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.

Development of a New Referral Tool to Identify Psoriasis Patients with Concomitant Psoriatic Arthritis: Results of the Prospective DAPPER Cohort.

Patients with psoriasis are at risk of developing psoriatic arthritis, which can lead to joint damage. While screening questionnaires have been developed, their performance varies. The objective of this study was to develop a referral tool for dermatologists to identify psoriasis patients with concomitant psoriatic arthritis for rheumatological referral. This study used data from the DAPPER study, in which psoriasis patients were screened by a rheumatologist for the presence of concomitant psoriatic arthritis. Multivariable regression analysis was used to identify predictive variables for the presence of concomitant psoriatic arthritis: treatment history with conventional systemic drugs (odds ratio (OR) 2.97, 95% confidence interval (95% CI) 1.01-8.74, p = 0.04), treatment history with biologicals/small molecule inhibitors (OR 2.90, 95% CI 1.52-5.53, p = 0.01), patient-reported history of joint pain not caused by trauma (OR 4.23, 95% CI 1.21-14.79, p = 0.01), patient-reported history of swollen joints (OR 4.25, 95% CI 2.17-8.32, p < 0.001), and patient-reported history of sausage-like swollen digits (OR 2.38, 95% CI 1.25-4.55, p = 0.01). Based on these variables, a referral tool was created with an area under the curve of 0.82. This referral tool could be used to aid dermatologists to identify psoriasis patients with concomitant psoriatic arthritis, who may benefit from rheumatological referral.

Determinants of work and social participation in patients with psoriatic arthritis in the Netherlands: an observational study.

BACKGROUND: Psoriatic arthritis can cause pain, disability, and permanent joint damage. This can lead to impairments in work and social participation. Little is known about the extent of these impairments in routine practice. With this study, we aim to examine the extent of work and activity impairment in (subgroups of) Dutch patients with psoriatic arthritis (PsA), and to examine determinants associated with this impairment. METHODS: This is an observational study using data collected from the electronic health records of PsA patients treated at the Sint Maartenskliniek, the Netherlands. Data about work and activity impairment were collected via the Work Productivity and Activity Impairment questionnaire. To compare our PsA-cohort with the Dutch general population, we used age- and sex-matched data derived from the Central Bureau of Statistics. Regression analyses were performed to examine determinants of work and activity impairment. RESULTS: In total, 246 patients were included, of which 126 (51.2%) were female. Mean age (S.D.) was 55.7 (13.2) years. Compared with the Dutch general population, work for pay (WFP) was significantly lower in PsA (52.9% versus 62.6%, P < 0.001). In PsA, younger age and better physical function were associated with WFP status (P < 0.05). Higher disease activity, worse physical function, and worse mental health-related quality of life were associated with both more work and activity impairment (P < 0.05). Furthermore, reaching low disease activity status (LDA) according to Psoriatic ArthritiS Disease Activity Score (PASDAS; ≤ 3.2) was associated with less work and activity impairment than reaching LDA according to DAS28-CRP (≤ 2.9) (P < 0.05). CONCLUSIONS: In PsA patients, worse physical function was associated with a lower likelihood of having WFP, and higher work and activity impairment. PASDAS LDA as a goal for treat to target, compared to DAS28-CRP, appears to favour the reduction of work and activity impairment.

Discovery of Psoriatic Arthritis in Psoriasis Patients for Early Rheumatological Referral (DAPPER) Study: A Prospective Observational Cohort.

Patients with psoriasis are at risk of developing psoriatic arthritis, which can lead to irreversible joint damage. However, a proportion of patients with psoriasis and concomitant psoriatic arthritis remain undiscovered in practice. The aims of this study were: to prospectively determine prevalence, characteristics, and disease burden of psoriatic arthritis in a psoriasis population; and to determine the prevalence and characteristics of patients with active psoriatic arthritis, who were not under rheumatological care. Patients with psoriasis were screened by a rheumatologist at the dermatology outpatient clinic for psoriatic arthritis. Patients with suspected active psoriatic arthritis who were not seeing a rheumatologist were referred to a rheumatologist for confirmation. The total prevalence of psoriatic arthritis in this observational, prospective cohort (n = 303) was 24%. Patients with psoriasis with concomitant psoriatic arthritis had longer duration of skin disease and more often a treatment history with systemic therapies. In this academic, specialized, setting, 2.3% of patients (n = 7), were not receiving rheumatological care despite having active psoriatic arthritis. These patients were characterized by a combination of low (perceived) disease burden and low yield of screening questionnaires, making it difficult for dermatologists to discover psoriatic arthritis in these patients. Thus, screening for more subtle active arthritis in patients with psoriasis in a dermatology setting could be improved.

