Treatment decisions in axial spondyloarthritis daily clinical practice are more than treat-to-target.

OBJECTIVE: 'Treat-to-target principles' are advised for axial spondyloarthritis (axSpA), although a clear target is not yet defined and targets do not always reflect inflammation. Treat-to-target use and motives for treatment choices in clinics are unknown. Therefore, we studied the presence of residual disease activity according physician's opinion, patient's opinion and composite indices and compared them to the subsequent treatment decisions. METHODS: This cross-sectional multicentre study included 249 patients with a clinical diagnosis of axSpA ≥6 months. Remission and low disease activity according to the BASDAI (<1.9 and <3.5, respectively) and physician's and patient's opinion were assessed. Questionnaires included patient-reported outcomes and patients and physicians completed questions regarding treatment decisions. RESULTS: A total of 115/249 (46%) patients were in remission according to the physician and 37% (n = 43) of these patients reached remission according to the BASDAI. In 51/83 (60%) of the patients with residual disease activity according to the physician and a BASDAI >3.5 the treatment was left unchanged, either because of low disease activity as rated by the physician [n = 15 (29%)] or because of a combination of low disease activity with non-inflammatory complaints or comorbidities [n = 11 (25%)]. Retrospective treat-to-target evaluations showed that treatments were most frequently intensified in patients with arthritis or inflammatory back pain and less often in patients with other (non-inflammatory) musculoskeletal comorbidities. CONCLUSION: This study shows that physicians do not always strictly apply treat-to-target in case of residual disease activity in axSpA. Usually, they accept low disease activity as satisfactory.

Young-GRAPPA (Y-GRAPPA) at the 2022 GRAPPA Annual Meeting: One Year in Y-GRAPPA. Where Do We Stand, Where Do We Go?

Young-GRAPPA (Y-GRAPPA) was introduced at the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting. Here we present the 1-year progress of Y-GRAPPA and future plans of this enthusiastic group of young clinicians and early career researchers interested in psoriasis and psoriatic arthritis.

Gender equity in academic rheumatology, current status and potential for improvement: a cross-sectional study to inform an EULAR task force.

OBJECTIVES: Evidence on the current status of gender equity in academic rheumatology in Europe and potential for its improvement is limited. The EULAR convened a task force to obtain empirical evidence on the potential unmet need for support of female rheumatologists, health professionals and non-clinical scientists in academic rheumatology. METHODS: This cross-sectional study comprised three web-based surveys conducted in 2020 among: (1) EULAR scientific member society leaders, (2) EULAR and Emerging EULAR Network (EMEUNET) members and (3) EULAR Council members. Statistics were descriptive with significance testing for male/female responses assessed by χ2 test and t-test. RESULTS: Data from EULAR scientific member societies in 13 countries indicated that there were disproportionately fewer women in academic rheumatology than in clinical rheumatology, and they tended to be under-represented in senior academic roles. From 324 responses of EULAR and EMEUNET members (24 countries), we detected no gender differences in leadership aspirations, self-efficacy in career advancement and work-life integration as well as the share of time spent on research, but there were gender differences in working hours and the levels of perceived gender discrimination and sexual harassment. There were gender differences in the ranking of 7 of 26 factors impacting career advancement and of 8 of 24 potential interventions to aid career advancement. CONCLUSIONS: There are gender differences in career advancement in academic rheumatology. The study informs a EULAR task force developing a framework of potential interventions to accelerate gender-equitable career advancement in academic rheumatology.

Proceedings of the 2021 GRAPPA-Collaborative Research Network (CRN) Meeting.

At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Collaborative Research Network (CRN) annual meeting, the GRAPPA-CRN group presented a number of project updates, including a pilot investigator-initiated study to evaluate liquid and tissue biomarkers associated with axial involvement in psoriatic arthritis (PsA). The GRAPPA-CRN session updated progress made with 3 parallel international research initiatives based on 3 previously defined unmet needs in PsA. The Health Initiatives in Psoriasis and PsOriatic arthritis ConsoRTium European States (HIPPOCRATES) is a European research consortium formed to address unmet clinical needs in PsA. The Preventing Arthritis in a multicenter Psoriasis At-Risk Population (PAMPA) is a US-based organization that has defined consensus terminology for preclinical phases of PsA and is interested in the transition process from psoriasis to PsA. An overview of the Accelerating Medicines Partnership Autoimmune and Immune-Mediated Diseases (AMP AIM) program 2.0, a consortium including GRAPPA-CRN members that addressed these 3 unmet needs in PsA, was also presented.

