Effects of targeted therapies on bone in rheumatic and musculoskeletal diseases.

Generalized bone loss (osteoporosis) and fragility fractures can occur in rheumatic and musculoskeletal diseases including rheumatoid arthritis and spondyloarthritis (SpA; including ankylosing spondylitis and psoriatic arthritis). In addition, rheumatoid arthritis can involve localized, periarticular bone erosion and, in SpA, local (pathological) bone formation can occur. The RANK-RANKL-osteoprotegerin axis and the Wnt-ß-catenin signalling pathway (along with its inhibitors sclerostin and Dickkopf 1) have been implicated in inflammatory bone loss and formation, respectively. Targeted therapies including biologic DMARDs and Janus kinase (JAK) inhibitors can stabilize bone turnover and inhibit radiographic joint damage, and potentially also prevent generalized bone loss. Targeted therapies interfere at various points in the mechanisms of local and generalized bone changes in systemic rheumatic diseases, and they effect biomarkers of bone resorption and formation, bone mass and risk of fragility fractures. Studies on the effects of targeted therapies on rates of fragility fracture are scarce. The efficacy of biologic DMARDs for arresting bone formation in axial SpA is debated. Improved understanding of the most relevant therapeutic targets and identification of important targeted therapies could lead to the preservation of bone in inflammatory rheumatic and musculoskeletal diseases.

Identification and Evaluation of Serum Protein Biomarkers That Differentiate Psoriatic Arthritis From Rheumatoid Arthritis.

OBJECTIVE: To identify serum protein biomarkers that might distinguish patients with early inflammatory arthritis (IA) with psoriatic arthritis (PsA) from those with rheumatoid arthritis (RA) and may be used to support appropriate early intervention. METHODS: The serum proteome of patients with PsA and patients with RA was interrogated using nano-liquid chromatography mass spectrometry (nano-LC-MS/MS) (n = 64 patients), an aptamer-based assay (SomaScan) targeting 1,129 proteins (n = 36 patients), and a multiplexed antibody assay (Luminex) for 48 proteins (n = 64 patients). Multiple reaction monitoring (MRM) assays were developed to evaluate the performance of putative markers using the discovery cohort (n = 60 patients) and subsequently an independent cohort of PsA and RA patients (n = 167). RESULTS: Multivariate machine learning analysis of the protein discovery data from the 3 platforms revealed that it was possible to differentiate PsA patients from RA patients with an area under the curve (AUC) of 0.94 for nano-LC-MS/MS, 0.69 for bead-based immunoassay measurements, and 0.73 for aptamer-based analysis. Subsequently, in the separate verification and evaluation studies, random forest models revealed that a subset of proteins measured by MRM could differentiate PsA and RA patients with AUCs of 0.79 and 0.85, respectively. CONCLUSION: We present a serum protein biomarker panel that can separate patients with early-onset IA with PsA from those with RA. With continued evaluation and refinement using additional and larger patient cohorts, including those with other arthropathies, we suggest that the panel identified here could contribute to improved clinical decision making.

Associations of vascular and bone status in arthritis patients.

