, also have power doppler ultrasound (PDUS+) joint inflammation. To understand the complex causes of pain, we performed clinical examination and patient-reported outcome measures (PROMs) plus comprehensive PDUS evaluation not previously combined. METHODS: In a cross-sectional study of sequential RA patients with at least moderate DAS28 erythrocyte sedimentation rate disease activity, we assessed 66/68 joints for swelling and tenderness, respectively, FM American College of Rheumatology 2010 diagnostic criteria, completed PROMs for function, quality of life and mood, alongside PDUS examination of 44 joints. Statistical analysis included logistic regression modelling and regularised (lasso) logistic regression methods. RESULTS: From 158 patients, 72 (46%) patients met FM criteria, with significantly worse tender joint counts and PROMs, but no differences in PDUS compared with the non-FM group. Categorising patients by PDUS+ joint presence and/or FM criteria, we identified four distinct groups: 43 (27.2%) patients with -FM-PD, 43 (27.2%) with -FM+PD, 42 (26.6%) with +FM-PD and 30 (19%) with +FM+PD. Both FM+ groups had worse PROMs for fatigue, mood and pain, compared with the FM- groups. We were unable to develop algorithms to identify different groups. CONCLUSION: The unexpected group -FM-PD group may have peripheral nociplastic pain, not commonly recognised in rheumatology. Only 46% of patients demonstrated PDUS+ inflammation. However clinical examination and PROMs did not reliably differentiate groups, emphasising PDUS remains an important tool.

A systematic review and meta-analysis of questionnaires to screen for pain sensitisation and neuropathic like pain in inflammatory arthritis.

BACKGROUND: Targeted pain relief is a major unmet medical need for patients with inflammatory arthritis (IA), where approximately 40% of patients experience persistent pain. Self-reported questionnaires which report on pain sensitivity and neuropathic like pain may provide an insight into certain pain types to guide targeted treatment. OBJECTIVE: In this systematic review and meta-analysis we evaluated self-reported pain sensitivity and neuropathic like pain in subjects with IA, as defined by questionnaires. METHODS: MEDLINE, Embase, Web of Science, PsycINFO and google scholar were searched for publications and conference abstracts, reporting on pain sensitivity and neuropathic pain using painDETECT, DN4, LANSS, CSI, PSQ and McGill pain questionnaire in adult patients with IA. Risk of bias was assessed using National Institute of Health Quality Assessment Tool. Meta-analysis according to individual questionnaire criteria, was undertaken. RESULTS: 63 studies (38 full text and 25 conference abstracts) were included in the review, reporting on a total of 13,035 patients. On meta-analysis, prevalence of pain sensitivity/neuropathic like pain in IA was 36% (95% CI 31-41%) according to painDETECT, 31% (95% CI 26-37%) according to the DN4, 40% (95% CI 32-49%) according to the LANSS and 42% (95% CI 34-51%) according to the CSI. On meta-regression, prevalence of pain sensitivity/neuropathic pain in RA was significantly lower than SpA (p = 0.01) and PsA (p = 0.002) using the painDETECT questionnaire. Across all questionnaires, pain sensitivity and neuropathic like pain were significantly associated with worse pain severity, disease activity, disability, quality of life and anxiety and depression measures. Studies reporting on whether neuropathic like pain is a predictor of treatment outcome were inconsistent. CONCLUSION: Pain sensitivity and neuropathic like pain contribute to pain perception in up to 42% of patients with IA. Despite substantial heterogeneity between studies on meta-analysis, this review highlights the large proportion of patients with IA who may experience pain due to underlying mechanisms other than, or in addition to, synovial inflammation.

A Comprehensive Review of Ixekizumab Efficacy in Nail Psoriasis from Clinical Trials for Moderate-to-Severe Psoriasis and Psoriatic Arthritis.