Gender equity in academic rheumatology: is there a gender gap at European rheumatology conferences?

OBJECTIVES: To obtain an overview of gender equity at European rheumatology conferences. METHODS: The proportion of women invited as either moderators or speakers to the European Alliance of Associations for Rheumatology (EULAR) annual congresses and national conferences in Europe was calculated from the published congress materials from EULAR annual congresses (2015-2019) and the 2019 national conferences of France, Germany, Italy, Spain and the UK. Data from EULAR congresses were further categorised by type of session. Significance testing was conducted using χ2 tests with the level of statistical significance set at p<0.05. RESULTS: The proportion of combined women moderators and speakers at EULAR varied from 40% to 43% between 2015 and 2019 with no obvious trend over time. There were higher proportions of women in the Health Professionals in Rheumatology and People with Arthritis and Rheumatism sessions (>50% consistently). However, these sessions represent <25% of EULAR congress invitations. Representation of women at the EULAR congress in 2019 (39.6%) was significantly higher than at the national congresses in France (28.6%) and Germany (29.6%) but similar to that observed in Italy (33.7%), Spain (41.7%) and the UK (42%). CONCLUSION: Women account for less than half of invited moderators and speakers at the conferences reviewed. Compared with historical EULAR data in 2003 (16%) and in 2004 (19%), the gender gap at EULAR congresses has narrowed considerably, but there remains a need to monitor and improve women's representation.

Young-GRAPPA at the Annual GRAPPA Meeting: Presentation of a New Group Within GRAPPA and Its Vision.

At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, a separate group was created (Young-GRAPPA) to address the challenges of young researchers and physicians beginning their careers. This paper presents the initial organizational framework and different components and aims of this group. We were able to enroll over 50 young researchers as a result of this meeting.

Proceedings of the 2020 GRAPPA Collaborative Research Network (CRN) Meeting.

At the 2020 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-Collaborative Research Network (CRN) annual meeting, the GRAPPA-CRN group presented a pilot investigator-initiated study protocol to test electronic case report forms (eCRFs) and proposed Standardized Operating Procedures (SOPs) to evaluate biomarkers of psoriatic arthritis (PsA) associated with axial disease. The progress on 3 studies was also presented: BioDAM PsA (Biomarkers as Predictors of structural DAMage in PsA; to validate soluble biomarkers as predictors of structural damage in PsA), PreventPsA (examining the development of PsA and risk factors among patients with psoriasis and no arthritis), and PredictORPsA (Predicting Treatment respOnse in patients with eaRly PsA; in collaboration with Pfizer using samples from the Oral Psoriatic Arthritis TriaL [OPAL], to identify biomarkers of treatment response). GRAPPA-CRN funding partnerships and applications are also underway with both the Innovative Medicines Initiative (IMI) in Europe and Accelerating Medicines Partnerships (AMP) 2.0 in the USA, and the progress of these applications and associated objectives were presented.

IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt.

Background: Psoriatic arthritis (PsA) is a chronic inflammatory joint disease within the spondyloarthritis spectrum. IL-12p40/IL-23p40 blockade reduces PsA disease activity, but its impact on synovial inflammation remains unclear. Objectives: To investigate the cellular and molecular pathways affected by IL-12p40/IL-23p40 blockade with ustekinumab in the synovium of PsA patients. Methods: Eleven PsA patients with at least one inflamed knee or ankle joint were included in a 24-week single-center open-label study and received ustekinumab 45 mg/sc according to standard care at week 0, 4, and 16. Besides clinical outcomes, synovial tissue (ST) samples were obtained by needle arthroscopy from an inflamed knee or ankle joint at baseline, week 12 and 24 and analyzed by immunohistochemistry, RNA-sequencing and real-time quantitative polymerase chain reaction (qPCR). Results: We obtained paired baseline and week 12, and paired baseline, week 12 and 24 ST samples from nine and six patients, respectively. Eight patients completed 24 weeks of clinical follow-up. At 12 weeks 6/11 patients met ACR20, 2/11 met ACR50 and 1/11 met ACR70 improvement criteria, at 24 weeks this was 3/8, 2/8 and 1/8 patients, respectively. Clinical and serological markers improved significantly. No serious adverse events occurred. We observed numerical decreases of all infiltrating cell subtypes at week 12, reaching statistical significance for CD68+ sublining macrophages. For some cell types this was even more pronounced at week 24, but clearly synovial inflammation was incompletely resolved. IL-17A and F, TNF, IL-6, IL-8, and IL-12p40 were not significantly downregulated in qPCR analysis of W12 total biopsies, only MMP3 and IL-23p19 were significantly decreased. RNA-seq analysis revealed 178 significantly differentially expressed genes between baseline and 12 weeks (FDR 0.1). Gene Ontology and KEGG terms enrichment analyses identified overrepresentation of biological processes as response to reactive oxygen species, chemotaxis, migration and angiogenesis as well as MAPK-ERK and PI3K-Akt signaling pathways among the downregulated genes and of Wnt signaling pathway among the upregulated genes. Furthermore, ACR20 responders and non-responders differed strikingly in gene expression profiles in a post-hoc exploratory analysis. Conclusions: Ustekinumab suppresses PsA synovial inflammation through modulation of multiple signal transduction pathways, including MAPK-ERK, Wnt and potentially PI3K-Akt signaling rather than by directly impacting the IL-17 pathway.