Defining the minimal important change (MIC) and meaningful change value (MCV) for the Psoriatic Arthritis Disease Activity Score (PASDAS) in a routine practice cohort of patients with psoriatic arthritis.

OBJECTIVE: The aim of the study was to determine the Minimal Important Change (MIC) values and Meaningful Change (MCV) values for the Psoriatic Arthritis Disease Activity Score (PASDAS) and the Standard Error of Measurement (s.e.m.) of the PASDAS. METHODS: The routine practice data for 544 patients with PsA was available for analysis. An anchor-based method using linear regression analyses was used to determine the MICs and MCVs for the PASDAS. With this anchor-based method, we compared changes in the PASDAS score with an external reference (anchor). The anchor question inquired whether the patient's well-being had changed since their previous visit. It consisted of a 7-point Likert scale (range: very much improved to very much deteriorated). Interperiod correlation matrix analysis was performed to determine the s.e.m. RESULTS: The overall MIC and MCV for the PASDAS were 0.67 (95% CI: 0.55, 0.79) and 1.34 (95% CI: 1.21, 1.46), respectively. Results for improvement and deterioration were 0.65 (95% CI: 0.46, 0.83) and 0.71 (95% CI: 0.49, 0.93) for the MIC, respectively, and 1.29 (95% CI: 1.11, 1.48) and 1.42 (95% CI: 1.19, 1.64) for the MCV, respectively. The s.e.m. was determined at 0.81. CONCLUSION: The MIC for the PASDAS is a tool for physicians treating patients with PsA enabling them to give context to the patient's perspective of disease activity, while the MCV might aid the use of the PASDAS in PsA clinical trials.

Being overweight is associated with not reaching low disease activity in women but not men with psoriatic arthritis.

OBJECTIVE: To assess sex differences in disease activity parameters and health-related quality of life in PsA, and to assess whether determinants associated with not reaching treatment target differed between men and women. METHODS: Routine practice data of 855 PsA patients, who were all tightly monitored and treated, was used. Sex differences including, but not limited to, PsA Disease Activity Score (PASDAS), skin/nail disease, SF-12 PCS/MCS, and inflammatory back pain (IBP) were assessed. Multivariate analyses were used to examine determinants associated with not reaching treatment target (PASDAS ≤ 3.2) in men and women. RESULTS: Women had worse scores for-among others-swollen and tender joints, CRP, enthesitis and function (all P < 0.001). Higher PASDAS scores were found for women [3.5 (1.5)] than men [2.7 (1.5), P < 0.001]. Likewise, women were more often not at PASDAS treatment target (OR = 2.03, P < 0.001). No difference in current medication use was found. Nail disease, IBP, number of DMARDs used (past and current), and BMI were associated with not reaching treatment target in the overall sample. For women, but not men, BMI was associated with not reaching PASDAS low disease activity (LDA) (OR between 2.41 and 3.43, P < 0.001). CONCLUSIONS: Women with PsA in a tightly monitored and treated setting have more severe disease than men. This is demonstrated by worse scores for women in both subjective and objective disease activity measures, in addition to women less often reaching the treatment target. Notably, being overweight is associated with higher disease activity in women, but not men.

Tumour necrosis factor inhibitor dose adaptation in psoriatic arthritis and axial spondyloarthritis (TAPAS): a retrospective cohort study.