Nail psoriasis is a difficult-to-treat manifestation of psoriatic disease affecting up to 80% of patients with psoriatic arthritis (PsA) and 40-60% of patients with plaque psoriasis (PsO). Ixekizumab (IXE), a high-affinity monoclonal antibody that selectively targets interleukin-17A, is approved for the treatment of patients with PsA and patients with moderate-to-severe PsO. This narrative review aims to summarize nail psoriasis data generated from IXE clinical trials in patients with PsA (SPIRIT-P1, SPIRIT-P2, and SPIRIT-H2H) and/or moderate-to-severe PsO (UNCOVER-1, -2, -3, IXORA-R, IXORA-S, and IXORA-PEDS) with an emphasis on head-to-head clinical trial data. Across numerous trials explored, IXE treatment was associated with greater improvement in resolution of nail disease versus comparators at week 24, results which were maintained up to and beyond week 52. Additionally, patients experienced higher rates of resolution of nail disease versus comparators at week 24 and maintained high levels of resolution up to week 52 and beyond. In both PsA and PsO, IXE demonstrated efficacy in treating nail psoriasis, and therefore may be an effective therapy option. Trial Registration: ClinicalTrials.gov identifier UNCOVER-1 (NCT01474512), UNCOVER-2 (NCT01597245), UNCOVER-3 (NCT01646177), IXORA-PEDS (NCT03073200), IXORA-S (NCT02561806), IXORA-R (NCT03573323), SPIRIT-P1 (NCT01695239), SPIRIT-P2 (NCT02349295), SPIRIT-H2H (NCT03151551).

Psoriatic and rheumatoid arthritis joints differ in the composition of CD8+ tissue-resident memory T cell subsets.

CD69+CD103+ tissue-resident memory T (TRM) cells are important drivers of inflammation. To decipher their role in inflammatory arthritis, we apply single-cell, high-dimensional profiling to T cells from the joints of patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA). We identify three groups of synovial CD8+CD69+CD103+ TRM cells: cytotoxic and regulatory T (Treg)-like TRM cells are present in both PsA and RA, while CD161+CCR6+ type 17-like TRM cells with a pro-inflammatory cytokine profile (IL-17A+TNFα+IFNγ+) are specifically enriched in PsA. In contrast, only one population of CD4+CD69+CD103+ TRM cells is detected and at similarly low frequencies in both diseases. Type 17-like CD8+ TRM cells have a distinct transcriptomic signature and a polyclonal, but distinct, TCR repertoire. Type 17-like cells are also enriched in CD8+CD103- T cells in PsA compared with RA. These findings illustrate differences in the immunopathology of PsA and RA, with a particular enrichment for type 17 CD8+ T cells in the PsA joint.

Type 17-specific immune pathways are active in early spondyloarthritis.

OBJECTIVE: Undifferentiated, early inflammatory arthritis (EIA) can differentiate into seropositive or seronegative rheumatoid arthritis (RA), peripheral spondyloarthritis (SpA) or remain as seronegative undifferentiated inflammatory arthritis (UIA). Little is known about immune pathways active in the early stages of SpA and seronegative UIA, in contrast to detailed knowledge of seropositive RA. The aim of this study was to examine if specific immune pathways were active in synovial CD4+ and CD8+ T cells in EIA. METHODS: Synovial fluid (SF) samples from 30 patients with EIA were analysed for expression of IL-17A, IFNγ and TNFα in CD8+ or CD4+ T cells. Final clinical diagnoses were made at least 12 months after sample collection, by two independent clinicians blind to the study data. RESULTS: Flow cytometry analysis of all EIA samples indicated considerable variation in synovial IL-17A+CD8+ T cells (Tc17) cell frequencies between patients. The group with a final diagnosis of SpA (psoriatic arthritis or peripheral SpA, n=14) showed a significant enrichment in the percentage of synovial Tc17 cells compared with the group later diagnosed with seronegative UIA (n=10). The small number of patients later diagnosed with seropositive RA (n=6) patients had few Tc17 cells, similar to our previous findings in established disease. In contrast, RA SF contained a significantly higher percentage of CD8+IFNγ+ T cells compared with SpA or seronegative UIA. CONCLUSION: These results suggest that adaptive T cell cytokine pathways differ not only between RA and SpA but also seronegative UIA early in the disease process, with a particular activation of Tc17 pathways in early SpA.

Optimising psoriatic arthritis therapy with immunological methods to increase standard evaluation: the protocol of an open-label multicentre, parallel-group, two-arm randomised controlled study evaluation precision medicine approach in the treatment of psoriatic arthritis.

