Drug effectiveness of 2nd and 3rd TNF inhibitors in psoriatic arthritis - relationship with the reason for withdrawal from the previous treatment.

OBJECTIVE: To investigate real-world retention and remission rates in PsA patients initiating a 2nd or 3rd TNFi and the association with reason for discontinuation from the previous TNFi-treatment. METHODS: Prospectively collected routine care data from 12 European registries were pooled. Retention rates (Kaplan-Meier estimation) and crude/LUNDEX-adjusted rates of Disease Activity Score 28 and Disease Activity index for PSoriatic Arthritis (DAS28 and DAPSA28) remission were calculated and compared with adjusted Cox regression analyses and Chi-squared test, respectively). RESULTS: We included 5233 (2nd TNFi) and 1906 (3rd TNFi) patients. Twelve-month retention rates for the 2nd and 3rd TNFi were 68% (95%CI: 67-70%) and 66% (64-68%), respectively. Patients who stopped the previous TNFi due to AE/LOE had 12-month retention rates of 66%/65% (2nd TNFi), and 65%/63% (3rd TNFi), respectively. Patients who stopped the previous TNFi due to LOE after less vs more than 24 weeks had 12-month retention rates of 54%/69% (2nd TNFi), and 58%/65% (3rd TNFi). Six-month crude/LUNDEX-adjusted DAS28 remission rates were 48%/35% and 38%/27%, and DAPSA28 remission rates were 19%/14% and 14%/10%, for the 2nd and 3rd TNFi. CONCLUSION: Two-thirds of patients remained on TNFi at 12months for both the 2nd and 3rd TNFi, while one-third and one-quarter of patients were in DAS28 remission after 6months on the 2nd and 3rd TNFi. While drug effectiveness was similar in patients who stopped the previous TNFi due to AE compared to overall LOE, drug effectiveness was better in patients who had stopped the previous TNF due to secondary LOE compared to primary LOE.

Patient-reported outcomes in axial spondyloarthritis and psoriatic arthritis patients treated with secukinumab for 24 months in daily clinical practice.

OBJECTIVES: In patients with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA) initiating secukinumab, we aimed to assess and compare the proportion of patients achieving 6-, 12- and 24-month patient-reported outcomes (PRO) remission and the 24-month retention rates. PATIENTS AND METHODS: Patients with axSpA or PsA from 16 European registries, who initiated secukinumab in routine care were included. PRO remission rates were defined as pain, fatigue, Patient Global Assessment (PGA) ≤2 (Numeric Rating Scale (NRS) 0-10) and Health Assessment Questionnaire (HAQ) ≤0.5, for both axSpA and PsA, and were calculated as crude values and adjusted for drug adherence (LUNDEX). Comparisons of axSpA and PsA remission rates were performed using logistic regression analyses (unadjusted and adjusted for multiple confounders). Kaplan-Meier plots with log-rank test and Cox regression analyses were conducted to assess and compare secukinumab retention rates. RESULTS: We included 3087 axSpA and 3246 PsA patients initiating secukinumab. Crude pain, fatigue, PGA and HAQ remission rates were higher in axSpA than in PsA patients, whereas LUNDEX-adjusted remission rates were similar. No differences were found between the patient groups after adjustment for confounders. The 24-month retention rates were similar in axSpA vs. PsA in fully adjusted analyses (HR [95 %CI] = 0.92 [0.84-1.02]). CONCLUSION: In this large European real-world study of axSpA and PsA patients treated with secukinumab, we demonstrate for the first time a comparable effectiveness in PRO remission and treatment retention rates between these two conditions when adjusted for confounders.

Can rheumatologists unequivocally diagnose axial spondyloarthritis in patients with chronic back pain of less than 2 years duration? Primary outcome of the 2-year SPondyloArthritis Caught Early (SPACE) cohort.