Proceedings of the 2020 GRAPPA Collaborative Research Network (CRN) Meeting.

At the 2020 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)- Collaborative Research Network (CRN) annual meeting, the GRAPPA-CRN group presented a pilot investigator-initiated study protocol to test electronic case report forms (eCRFs) and proposed Standardized Operating Procedures (SOPs) to evaluate biomarkers of psoriatic arthritis (PsA) associated with axial disease. The progress on 3 studies was also presented: BioDAM PsA (Biomarkers as Predictors of structural DAMage in PsA; to validate soluble biomarkers as predictors of structural damage in PsA), PreventPsA (examining the development of PsA and risk factors among patients with psoriasis and no arthritis), and PredictORPsA (Predicting Treatment respOnse in patients with eaRly PsA; in collaboration with Pfizer using samples from the Oral Psoriatic Arthritis TriaL [OPAL], to identify biomarkers of treatment response). GRAPPA-CRN funding partnerships and applications are also underway with both the Innovative Medicines Initiative (IMI) in Europe and Accelerating Medicines Partnerships (AMP) 2.0 in the USA, and the progress of these applications and associated objectives were presented.

Performance of composite measures used in a trial of etanercept and methotrexate as monotherapy or in combination in psoriatic arthritis.

OBJECTIVES: To examine which composite measures are most sensitive to change when measuring psoriatic arthritis (PsA) disease activity, analyses compared the responsiveness of composite measures used in a 48-week randomized, controlled trial of MTX and etanercept in patients with PsA. METHODS: The trial randomised 851 patients to receive weekly: MTX (20 mg/week), etanercept (50 mg/week) or MTX plus etanercept. Dichotomous composite measures examined included ACR 20/50/70 responses, minimal disease activity (MDA) and very low disease activity (VLDA). Continuous composite measures examined included Disease Activity Score (28 joints) using CRP (DAS28-CRP), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), Disease Activity for Psoriatic Arthritis (DAPSA) and Psoriatic Arthritis Disease Activity Score (PASDAS). RESULTS: At week 24, etanercept-treated groups were significantly more effective than MTX monotherapy to achieve ACR 20 (primary end point) and MDA (key secondary end point). When examining score changes from baseline at week 24 across the five continuous composite measures, PASDAS demonstrated relatively greater changes in the etanercept-treated groups compared with MTX monotherapy and had the largest effect size and standardized response. Joint count changes drove overall score changes at week 24 from baseline in all the continuous composite measures except for PASDAS, which was driven by the Physician and Patient Global Assessments. CONCLUSION: PASDAS was the most sensitive continuous composite measure examined with results that mirrored the protocol-defined primary and key secondary outcomes. Composite measures with multiple domains, such as PASDAS, may better quantify change in PsA disease burden. TRAIL REGISTRATION: https://ClinicalTrials.gov, number NCT02376790.

Anti-IL-17A treatment reduces serum inflammatory, angiogenic and tissue remodeling biomarkers accompanied by less synovial high endothelial venules in peripheral spondyloarthritis.

Spondyloarthritis (SpA) is characterized by inflammation and new bone formation. The exact pathophysiology underlying these processes remains elusive. We propose that the extensive neoangiogenesis in SpA could play a role both in sustaining/enhancing inflammation and in new bone formation. While ample data is available on effects of anti-TNF on angiogenesis, effects of IL-17A blockade on serum markers are largely unknown. We aimed to assess the impact of secukinumab (anti-IL-17A) on synovial neoangiogenesis in peripheral SpA, and how this related to changes in inflammatory and tissue remodeling biomarkers. Serum samples from 20 active peripheral SpA patients included in a 12 week open-label trial with secukinumab were analyzed for several markers of angiogenesis and tissue remodeling. Synovial biopsies taken before and after treatment were stained for vascular markers. Serum levels of MMP-3, osteopontin, IL-6 (all P < 0.001), IL-31, S100A8, S100A9, Vascular Endothelial Growth Factor A (VEGF-A), IL-33, TNF-α (all P < 0.05) decreased significantly upon anti-IL17A treatment. Secukinumab treatment resulted in a decrease in the number of synovial high endothelial venules and lymphoid aggregate score. These results indicate that anti-IL-17A not only diminishes inflammation, but also impacts angiogenesis and tissue remodeling/new bone formation. This may have important implications for disease progression and/or structural damage.