OBJECTIVES: We investigated the effect of disease activity-guided dose optimization (DAGDO) of TNF inhibitor (TNFi) on disease activity and TNFi dose in PsA and axial spondyloarthritis (axSpA) patients with low disease activity (LDA). METHODS: A retrospective cohort study was conducted in PsA and axSpA patients doing well on TNFi and eligible for TNFi DAGDO. Three different treatment periods were defined: (i) full dose continuation period, (ii) TNFi DAGDO period, and (iii) period with stable TNFi dose after DAGDO. A mixed-model analysis was used to estimate mean Disease Activity Score 28-joint count CRP (DAS28-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) during these periods, and a mean percentage of the daily defined dose (%DDD) was calculated as secondary outcome. RESULTS: Three hundred and twenty-four patients (153 PsA and 171 axSpA) were included, with a mean of 6.5 DAS28-CRP and 6.4 BASDAI measurements and a median follow-up duration of 46 and 44 months, respectively. A corrected difference of 0.06 (95% CI: -0.09, 0.21) in mean DAS28-CRP was found for the TNFi DAGDO period and 0.03 (95% CI: -0.14, 0.20) for the period with stable TNFi dose, compared with full dose continuation period. Differences for BASDAI were 0.03 (95% CI: -0.21, 0.27) and 0.05 (95% CI: -0.24, 0.34), respectively. The mean %DDD for the three treatment periods was for PsA 108%, 62% and 78%, and for axSpA 108%, 62% and 72%, respectively. CONCLUSION: DAGDO of TNFi reduces drug exposure and has no negative effects on disease activity in PsA and axSpA patients compared with full dose continuation.

Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis (COMPLETE-PsA): a double-blind, placebo-controlled, randomised, trial.

BACKGROUND: Conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) are the preferred first-line treatment in patients with psoriatic arthritis, although there is a paucity of evidence for the efficacy of conventional synthetic DMARDs and especially their combination. We aimed to investigate whether a combination of methotrexate plus leflunomide is superior to methotrexate monotherapy at improving disease activity in patients with psoriatic arthritis. METHODS: This single centre, investigator-initiated, double-blind, randomised, placebo-controlled trial was conducted at Sint Maartenskliniek in the Netherlands (locations included Boxmeer, Geldrop, Woerden, and Nijmegen). Patients aged 16 years or older with a clinical diagnosis of psoriatic arthritis and active disease (defined as two or more swollen joints; dactylitis counting as one swollen joint) were included. Patients were randomly allocated (1:1) and stratified by high disease activity (psoriatic arthritis disease activity score [PASDAS] ≥5·4) to either methotrexate plus leflunomide (combination therapy) or methotrexate plus placebo (monotherapy), using computer-generated stratified variable block randomisation. In both groups, patients received oral methotrexate 15 mg per week for the first 4 weeks and 25 mg per week thereafter combined with two leflunomide 10 mg tablets once per day or two placebo tablets. During the study period, the patients, nurses, researchers, and treating physicians were all masked to treatment allocation. The primary outcome was the difference in mean PASDAS at week 16, adjusted for baseline PASDAS, between the combination and monotherapy groups, assessed in the intention-to-treat population. This trial was registered with the Netherlands Trial Register (NL7404) on Dec 3, 2018. FINDINGS: Between Feb 19, 2019, and March 11, 2021, 82 patients were screened for eligibility. Four patients were ineligible and 78 were enrolled and randomly assigned to either methotrexate plus leflunomide (n=39) or methotrexate plus placebo (n=39). 50 (64%) of 78 patients were male, 28 (36%) were female, and the median age of patients was 55·0 years (IQR 42·0-64·0). Methotrexate plus leflunomide combination therapy was superior to methotrexate monotherapy at week 16 (PASDAS 3·1 [SD 1·4] vs 3·7 [SD 1·3]; treatment difference -0·6, 90% CI -1·0 to -0·1; p=0·025). There were no study deaths. The most frequently occurring adverse events were nausea or vomiting (17 [44%] of 39 patients in the methotrexate plus leflunomide group vs 11 [28%] of 39 in the methotrexate plus placebo group), tiredness (9 [23%] vs 13 [33%]) and elevated alanine aminotransferase (12 [31%] vs 7 [18%]. Generally, the incidence of mostly mild adverse events was higher in the methotrexate plus leflunomide group than in the methotrexate plus placebo group. INTERPRETATION: Methotrexate plus leflunomide combination therapy results in greater improvement in disease activity according to PASDAS in patients with psoriatic arthritis. However, methotrexate plus leflunomide combination therapy is less well tolerated than methotrexate monotherapy. FUNDING: Regional Junior Researcher Grant from the Sint Maartenskliniek.

Blood-Based Immune Profiling Combined with Machine Learning Discriminates Psoriatic Arthritis from Psoriasis Patients.

