Tolerability of low to moderate biomechanical stress during leisure sport activity in patients with psoriasis and psoriatic arthritis.

OBJECTIVES: To assess the impact of low to moderate biomechanical stress on entheses in patients with psoriasis and psoriatic arthritis (PsA). METHODS: We conducted a prospective interventional study on a cohort of psoriasis and PsA patients who underwent a 60 min badminton training session. Pain assessment by Visual Analogue Scale (VAS), physical examination of 29 entheses (SPARCC, LEI, MASES) and bilateral ultrasound at the lateral humeral epicondyle, inferior patellar pole and Achilles tendon were performed before and after training. Ultrasound changes were assessed using the OMERACT scoring system. A follow-up assessment of pain and adverse events was performed at 1 week. RESULTS: Sixteen patients were included (n=7 PsA; n=9 psoriasis) and 196 entheseal ultrasound scans were acquired. At baseline, median VAS pain (IQR) was 0.5 cm (0-2.3) and the total number of tender entheses was 12/464. Mean (min; max) Disease Activity Index for Psoriatic Arthritis was 6.1 (0.8; 19) and 5/7 PsA patients had an Minimal Disease Activity status. After training, no significant change in VAS pain (0.0 cm (0.0-2.0)) nor in tender entheses (13/464) emerged. Four patients (n=2 PsA, n=2 psoriasis) developed a grade-1 power Doppler-signal at six entheses, which, however, remained non-tender. At 1 week, median VAS pain remained stable (0.0 cm (0.0-3.0); p>0.05) and only one participant with active PsA at baseline reported increased arthralgias in three joints. CONCLUSIONS: Low to moderate physical strain, as in the context of leisure sport activity, seems well tolerated in psoriatic patients without increases in tenderness, pain and ultrasound-proven inflammation. Evidence-based recommendations for physical activity in PsA are direly needed and larger controlled studies should be conducted to define safe exercise thresholds.

An international multi-centre analysis of current prescribing practices and shared decision-making in psoriatic arthritis.

OBJECTIVES: Shared decision-making (SDM) is advocated to improve patient outcomes in Psoriatic arthritis (PsA). We analysed current prescribing practices and the extent of SDM in PsA across Europe. METHODS: The ASSIST study was a cross-sectional observational study of PsA patients aged ≥18 years attending face-to-face appointments between July 2021-March 2022. Patient demographics, current treatment and treatment decisions were recorded. SDM was measured by the clinician's effort to collaborate (CollaboRATE questionnaire) and patient communication confidence (PEPPI-5 tool). RESULTS: 503 patients were included from 24 centres across the UK, France, Germany, Italy and Spain. Physician- and patient-reported measures of disease activity were highest in the UK. Conventional synthetic DMARDs constituted a higher percentage of current PsA treatment in UK than continental Europe (66.4% vs 44.9%), which differed from biologic DMARDs (36.4% vs 64.4%). Implementing treatment escalation was most common in the UK. CollaboRATE and PEPPI-5 scores were high across centres. Of 31 patients with low CollaboRATE scores (<4.5), no patients with low PsAID-12 scores (<5) had treatment escalation. However, of 465 patients with CollaboRATE scores ≥4.5, 59 patients with low PsAID-12 scores received treatment escalation. CONCLUSIONS: Higher rates of treatment escalation seen in the UK may be explained by higher disease activity and a younger cohort. High levels of collaboration in face-to-face PsA consultations suggests effective implementation of the SDM approach. Our data indicate that, in patients with mild disease activity, only those with higher perceived collaboration underwent treatment escalation. Prospective studies should examine the impact of SDM on PsA patient outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT05171270.

Treatment with Upadacitinib in Active Psoriatic Arthritis: Efficacy and Safety Data of the First 192 Patients from the UPJOINT Study, a Multicentre, Observational Study in Clinical Practice.