OBJECTIVES: To investigate the prevalence of axial spondyloarthritis (axSpA) in patients with chronic back pain (CBP) of less than 2 years (2y) duration referred to the rheumatologist, the development of diagnosis over time, and patient characteristics of those developing definite (d-)axSpA over 2y. METHODS: We analysed the 2y data from SPondyloArthritis Caught Early, a European cohort of patients (<45 years) with CBP (≥3 months, ≤2y) of unknown origin. The diagnostic workup comprised evaluation of clinical SpA features, acute phase reactants, HLA-B27, radiographs and MRI (sacroiliac joints and spine), with repeated assessments. At each visit (baseline, 3 months, 1y and 2y), rheumatologists reported a diagnosis of axSpA or non-axSpA with level of confidence (LoC; 0-not confident at all to 10-very confident). MAIN OUTCOME: axSpA diagnosis with LoC≥7 (d-axSpA) at 2y. RESULTS: In 552 patients with CBP, d-axSpA was diagnosed in 175 (32%) at baseline and 165 (30%) at 2y. Baseline diagnosis remained rather stable: at 2y, baseline d-axSpA was revised in 5% of patients, while 8% 'gained' d-axSpA. Diagnostic uncertainty persisted in 30%. HLA-B27+ and baseline sacroiliitis imaging discriminated best 2y-d-axSpA versus 2y-d-non-axSpA patients. Good response to non-steroidal anti-inflammatory drugs and MRI-sacroiliitis most frequently developed over follow-up in patients with a new d-axSpA diagnosis. Of the patients who developed MRI-sacroiliitis, 7/8 were HLA-B27+ and 5/8 male. CONCLUSION: A diagnosis of d-axSpA can be reliably made in nearly one-third of patients with CBP referred to the rheumatologist, but diagnostic uncertainty may persist in 5%-30% after 2y. Repeated assessments yield is modest, but repeating MRI may be worthwhile in male HLA-B27+ patients.

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.

Predictors of DAPSA28 remission in patients with psoriatic arthritis initiating a first TNF inhibitor: results from 13 European registries.

OBJECTIVES: In bio-naïve patients with PsA initiating a TNF inhibitor (TNFi), we aimed to identify baseline predictors of Disease Activity index for PsA in 28 joints (DAPSA28) remission (primary objective) and DAPSA28 moderate response at 6 months, as well as drug retention at 12 months across 13 European registries. METHODS: Baseline demographic and clinical characteristics were retrieved and the three outcomes investigated per registry and in pooled data, using logistic regression analyses on multiply imputed data. In the pooled cohort, selected predictors that were either consistently positive or negative across all three outcomes were defined as common predictors. RESULTS: In the pooled cohort (n = 13 369), 6-month proportions of remission, moderate response and 12-month drug retention were 25%, 34% and 63% in patients with available data (n = 6954, n = 5275 and n = 13 369, respectively). Five common baseline predictors of remission, moderate response and 12-month drug retention were identified across all three outcomes. The odds ratios (95% CIs) for DAPSA28 remission were: age, per year: 0.97 (0.96-0.98); disease duration, years (<2 years as reference): 2-3 years: 1.20 (0.89-1.60), 4-9 years: 1.42 (1.09-1.84), ≥10 years: 1.66 (1.26-2.20); men vs women: 1.85 (1.54-2.23); CRP of >10 vs ≤10 mg/l: 1.52 (1.22-1.89) and 1 mm increase in patient fatigue score: 0.99 (0.98-0.99). CONCLUSION: Baseline predictors of remission, response and adherence to TNFi therapy were identified, of which five were common for all three outcomes, indicating that the predictors emerging from our pooled cohort may be considered generalizable from country level to disease level.

Sex Differences in the Effectiveness of First-Line Tumor Necrosis Factor Inhibitors in Psoriatic Arthritis: Results From the European Spondyloarthritis Research Collaboration Network.