GRAPPA Trainees Symposium 2019: A Report from the GRAPPA 2019 Annual Meeting.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held a trainees symposium at its 2019 annual meeting in Paris, France. Rheumatology and dermatology trainees engaged in psoriasis or psoriatic arthritis research presented their work. This report briefly reviews 5 oral presentations and 19 posters presented at the meeting.

Proceedings of the 2019 GRAPPA Collaborative Research Network Meeting.

At the 2019 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis-Collaborative Research Network annual meeting, the group presented its progress in selecting a database platform; items to include in an electronic case report form (eCRF); and standardized operating procedures (SOP) for the collection, processing, storage, and transport of biomaterial. A pilot investigator-initiated study was also proposed that, in addition to addressing an area of unmet need, would allow for the testing of both the eCRF and SOP.

Interleukin 17A and IL-17F Expression and Functional Responses in Rheumatoid Arthritis and Peripheral Spondyloarthritis.

OBJECTIVE: Targeting the interleukin 17 (IL-17) axis is efficacious in psoriasis and spondyloarthritis (SpA), but not in rheumatoid arthritis (RA). We investigated potential differences in tissue expression and function of IL-17A and IL-17F in these conditions. METHODS: mRNA expression of cytokines and their receptors was assessed by quantitative PCR in psoriasis skin samples, in SpA and RA synovial tissue (ST) samples and in fibroblast-like synoviocytes (FLS). Cytokines were measured in synovial fluid (SF) and FLS supernatants by ELISA. FLS were stimulated with IL-17A or IL-17F cytokines supplemented with tumor necrosis factor (TNF), or with pooled SF from patients with SpA or RA. RESULTS: Levels of IL-17A (P = 0.031) and IL-17F (P = 0.017) mRNA were lower in psoriatic arthritis ST compared to paired psoriasis skin samples. The level of IL-17A mRNA was 2.7-fold lower than that of IL-17F in skin (P = 0.0078), but 17.3-fold higher in ST (P < 0.0001). In SF, the level of IL-17A protein was 37.4-fold higher than that of IL-17F [median 292.4 (IQR 81.4-464.2) vs median 7.8 (IQR 7.7-8.7) pg/mL; P < 0.0001]. IL-17A and IL-17F mRNA and protein levels did not differ in SpA compared to RA synovitis samples, and neither were the IL-17 receptors IL-17RA and IL-17RC, or the TNF receptors TNFR1 and TNR2, differentially expressed between SpA and RA ST, nor between SpA and RA FLS. SpA and RA FLS produced similar amounts of IL-6 and IL-8 protein upon stimulation with IL-17A or IL-17F cytokines, supplemented with 1 ng/ml TNF. Pooled SpA or RA SF samples similarly enhanced the inflammatory response to IL-17A and IL-17F simulation in FLS. CONCLUSION: The IL-17A/IL-17F expression ratio is higher in SpA synovitis compared to psoriasis skin. Expression of IL-17A and IL-17F, and the functional response to these cytokines, appear to be similar in SpA and RA synovitis.

Sustained remission with methotrexate monotherapy after 22-week induction treatment with TNF-alpha inhibitor and methotrexate in early psoriatic arthritis: an open-label extension of a randomized placebo-controlled trial.

