Characteristics and burden of disease in patients with radiographic versus non-radiographic axial spondyloarthritis in the ASRI cohort.

BACKGROUND: Axial spondyloarthritis (axSpA) comprises patients with both radiographic and non-radiographic features. Previous studies have shown similar burden of disease between these two groups. AIMS: The Ankylosing Spondylitis Registry of Ireland (ASRI) was formed with the objective to measure the burden of axial spondyloarthritis in the population and identify early predictors of a poor outcome. For this analysis, the ASRI database was used to compare the characteristics and burden of disease in patients with radiographic versus non-radiographic axial spondyloarthritis. METHODS: Patients with radiographic axial spondyloarthritis (r-axSpA) were defined as those with X-ray evidence of sacroiliitis. Patients with non-radiographic axial spondyloarthritis (nr-axSpA) were defined as having MRI evidence of sacroiliitis but no X-ray evidence of sacroiliitis. RESULTS: In total, 764 patients were included. Analysis of radiographic status showed 88.1% (n = 673) of patients with r-axSpA and 11.9% (n = 91) with nr-axSpA (Table 1). Patients with nr-axSpA were younger (41.3 vs. 46.6 years, p < 0.01), had shorter disease duration (14.8 vs. 20.2 years, p < 0.01) and had lower proportion of males (66.6% vs. 78.4%, p = 0.02) with lower frequency of HLA-B27 positivity (73.6% vs. 90.5%, p < 0.01). The nr-axSpA group had lower BASDAI (3.37 vs. 4.05, p = 0.01), BASFI (2.46 vs. 3.88, p < 0.01), BASMI (2.33 vs. 4.34, p < 0.01), ASQoL (5.2 vs. 6.67, p = 0.02) and HAQ scores (0.38 vs. 0.57, p < 0.01). There were no significant differences in the prevalence of extra-musculoskeletal manifestations or use of medications. CONCLUSIONS: This study provides evidence to suggest that the burden of disease is less in patients with non-radiographic axial spondyloarthritis than radiographic axial spondyloarthritis.

What to expect when women with axial spondyloarthritis are expecting: Prevalence of complications of pregnancies in women with axial spondyloarthritis.

BACKGROUND: Understanding of axSpA is evolving rapidly. Unfortunately, for women with axSpA there is limited data available on pregnancy complications. The Ankylosing Spondylitis Registry of Ireland (ASRI) is a source of epidemiological data on axSpA in Ireland. The aim of this study was to examine the prevalence of pregnancy and fetal complications in axSpA women. METHODS: The ASRI records cross-sectional information on demographics, imaging, treatment, and patient outcomes. A dedicated section collects data on pregnancy, fertility and breastfeeding. For each axSpA woman, data on all pregnancies was recorded. Results were compared to global reference norms (GRN). All patients were diagnosed with axSpA by a Rheumatologist and met the ASAS classification criteria. Informed consent was obtained from all patients, with ethical approval obtained from local hospital ethics committees. RESULTS: Data was available on 98 women with axSpA. There were 335 pregnancies resulting in 279 live births. Of these pregnancies 51.6% (173) were uncomplicated and 48.5% (162) were complicated, with 13.1% (44) encountering multiple complications. Preterm birth (12.5 % vs 5.2%, p<0.01) and preeclampsia (6.8 % vs 2.8%, p<0.01) were more prevalent in axSpA pregnancies than GRN. Low birth weight was more prevalent in axSpA pregnancies (8.2 % vs 2.9%, p<0.01), however small for gestational age was less prevalent (5.4 % vs 11%, p<0.01). CONCLUSIONS: Preterm birth, preeclampsia and low birth weight are significantly more prevalent in pregnancies of axSpA women. Furthermore, there is a high prevalence of complications in axSpA pregnancies overall. These results provide essential insight into the impact of axSpA in pregnancy and call for further research to understand the pathogenesis of these complications.

Central Obesity in Axial Spondyloarthritis: The Missing Link to Understanding Worse Outcomes in Women?