OBJECTIVE: Women with psoriatic arthritis (PsA) may have reduced tumor necrosis factor inhibitor (TNFi) effectiveness compared to men. We examined sex differences in treatment response and retention rates during 24 months of follow-up among patients with PsA initiating their first TNFi. METHODS: Data from patients with PsA across 13 European Spondyloarthritis Research Collaboration Network registries starting their first TNFi were pooled. Logistic regression was used to analyze the association between sex and treatment response using low disease activity (LDA) according to the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) (<3.2) at six months as the primary outcome. Analyses were adjusted for age, country, conventional synthetic disease-modifying antirheumatic drug treatment, and TNFi start year. Retention rates were explored using the Kaplan-Meier estimator. RESULTS: We analyzed the treatment response of 7,679 patients with PsA (50% women) with available data on LDA at six months. At baseline, women and men had similar characteristics, including mean DAS28-CRP (women vs men, 4.4 [SD 1.2] vs 4.2 [SD 1.2]), though patient-reported outcome measures were worse in women. At six months, 64% of women and 78% of men had LDA (relative risk [RR] 0.82; 95% confidence interval [CI] 0.80-0.84). This difference was similar after adjustment (RR 0.83; 95% CI 0.81-0.85). TNFi retention rates were evaluated in 17,842 patients with PsA. Women had significantly lower retention rates than men at all time points (women 79%, 64%, and 50% vs men 88%, 77%, and 64% at 6, 12, and 24 months, respectively). CONCLUSION: Despite comparable disease characteristics at baseline, women with PsA have reduced treatment response and retention rates to their first TNFi, highlighting the need to consider sex differences in PsA research and management.

Pathophysiology and immunolgical basis of axial spondyloarthritis.

Over the recent years the wider availability and application of state-of-the-art immunological technologies greatly advanced the insight into the mechanisms that play an important role in axial spondyloarthritis (axSpA) pathophysiology. This increased understanding has facilitated the development of novel treatments that target disease relevant pathways, hereby improving outcome for axSpA patients. In axSpA pathophysiology genetic and environmental factors as well as immune activation by mechanical or bacterial stress resulting in a chronic inflammatory response have a central role. The TNF and IL-23/IL-17 immune pathways play a pivotal role in these disease mechanisms. This review provides an outline of the immunological basis of axSpA with a focus on key genetic risk factors and their link to activation of the pathological immune response, as well as on the role of the gut and entheses in the initiation of inflammation with subsequent new bone formation in axSpA.

Differences and similarities between the EULAR/ASAS-EULAR and national recommendations for treatment of patients with psoriatic arthritis and axial spondyloarthritis across Europe.

This is the first report comparing EULAR and national treatment recommendations for PsA patients across Europe, and the first this decade to compare ASAS-EULAR and national treatment recommendations in axSpA patients. An electronic survey was completed from October 2021-April 2022 by rheumatologists in 15 European countries. One and four countries followed all EULAR and ASAS-EULAR recommendations, respectively. Five countries had no national treatment recommendations for PsA and/or axSpA, but followed other regulations. In several countries, national treatment recommendations predated the most recent EULAR/ASAS-EULAR recommendations. Entry criteria for starting biologic/targeted synthetic disease-modifying anti-rheumatic drugs varied considerably. In several countries, for PsA patients with significant skin involvement, interleukin-17 inhibitors were not given preference. The positioning of Janus Kinase inhibitors differed and Phosphodiesterase-4 inhibitors were not in use/reimbursed in most countries. This study may motivate European countries to update their national treatment recommendations, to align them better with the latest international recommendations.

ASAS consensus definition of early axial spondyloarthritis.

OBJECTIVES: To develop a consensual definition for the term 'early axial spondyloarthritis-axSpA'-and 'early peripheral spondyloarthritis-pSpA'. METHODS: The ASAS (Assessment of SpondyloArthritis international Society-Spondyloarthritis EARly definition) steering committee convened an international working group (WG). Five consecutive steps were followed: (1) systematic literature review (SLR); (2) discussion of SLR results within the WG and ASAS community; (3) a three-round Delphi survey inviting all ASAS members to select the items that should be considered for the definition; (4) presentation of Delphi results to the WG and ASAS community and (5) ASAS voting and endorsement (2023 annual meeting). RESULTS: Following the SLR, consensus was to proceed with an expert-based definition for early axSpA (81% in favour) but not for pSpA (54% against). Importantly, early axSpA should be based on symptom duration taking solely axial symptoms into account. 151-164 ASAS members participated in the Delphi surveys. Consensus was achieved for considering the following items within early axSpA definition: duration of symptoms ≤2 years; axial symptoms defined as cervical/thoracic/back/buttock pain or morning stiffness; regardless of the presence/absence of radiographic damage. The WG agreed that in patients with a diagnosis of axSpA 'early axSpA' should be defined as a duration of ≤2 years of axial symptoms. Axial symptoms should include spinal/buttock pain or morning stiffness and should be considered by a rheumatologist as related to axSpA. The ASAS community endorsed this proposal (88% in favour). CONCLUSIONS: Early axSpA has newly been defined, based on expert consensus. This ASAS definition should be adopted in research studies addressing early axSpA.