Cardiovascular (CV) disease and osteoporosis (OP) have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Bone and vascular biomarkers and parameters along with the effect of 1-year anti-TNF therapy on these markers were assessed in order to determine correlations between vascular pathophysiology and bone metabolism in RA and AS. Thirty-six patients treated with etanercept or certolizumab pegol and 17 AS patients treated with ETN were included in a 12-month follow-up study. Bone and vascular markers were previously assessed by ELISA. Bone density was measured by DXA and quantitative CT (QCT). Flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) were assessed by ultrasound. Multiple correlation analyses indicated associations between bone and vascular markers. Osteoprotegerin, sclerostin and cathepsin K were significantly associated with FMD, IMT and PWV, respectively (p < 0.05). Moreover, total and trabecular BMD determined by QCT inversely correlated with IMT (p < 0.05). On the other hand, among vascular parameters, platelet-derived growth factor BB and IMT correlated with DXA femoral and QCT total BMD, respectively (p < 0.05). In the RM-ANOVA analysis, anti-TNF treatment together with baseline osteocalcin, procollagen 1 N-terminal propeptide (P1NP) or vitamin D3 levels determined one-year changes in IMT (p < 0.05). In the MANOVA analysis, baseline disease activity indices (DAS28, BASDAI), the one-year changes in these indices, as well as CRP exerted effects on multiple correlations between bone and vascular markers (p < 0.05). As the pattern of interactions between bone and vascular biomarkers differed between baseline and after 12 months, anti-TNF therapy influenced these associations. We found a great number of correlations in our RA and AS patients undergoing anti-TNF therapy. Some of the bone markers have been associated with vascular pathophysiology, while some vascular markers correlated with bone status. In arthritis, systemic inflammation and disease activity may drive both vascular and bone disease.

Peripheral quantitative computed tomography in the assessment of bone mineral density in anti-TNF-treated rheumatoid arthritis and ankylosing spondylitis patients.

INTRODUCTION: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are associated with osteoporosis. There have not been many peripheral quantitative computed tomography (QCT) studies in patients receiving biologics. We assessed volumetric and areal bone mineral density (BMD) by forearm QCT and dual-energy X-ray absorptiometry (DXA), respectively in addition to laboratory biomarkers in these arthritides. METHODS: Forty RA and AS patients treated with either etanercept (ETN) or certolizumab pegol (CZP) were undergoing follow-ups for one year. Volumetric and areal BMD, as well as parathyroid hormone (PTH), osteocalcin, RANKL, 25-hydroxyvitamin D (VITD), P1NP, CTX, sclerostin (SOST), Dickkopf 1 (DKK-1) and cathepsin K (CATHK) were determined. RESULTS: We did not observe any further bone loss during the 12-month treatment period. Volumetric and areal BMD showed significant correlations with each other (p<0.017 after Bonferroni's correction). Trabecular QCT BMD at baseline (p=0.015) and cortical QCT BMD after 12 months (p=0.005) were inversely determined by disease activity at baseline in the full cohort. Trabecular QCT BMD at baseline also correlated with CTX (p=0.011). In RA, CRP negatively (p=0.014), while SOST positively (p=0.013) correlated with different QCT parameters. In AS, RANKL at baseline (p=0.014) and after 12 months (p=0.007) correlated with cortical QCT BMD. In the full cohort, 12-month change in QTRABBMD was related to TNF inhibition together with elevated VITD-0 levels (p=0.031). Treatment and lower CATHK correlated with QCORTBMD changes (p=0.006). In RA, TNF inhibition together with VITD-0 (p<0.01) or CATHK-0 (p=0.002), while in AS, treatment and RANKL-0 (p<0.05) determined one-year changes in QCT BMD. CONCLUSIONS: BMD as determined by QCT did not change over one year of anti-TNF treatment. Disease activity, CATHK, RANKL and VITD may be associated with the effects of anti-TNF treatment on QCT BMD changes. RA and AS may differ in this respect.

Comparison of Composite Measure Remission Targets in Psoriatic Arthritis.