BACKGROUND: If TNF inhibitors are initiated in the early stages of psoriatic arthritis, this could potentially modulate disease and therefore allow us to discontinue the TNF inhibitor after achieving remission. OBJECTIVE: To investigate whether remission induced by tumour necrosis factor alpha inhibitor (TNFi) and methotrexate in patients with early psoriatic arthritis is sustained after withdrawal of TNFi. METHODS: Open-label extension of a recently published double-blind, randomized placebo-controlled trial. Patients with psoriatic arthritis fulfilling the CASPAR criteria and with active disease at baseline (swollen and tender joint count ≥ 3) were randomized to either golimumab and methotrexate or matched placebo and methotrexate. Patients in Disease Activity Score (DAS) remission at week 22 continued in the open-label extension on methotrexate monotherapy. The primary end point was the percentage of patients in DAS-CRP remission (DAS < 1.6) at week 50. RESULTS: Eight patients from the original placebo group and 18 patients from the original TNFi group continued in the extension phase. At week 50, 6 out of 8 (75%) patients from the original MTX (methotrexate) group versus 10 out of 18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission (p = 0.347). Considering the total study population, 6 out of 24 (25%) of the original MTX group versus 10 out of 26 (38.5%) of the original MTX+TNFi group were in DAS remission at week 50 (p = 0.308). CONCLUSIONS: Remission achieved by initial combination treatment with TNFi and methotrexate in early psoriatic arthritis is maintained on methotrexate monotherapy in approximately half of the patients. TRIAL REGISTRATION: Registered at Clinicaltrials.gov with number NCT01871649 on June 7, 2013.

Achieving remission in psoriatic arthritis by early initiation of TNF inhibition: a double-blind, randomised, placebo-controlled trial of golimumab plus methotrexate versus placebo plus methotrexate.

OBJECTIVES: Early initiation of effective treatment favours remission in rheumatoid arthritis, but it remains unknown if the same concept applies to psoriatic arthritis (PsA). Therefore, this study investigated whether the combination of golimumab plus methotrexate (MTX) as a first-line treatment is superior to MTX alone in inducing remission in PsA. METHODS: This investigator-initiated, multicentre, double-blind, randomised, placebo-controlled trial included 51 MTX and bDMARD-naive patients with PsA fulfilling the CASPAR criteria and with active disease at baseline (≥3 swollen joint count/tender joint count). Patients were randomised to golimumab (50 mg SC monthly)+MTX (n=26) (TNFi arm) or matched placebo+MTX (n=25) (MTX arm). MTX was started 15 mg/week and increased to 25 mg/week over 8 weeks. The primary endpoint was percentage of patients achieving Disease Activity Score (DAS) remission (<1.6) at week 22. Safety was assessed throughout the study. RESULTS: The primary efficacy endpoint was achieved by 81% in the TNFi arm versus 42 % in the MTX arm (p=0.004). This difference in DAS remission was already observed at week 8. A significant difference in favour of the golimumab+MTX arm at week 22 was also observed for other response criteria such as MDA, ACR20/50/70, disease measures and patient-reported outcomes. The occurrence rates of adverse event and treatment-emergent adverse event were similar in both arms. CONCLUSIONS: In patients with early PsA, DAS remission at week 22 was almost doubled with golimumab+MTX versus MTX alone. This double-blind, randomised, placebo-controlled study supports the concept that early initiation of TNFi in patients with PsA favours remission. TRIAL REGISTRATION NUMBER: NCT01871649.

Histologic evidence that mast cells contribute to local tissue inflammation in peripheral spondyloarthritis by regulating interleukin-17A content.

OBJECTIVES: Synovial mast cells contain IL-17A, a key driver of tissue inflammation in SpA. A recent in vitro study showed that tissue-derived mast cells can capture and release exogenous IL-17A. The present study aimed to investigate if this mechanism could contribute to tissue inflammation in SpA. METHODS: Potential activation of mast cells by IL-17A was assessed by gene expression analysis of the Laboratory of Allergic Diseases 2 (LAD2) mast cell line. The presence of IL-17A-positive mast cells was assessed by immunohistochemistry in synovial tissue obtained before and after secukinumab treatment, as well as in skin and gut tissues from SpA-related conditions. RESULTS: IL-17A did not induce a pro-inflammatory response in human LAD2 mast cells according to the canonical IL-17A signalling pathway. In SpA synovial tissue, the percentage of IL-17A-positive mast cells increased upon treatment with secukinumab. IL-17A-positive mast cells were also readily detectable in non-inflamed barrier tissues such as skin and gut. In non-inflamed dermis and gut submucosa, IL-17A-positive mast cells are the most prevalent IL-17A-positive cells in situ. Compared with non-inflamed tissues, both total mast cells and IL-17A-positive mast cells were increased in psoriatic skin dermis and in submucosa from inflammatory bowel disease gut. In contrast, the proportion of IL-17A-positive mast cells was strikingly lower in the inflamed compared with non-inflamed gut lamina propria. CONCLUSION: IL-17A-positive mast cells are present across SpA target tissues and correlate inversely with inflammation, indicating that their IL-17A content can be regulated. Tissue-resident mast cells may act as IL-17A-loaded sentinel cells, which release IL-17A to amplify tissue inflammation.