Two-year imaging outcomes from a phase 3 randomized trial of secukinumab in patients with non-radiographic axial spondyloarthritis.

BACKGROUND: Radiographic progression and course of inflammation over 2 years in patients with non-radiographic axial spondyloarthritis (nr-axSpA) from the phase 3, randomized, PREVENT study are reported here. METHODS: In the PREVENT study, adult patients fulfilling the Assessment of SpondyloArthritis International Society classification criteria for nr-axSpA with elevated CRP and/or MRI inflammation received secukinumab 150 mg or placebo. All patients received open-label secukinumab from week 52 onward. Sacroiliac (SI) joint and spinal radiographs were scored using the modified New York (mNY) grading (total sacroiliitis score; range, 0-8) and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS; range, 0-72), respectively. SI joint bone marrow edema (BME) was assessed using the Berlin Active Inflammatory Lesions Scoring (0-24) and spinal MRI using the Berlin modification of the AS spine MRI (ASspiMRI) scoring (0-69). RESULTS: Overall, 78.9% (438/555) of patients completed week 104 of the study. Over 2 years, minimal changes were observed in total radiographic SI joint scores (mean [SD] change, - 0.04 [0.49] and 0.04 [0.36]) and mSASSS scores (0.04 [0.47] and 0.07 [0.36]) in the secukinumab and placebo-secukinumab groups. Most of the patients showed no structural progression (increase ≤ smallest detectable change) in SI joint score (87.7% and 85.6%) and mSASSS score (97.5% and 97.1%) in the secukinumab and placebo-secukinumab groups. Only 3.3% (n = 7) and 2.9% (n = 3) of patients in the secukinumab and placebo-secukinumab groups, respectively, who were mNY-negative at baseline were scored as mNY-positive at week 104. Overall, 1.7% and 3.4% of patients with no syndesmophytes at baseline in the secukinumab and placebo-secukinumab group, respectively, developed ≥ 1 new syndesmophyte over 2 years. Reduction in SI joint BME observed at week 16 with secukinumab (mean [SD], - 1.23 [2.81] vs - 0.37 [1.90] with placebo) was sustained through week 104 (- 1.73 [3.49]). Spinal inflammation on MRI was low at baseline (mean score, 0.82 and 1.07 in the secukinumab and placebo groups, respectively) and remained low (mean score, 0.56 at week 104). CONCLUSION: Structural damage was low at baseline and most patients showed no radiographic progression in SI joints and spine over 2 years in the secukinumab and placebo-secukinumab groups. Secukinumab reduced SI joint inflammation, which was sustained over 2 years. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02696031.

EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.

The 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.

Hyaluronic Acid in Synovial Fluid Prevents Neutrophil Activation in Spondyloarthritis.

Spondyloarthritis (SpA) patients suffer from joint inflammation resulting in tissue damage, characterized by the presence of numerous neutrophils in the synovium and synovial fluid (SF). As it is yet unclear to what extent neutrophils contribute to the pathogenesis of SpA, we set out to study SF neutrophils in more detail. We analyzed the functionality of SF neutrophils of 20 SpA patients and 7 disease controls, determining ROS production and degranulation in response to various stimuli. In addition, the effect of SF on neutrophil function was determined. Surprisingly, our data show that SF neutrophils in SpA patients have an inactive phenotype, despite the presence of many neutrophil-activating stimuli such as GM-CSF and TNF in SF. This was not due to exhaustion as SF neutrophils readily responded to stimulation. Therefore, this finding suggests that one or more inhibitors of neutrophil activation may be present in SF. Indeed, when blood neutrophils from healthy donors were activated in the presence of increasing concentrations of SF from SpA patients, degranulation and ROS production were dose-dependently inhibited. This effect was independent of diagnosis, gender, age, and medication in the patients from which the SF was isolated. Treatment of SF with the enzyme hyaluronidase strongly reduced the inhibitory effect of SF on neutrophil activation, indicating that hyaluronic acid that is present in SF may be an important factor in preventing SF neutrophil activation. This finding provides novel insights into the role of soluble factors in SF regulating neutrophil function and may lead to the development of novel therapeutics targeting neutrophil activation via hyaluronic acid or associated pathways.