INTRODUCTION: Psoriatic arthritis (PsA) affects around 150 000 people in the UK of whom around 50% require treatment with biologics. The most used biologics for PsA target tumour necrosis factor (TNF) or interleukin-17A (IL-17A). About 50% of patients respond to each, but it is not currently possible to predict response for individual patients, necessitating sequential treatment steps. A recent proof of concept study in PsA suggested that using peripheral immunophenotype to choose therapy could improve time to treatment response.This study will test the hypothesis, within an open-label parallel-group biomarker-stratified multicentre randomised controlled trial, which the baseline proportion of CD4+T cells with an activated type 17 immunophenotype (Th17 levels) predicts response to IL-17A or TNF inhibitors in PsA. Additional analyses will identify if the model can be refined by combining additional clinical and immunophenotypic factors. Statistical modelling will be used to predict the likely effectiveness of these approaches compared with standard care. METHODS AND ANALYSIS: Patients with PsA eligible to start their first biologic as part of standard care are recruited and baseline blood tests are taken for immunophenotyping. Participants are stratified equally by Th17 levels and randomised 1:1 to receive either TNF (adalimumab) or IL-17A (secukinumab) inhibitors. The primary analysis will establish the interaction between baseline immunophenotype and treatment on the primary outcome (achievement of minimal disease activity criteria at week 24). In secondary analysis, modelling will identify if this prediction model can be optimised further by incorporating clinical phenotypes and additional immunophenotyping techniques. ETHICS AND DISSEMINATION: Ethical approval for the study was granted by the North West Preston Research Ethics Committee (ref 21/NW/0016). Dissemination will be via conference presentations and peer-reviewed publications, aiming to impact on treatment guidelines. TRIAL REGISTRATION NUMBER: ISRCTN17228602.

In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses.

Th17 cells are a recently defined subset of proinflammatory T cells that contribute to pathogen clearance and tissue inflammation by means of the production of their signature cytokine IL-17A (henceforth termed IL-17). Although the in vitro requirements for human Th17 development are reasonably well established, it is less clear what their in vivo requirements are. Here, we show that the production of IL-17 by human Th17 cells critically depends on both the activation status and the anatomical location of accessory cells. In vivo activated CD14+ monocytes were derived from the inflamed joints of patients with active rheumatoid arthritis (RA). These cells were found to spontaneously and specifically promote Th17, but not Th1 or Th2 responses, compared with resting CD14+ monocytes from the blood. Surprisingly, unlike Th17 stimulation by monocytes that were in vitro activated with lipopolysaccharide, intracellular IL-17 expression was induced by in vivo activated monocytes in a TNF-alpha- and IL-1beta-independent fashion. No role for IL-6 or IL-23 production by either in vitro or in vivo activated monocytes was found. Instead, in vivo activated monocytes promoted Th17 responses in a cell-contact dependent manner. We propose that, in humans, newly recruited memory CD4(+) T cells can be induced to produce IL-17 in nonlymphoid inflamed tissue after cell-cell interactions with activated monocytes. Our data also suggest that different pathways may be utilized for the generation of Th17 responses in situ depending on the site or route of accessory cell activation.

Clinically relevant patient clusters identified by machine learning from the clinical development programme of secukinumab in psoriatic arthritis.

OBJECTIVES: Identify distinct clusters of psoriatic arthritis (PsA) patients based on their baseline articular, entheseal and cutaneous disease manifestations and explore their clinical and therapeutic value. METHODS: Pooled baseline data in PsA patients (n=1894) treated with secukinumab across four phase 3 studies (FUTURE 2-5) were analysed to determine phenotypes based on clusters of clinical indicators. Finite mixture models methodology was applied to generate clinical clusters and mean longitudinal responses were compared between secukinumab doses (300 vs 150 mg) across identified clusters and clinical indicators through week 52 using machine learning (ML) techniques. RESULTS: Seven distinct patient clusters were identified. Cluster 1 (very-high (VH) - SWO/TEN (swollen/tender); n=187) was characterised by VH polyarticular burden for both tenderness and swelling of joints, while cluster 2 (H (high) - TEN; n=251) was marked by high polyarticular burden in tender joints and cluster 3 (H - Feet - Dactylitis; n=175) by high burden in joints of feet and dactylitis. For cluster 4 (L (Low) - Nails - Skin; n=209), cluster 5 (L - skin; n=283), cluster 6 (L - Nails; n=294) and cluster 7 (L; n=495) articular burden was low but nail and skin involvement was variable, with cluster 7 marked by mild disease activity across all domains. Greater improvements in the longitudinal responses for enthesitis in cluster 2, enthesitis and Psoriasis Area and Severity Index (PASI) in cluster 4 and PASI in cluster 6 were shown for secukinumab 300 mg compared with 150 mg. CONCLUSIONS: PsA clusters identified by ML follow variable response trajectories indicating their potential to predict precise impact on patients' outcomes. TRIAL REGISTRATION NUMBERS: NCT01752634, NCT01989468, NCT02294227, NCT02404350.