OBJECTIVE: To identify (1) which composite measure is the most stringent target of remission; and (2) which disease component target proves the most difficult to achieve in the different states of minimal disease activity (MDA), Composite Psoriatic Disease Activity Index (CPDAI), Disease Activity Index for Psoriatic Arthritis (DAPSA), and clinical DAPSA (cDAPSA) in patients with psoriatic arthritis (PsA). METHODS: There were 258 patients with PsA recruited. Disease remission was evaluated comparing 4 different composite measures and using remission cutoffs as previously proposed (very low disease activity [VLDA], CPDAI ≤ 2, DAPSA ≤ 4, cDAPSA ≤ 4). RESULTS: Patients met VLDA criteria (MDA 7/7) in 9.0% of visits, DAPSA remission in 19.8%, cDAPSA remission in 23.4% and CPDAI remission in 30.2%. Of 258 patients, MDA criteria (≥ 5/7) were fulfilled in 46.5%. Of those in MDA, VLDA criteria were reached in 25.0%. Patients met the pain visual analog scale (VAS) target in 57.5% of visits when they were in MDA, 43.3% when in low disease activity (MDA 5-6/7), and 44.8% when in CPDAI remission. Multivariate regression analysis revealed that pain VAS was the least likely target to be achieved. Patients with inflammatory-type back pain had significantly higher pain scores; further, a significant relationship was seen between Bath Ankylosing Spondylitis Disease Activity Index and pain VAS. CONCLUSION: Based on our analysis, VLDA proved the most stringent target of disease remission in PsA compared to CPDAI, DAPSA, and cDAPSA. The pain VAS target of ≤ 1.5 cm was the most difficult component to achieve. CPDAI ≤ 2 was found to be the least stringent remission target; however, measurements of axial involvement, which contributed to the elevated pain VAS score in patients not achieving VLDA, were included as a domain in CPDAI only.

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.

Effects of 1-year anti-TNF-α therapies on bone mineral density and bone biomarkers in rheumatoid arthritis and ankylosing spondylitis.

OBJECTIVES: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) have been associated with generalized and localized bone loss. We conducted a comprehensive study using imaging (dual-energy X-ray absorptiometry, DXA) and laboratory biomarkers in order to determine bone health and to study the effects of anti-tumor necrosis factor (TNF) biologics in RA and AS. PATIENTS AND METHODS: Thirty-six RA and 17 AS patients undergoing 1-year etanercept (ETN) or certolizumab-pegol (CZP) therapy were studied. Bone density was assessed by DXA at baseline and after 12 months. Serum C-reactive protein (CRP), calcium, phosphate, parathyroid hormone (PTH), vitamin D3, osteocalcin, procollagen type I N-propeptide (P1NP), C-terminal telopeptide (ßCTX), osteoprotegerin, sclerostin (SOST), Dickkopf-1 (DKK-1), soluble receptor activator nuclear kappa B ligand (sRANKL), and cathepsin K (cathK) levels were determined at baseline and after 6 and 12 months. RESULTS: TNF-α inhibition was clinically effective. Anti-TNF-α halted further bone loss over 1 year. In general, anti-TNF therapy significantly increased P1NP, SOST levels, and the P1NP/ßCTX ratios, while decreased DKK-1 and CathK production at different time points in most patient subsets. In the full cohort and in RA, baseline and/or 12-month bone mineral density (BMD) at multiple sites exerted inverse relationships with CRP and ßCTX, and positive correlation with SOST. In AS, L2-4 BMD after 1-year biologic therapy inversely correlated with baseline ßCTX, while femoral neck BMD rather showed inverse correlations with CRP. CONCLUSIONS: Anti-TNF therapy slowed down generalized bone loss, in association with clinical improvements, in both diseases. TNF blockade may enhance bone formation and suppress joint destruction. Anti-TNF therapy may act inversely on DKK-1 and SOST. Independent predictors of BMD were SOST and ßCTX in RA, whilst CRP in AS.Key Points• One-year anti-TNF therapy halted generalized bone loss in association with clinical improvement in arthritides.• Anti-TNF therapy may inversely act on DKK-1 and SOST.• Independent predictors of BMD were SOST and ßCTX in RA, while CRP in AS.

Cardiovascular Comorbidities in Psoriatic Disease.