OBJECTIVE: To determine (1) the prevalence of central obesity in axial spondyloarthritis (axSpA) and its effect on disease-related outcomes and (2) how this differs between sexes. METHODS: Data were extracted from the Ankylosing Spondylitis Registry of Ireland. Patients with physical measurements for the calculation of anthropometric measures were included. BMI and waist-to-hip ratio (WHR) were used to compare classifications of obesity. Comparison analyses based on sex and central obesity were carried out. Multivariate analysis examined the effects of these factors on the following patient-reported outcomes: the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire, and the Health Assessment Questionnaire (HAQ). RESULTS: In total, 753 patients were included in the analysis. Of these patients, 29.6% (n = 223) were classified as obese based on their BMI, and 41.3% (n = 311) were classified as centrally obese according to the WHR. The prevalence of central obesity was significantly higher among women with axSpA compared to men (71.6% vs 29.9%, P < 0.01). Central obesity had a clear effect on patient outcomes, regardless of sex. Presence of central obesity was associated with significantly worse BASFI scores (P < 0.01), HAQ scores (P < 0.01), and ASQoL questionnaire scores (P = 0.01), with a nonsignificant trend toward worse BASDAI scores (P = 0.07). CONCLUSION: There was a high prevalence of central obesity as assessed by the WHR in axSpA, most notably among women with axSpA. This modifiable comorbidity was significantly associated with worse quality of life, greater impairment of functional ability, and a trend toward worse disease activity. Regular use of the WHR to screen for central obesity as part of an axSpA assessment would provide an opportunity for prompt identification and intervention for at-risk patients.

Advances in treatment of axial spondyloarthritis are associated with improved patient outcomes: data from the Ankylosing Spondylitis Registry of Ireland (ASRI).

The Ankylosing Spondylitis Registry of Ireland (ASRI) captures both radiographic and non-radiographic axial spondyloarthritis (axSpA) in a large, well characterised cohort. This is a valuable resource for studies in therapeutics and burden of disease, following a period of rapid change in the field of axSpA. This study aims to perform a focused analysis on patient outcomes and pattern of medication usage in axSpA. This is a cross-sectional study of registry data on 885 patients with confirmed axSpA as per the ASAS criteria for axSpA, as diagnosed by a Rheumatologist. Analysis was performed using IBM SPSS version 26. Patients were analysed on the basis of treatment categorised as: no medication, NSAIDs, biologics or combination therapy. Statistical significance was indicated by p value of < 0.05. Currently 885 patients are enrolled in the ASRI, made up of 72.5% (642) males and 26.9% (238) females. The majority of the cohort was categorized as radiographic axSpA 78.3% (693), with 21.7% (192) meeting criteria for non-radiographic disease. Overall 40.6% (359) reported at least one comorbidity. Older age was associated with no medications compared to those on biologic therapy (50.3 vs 45, p = 0.01). Lower levels of disease activity and higher quality of life were noted in those on biologics as compared to NSAIDs alone. This analysis provides detailed epidemiological data on axSpA from a large national registry. These results detail significant differences in prescribing patterns and impact on patient outcomes in axSpA. Ongoing development of registries provides a valuable insight into the real-world effects of axSpA.

Loss of balance between protective and pro-inflammatory synovial tissue T-cell polyfunctionality predates clinical onset of rheumatoid arthritis.

OBJECTIVES: This study investigates pathogenic and protective polyfunctional T-cell responses in patient with rheumatoid arthritis (RA), individuals at risk (IAR) and healthy control (HC) synovial-tissue biopsies and identifies the presence of a novel population of pathogenic polyfunctional T-cells that are enriched in the RA joint prior to the development of clinical inflammation. METHODS: Pathway enrichment analysis of previously obtained RNAseq data of synovial biopsies from RA (n=118), IAR (n=20) and HC (n=44) was performed. Single-cell synovial tissue suspensions from RA (n=10), IAR (n=7) and HC (n=7) and paired peripheral blood mononuclear cells (PBMC) were stimulated in vitro and polyfunctional synovial T-cell subsets examined by flow cytometric analysis, simplified presentation of incredibly complex evaluations (SPICE) and FlowSom clustering. Flow-imaging was utilised to confirm specific T-cell cluster identification. Fluorescent lifetime imaging microscopy (FLIM) was used to visualise metabolic status of sorted T-cell populations. RESULTS: Increased plasticity of Tfh cells and CD4 T-cell polyfunctionality with enriched memory Treg cell responses was demonstrated in RA patient synovial tissue. Synovial-tissue RNAseq analysis reveals that enrichment in T-cell activation and differentiation pathways pre-dates the onset of RA. Switch from potentially protective IL-4 and granulocyte macrophage colony stimulating factor (GMCSF) dominated polyfunctional CD4 T-cell responses towards pathogenic polyfunctionality is evident in patient with IAR and RA synovial tissue. Cluster analysis reveals the accumulation of highly polyfunctional CD4+ CD8dim T-cells in IAR and RA but not HC synovial tissue. CD4+ CD8dim T-cells show increased utilisation of oxidative phosphorylation, a characteristic of metabolically primed memory T-cells. Frequency of synovial CD4+ CD8dim T-cells correlates with RA disease activity. CONCLUSION: Switch from potentially protective to pathogenic T-cell polyfunctionality pre-dates the onset of clinical inflammation and constitutes an opportunity for therapeutic intervention in RA.