Psoriasis (Pso) is a chronic inflammatory skin disease, and up to 30% of Pso patients develop psoriatic arthritis (PsA), which can lead to irreversible joint damage. Early detection of PsA in Pso patients is crucial for timely treatment but difficult for dermatologists to implement. We, therefore, aimed to find disease-specific immune profiles, discriminating Pso from PsA patients, possibly facilitating the correct identification of Pso patients in need of referral to a rheumatology clinic. The phenotypes of peripheral blood immune cells of consecutive Pso and PsA patients were analyzed, and disease-specific immune profiles were identified via a machine learning approach. This approach resulted in a random forest classification model capable of distinguishing PsA from Pso (mean AUC = 0.95). Key PsA-classifying cell subsets selected included increased proportions of differentiated CD4+CD196+CD183-CD194+ and CD4+CD196-CD183-CD194+ T-cells and reduced proportions of CD196+ and CD197+ monocytes, memory CD4+ and CD8+ T-cell subsets and CD4+ regulatory T-cells. Within PsA, joint scores showed an association with memory CD8+CD45RA-CD197- effector T-cells and CD197+ monocytes. To conclude, through the integration of in-depth flow cytometry and machine learning, we identified an immune cell profile discriminating PsA from Pso. This immune profile may aid in timely diagnosing PsA in Pso.

Clinical, laboratory, and genetic markers for the development or presence of psoriatic arthritis in psoriasis patients: a systematic review.

Twenty to thirty percent of psoriasis (Pso) patients will develop psoriatic arthritis (PsA). Detection of Pso patients that are (at risk for) developing PsA is essential to prevent structural damage. We conducted a systematic search of five bibliographic databases, up to May 2020. We searched for studies assessing markers (clinical, laboratory, genetic) associated with the development or presence of PsA in Pso patients. Study selection and quality assessment of the included studies was performed, followed by a qualitative best evidence synthesis to determine the level of evidence for a marker and its association with concomitant/developing PsA in Pso. Overall, 259 possible markers were identified in 119 studies that met the inclusion criteria. Laboratory markers related to inflammation and bone metabolism reached a strong level of evidence for the association (not prediction) of PsA in Pso. Only CXCL10 showed strong evidence for a positive predictive value for PsA in Pso. The importance of timely detecting PsA in a Pso population, and finding more (bio)markers contributing to early detection, remains high.

GRAPPA Trainee Symposium 2020: A Summary of Oral and Poster Presentations.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held a trainee symposium at its 2020 virtual meeting. Dermatology and rheumatology trainees presented their work on psoriasis and psoriatic arthritis. This report briefly reviews the 5 oral presentations and 25 posters presented at the event.

GRAPPA Trainee Symposium 2020: A Summary of Oral and Poster Presentations.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) held a trainee symposium at its 2020 virtual meeting. Dermatology and rheumatology trainees presented their work on psoriasis and psoriatic arthritis. This report briefly reviews the 5 oral presentations and 25 posters presented at the event.

Measuring disease activity in psoriatic arthritis: PASDAS implementation in a tightly monitored cohort reveals residual disease burden.

OBJECTIVES: We aimed to investigate the disease activity and overall disease burden of (subgroups of) patients with PsA using the Psoriatic Arthritis Disease Activity Score (PASDAS) in an already tightly monitored cohort. METHODS: This is a cross-sectional study evaluating data from the first visit of 855 PsA patients after implementation of the PASDAS in our tightly monitored cohort [e.g. DAS 28 (DAS28) was provided as an anchor]. Differences in clinical outcomes between subgroups of patients using established cut-offs for disease activity status [i.e. very low (VLDA), low (LDA), moderate (MDA), and high disease activity (HDA)] were examined. RESULTS: Based on the PASDAS, 53.1% of patients were in VLDA/LDA. 29.5% of patients had ≥1 swollen joint, 20.6% had ≥1 enthesitis index point and 3.0% had active dactylitis. Based on DAS28, 77.5% of the patients were in VLDA/LDA. Patients reaching both DAS28 VLDA/LDA status and PASDAS VLDA/LDA status [N = 445 (52.0%)] were compared with patients reaching only DAS28 VLDA/LDA status [N = 218 (25.5%)]. For these latter patients, significantly worse scores on separate parameters were found in measures used for PASDAS/DAS28 calculation (e.g. swollen and tender joint count and patient's visual analogue scale global disease activity) as well as other disease measures (e.g. function and inflammatory back pain). This result remained, even when the stricter VLDA cut-off was used for the DAS28. CONCLUSION: PASDAS implementation uncovered relevant residual disease activity in a quarter of patients previously assessed as being in DAS28 VLDA/LDA, underscoring the potential value of PASDAS measurements in PsA clinical care.

