Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression.

Immune checkpoint blockade with therapeutic anti-cytotoxic T lymphocyte-associated antigen (CTLA)-4 (Ipilimumab) and anti-programmed death (PD)-1 (Nivolumab and Pembrolizumab) antibodies alone or in combination has shown remarkable efficacy in multiple cancer types, concomitant with immune-related adverse events, including arthralgia and inflammatory arthritis (IA) in some patients. Herein, using Nivolumab (anti-PD-1 antagonist)-responsive genes along with transcriptomics of synovial tissue from multiple stages of rheumatoid arthritis (RA) disease progression, we have interrogated the activity status of PD-1 pathway during RA development. We demonstrate that the expression of PD-1 was increased in early and established RA synovial tissue compared to normal and OA synovium, whereas that of its ligands, programmed death ligand-1 (PD-L1) and PD-L2, was increased at all the stages of RA disease progression, namely arthralgia, IA/undifferentiated arthritis, early RA and established RA. Further, we show that RA patients expressed PD-1 on a majority of synovial tissue infiltrating CD4+ and CD8+ T cells. Moreover, enrichment of Nivolumab gene signature was observed in IA and RA, indicating that the PD-1 pathway was downregulated during RA disease progression. Furthermore, serum soluble (s) PD-1 levels were increased in autoantibody positive early RA patients. Interestingly, most of the early RA synovium tissue sections showed negative PD-L1 staining by immunohistochemistry. Therefore, downregulation in PD-1 inhibitory signaling in RA could be attributed to increased serum sPD-1 and decreased synovial tissue PD-L1 levels. Taken together, these data suggest that agonistic PD1 antibody-based therapeutics may show efficacy in RA treatment and interception

A prospective study of respiratory ciliary structure and function after stem cell transplantation

We prospectively investigated the morphological and ciliary function abnormalities in 19 consecutive Chinese patients undergoing hemopoietic stem cell transplantation (HSCT) and studied their relationship with pulmonary complications. The percentage of structural ciliary abnormalities preceding HSCT was comparable to normal controls, but increased up to 1-year post-HSCT. However, the abnormalities did not correlate with ciliary or pulmonary function. Ciliary beat frequency (CBF) for patients undergoing autologous and allogeneic SCT was lower than that of matched controls, with a further decline at one year. There was, however, no significant change in pulmonary function for the whole cohort. There was considerable variation in CBF and ciliary abnormalities in all cases during 3-month interval assessments. Regular ciliary assessment did not predict the only two patients who eventually suffered from bronchiolitis obliterans (BO). We conclude that structural and functional ciliary abnormalities are common in recipients of HSCT, and predict post-HSCT deterioration. However, there is no evidence to show that CBF monitoring may be of prospective benefit. © Nature Publishing Group. All rights reserved.link_to_subscribed_fulltex

Fatigue in psoriatic arthritis - a cross-sectional study of 246 patients from 13 countries

Objectives: Fatigue is an aspect of psoriatic arthritis (PsA), which is important to patients. The objective was to evaluate magnitude of fatigue in PsA patients and to assess factors that might explain high levels of fatigue. Methods: This was an ancillary analysis of a cross-sectional study in 13 countries of unselected PsA patients who fulfilled the CASPAR criteria. Patient-perceived importance of fatigue was assessed through a priority exercise. Levels of fatigue were assessed by a numeric rating scale (range 0–10). Factors potentially associated with fatigue > 5/10: i.e., demographic variables (age, gender, disease duration, education level) and disease related characteristics including joint counts, C-reactive protein, skin psoriasis, axial involvement, enthesitis, dactylitis, structural damage, were assessed by univariate, multivariate logistic and multiple linear regression. Results: In all, 246 patients were analysed: mean ± standard deviation age 51.2 ± 13.0 years, mean disease duration 9.9 ± 10.1 years, mean DAS28 3.5 ± 1.3. Fatigue was ranked second in patient-perceived importance, after pain. Magnitude of fatigue was high: mean fatigue 5.0 ± 3.0. Fatigue > 5/10 was well explained (variance explained 73%) by skin psoriasis (odds ratio 4.67 [95% confidence interval 1.05; 20.72]), tender joints (1.30 [1.01; 1.68]) and lower education level (1.09 [1.02; 1.23]). In the multiple linear regression model, fatigue was explained by skin psoriasis, tender joints, enthesitis, female gender, education level. Conclusions: Fatigue is a priority for PsA patients. Fatigue levels were high in these patients and fatigue > 5/10 was mainly associated with disease-related factors but also patient-related variables, indicating that the etiology of fatigue in PsA is multifactorial