Functionally Mature CD1c+ Dendritic Cells Preferentially Accumulate in the Inflammatory Arthritis Synovium.

Objective: To examine the role of synovial CD1c+DCs in patients with Inflammatory Arthritis (IA) with a specific focus on the transcriptional and maturation signatures that govern their function. Methods: RNA sequencing was performed on healthy control (HC) peripheral blood (PB), IA PB, and IA synovial fluid (SF) CD1c+DCs. Multiparametric flow-cytometry and SPICE analysis were used to examine site [SF and Synovial Tissue (ST) CD1c+DCs] and disease specific characteristics of CD1c+DCs, while functional assays such as antigen processing, activation, and MMP production were also performed. Results: Increased frequency of CD1c+DCs (p<0.01) with a concomitant increase in CD80, CCR7 (p<0.01), and CXCR3 (p<0.05) expression was identified in IA PB compared to HC PB. Enrichment of CD1c+DCs was identified in IA synovial tissue (ST) (p<0.01) and IA SF (p<0.0001) compared to IA PB, while RNAseq revealed distinct transcriptional variation between PB and SF CD1c+DCs. Flow cytometry revealed increased expression of CD83, CD80, PD-L1, and BTLA (all p<0.05) in IA SF CD1c+DCs compared to PB, while SPICE identified synovial cells with unique co-expression patterns, expressing multiple DC maturation markers simultaneously. Functionally, synovial CD1c+DCs are hyper-responsive to TLR7/8 ligation (p<0.05), have decreased antigen processing capacity (p=0.07), and display dysregulated production of MMPs. Finally, examination of both synovial CD1c+DCs and synovial CD141+DCs revealed distinct maturation and transcriptomic profiles. Conclusion: Synovial CD1c+DCs accumulate in the inflamed IA synovium in a variety of distinct poly-maturational states, distinguishing them transcriptionally and functionally from CD1c+DCs in the periphery and synovial CD141+DCs.

The effects of alcohol consumption and its associations with disease activity among 979 patients with inflammatory arthritis.

OBJECTIVE: The role of alcohol in inflammatory disease remains debated. This study explores the relationship between alcohol and disease activity in patients with inflammatory arthritis. METHODS: Patients attending a rheumatology clinic between 2010 and 2020 were prospectively followed. Information on demographics, alcohol use, smoking habits and disease outcome measures were collected from these patients. Statistical analysis included univariate and multivariate linear and binary logistic regressions, Mann-Whitney U tests and one-way analysis of variance with Tukey's honest significant difference (HSD) test. RESULTS: Of the 979 analysed patients, 62% had rheumatoid arthritis (RA), 26.7% had psoriatic arthritis (PsA) and 11.2% had ankylosing spondylitis. Mean DAS28-CRP (Disease Activity Score 28 - C-reactive protein) in RA and PsA at 1 year was 2.96±1.39, and 64.2% of patients were in remission (DAS28-CRP ≤2.6 or BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) ≤4). Both male gender and risky drinking (>15 units of weekly alcohol) were significantly associated with remission. Compared with women, men had an OR of 1.8 (1.1, 2.5) (p=0.034) for any alcohol consumption and 6.9 (4.7, 9.1) (p=0.001) for drinking at least 15 weekly drinks. When adjusted for gender, there was no association between alcohol and disease activity. Yet, when adjusted for alcohol consumption, gender still significantly influenced disease activity. CONCLUSION: While it may appear that alcohol is linked to remission in inflammatory arthritis, when adjusted for gender, it is not. Men with inflammatory arthritis drink significantly more than women and have less severe disease activity.