INTRODUCTION: Our aim was to investigate the efficacy and safety of upadacitinib (UPA) in patients with either oligo- or polyarticular active psoriatic arthritis (PsA) using routine clinical practice data from an observational, prospective, multicentre study. METHODS: This interim analysis contains upadacitinib efficacy and safety data from the UPJOINT study, collected from baseline to the week 24 visit with a focus on composite measures, clinical assessments and patient-reported outcomes, amongst others, including minimal disease activity (MDA), very low disease activity (VLDA), Disease Activity Index for Psoriatic Arthritis (DAPSA), Leeds Enthesitis Index (LEI), resolution of dactylitis and nail psoriasis and body surface area affected by skin psoriasis (BSA). RESULTS: A total of 296 patients with baseline data and 192 with completed week 24 visits were included in the analysis. The proportion of patients achieving MDA increased from 2.7% at baseline to 39.1% at week 24 (95% CI 32.1, 46.3). Similarly, the number of patients in DAPSA remission (DAPSA ≤ 4) increased from 0 at baseline to 32 (16.7%) by week 24. At that time, 59.4% of the patients were either in DAPSA remission or had low disease activity (DAPSA ≤ 14). During the 24 weeks time frame, the proportion of patients with BSA ≤ 3 increased from 80.7% to 91.1%. Furthermore, at weeks 12 and 24, 45.14% and 47.19% of affected patients showed a resolution of enthesitis. Active dactylitis and nail psoriasis at baseline were reported to affect 10.5% and 22.0%, decreasing to 2.6% and 5.7% at week 24, respectively. The safety findings are consistent with the known safety profile of upadacitinib in rheumatoid arthritis and PsA; no new safety risks were identified. CONCLUSION: The data from this study confirm the findings of previous randomized controlled trials suggesting UPA is an effective treatment for active PsA without any new safety signals in patients from daily clinical practice. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04758117.

Upadacitinib is an antirheumatic medical therapy approved for treating psoriatic arthritis with insufficient response to previous conventional or biological therapies (DMARD-IR). Psoriatic arthritis is a chronic inflammatory disease affecting the joints, spine, tendons/entheses, skin, nails and other parts of the musculoskeletal system. Early diagnosis and treatment initiation are essential for patients with psoriatic arthritis given the potentially irreversible damage to joints, spine, and entheses and the considerable impact on quality of life. The results presented in this manuscript help clinicians evaluate whether the efficacy and the safety profile of upadacitinib found in previous clinical trials can be reproduced in patients seen in daily clinical practice. This analysis presents descriptive data on the real-world efficacy and safety of upadacitinib, measured by clinical and patient-reported outcomes assessed in four visits over 24 weeks. In summary, our findings confirm the results of previous clinical trials showing that upadacitinib effectively reduces symptom severity of PsA and substantially increases the proportion of patients achieving treatment goals relevant to clinical practice, such as remission or very low disease activity. In addition, safety data were consistent with previous studies of upadacitinib in rheumatoid arthritis or psoriatic arthritis; no new risks to the patients' safety were identified.

Enhancing student understanding of rheumatic disease pathologies through augmented reality: findings from a multicentre trial.

OBJECTIVE: The possibility of combining real and virtual environments is driving the increased use of augmented reality (AR) in education, including medical training. The aim of this multicentre study was to evaluate the students' perspective on the AR-based Rheumality GO!® app as a new teaching concept, presenting six real anonymised patient cases with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA). METHODS: The study encompassed 347 undergraduate medical students (232 women and 115 men) from four medical universities in Germany (Jena, Bad Nauheim/Gießen, Nuremberg, Erlangen). The course was divided into a theoretical refresher lecture followed by six AR-based cases in each of the three indications presented in the Rheumality GO!® app. All participants evaluated the course after completion, assessing the benefit of the app from a student´s perspective using a questionnaire with 16 questions covering six subject areas. RESULTS: The use of the AR-based app Rheumality GO!® improved the understanding of pathologies in RA, PsA, and axSpA for 99% of the participants. For 98% of respondents, the concept of AR with real patient data has made a positive impact on the teaching environment. On the other hand, 82% were in favour of the use of virtual tools (e.g. AR) in addition to this conventional approach. CONCLUSION: The results of our survey showed that from medical students' perspective, an AR-based concept like the Rheumality GO!® app can complement rheumatology teaching in medical school as an effective and attractive tool though not replace bedside teaching.

Association of Structural Entheseal Lesions With an Increased Risk of Progression From Psoriasis to Psoriatic Arthritis.