Determinants of patient-physician discordance in global assessment in psoriatic arthritis: a multicenter European study

Objective: Patient-physician discordance in global assessment of disease activity concerned one third of patients but what does it reflect? We aimed to assess patient-physician discordance in psoriatic arthritis (PsA) and patient-reported domains of health (physical and psychological) associated to discordance. Methods: The PsAID (Psoriatic Arthritis Impact of Disease) cross-sectional multicenter European study of patients with PsA according to expert opinion was analysed. Patient- and Physician-Global Assessment (PGA and PhGA) were rated with a 0-10 numeric rating scale. Discordance was defined as the difference (PGA–PhGA) and as the absolute difference |PGA-PhGA|≥3 points. Determinants of (PGA-PhGA) were assessed by a stepwise multivariate linear regression among 12 physical and psychological aspects of impact: pain, skin problems, fatigue, ability to work/leisure, functional incapacity, feeling of discomfort, sleep disturbance, anxiety/fear, coping, embarrassment/shame, social participation and depressive affects. Results: In 460 patients (mean age 50.6±12.9 years, 52.2% female, mean disease duration 9.5±9.5 years, mean DAPSA 30.8±32.4, 40.4% treating by biologics), mean PGA was higher than mean PhGA with a mean absolute difference of 1.9±1.8 points. Discordance defined by |PGA-PhGA|≥3/10 concerned 134 (29.1%) patients and 115 (85.8% of patients with discordance) had PGA>PhGA. Higher fatigue (β=0.14), lower self-perceived coping (β=0.23) and impaired social participation (β=0.16) were independently associated with a higher difference (PGA-PhGA). Conclusion: Discordance concerned 29.1% of these patient/physician dyads, mainly by PGA>PhGA. Factors associated with discordance were psychological rather than physical domains of health. Discordance was more frequent in patients in remission, indicating more work is needed on the patient perspective regarding disease activity

Patient global assessment in psoriatic arthritis – what does it mean? An analysis of 223 patients from the Psoriatic arthritis impact of disease (PsAID) study

Objective: Patient global assessment is a key outcome measure in psoriatic arthritis. To explore the meaning of patient global assessment in psoriatic arthritis by examining associations to domains of health assessed by the Psoriatic arthritis impact of disease score. Methods: Post-hoc analysis of a multicentre cross-sectional study of patients with psoriatic arthritis. Data collection included patient global assessment, specific joint and skin global patient assessments, Psoriatic arthritis impact of disease questions covering physical (including joints and skin), psychological and social impact, and other comparator outcomes. Univariate analyses (Pearson correlation) and multivariate linear regression were performed to explain patient global assessment and the specific joint and skin global patient assessments. Results: Among 223 patients (mean age: 51.0 [standard deviation, ±13.3] years; mean disease duration: 9.9 [±10.1] years; mean swollen joint count: 4.1 [±5.1]; 84.3% with current psoriasis [mainly of less than 5% body surface area]), 50.2% were females. Mean patient global assessment was 4.8 (±2.7), mean joint and skin patient assessments were respectively 5.6 (±2.5) and 4.1 (±3.0). Intraclass correlation between patient global assessment and joint or skin patient assessment was respectively 0.71 (95% confidence interval, 0.64–0.77) and 0.52 (95% confidence interval, 0.42–0.60). In multivariate analyses, patient global assessment was explained (R2 of model: 0.754) by coping (β = 0.287); pain (β = 0.240); work and/or leisure activities (β = 0.141); and anxiety (β = 0.109). Conclusions: Patient global assessment in psoriatic arthritis was explained mainly by physical, but also psychological aspects of the disease