Immunogenicity and 1-year boostability of a three-dose intramuscular rabies pre-exposure prophylaxis schedule in adults receiving immunosuppressive monotherapy: a prospective single-centre clinical trial.

BACKGROUND: For immunocompromised patients (ICPs), administration of rabies immunoglobulins (RIG) after exposure is still recommended regardless of prior vaccination, due to a lack of data. We aimed to assess the 1-year boostability of a three-dose rabies pre-exposure prophylaxis (PrEP) schedule in individuals using immunosuppressive monotherapy. METHODS: In this prospective study, individuals on immunosuppressive monotherapy with a conventional immunomodulator (cIM) or a TNF-alpha inhibitor (TNFi) for a chronic inflammatory disease received a three-dose intramuscular PrEP schedule (days 0,7,21-28) with 1 mL Rabipur®, followed by a two-dose simulated post-exposure prophylaxis (PEP) schedule (days 0,3) after 12 months. Rabies neutralizing antibodies were assessed at baseline, on day 21-28 (before the third PrEP dose), day 60, month 12 and month 12 + 7 days. The primary outcome was 1-year boostability, defined as the proportion of patients with a neutralizing antibody titre of ≥ 0.5 IU/mL at month 12 + 7 days. Secondary outcomes were geometric mean titres (GMTs) and factors associated with the primary endpoint. RESULTS: We included 56 individuals, of whom 52 completed the study. The 1-year boostability was 90% (47/52) with a GMT of 6.16 (95% CI 3.83-9.91). All participants seroconverted at some point in the study. Early response to PrEP (at day 21-28) was significantly associated with 100% boostability (Odds Ratio 51; 95% confidence interval [5.0-6956], P < 0.01). The vaccination schedule was safe and well tolerated. No vaccine-related serious adverse events occurred. CONCLUSION: In patients using immunosuppressive monotherapy, a three-dose rabies PrEP schedule followed by a two-dose PEP schedule is immunogenic, with all patients seroconverting at some point in the study. Although boostability 7 days after PEP was not 100%, nobody would wrongly be denied RIG when only administered to those who responded early to PrEP while reducing the administration of RIG by 73%.

18F-sodium fluoride PET-CT visualizes both axial and peripheral new bone formation in psoriatic arthritis patients.

PURPOSE: As bone formation is associated with psoriatic arthritis (PsA), positron emission tomography (PET) using a 18F-Fluoride tracer may enable sensitive detection of disease activity. Our primary aim was to determine the feasibility of whole-body 18F-sodium fluoride PET-CT in clinically active PsA patients to depict new bone formation (as a reflection of disease activity) at peripheral joints and entheses. Our secondary aim was to describe 18F-sodium fluoride findings in the axial skeleton. METHODS: Sixteen patients (female 10/16, age 50.6 ± 8.9 years) with PsA fulfilling CASPAR criteria or with a clinical diagnosis of PsA according to the treating rheumatologist and with ≥ 1 clinically active enthesitis site were included. Of each patient, a whole-body 18F-sodium fluoride PET-CT scan was performed. All scans were scored for PET-positive lesions at peripheral joints, enthesis sites and the spine. Clinical disease activity was assessed by swollen/tender joint count 44, enthesitis according to MASES and SPARCC scores. RESULTS: Out of 1088 evaluated joints, 109 joints showed PET enhancement, mainly in the interphalangeal and metatarsal joints of the feet (14/109, 12.9%) and the distal interphalangeal joints of the hands (14/109, 12.9%). PET positivity was found at 44/464 enthesis sites, mainly at the patella tendon insertion (11/44, 25%) and quadriceps tendon insertion (10/44, 22.7%). Of the PET-positive joints and enthesis sites, respectively 18.2% and 29.5% were clinically positive; 81.8% and 70.5% of the PET-positive joints and entheses respectively were clinically asymptomatic. In 11 patients, ≥ 1 axial PET-positive lesion was observed, mainly in the cervical spine. CONCLUSIONS: New molecular bone formation was observed on 18F-sodium fluoride PET-CT scans, in all domains in which PsA disease activity can be observed, with a substantial part showing no clinical symptoms. CLINICAL TRIAL REGISTRATION: EudraCT: 2017-004,850-40, registered on 13 December 2017.