OBJECTIVE: To test whether the presence of structural entheseal lesions in psoriasis patients influences the risk of progression to psoriatic arthritis (PsA). METHODS: We conducted a prospective cohort study of psoriasis patients without clinical evidence of musculoskeletal involvement who underwent baseline assessment of structural entheseal lesions and volumetric bone mineral density (vBMD) at entheseal and intraarticular sites by high-resolution peripheral quantitative computed tomography. Adjusted relative risks of developing PsA associated with baseline vBMD and the presence of structural entheseal lesions were calculated using multivariable Cox regression models. RESULTS: The cohort included 114 psoriasis patients (72 men and 42 women) with a mean ± SD follow-up duration of 28.2 ± 17.7 months, during which 24 patients developed PsA (9.7 per 100 patient-years [95% confidence interval (95% CI) 6.2-14.5]). Patients with structural entheseal lesions were at higher risk of developing PsA compared to patients without such lesions (21.4 per 100 patient-years [95% CI 12.5-34.3]; hazard ratio [HR] 5.10 [95% CI 1.53-16.99], P = 0.008). With respect to vBMD, a 1-SD increase in entheseal, but not intraarticular, vBMD was associated with an ~30% reduced risk of progression to PsA. Especially, higher cortical vBMD at entheseal segments was associated with a lower risk of developing PsA (HR 0.32 per 1 SD [95% CI 0.14-0.71]), and the association remained robust after multiple imputation of missing data (HR 0.64 [95% CI 0.42-0.98]). CONCLUSION: The presence of structural entheseal lesions as well as low cortical vBMD at entheseal segments are associated with an increased risk of developing PsA in patients with psoriasis.

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort.

OBJECTIVE: To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. RESULTS: In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). CONCLUSION: IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.

Similar Impact of Psoriatic Arthritis and Rheumatoid Arthritis on Objective and Subjective Parameters of Hand Function.

OBJECTIVE: The objective of this study was to compare the impact of psoriatic disease (psoriatic arthritis [PsA] and psoriasis) and rheumatoid arthritis (RA) on objective and subjective parameters of hand function. METHODS: Hand function was determined in this cross-sectional study by 1) vigorimetric grip strength, 2) the Moberg Picking-Up Test used for assessing fine-motor skills, and 3) self-reported hand function (Michigan Hand Questionnaire). Mixed-effects linear regression models were used to test the relation of hand function with disease group, age, and sex. RESULTS: Two hundred ninety-nine subjects were tested, 101 with RA, 92 with PsA, and 106 nonarthritic controls (51 with psoriasis and 55 healthy controls [HCs]). Regression analysis showed that hand function was influenced by age, sex, disease group, and hand dominance (P < 0.001 for all). The impact of PsA and RA on hand function was comparable and generally more pronounced in women. Both PsA and RA led to significantly enhanced age-related loss of grip strength, fine-motor skills, and self-reported hand function in patients with PsA and RA compared with HCs. In addition, patients with psoriasis showed significant impairment of hand function compared with HCs. CONCLUSION: RA and PsA have a comparable impact on the decline of strength, fine-motor skills, and self-reported function of the hand. Unexpectedly, patients with psoriasis also show impaired hand function that follows a similar pattern as observed in patients with PsA.

Secukinumab leads to shifts from stage-based towards response-based disease clusters-comparative data from very early and established psoriatic arthritis.

BACKGROUND: Limited information exists about the very early forms of psoriatic arthritis. In particular, differences and responsiveness of patient-reported outcomes (PROs) in very early as compared to established PsA have not been investigated to date. METHODS: Cross-sectional and prospective longitudinal evaluation of PROs related to pain (VAS), physical function (HAQ-DI, SF-36 physical), mental function (SF-36 mental), impact of psoriatic skin (DLQI), joint (PsAID), and global disease (VAS) in two small prospective observational studies on secukinumab 300 mg over 6 months in very early disease patients (IVEPSA study, N = 20) and established PsA (PSARTROS study, N = 20). Cluster analysis was performed at baseline and 24-weeks of follow-up. RESULTS: While responses in pain and physical activity-related PROs to secukinumab were more pronounced in established PsA than a very early disease, effects on PROs related to general health perception, as well as those related to emotional and mental well-being, were modified in a similar way in very early disease and established PsA. Cluster analysis based on global disease activity and PROs showed that baseline clusters reflected very early disease and established PsA, while after secukinumab treatment these clusters were abolished and new clusters based on differential responses to physically and mentally oriented PROs formed. CONCLUSIONS: Inhibition of IL-17A by secukinumab leads to comprehensive improvement of general health perception and mental well-being in very early and established PsA, while overall responses in pain and physical activity are more pronounced in established disease. Most importantly, treatment restructures the original patients' clusters based on disease stage and leads to the formation of new clusters that reflect their response in physical and mental-orientated PROs. TRIAL REGISTRATION: NCT02483234 , registered 26 June 2015, retrospectively registered.

JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function.

Janus kinase (JAK)-mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of ß-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.

I Would Never Take Preventive Medication! Perspectives and Information Needs of People Who Underwent Predictive Tests for Rheumatoid Arthritis.

OBJECTIVE: Little is known about the experiences, values, and needs of people without arthritis who undergo predictive biomarker testing for the development of rheumatoid arthritis (RA). Our study aimed to explore the perspectives of these individuals and describe their information needs. METHODS: A qualitative, multicenter interview study with a thematic analysis was conducted in Austria, Germany and the UK. Individuals were interviewed who underwent predictive biomarker testing for RA and had a positive test result but no diagnosis of any inflammatory joint disease. Participants included patients with arthralgia and asymptomatic individuals. Information and education needs were developed from the qualitative codes and themes using the Arthritis Educational Needs Assessment Tool as a frame of reference. RESULTS: Thematic saturation was reached in 34 individuals (76% female, 24 [71%] with arthralgia, and 10 [29%] asymptomatic individuals). Thirty-seven codes were summarized into 4 themes: 1) decision-making around whether to undergo initial predictive testing, 2) willingness to consider further predictive tests, and/or 3) preventive interventions, including medication, and 4) varying reactions after receiving a positive test result. Individuals with arthralgia were more likely to be willing to take preventive action, undergo further testing, and experience psychological distress than asymptomatic individuals. All participants expressed the need for tailored, patient-understandable information. CONCLUSION: Individuals at risk of RA are currently the subjects of research aimed at developing better predictive strategies and preventive approaches. Their perceptions and needs should be addressed to inform the future development of interventions combined with education.

Effect of disease-modifying anti-rheumatic drugs on bone structure and strength in psoriatic arthritis patients.

OBJECTIVES: To address whether the use of methotrexate (MTX) and biological disease-modifying anti-rheumatic drugs (bDMARDs) impacts bone structure and biomechanical properties in patients with psoriatic arthritis (PsA). METHODS: This is a cross-sectional study in PsA patients receiving no DMARDs, MTX, or bDMARDs. Volumetric bone mineral densities (vBMDs), microstructural parameters, and biomechanical properties (stiffness/failure load) were determined by high-resolution peripheral quantitative CT and micro-finite element analysis in the respective groups. Bone parameters were compared between PsA patients with no DMARDs and those receiving any DMARDs, MTX, or bDMARDs, respectively. RESULTS: One hundred sixty-five PsA patients were analyzed, 79 received no DMARDs, 86 received DMARDs, of them 52 bDMARDs (TNF, IL-17- or IL-12/23 inhibitors) and 34 MTX. Groups were balanced for age, sex, comorbidities, functional index, and bone-active therapy, while disease duration was longest in the bDMARD group (7.8 ± 7.4 years), followed by the MTX group (4.6 ± 7.4) and the no-DMARD group (2.9 ± 5.2). No difference in bone parameters was found between the no-DMARD group and the MTX group. In contrast, the bDMARD group revealed significantly higher total (p = 0.001) and trabecular vBMD (p = 0.005) as well as failure load (p = 0.012) and stiffness (p = 0.012). In regression models, age and bDMARDs influenced total vBMD, while age, sex, and bDMARDs influenced failure load and stiffness. CONCLUSION: Despite longer disease duration, bDMARD-treated PsA patients benefit from higher bone mass and better bone strength than PsA patients receiving MTX or no DMARDs. These data support the concept of better control of PsA-related bone disease by bDMARDs.

Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation-data from the prospective IVEPSA study.

BACKGROUND: A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis (PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes. METHODS: Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks. RESULTS: Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks. CONCLUSIONS: These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals. TRIAL REGISTRATION: Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015.

Low-Dose Radiotherapy Ameliorates Advanced Arthritis in hTNF-α tg Mice by Particularly Positively Impacting on Bone Metabolism.

Inflammation and bone erosion are central in rheumatoid arthritis (RA). Even though effective medications for control and treatment of RA are available, remission is only seen in a subset of patients. Treatment with low-dose radiotherapy (LD-RT) which has been already successfully used for amelioration of symptoms in benign diseases should be a promising approach to reduce pain, inflammation, and particularly bone erosion in patients with RA. Even though anti-inflammatory effects of LD-RT are already described with non-linear dose response relationships, and pain-reducing effects have been clinically observed, the underlying mechanisms are widely unknown. Besides immune cells many other cell types, such as fibroblast-like synoviocytes (FLS), osteoclasts, and osteoblast are present in the affected joint and might be modulated by LD-RT. For this study, these cell types were obtained from human tumor necrosis factor-α transgenic (hTNF-α tg) mice and were consecutively exposed to different doses of ionizing radiation (0.1, 0.5, 1.0, and 2.0 Gy, respectively) in vitro. In order to study the in vivo effects of LD-RT within the arthritic joint, hind paws of arthritic hTNF-α tg mice were locally irradiated with 0.5 Gy, a single dose per fraction that is known for good clinical responses. Starting at a dose of 0.5 Gy, proliferation of FLS was reduced and apoptosis significantly enhanced with no changes in necrosis. Further, expression of RANK-L was slightly reduced following irradiation with particularly 0.5 Gy. Starting from 0.5 Gy, the numbers of differentiated osteoclasts were significantly reduced, and a lower bone resorbing activity of treated osteoclasts was also observed, as monitored via pit formation and Cross Laps presence. LD-RT had further a positive effect on osteoblast-induced mineralization in a discontinuous dose response relationship with 0.5 Gy being most efficient. An increase of the gene expression ratio of OPG/RANK-L at 0.1 and 0.5 Gy and of production of OPG at 0.5 and 1.0 Gy was observed. In vivo, LD-RT resulted in less severe arthritis in arthritic hTNF-α tg mice and in significant reduction of inflammatory and erosive area with reduced osteoclasts and neutrophils. Locally applied LD-RT can, therefore, induce a beneficial micro-environment within arthritic joints by predominantly positively impacting on bone metabolism.

Simultaneous quantification of bone erosions and enthesiophytes in the joints of patients with psoriasis or psoriatic arthritis - effects of age and disease duration.

BACKGROUND: Comprehensive simultaneous quantification of bone erosion and enthesiophytes in the joints of patients with psoriatic arthritis (PsA) has not been performed. Herein, we aimed to compare the extent of bone erosion and enthesiophytes in patients with PsA, psoriasis (PSO) and healthy controls, assess the influence of age and disease duration on the development of erosions and enthesiophytes and define their impact on physical function. METHODS: Patients with PsA or with PSO and controls were analysed by high-resolution peripheral quantitative computed tomography (HR-pQCT). The extent of bone erosions and enthesiophytes was assessed and plotted according to different categories of age, duration of PSO and duration of PsA, respectively. In addition, demographic and disease-specific data, including physical function (health assessment questionnaire) were collected. RESULTS: A total of 203 patients were analysed; 101 had PsA, 55 had PSO and 47 were healthy individuals. Patients with PsA had significantly more and larger erosions (p = 0.002/p = 0.003) and enthesiophytes (p < 0.001) compared to patients with PSO and healthy controls. Patients with PSO and healthy controls did not differ in erosions, while enthesiophytes were more frequent in patients with PSO than in healthy controls. Bone erosions, but not enthesiophytes, showed strong age-dependency in all three groups. In contrast, enthesiophytes were mostly influenced by the duration of PSO and PsA and, in contrast to bone erosions, were associated with poorer physical function. CONCLUSIONS: Bone erosions are age-dependent, enhanced in PsA and increase with disease duration. Enthesiophytes are less age-dependent, are enhanced in both PSO and PsA and strongly influenced by disease duration. Enthesiophytes impact physical function in PsA suggesting the need for early therapeutic interventions to prevent damage.