Comparing methotrexate monotherapy with methotrexate plus leflunomide combination therapy in psoriatic arthritis: protocol of a randomized, placebo-controlled, double-blind clinical trial (COMPLETE-PsA).

BACKGROUND: Both methotrexate (MTX) and leflunomide (LEF) are registered and regularly prescribed as first-line treatments for the use in patients with psoriatic arthritis (PsA) and they are occasionally used in combination. However, evidence about their individual, and especially combined efficacy, in PsA is lacking. The aim of this study is to compare the effectiveness and safety of MTX and LEF combination therapy to MTX monotherapy in patients with PsA. METHODS: COMPLETE-PsA is a randomized, placebo-controlled, double-blind clinical trial. Disease-modifying antirheumatic drug (DMARD)-untreated patients (n = 78) with clinical diagnosis of active (i.e. ≥2 swollen joints) PsA will be randomized 1:1 (stratified for high disease activity, Psoriatic Arthritis Disease Activity Score [PASDAS] ≥ 5.4) to the combination or monotherapy. The intervention group receives MTX 25 mg (oral or subcutaneous) once weekly plus LEF 20 mg daily, and the control group receives the same but with placebo instead of LEF daily. Primary endpoint is between-group difference in PASDAS at 16 weeks, adjusted for baseline PASDAS. Key secondary parameters include between-group comparisons in change in Disease Activity in Psoriatic Arthritis (DAPSA) score, skin score, enthesitis score, dactylitis score, and swollen/tender joint count, as well as the proportion of patients fulfilling minimal disease activity (MDA), American College of Rheumatology (ACR) 20/50/70 response criteria at week 16. Furthermore, safety, function and quality of life (Health Assessment Questionnaire [HAQ], Psoriatic Arthritic Impact of Disease [PSAID], Short Form 12 [SF-12]) will be assessed. DISCUSSION: This is, to our knowledge, the first randomized, placebo-controlled, double-blind clinical trial assessing the effectiveness of MTX and LEF combination therapy in patients with PsA. The study will provide important information for treatment strategies and treatment recommendations. TRIAL REGISTRATION: Dutch Trial Register NTR7632 (3 December 2018). CMO NL66544.091.18 (19 November 2018).

Dose reduction and withdrawal strategy for TNF-inhibitors in psoriatic arthritis and axial spondyloarthritis: design of a pragmatic open-label, randomised, non-inferiority trial.

BACKGROUND: Tumour necrosis factor inhibitors (TNFi) are effective in the treatment of patients with spondyloarthritis (SpA), including psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA). However, these drugs come with some disadvantages such as adverse events, practical burden for patients and high costs. Dose optimisation of TNFi after patients have reached low disease activity (LDA) has been shown feasible and safe in rheumatoid arthritis (RA). However, data on TNFi dose optimisation in PsA and axSpA are scarce, especially pragmatic, randomised strategy studies. METHODS: We developed an investigator-driven, pragmatic, open-label, randomised, controlled, non-inferiority trial (DRESS-PS) to compare the effects of a disease activity-guided treat-to-target strategy with or without a tapering attempt in patients with SpA (PsA and axSpA combined), ≥ 16 years of age, who are being treated with TNFi, and have had at least 6 months of low disease activity. The primary outcome is the percentage of patients in LDA after 12 months of follow up. Patients are assessed at baseline, 3, 6, 9, and 12 months of follow up. Bayesian power analyses with a weakened prior based on a similar study performed in RA resulted in a sample size of 95 patients in total. DISCUSSION: More knowledge on disease activity-guided treatment algorithms would contribute to better treatment choices and cost savings and potentially decrease the risk of side effects. In this article we elucidate some of our design choices on TNFi dose optimisation and its clinical and methodological consequences. TRIAL REGISTRATION: Dutch Trial Register, NL6771. Registered on 27 November 2018 (CMO NL66181.091.18, 23 October 2018).

Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food-borne bacterial pathogens.

Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron-deficient, normal iron, or high iron diets and after 2 weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron- and infection-induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin-2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron-deficient diet after infection. Next, mice on the iron-deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host-pathogen interface may highly depend on host iron status, immune status, and gut microbiota composition.