Synovial gene signatures associated with the development of rheumatoid arthritis in at risk individuals: A prospective study.

OBJECTIVE: To identify molecular changes in synovium before arthritis development in individuals at risk of developing rheumatoid arthritis (RA). MATERIALS AND METHODS: We included 67 IgM rheumatoid factor and/or anti-citrullinated protein antibody positive individuals with arthralgia but without arthritis. Synovial biopsies were collected after which individuals were prospectively followed for at least 2 years during which 17 developed arthritis. An exploratory genome-wide transcriptional profiling study was performed in 13 preselected individuals to identify transcripts associated with arthritis development (n = 6). Findings were validated using quantitative real-time PCR and immunohistochemistry in the total cohort. RESULTS: Microarray-based survival analyses identified 5588 transcripts whose expression levels in synovium were significantly associated with arthritis development. Pathway analysis revealed that synovial tissue of at risk individuals who later developed arthritis display higher expression of genes involved in adaptive immune response-related pathways compared to at risk individuals who did not develop arthritis. Lower expression was observed for genes involved in extracellular matrix receptor interaction, Wnt-mediated signal transduction and lipid metabolism. Two-way hierarchical clustering analyses of a 27-gene signature separated the total at risk cohort into two groups, where pre-RA individuals preferred to cluster together. Immunohistochemistry studies revealed more podoplanin positive cells and lower lipid droplet staining in synovial tissue from pre-RA individuals. CONCLUSION: Synovial alterations in adaptive immune response and lipid metabolism are associated with future development of arthritis. Since this data show synovial changes without overt cellular infiltration, these may be attributed to preclinical changes in resident synovial tissue cells such as fibroblasts, macrophages and tissue resident T cells.

Ultrasound-guided lymph node biopsy sampling to study the immunopathogenesis of rheumatoid arthritis: a well-tolerated valuable research tool.

BACKGROUND: Analyses of lymphoid organs are required to further elucidate the pathogenesis of inflammatory diseases like rheumatoid arthritis (RA). Yet, invasive tissue collection methods are scarcely applied, because they are often considered burdensome, although patients do not always consider invasive methods as a high burden. We aimed to investigate the perspectives of study participants undergoing ultrasound-guided inguinal lymph node (LN) needle biopsy sampling and determine the molecular and cellular quantity and quality of LN biopsies. METHODS: Together with patient research partners, questionnaires were developed to evaluate the motives, expectations, and experiences of participants undergoing a LN biopsy. Healthy controls and RA(-risk) patients were asked to complete these questionnaires before and after the procedure. RNA and lymphocyte yields from obtained LN biopsies were also calculated. RESULTS: We included 50 individuals, of which 43 (86%) reported their pre- and post-procedure experiences. The median reported pain on a 5-point Likert scale (1 not to 5 very painful) was 1. Interestingly, almost all (n = 32; 74%) study participants would undergo a second procedure and more than half (n = 23; 54%) would encourage others to take part in the LN biopsy study. Motives for current and future participation were mostly altruistic. Inguinal hematoma occurred frequently, but no other significant or unexpected complications ensued. The LN biopsies yielded sufficient and high-quality RNA and lymphocyte numbers. CONCLUSIONS: Ultrasound-guided inguinal LN biopsy sampling is well-tolerated, safe, and provides sufficient material for further molecular and cellular analyses. Our participants' positive experiences endorse the application of this research tool to further elucidate the pathogenesis of RA and other inflammatory diseases.

Measuring quality of life of patients with axial spondyloarthritis for economic evaluation.