A comparative analysis of articular bone in large cohort of patients with chronic inflammatory diseases of the joints, the gut and the skin.

Chronic inflammatory diseases are associated with bone loss. While the occurrence of systemic bone loss is well described in chronic inflammatory diseases, the impact of these conditions on articular bone has not been systematically investigated. Recent refinements in high-resolution CT assessment of the joints now allow the accurate measure of articular bone composition. In this study 476 subjects comprising healthy individuals and patients with anticitrullinated protein antibody (ACPA)-positive rheumatoid arthritis (RA), ACPA-negative RA, Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PsO) and psoriatic arthritis (PsA) were subjected to high-resolution quantitative computed tomography (HR-pQCT) of the hand. Metacarpal heads were assessed for total, trabecular and cortical volumetric bone mineral density (vBMD). Only ACPA+RA, but not the remaining inflammatory diseases (ACPA-RA, CD, UC, PsO, PsA) showed significant (p < 0.001) loss of articular bone affecting both the trabecular and the cortical compartments. Age and body mass index were also associated with articular bone changes, the former with lower, the latter with higher articular bone mass. In multivariate models, presence of ACPA+RA was an independent factor for articular bone loss. Among chronic inflammatory diseases ACPA+RA is the most potent precipitator for articular bone loss pointing out the role of autoimmunity in the development of articular bone disease in the context of chronic inflammatory disease.

Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study.

BACKGROUND: Although the effects of interleukin-17A (IL-17A) inhibition on the signs and symptoms of psoriatic arthritis (PsA) are well defined, little is known about its impact of local inflammatory and structural changes in the joints. The PSARTROS study was designed to elucidate the effects of IL-17A inhibition on inflammation and bone changes in joints affected by PsA. METHODS: This was a prospective open-label study in 20 patients with active PsA receiving 24 weeks of treatment with the IL-17A inhibitor secukinumab. Magnetic resonance imaging (MRI), power Doppler ultrasound (PDUS), and high-resolution peripheral quantitative computer tomography (HR-pQCT) of the hands were performed at baseline and after 24 weeks to assess synovitis, periarticular inflammation, bone erosion, enthesiophyte formation, and bone structure. Demographic and clinical measures of joint disease (DAPSA and DAS28-ESR), skin disease (PASI and BSA), and composite measures (minimal disease activity, or MDA) were also recorded. RESULTS: Treatment with secukinumab led to significant improvement of signs and symptoms of PsA; 46% reached MDA and 52% DAPSA low disease activity. MRI synovitis (P = 0.034) and signal in PDUS (P = 0.030) significantly decreased after 24 weeks of treatment. Bone erosions in MRI and HR-pQCT and enthesiophytes in the HR-pQCT did not show any progression, and structural integrity and functional bone strength remained stable. CONCLUSIONS: IL-17 inhibition by secukinumab over 24 weeks led to a significant decrease of synovial inflammation and no progression of catabolic and anabolic bone changes in the joints of patients with PsA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02483234 , June 26, 2015; retrospectively registered.

Interleukin-36 receptor mediates the crosstalk between plasma cells and synovial fibroblasts.

The IL-1 family member IL-36α has proinflammatory and pathogenic properties in psoriasis. IL-36α binds to the IL-36 receptor leading to nuclear factor kappa B/mitogen activated protein kinase mediated cytokine release. The IL-36R antagonist prevents recruitment of IL-1 receptor accessory protein and therefore IL-36-dependent cell activation. In inflamed human tissue, we previously could show that resident B cells and plasma cells (PC) express IL-36α. Further, fibroblast-like synoviocytes (FLS) produced proinflammatory cytokines upon IL-36α-stimulation. We hypothesize an IL-36-specific crosstalk between B cells/PCs and FLS permitting a proinflammatory B cell niche. Here, we firstly demonstrated that B cell lines and B cells from healthy donors express IL-36α and stimulation increased IL-36α in B cells and primary plasmablasts/PCs. Moreover, FLS respond specifically to IL-36α by proliferation and production of matrix metalloproteinases via p38/HSP27 signaling. Importantly, IL-36R-deficiency abrogated IL-36α-induced production of inflammatory mediators in FLS and changed the intrinsic FLS-phenotype. Using an in vitro co-culture system, we could show that IL-36R-deficient FLS had a limited capacity to support PC survival compared to wild-type FLS. Hence, we demonstrated an IL-36R-dependent crosstalk between B cells/PCs and FLS. Our data support the concept of initiation and maintenance of a proinflammatory niche by B cells in the joints.