Psoriatic disease (PsD) is a multisystem inflammatory disorder with a high prevalence of cardiovascular (CV) risk factors contributing to accelerated atherosclerosis and its sequelae. Imaging studies, notably with ultrasound, computed tomography, and positron emission tomography (PET) scanning have confirmed significant atherosclerotic change with plaque formation and vessel stenosis. Atherosclerosis is likely driven by a combination of traditional risk factors which occur more frequently in PsD and by systemic inflammation with associated pro-inflammatory cytokine production. While the mechanisms driving atherosclerosis in PsD are incompletely understood, it is now best practice to try to minimize the impact of CV risk factors by regular assessment, prevention, and treatment and also by ensuring that inflammatory musculoskeletal and cutaneous disease is adequately suppressed. Future studies need to focus on improving our understanding of the mechanisms driving atherosclerosis and, as a consequence, developing more rationale approaches to prevention and treatment.

Cardiovascular Diseases in Psoriasis and Psoriatic Arthritis.

Patients with psoriatic disease have an increased risk of developing cardiovascular (CV) events. Recent advances in imaging and biomarker research provide insights into the underlying mechanisms that link these conditions. Here, we summarize recent work in this field that was presented at the July 2018 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting in Toronto, Ontario, Canada. The presentations highlighted recent data about the association between psoriasis and vascular inflammation, the use of coronary angiogram to investigate CV outcomes, new approaches for CV risk stratification, and the shared pathomechanisms of psoriasis and atherosclerosis.

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.

Effects of targeted therapies on the bone in arthritides.

Inflammatory arthritides, such as rheumatoid arthritis (RA) and spondyloarthritides (SpA) have been associated with both localized bone resorption and/or formation, and generalized osteoporosis. Systemic inflammation may be the major driver for bone loss in arthritis. In RA and peripheral SpA the RANK-RANKL-OPG network is involved in bone resorption, while in axial SpA the Wnt-ß-catenin axis and its inhibitors (DKK-1, sclerostin) are the most relevant. Targeted therapies including biologics and small molecule tyrosine kinase inhibitors may interfere with inflammatory bone metabolism. Most of these compounds are able to slow down radiographic progression and osteoporosis in arthritides. In very early cases of non-radiological SpA, there may be a window of opportunity allowing to prevent syndesmophyte formation. The inability of targeted therapies to increase the production of DKK-1 and sclerostin may explain the lack of efficacy of TNF inhibitors to halt syndesmophyte formation in SpA. Further clinical trials are needed to better understand the bone effects of targeted therapies.

Striking difference of periarticular bone density change in early psoriatic arthritis and rheumatoid arthritis following anti-rheumatic treatment as measured by digital X-ray radiogrammetry.

OBJECTIVES: To examine changes in hand BMD as measured by digital X-ray radiogrammetry (DXR-BMD) in early PsA compared with RA patients prior to and 3 and 12 months after introducing an antirheumatic treatment. Further, to identify predictors for hand bone loss at the time of disease presentation. METHODS: Recent-onset, active, treatment-naïve patients were recruited. Clinical assessment, hand X-rays and DXR were obtained at 0, 3 and 12 months. Mean DXR-BMD for both hands and changes in DXR-BMD (mg/cm(2)/month) were compared between the two groups. We compared baseline disease characteristics of patients with normal hand DXR-BMD with those with bone loss. Logistic regression analyses were performed to identify predictors of hand BMD loss. RESULTS: A total of 64 patients were included. Hand DXR-BMD decreased in RA throughout the study (P = 0.043). Changes in periarticular bone density over 12 months differed between PsA and RA (P = 0.001). Hand bone loss at 3 months was associated with elevated BMI [odds ratio (OR) = 3.59, P = 0.041] and heavier alcohol intake (OR = 1.13, P = 0.035). Diagnosis of RA (OR = 57.48, P = 0.008), heavier alcohol intake (OR = 1.27, P = 0.012) and higher swollen joint count (SJC28) (OR = 1.5, P = 0.036) were independent predictors for hand bone loss in the first year. CONCLUSION: Following treatment, we found ongoing hand bone loss in RA and unchanged periarticular bone density in PsA, supporting the hypothesis that different pathomechanisms are involved in hand bone remodelling in PsA. Presence of RA, heavier alcohol intake and higher SJC were identified as independent predictors for hand bone loss over 1 year.