Long-term remission and biologic persistence rates: 12-year real-world data.

BACKGROUND: Biologic therapies have greatly improved outcomes in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Yet, our ability to predict long-term remission and persistence or continuation of therapy remains limited. This study explores predictors of remission and persistence of the initial biologic therapy in patients after 12 years. Furthermore, outcomes with adalimumab and etanercept are compared. PATIENTS AND METHODS: RA and PsA patients were prospectively recruited from a biologic clinic. Outcomes on commencing therapy, at 1 year and 12 years were reviewed. Demographics, medications, morning stiffness, patient global health score, tender and swollen joint counts, antibody status, CRP and HAQ were collected. Outcomes at 1 year and 12 years are reported and predictors of biologic persistence and EULAR-defined remission (DAS28-CRP < 2.6) are examined with univariate and multivariate analysis. RESULTS: A total of 403 patients (274 RA and 129 PsA) were analysed. PsA patients were more likely to be male, in full-time employment and have completed higher education. PsA had higher remission rates than RA at both 1 year (60.3% versus 34.5%, p < 0.001) and 12 years (91.3% versus 60.6%, p < 0.001). This difference persisted when patients were matched for baseline disease activity (p < 0.001). Biologic continuation rates were high for RA and PsA at 1 year (49.6% versus 58.9%) and 12 years (38.2% versus 52.3%). In PsA, patients starting on etanercept had lower CRP at 12 years (p = 0.041). Multivariate analysis showed 1-year continuation [OR 4.28 (1.28-14.38)] and 1-year low-disease activity [OR 3.90 (95% CI 1.05-14.53)] was predictive of a 12-year persistence. Persistence with initial biologic at 12 years [OR 4.98 (95% CI 1.83-13.56)] and male gender [OR 4.48 (95% CI 1.25-16.01)] predicted 12 year remission. CONCLUSIONS: This is the first study to show better response to biologic therapy in PsA compared to RA at 12 years. Long-term persistence with initial biologic agent was high and was predicted by biologic persistence and low-disease activity at 1 year. Interestingly, PsA patients had higher levels of employment, educational attainment, and long-term remission rates compared to RA patients.

Rheumatoid arthritis CD14+ monocytes display metabolic and inflammatory dysfunction, a phenotype that precedes clinical manifestation of disease.

INTRODUCTION: This study investigates the metabolic activity of circulating monocytes and their impact on pro-inflammatory responses in RA and explores whether this phenotype is already primed for inflammation before clinical manifestations of disease. METHODS: Blood was collected and CD14+ monocytes isolated from healthy control donors (HC), individuals at-risk (IAR) and RA patients. Monocyte frequency in blood and synovial tissue was assessed by flow cytometry. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT-PCR, Western blot, migration assays, Seahorse-XFe-technology, mitotracker assays and transmission electron microscopy. Transcriptomic analysis was performed on HC, IAR and RA synovial tissue. RESULTS: CD14+ monocytes from RA patients are hyper-inflammatory following stimulation, with significantly higher expression of cytokines/chemokines than those from HC. LPS-induced RA monocyte migratory capacity is consistent with increased monocyte frequency in RA synovial tissue. RA CD14+ monocytes show enhanced mitochondrial respiration, biogenesis and alterations in mitochondrial morphology. Furthermore, RA monocytes display increased levels of key glycolytic enzymes HIF1α, HK2 and PFKFB3 and demonstrate a reliance on glucose consumption, blockade of which abrogates pro-inflammatory mediator responses. Blockade of STAT3 activation inhibits this forced glycolytic flux resulting in metabolic reprogramming and resolution of inflammation. Interestingly, this highly activated monocytic phenotype is evident in IAR of developing disease, in addition to an enhanced monocyte gene signature observed in synovial tissue from IAR. CONCLUSION: RA CD14+ monocytes are metabolically re-programmed for sustained induction of pro-inflammatory responses, with STAT3 identified as a molecular regulator of metabolic dysfunction. This phenotype precedes clinical disease onset and may represent a potential pathway for therapeutic targeting early in disease.

The Phenotype of Axial Spondyloarthritis: Is It Dependent on HLA-B27 Status?