Polyfunctional, Proinflammatory, Tissue-Resident Memory Phenotype and Function of Synovial Interleukin-17A+CD8+ T Cells in Psoriatic Arthritis.

OBJECTIVE: Genetic associations imply a role for CD8+ T cells and the interleukin-23 (IL-23)/IL-17 axis in psoriatic arthritis (PsA) and other spondyloarthritides (SpA). IL-17A+CD8+ (Tc17) T cells are enriched in the synovial fluid (SF) of patients with PsA, and IL-17A blockade is clinically efficacious in PsA/SpA. This study was undertaken to determine the immunophenotype, molecular profile, and function of synovial Tc17 cells in order to elucidate their role in PsA/SpA pathogenesis. METHODS: Peripheral blood (PB) and SF mononuclear cells were isolated from patients with PsA or other types of SpA. Cells were phenotypically, transcriptionally, and functionally analyzed by flow cytometry (n = 6-18), T cell receptor ß (TCRß) sequencing (n = 3), RNA-Seq (n = 3), quantitative reverse transcriptase-polymerase chain reaction (n = 4), and Luminex or enzyme-linked immunosorbent assay (n = 4-16). RESULTS: IL-17A+CD8+ T cells were predominantly TCRαß+ and their frequencies were increased in the SF versus the PB of patients with established PsA (P < 0.0001) or other SpA (P = 0.0009). TCRß sequencing showed that these cells were polyclonal in PsA (median clonality 0.08), while RNA-Seq and deep immunophenotyping revealed that PsA synovial Tc17 cells had hallmarks of Th17 cells (RORC/IL23R/CCR6/CD161) and Tc1 cells (granzyme A/B). Synovial Tc17 cells showed a strong tissue-resident memory T (Trm) cell signature and secreted a range of proinflammatory cytokines. We identified CXCR6 as a marker for synovial Tc17 cells, and increased levels of CXCR6 ligand CXCL16 in PsA SF (P = 0.0005), which may contribute to their retention in the joint. CONCLUSION: Our results identify synovial Tc17 cells as a polyclonal subset of Trm cells characterized by polyfunctional, proinflammatory mediator production and CXCR6 expression. The molecular signature and functional profiling of these cells may help explain how Tc17 cells can contribute to synovial inflammation and disease persistence in PsA and possibly other types of SpA.

Precision medicine in psoriatic arthritis: how should we select targeted therapies?

Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis associated with psoriasis. Patients manifest variable presentations with potential involvement of peripheral joints, spine, tendons, skin, and nails. There has been a rapid expansion in targeted treatment options for patients with PsA, but typically less than half of those who receive therapy achieve optimal treatment targets. Many patients respond to second-line or third-line biological therapies, but little evidence exists to guide the choice of therapeutics for each individual. At present, choice of therapy is driven by active clinical disease domains, clinician familiarity with existing treatments, and cost. Here, we review recent data that highlight the potential for personalised, or precision, medicine in PsA and other forms of inflammatory arthritis, noting that this research is still at a preliminary stage. In the future, a combination of detailed immunophenotyping and sophisticated statistical analyses should help to facilitate a personalised medicine approach in PsA, following examples from other clinical areas, such as oncology. This change in approach to the treatment of PsA has the potential to maximise outcomes for patients and to provide optimal therapies without delay.