Developing clinically relevant biomarkers in inflammatory arthritis: A multiplatform approach for serum candidate protein discovery.

PURPOSE: To identify candidate biomarkers that have the potential to distinguish between patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA) and explore the value of combining different protein discovery platforms for the development of a multiplexed protein biomarker panel. EXPERIMENTAL DESIGN: Serum samples from 32 patients (PsA; n = 16 and RA; n = 16) defined as active, early onset, and treatment naïve were analyzed using unbiased label-free LC-MS/MS, a microsphere bead-based immunoassay (Luminex xMAP) and an aptamer-based assay (SOMAscan). RESULTS: LC-MS/MS was used to quantify 324 proteins, while the Luminex xMAP targeted 48 proteins and SOMAscan supported the measurement of 1129 proteins. The combined data from these techniques gave reproducible quantification of 1501 proteins in total. Of these, 42 (LC-MS/MS), 3 (Luminex xMAP), and 127 (SOMAscan) proteins were found to be differentially expressed between PsA and RA (p < 0.05). CONCLUSION AND CLINICAL RELEVANCE: Using three different and potentially complementary proteomic platforms we identified a total of 172 proteins that are differentially expressed in patients with PsA compared to RA. These proteins collectively represent candidates for inclusion in a protein signature that could be developed as a diagnostic test to discriminate patients with PsA from RA and therefore be of clinical utility.

GRAPPA Trainees Symposium 2013: a report from the GRAPPA 2013 Annual Meeting.

At the 2013 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) in Toronto, Ontario, Canada, 26 dermatology and rheumatology fellows engaged in psoriasis or psoriatic arthritis research were invited to present their work at the Trainees Symposium, which preceded the annual meeting and was also attended by GRAPPA members from around the world. Herein, we provide a brief overview of the 6 oral presentations and 25 posters presented, which reflect the focus and diversity of current basic and clinical research in psoriatic disease.

Th17 and Th22 cells in psoriatic arthritis and psoriasis.

INTRODUCTION: The aim of this study was to characterize interleukin 17 (IL-17) and interleukin 22 (IL-22) producing cells in peripheral blood (PB), skin, synovial fluid (SF) and synovial tissue (ST) in patients with psoriasis (Ps) and psoriatic arthritis (PsA). METHODS: Flow cytometry was used to enumerate cells making IL-22 and IL-17, in skin and/or SF and PB from 11 patients with Ps and 12 patients with PsA; skin and PB of 15 healthy controls and SF from rheumatoid arthritis (RA) patients were used as controls. Expression of the interleukin 23 receptor (IL-23R) and chemokine receptors CCR4 and CCR6 was examined. Secretion of IL-17 and IL-22 was measured by ELISA. ST was analysed by immunohistochemical staining of IL-17 and IL-22. RESULTS: Increased frequencies of IL-17+ and IL-22+ CD4+ T cells were seen in PB of patients with PsA and Ps. IL-17 secretion was significantly elevated in both PsA and Ps, whilst IL-22 secretion was higher in PsA compared to Ps and healthy controls. A higher proportion of the CD4+ cells making IL-17 or IL-22 expressed IL-23R and frequencies of IL-17+, CCR6+ and CCR4+ T cells were elevated in patients with Ps and those with PsA. In patients with PsA, CCR6+ and IL-23R + T cells numbers were elevated in SF compared to PB. Increased frequencies of IL-17+ and IL-22+ CD4+ T cells were demonstrated in Ps skin lesions. In contrast, whilst elevated frequencies of CD4+ IL-17+ cells were seen in PsA SF compared to PB, frequencies of CD4+ IL-22+ T cells were lower. Whereas IL-17 expression was equivalent in PsA, osteoarthritis (OA) and RA ST, IL-22 expression was higher in RA than either OA or PsA ST, in which IL-22 was strikingly absent. CONCLUSIONS: Elevated frequencies of IL-17 and IL-22 producing CD4+ T cells were a feature of both Ps and PsA. However their differing distribution at disease sites, including lower frequencies of IL-22+ CD4+ T cells in SF compared to skin and PB, and lack of IL-22 expression in ST suggests that Th17 and Th22 cells have common, as well as divergent roles in the pathogenesis of Ps and PsA.