OBJECTIVE: To describe the radiographic phenotype of axial spondyloarthritis (SpA) according to the presence of HLA-B27. METHODS: An international collaboration compared the radiographic phenotype of axial SpA according to HLA-B27 status. Patients with ankylosing spondylitis (AS) and axial psoriatic arthritis (PsA) were collected. Radiographs were read centrally, blinded to clinical details. The symmetry of the sacroiliac joints and lumbar syndesmophytes and the morphology of syndesmophytes (typical marginal versus atypical chunky), together with the modified Stoke Ankylosing Spondylitis Spine Score and the Psoriatic Arthritis Spondylitis Radiographic Index, were recorded. RESULTS: A total of 244 patients with PsA and 198 patients with AS were included. In PsA, 60 patients (25%) were HLA-B27 positive while in AS, 148 patients (75%) were HLA-B27 positive. Patients with HLA-B27 were younger and more often male and had a longer duration of disease. In multivariable logistic regression, HLA-B27 was significantly associated with syndesmophyte symmetry (odds ratio [OR] 3.02 [95% confidence interval (95% CI) 1.38, 6.61]) and marginal syndesmophytes (OR 1.97 [95% CI 1.16, 3.36]) but not with sacroiliac symmetry. Mean radiographic scores were higher for patients with HLA-B27. CONCLUSION: Patients with axial SpA who are positive for HLA-B27 have more severe radiographic damage, more marginal syndesmophytes, and more frequent syndesmophyte symmetry compared to patients who are negative for HLA-B27.

Bristol rheumatoid arthritis fatigue scale is valid in patients with psoriatic arthritis and is associated with overall severe disease and higher comorbidities.

AIMS: To (1) determine the reliability and validity of the Bristol Rheumatoid Arthritis Fatigue scale (BRAF-NRS) in patients with psoriatic arthritis (PsA) and (2) examine possible clinical associations of worse fatigue in PsA. METHODS: Study phase 1: BRAF-NRS scale validation cohort. A consecutive cohort of 70 PsA patients was recruited to complete the 3-item BRAF-NRS and the 13-item Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) questionnaires, alongside disease activity assessment. All patients also completed the BRAF-NRS questionnaire, 1 day later. Study phase 2: Identifying the potential clinical associations of fatigue by using BRAF-NRS (n = 283). A second cohort of 283 PsA patients underwent detailed skin and rheumatologic assessments including disease activity measures. Comorbidities were measured using the Charlson comorbidity index (CCI). Factors predicting worse fatigue as measured by BRAF-NRS were determined using regression analysis. RESULTS: In phase 1, 67 out of 70 patients from the first cohort had complete assessments. The internal consistency of BRAF-NRS as measured by Cronbach's alpha was 0.92. Test-retest reliability as measured by the intra-class correlation coefficient was 0.97. There was excellent correlation between the BRAF-NRS and FACIT-F score(r = - 0.83) (p = <0.001, 95% CI - 0.74 to - 0.91). In phase 2, using data from the second cohort of 283 PsA patients, possible clinical associations of worse fatigue were examined. On multiple linear regression analyses, the model predicted significant association of worse fatigue scores with low education status (p = 0.03), number of deformed joints (p = 0.01), not achieving minimal disease activity state (p < 0.001), higher CCI scores, and worse health assessment questionnaire score (p < 0.001). CONCLUSIONS: BRAF-NRS is a reliable, reproducible, and valid instrument for measuring fatigue in PsA. Fatigue in PsA is associated with low education status and overall more severe disease.Key Points• Fatigue is increasingly recognized as an important measure to examine among patients with PsA, but the available valid fatigue scores in PsA are relatively long and time-consuming especially when other core domains also need to be measured• BRAF-NRS is a short, easily readable, only 3-item tool to measure fatigue, and this is the first study which has examined its performance among the patients with PsA. Our results show that it is a reliable, reproducible, and valid (construct validity) instrument for measuring fatigue in PsA• This study also clearly showed a significant positive relationship between fatigue and comorbidities, and it was also found that comorbidities play the largest role in the multivariate model.

Multimorbidity in Axial Spondyloarthropathy and Its Association with Disease Outcomes: Results from the Ankylosing Spondylitis Registry of Ireland Cohort.