Group for Research and Assessment of Psoriasis and Psoriatic Arthritis/Outcome Measures in Rheumatology consensus‐based recommendations and research agenda for use of composite measures and treatment targets in psoriatic arthritis

Background Many composite disease activity measures and targets have been developed for psoriatic arthritis (PsA). This GRAPPA-OMERACT work stream aimed to further the development of consensus among physicians and patients. Methods Prior to the meeting, physicians and patients were surveyed on outcome measures. A consensus meeting (26 rheumatologists, dermatologists, and patient representatives) reviewed evidence on composite measures and potential treatment targets, plus survey results. After discussions, participants voted on proposals for use and consensus was established in a second survey. Results Survey results from 128 HCPS and 139 patients were analysed alongside a SLR summarising evidence. A weighted vote was cast for composite measures (for RCTs, most popular measures were PASDAS [40 votes] and GRACE [28 votes]; for clinical practice, most popular were 3-VAS [45 votes], DAPSA [26 votes]). After discussion there was no consensus on a composite measure. The group agreed that several composite measures could be used. Future studies should allow further validation and comparison. The group unanimously agreed that remission should be the ideal target with minimal/low disease activity a feasible alternative. The target should include assessment of musculoskeletal disease, skin and health related quality of life. The group recommended a target of treatment as VLDA, or MDA. Conclusions Consensus was not reached on a continuous measure of disease activity. In the interim the group recommends several composites. Consensus was reached on a treatment target of VLDA/MDA. An extensive research agenda was composed and recommends that data on all PsA clinical domains be collected in ongoing studies.</p

Group for Research and Assessment of Psoriasis and Psoriatic Arthritis/Outcome Measures in Rheumatology Consensus-Based Recommendations and Research Agenda for Use of Composite Measures and Treatment Targets in Psoriatic Arthritis

Objective A meeting was convened by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and Outcome Measures in Rheumatology (OMERACT) to further the development of consensus among physicians and patients regarding composite disease activity measures and targets in psoriatic arthritis (PsA). Methods Prior to the meeting, physicians and patients completed surveys on outcome measures. A consensus meeting of 26 rheumatologists, dermatologists, and patient research partners reviewed evidence on composite measures and potential treatment targets plus results of the surveys. The meeting consisted of plenary presentations, breakout sessions, and group discussions. International experts including members of GRAPPA and OMERACT were invited to the meeting, including the developers of all of the measures discussed. After discussions, participants voted on proposals for use, and consensus was established in a second survey. Results Survey results from 128 health care professionals and 139 patients were analyzed alongside a systematic literature review summarizing evidence. A weighted vote was cast for composite measures. For randomized controlled trials, the most popular measures were the PsA disease activity score (40 votes) and the GRAPPA composite index (28 votes). For clinical practice, the most popular measures were an average of scores on 3 visual analog scales (45 votes) and the disease activity in PsA score (26 votes). After discussion, there was no consensus on a composite measure. The group agreed that several composite measures could be used and that future studies should allow further validation and comparison. The group unanimously agreed that remission should be the ideal target, with minimal disease activity (MDA)/low disease activity as a feasible alternative. The target should include assessment of musculoskeletal disease, skin disease, and health‐related quality of life. The group recommended a treatment target of very low disease activity (VLDA) or MDA. Conclusion Consensus was not reached on a continuous measure of disease activity. In the interim, the group recommended several composites. Consensus was reached on a treatment target of VLDA/MDA. An extensive research agenda was composed and recommends that data on all PsA clinical domains be collected in ongoing studies