Periarticular bone gain at proximal interphalangeal joints and changes in bone turnover markers in response to tumor necrosis factor inhibitors in rheumatoid and psoriatic arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are characterized by periarticular bone erosion; periarticular bone formation is a feature in PsA. The effect of anti-tumor necrosis factor-α (TNF-α) on periarticular bone remodeling is unclear in both diseases. Our aim was to assess the response of bone turnover markers (BTM) and hand bone mineral density (BMD) to anti-TNF over 3 years in RA and PsA. METHODS: We measured serum bone-specific alkaline phosphatase (bone ALP), procollagen type-I N-propeptide (PINP), intact osteocalcin, C-terminal cross-linking telopeptides (CTX-I), urinary N-terminal cross-linking telopeptide of type-I collagen (NTX-I), and free deoxypyridinoline crosslinks (fDPD) at baseline, 1, 12, and 36 months. BMD measurements (hands/spine/hip) were obtained at 3 timepoints. RESULTS: We recruited 62 patients (RA 35; PsA 27). BTM correlated significantly with hand BMD but not with central BMD. Low hand BMD was associated with RA and increased BTM. Following anti-TNF therapy, hip BMD declined while spine and hand BMD were unchanged. Periarticular BMD at proximal interphalangeal (PIP) joints increased while it decreased at metacarpophalangeal joints. Bone ALP increased steadily and was always higher in PsA. PINP and intact osteocalcin increased to a lesser extent, but resorption markers did not change. CONCLUSION: At baseline, hand BMD was inversely associated with BTM. Bone formation rather than resorption markers better showed the bone response to anti-TNF. Despite a lack of effect on central BMD, the modest effect of anti-TNF on PIP BMD may provide evidence that BTM reflect specifically bone remodeling activity at periarticular sites of inflammation in RA and PsA.

Angiogenesis and vasculogenesis in rheumatoid arthritis.

PURPOSE OF REVIEW: Angiogenesis is the formation of new capillaries from pre-existing vessels, whereas vasculogenesis is de-novo capillary formation from endothelial precursor cells (EPCs). Current understanding of the role of angiogenesis and vasculogenesis in rheumatoid arthritis (RA) and possibilities of therapeutic intervention should be summarized. RECENT FINDINGS: There have been many recent studies on the role of the hypoxia and hypoxia-inducible factor (HIF)-vascular endothelial growth factor (VEGF)-angiopoietin axis in angiogenesis associated with RA. The role of additional growth factors, chemokines, cytokines, matrix components and adhesion molecules has been further characterized. Macrophage migration inhibitory factor (MIF) may link inflammation, angiogenesis and atherosclerosis. Junctional adhesion molecules (JAMs) and focal adhesion kinases (FAKs) have recently been implicated in inflammatory angiogenesis. Novel information regarding the role of serum amyloid A (SAA) and sphingosine kinase has become available. Most of these angiogenic factors have recently been targeted using various techniques and arthritis models. Whereas angiogenesis is abundant in RA, there is defective EPC function and vasculogenesis leading to atherosclerosis and vascular disease in arthritis. Treatment with EPCs already under investigation in vascular diseases may also be attempted in RA. SUMMARY: Targeting angiogenesis and restoration of vasculogenesis may be beneficial for the therapy and outcome of RA.