OBJECTIVE: Multimorbidity, the coexistence of 2 or more conditions in an individual, is associated with morbidity and mortality in the general population. This study aims to describe the prevalence of multimorbidity in axial spondyloarthropathy (axSpA) and assess its association with disease outcome measures. METHODS: This cross-sectional study was conducted within the Ankylosing Spondylitis Registry of Ireland (ASRI) cohort. Structured standardized assessment was performed. Multimorbidity was considered as the presence of at least 1 physician-diagnosed chronic condition (excluding extraarticular manifestations) in addition to axSpA. Validated outcome measures were collected: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), Health Assessment Questionnaire (HAQ), AS Quality of Life (ASQoL), and Bath AS Metrology Index (BASMI). Adjusted multiple regression was performed to investigate the association between multimorbidity and disease outcomes. RESULTS: A total of 734 patients from 12 centers were included: 77% male, mean (SD) age 45 (12) years. Of the cohort, 55% (n = 403) were multimorbid. Multimorbid patients were significantly (p < 0.01) older than axSpA-only patients [50 (12) vs 40 (11) yrs]. Obesity was the most prevalent chronic condition, affecting 27%. Multimorbid patients had more severe disease than patients with axSpA only. After adjusting for confounders, multimorbidity was associated with higher BASDAI (ß 0.7, 95% CI 0.34-1.05), BASMI (ß 0.45, 95% CI 0.09-0.80), BASFI (ß 0.5, 95% CI 0.23-0.78), HAQ (ß 0.07, 95% CI 0.00-0.13), and ASQoL (ß 0.87, 95% CI 0.28-1.46). CONCLUSION: Multimorbidity is prevalent in axSpA and is associated with more severe disease.

Ustekinumab for refractory giant cell arteritis: A prospective 52-week trial.

OBJECTIVES: Giant cell arteritis (GCA) is the most common form of systemic vasculitis. Glucocorticoids are an effective treatment but have significant adverse events and relapses are common. Interleukins 12 (IL-12) and 23 (IL-23) stimulate TH1 and TH17 responses and are implicated in the pathogenesis of GCA. The aim of this study was to evaluate the efficacy and safety of IL-12/23 blockade with ustekinumab in GCA. METHODS: We performed a prospective open label study of ustekinumab in patients with refractory GCA. Ustekinumab 90mg was administered subcutaneously every 12 weeks. The primary outcome was the comparison of the median glucocorticoid dose prior to commencement of ustekinumab and at 52 weeks. Secondary outcomes included physician assessed relapse, acute phase reactants, and imaging assessment of large vessel vasculitis (LVV). RESULTS: Twenty-five GCA patients received ustekinumab. All patients had failed to taper glucocorticoids despite addition of a median of 1 other immunosuppressive agent. At week 52, median (IQR) daily prednisolone dose decreased from 20 (15, 25)mg to 5 (2.5, 5)mg (p < 0.001). Six patients (24%) stopped prednisolone completely. No patient experienced a relapse of GCA while receiving ustekinumab. Median (IQR) CRP decreased significantly from 12.9 (5.3, 42) to 6 (2.6, 12.5)mg/L (p = 0.006). CT angiography demonstrated improvement of LVV in all patients studied. No unexpected adverse events were observed with ustekinumab. CONCLUSIONS: Ustekinumab may be effective for the treatment of GCA and warrants further assessment in a randomized controlled trial.

Higher Coronary Plaque Burden in Psoriatic Arthritis Is Independent of Metabolic Syndrome and Associated With Underlying Disease Severity.