Full Length Interleukin 33 Aggravates Radiation-Induced Skin Reaction.

The interleukin (IL)-1 family member IL-33 has been described as intracellular alarmin with broad roles in wound healing, skin inflammation but also autoimmunity. Its dichotomy between full length (fl) IL-33 and the mature (m) form of IL-33 and its release by necrosis is still not fully understood. Here, we compare functional consequences of both forms in the skin in vivo, and therefore generated two lines of transgenic mice which selectively overexpress mmIL-33 and flmIL-33 in basal keratinocytes. Transgene mRNA was expressed at high level in skin of both lines but not in organs due to the specific K14 promoter. We could demonstrate that transgenic overexpression of mmIL-33 in murine keratinocytes leads to a spontaneous skin inflammation as opposed to flmIL-33. K14-mmIL-33 mice synthesize and secrete high amounts of mmIL-33 along with massive cutaneous manifestations, like increased epidermis and dermis thickness, infiltration of mast cells in the epidermis and dermis layers and marked hyperkeratosis. Using skin inflammation models such as IL-23 administration, imiquimod treatment, or mechanical irritation did not lead to exacerbated inflammation in the K14-flmIL-33 strain. As radiation induces a strong dermatitis due to apoptosis and necrosis, we determined the effect of fractionated radiation (12 Gy, 4 times). In comparison to wild-type mice, an increase in ear thickness in flmIL-33 transgenic mice was observed 25 days after irradiation. Macroscopic examination showed more severe skin symptoms in irradiated ears compared to controls. In summary, secreted mmIL-33 itself has a potent capacity in skin inflammation whereas fl IL-33 is limited due to its intracellular retention. During tissue damage, fl IL-33 exacerbated radiation-induced skin reaction.

Development of three-dimensional prints of arthritic joints for supporting patients' awareness to structural damage.

BACKGROUND: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) result in severe joint destruction and functional disability if left untreated. We aim to develop tools that help patients with RA and PsA to understand and experience the impact of inflammatory joint disease on the integrity of their (juxta-articular) bone and increase adherence to medical treatment. In this study, we used high-resolution peripheral quantitative computed tomography (HR-pQCT) to develop 3D prototypes of patients' finger joints. METHODS: HR-pQCT (XtremeCT, Scanco) measurements were performed in healthy individuals and patients with inflammatory joint disease, followed by a 3D print using the objet30 printer. Healthy participants (n = 10), and patients (n = 15 with RA and 15 with PsA) underwent a detailed, standardized interview with demonstration of printed joints. RESULTS: Utilizing HR-pQCT images of metacarpophalangeal (MCP) heads, high quality and exact 3D prints as prototypes were created. Erosions in different sizes and the trabecular network printed in detail were visualized, demonstrating structural reduction in arthritic vs. healthy bone. After demonstration of 3D prints (healthy vs. erosive joint, visual and haptic) 26/39 (66%) participants (including healthy volunteers) were deeply affected, often quoting "shock". Of the patients with RA and PsA, 13/15 (86%) and 11/15 (73%), respectively, stated that they would rethink their attitude to medication adherence. More importantly, 21/24 patients with RA or PsA (87.5%) expressed that they would have wished to see such 3D prints during their first disease-specific conversations. CONCLUSION: Using arthro-haptic 3D printed prototypes of joints may help to better understand the impact of inflammatory arthritides on bone integrity and long-term damage.

Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs.

OBJECTIVE: To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy. METHODS: Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0-1/10, 2-5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0-3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse. RESULTS: Patients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0-1/10 reactivities) to 34% (2-5/10) and 55% (>5/10). With respect to specificity groups (0-3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively. CONCLUSIONS: The data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy. TRIAL REGISTRATION NUMBER: 2009-015740-42; Results.