OBJECTIVES: To estimate the relationship between EQ5D (three levels, UK version) and the Ankylosing Spondylitis Disease Activity Score (ASDAS) for use in the economic evaluation of health technologies for people with axial spondyloarthritis (axSpA). To compare against the relationship with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). METHODS: An electronic, prospective, Portuguese, nationwide, rheumatic disease register (Reuma.pt) provided data on 1140 patients (5483 observations) with a confirmed diagnosis of axSpA. We estimated models of EQ5D as a function of ASDAS, alone or in combination with measures of functional impairment, using bespoke mixture models which reflect the complex distributional features of EQ5D. The SPondyloArthritis Caught Early cohort provided data from 344 patients (1405 observations) in four European countries and was used for validation. A previously published model of BASDAI/Bath Ankylosing Spondylitis Functional Index (BASFI) was also used to generate predicted EQ5D scores and model performance compared. RESULTS: A non-linear relationship exists between EQ5D from ASDAS. The final model included ASDAS, ASDAS squared, age and age squared and demonstrated close fit in both datasets except where data were sparse for patients with very high levels of disease activity (ASDAS >4). This finding held in the validation dataset. Models that included BASFI improved model fit. The ASDAS based models fit the data marginally less well than models using BASDAI. CONCLUSIONS: Mapping models linking ASDAS to EQ5D allow results from clinical studies to be used in economic evaluation of health technologies with confidence. There is some loss of information compared with BASDAI but this has only a marginal impact.

Impact of Adalimumab Treatment on Interleukin-17 and Interleukin-17 Receptor Expression in Skin and Synovium of Psoriatic Arthritis Patients with Mild Psoriasis.

Interleukin (IL)-17 and tumor necrosis factor-alpha (TNF)-α are key players in psoriatic arthritis (PsA) pathogenesis. While both cytokines can be therapeutically targeted with beneficial clinical outcome, it is unclear whether inhibiting one cytokine will affect the other at sites of inflammation. If both act independently, this might provide a rationale for dual or combined inhibition of both cytokines. Here, we evaluated the effect of TNF blockade in PsA patients on IL-17 levels in both skin and synovial tissue biopsies. PsA patients with mild psoriatic skin lesions were randomized to receive either adalimumab or placebo for four weeks. Synovial and skin biopsies were obtained at weeks zero and four. Skin from healthy donors (HDs) was used for comparison. Expression of IL-17A, IL-17F, IL-17RA and IL-17RC was assessed by immunohistochemistry and analyzed with digital image analysis. We found relatively low levels of IL-17 and its receptors in the skin of PsA patients compared to HD, and only IL-17F in the dermis of lesional psoriatic skin was significantly higher compared to HD skin (p = 0.0002). Histologically IL-17A, IL-17F, IL-17RA and IL-17RC in skin and synovial tissue were not downregulated by adalimumab treatment. Thus, in this cohort of PsA patients with mild psoriasis, TNF blockade did not affect the protein levels of IL-17 cytokines and its receptors in skin and synovium, despite reduced cellular inflammation and improved clinical outcome for joint involvement.

The Role of the Lymphatic System in the Pathogenesis and Treatment of Inflammatory Bowel Disease.

Although the number of therapeutic options for the treatment of inflammatory bowel disease (IBD) has increased in recent years, patients suffer from decreased quality of life due to non-response or loss of response to the currently available treatments. An increased understanding of the disease's etiology could provide novel insights for treatment strategies in IBD. Lymphatic system components are generally linked to immune responses and presumably related to inflammatory diseases pathophysiology. This review aims to summarize findings on immune-mediated mechanisms in lymphoid tissues linked with IBD pathogenesis and (potential) novel treatments. Enhanced innate and adaptive immune responses were observed in mesenteric lymph nodes (MLNs) and other lymphoid structures, such as Peyer's patches, in patients with IBD and in animal models. Furthermore, the phenomenon of lymphatic obstruction in the form of granulomas in MLNs and lymphatic vessels correlates with disease activity. There is also evidence that abnormalities in the lymphatic stromal components and lymph node microbiome are common in IBD and could be exploited therapeutically. Finally, novel agents targeting lymphocyte trafficking have been added to the treatment armamentarium in the field of IBD. Overall, gut-associated lymphoid tissue plays a key role in IBD immunopathogenesis, which could offer novel therapeutic targets.

Dual Blockade of TNF and IL-17A Inhibits Inflammation and Structural Damage in a Rat Model of Spondyloarthritis.

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human ß2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.