OBJECTIVE: To examine the effect of metabolic syndrome and psoriatic disease-related variables on coronary plaque burden in psoriatic arthritis (PsA) patients. METHODS: Fifty PsA patients without symptoms of coronary artery disease (CAD) (25 with metabolic syndrome and 25 without metabolic syndrome) and 50 age- and sex-matched controls underwent 64-slice coronary computed tomography angiography. Plaque localization, segment involvement score (SIS), segment stenosis score (SSS), and total plaque volume (TPV) were calculated. Plaques were classified as calcified, mixed, or noncalcified. Kruskal-Wallis test, rank correlations, and linear regression analyses were used to study the relationship between PsA, metabolic syndrome, and plaque burden. RESULTS: Plaques were found in 76% of PsA patients versus 44% of controls (P = 0.001), and a higher proportion of patients with PsA had affected coronary vessels (P = 0.007). SIS, SSS, and TPV were greater in PsA patients than controls (P = 0.003, P = 0.001, and P ≤ 0.001, respectively). More PsA patients had mixed plaques, and mixed plaque volume was higher than in controls (P < 0.001). PsA patients with metabolic syndrome and those without metabolic syndrome had similar plaque burdens and types. SIS, SSS, and TPV did not show significant relationships with features of metabolic syndrome, but did significantly correlate with disease activity measures. TPV was associated with a diagnosis of PsA (B = 0.865, P = 0.008), but not with metabolic syndrome. Age, highest C-reactive protein level, highest swollen joint count, disease duration, and plasma glucose level were independent predictors of higher plaque burden in PsA. CONCLUSION: PsA is associated with accelerated coronary plaque formation, particularly mixed plaques, independent of metabolic disease. Psoriatic disease activity and severity may predict coronary plaque burden better than traditional risk factors.

Abatacept reduces synovial regulatory T-cell expression in patients with psoriatic arthritis.

BACKGROUND: The aim was to study changes in immunohistochemical expression markers of synovial and skin inflammation, clinical outcomes and magnetic resonance imaging (MRI) scores with abatacept treatment in patients with psoriatic arthritis (PsA). METHODS: Biological-treatment-naïve PsA patients with active disease including synovitis of a knee were enrolled in this single-centre, crossover study. Patients were randomised to receive intravenous abatacept 3 mg/kg of body weight or placebo infusion on day 1, 15 and 29; thereafter abatacept 10 mg/kg of body weight was administered every 28 days for 5 months. Clinical data were collected at each visit. Synovial biopsy of the involved knee was obtained at baseline and 2 and 6 months. MRI of the same knee and skin biopsy was performed prior to arthroscopy. RESULTS: Fifteen patients were recruited. Significant improvements in the joint-related measures were observed; 90% were European League Against Rheumatism criteria responders and 30% achieved psoriasis area severity index (PASI)50 at 6 months. Reduction in synovitis (P = 0.016) and vascularity (P = 0.039) macroscopic scores consistent with decrease in total MRI score (P = 0.016) were noticed. Abatacept decreased the immunohistological expression of FOXP3+ cells (P = 0.027), specifically the expression of CD4+FOXP3+ regulatory T cells (Tregs) (P = 0.008) in the synovium over 6 months. There was no significant clinical or immunohistological change in any of the skin measures. CONCLUSION: This is the first study assessing synovial and psoriatic skin immunpathological changes following abatacept treatment in PsA. Reduction in Treg expression in the synovium but not in the psoriatic lesion suggests abnormal Treg function in PsA with differential suppressive capacity in the synovium compared to the lesional skin. The results of this study demonstrate that abatacept 10 mg/kg of body weight might be an effective treatment option for joint disease in patients with PsA. TRIAL REGISTRATION: Irish Health Products Regulatory Authority. TRIAL REGISTRATION NUMBER: CT 900/489/1 - Abatacept (case number: 2077284, EudraCT Number: 2009-017525-19, Protocol number: 77777). Registered on 12 March 2010.

MicroRNA-302d targets IRF9 to regulate the IFN-induced gene expression in SLE.

Systemic lupus erythematosus (SLE) is a complex disease targeting multiple organs as a result of overactivation of the type I interferon (IFN) system, a feature currently being targeted by multiple biologic therapies against IFN-α. We have identified an estrogen-regulated microRNA, miR-302d, whose expression is decreased in SLE patient monocytes and identify its target as interferon regulatory factor (IRF)-9, a critical component of the transcriptional complex that regulates expression of interferon-stimulated genes (ISGs). In keeping with the reduced expression of miR-302d in SLE patient monocytes, IRF9 levels were increased, as was expression of a number of ISGs including MX1 and OAS1. In vivo evaluation revealed that miR-302d protects against pristane-induced inflammation in mice by targeting IRF9 and hence ISG expression. Importantly, patients with enhanced disease activity have markedly reduced expression of miR-302d and enhanced IRF9 and ISG expression, with miR-302d negatively correlating with IFN score. Together these findings identify miR-302d as a key regulator of type I IFN driven gene expression via its ability to target IRF9 and regulate ISG expression, underscoring the importance of non-coding RNA in regulating the IFN pathway in SLE.