Douglas J. Veale

2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative

OBJECTIVE The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative

Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusions The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update

Background Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. Methods A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. Results The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. Conclusions These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.

DISTINCT VASCULAR PATTERNS OF EARLY SYNOVITIS IN PSORIATIC, REACTIVE, AND RHEUMATOID ARTHRITIS

OBJECTIVE To examine the macroscopic vascular pattern of early synovitis in psoriatic arthritis (PsA), reactive arthritis (ReA), and rheumatoid arthritis (RA) and to assess the reliability of the grading features for synovitis. METHODS Forty-four patients (14 PsA, 12 ReA, and 18 RA) with knee synovitis who were undergoing arthroscopy were assessed. Video recordings of the examination were scored independently by 3 arthroscopists who were blinded to the patients identity and clinical details. Features of vascularity, villous formation, pannus, granularity, and capillary hyperemia were recorded and kappa values (-1<kappa<1) were calculated to assess interobserver reliability. RESULTS The interobserver reliability between experienced observers was high (kappa> or =0.8) for features of vascularity, villous hypertrophy, and pannus. Seventy-three percent of the PsA and ReA patients had predominantly tortuous, bushy vessels; 89% of the RA patients had mainly straight, branching vessels. CONCLUSION The distinct vascular patterns in PsA and ReA compared with those in RA may reflect different specific vascular factors in the pathogenesis of these arthritides. Vascularity and villous hypertrophy are the most reliable features of synovitis grading.

Immunopathology of psoriasis and psoriatic arthritis

Psoriatic arthritis (PsA) is characterised by several unique clinical features that differentiate it from rheumatoid arthritis (RA). Attempts to identify immunopathological mechanisms, some shared with psoriasis, that underlie these differences from RA have been most challenging. Recent research studies, however, highlight novel findings in PsA at the molecular, cellular, and tissue levels that form the basis for a new understanding of this relatively common form of inflammatory arthritis. In particular, the availability of new, biological antitumour necrosis factor α therapies have allowed further insight into the immunopathology of psoriasis and PsA. This brief review focuses on immunohistological studies in psoriatic skin, PsA synovium, and bone to demonstrate how these data advance our knowledge of disease pathogenesis.

Macrovascular disease and systemic sclerosis

OBJECTIVE To determine if macrovascular disease is more prevalent in systemic sclerosis (SSc) compared with unaffected subjects. METHODS 54 patients with SSc (both limited and diffuse disease) and 43 unaffected control subjects of similar age and sex were recruited. All subjects underwent a basic screen for conventional atherosclerotic disease risk factors. All had non-invasive vascular assessments—that is, carotid duplex scanning and measurement of ankle brachial blood pressure index—to identify the presence of asymptomatic peripheral vascular disease. RESULTS 33 of 52 (64%) patients had carotid artery disease compared with only 15 of 42 (35%) controls (p=0.007). Eleven (21%) of these patients had moderate disease compared with only two (5%) controls (NS). Nine of 53 (17%) SSc patients had evidence of peripheral arterial disease compared with no controls. This result was also statistically significant (p=0.003). There were no significant differences in the basic risk factor profile, which included cigarette smoking, systolic and diastolic blood pressure, cholesterol, trigyceride and glucose concentrations. CONCLUSION Macrovascular disease is more common in SSc. Screening of these patients may allow identification of “at risk” patients at an early stage and allow the study of treatments to attenuate the high rate of cardiovascular mortality in these patients.

Quantitative microscopic analysis of inflammation in rheumatoid arthritis synovial membrane samples selected at arthroscopy compared with samples obtained blindly by needle biopsy

OBJECTIVE To evaluate microscopic measures of inflammation in rheumatoid arthritis synovial tissue samples selected at arthroscopy compared with those obtained blindly by needle biopsy from the suprapatellar pouch (SPP) of the same joint. METHODS Samples were selected at knee arthroscopy from the SPP and the lateral and medial gutters. Immediately following arthroscopy, a biopsy needle was inserted through the same portal into the SPP by a second investigator, and 3 further samples were obtained blindly. Using standard immunohistologic methods, all samples were analyzed by a single investigator without knowledge of the original tissue location and biopsy technique. Following staining with anti-CD3 and anti-CD68 monoclonal antibodies, T lymphocyte and macrophage infiltration were measured by quantitative analysis. RESULTS Synovial tissues from 14 patients were analyzed. In comparing microscopic measures of inflammation using the 2 procedures, mean scores of lining cell depth and the percentage of CD68+ cells in the lining layer correlated positively (tau = 0.59, P = 0.003 and tau = 0.73, P = 0.0003, respectively). In the sublining layer, CD3+ cell counts also correlated significantly (tau = 0.71, P = 0.0004). Sublining CD68+ cell counts did not correlate. This was explained by the observation that CD68+ cell infiltration in areas adjacent to articular cartilage was significantly greater than in the SPP (P = 0.01), suggesting preferential trafficking to this site by macrophages, but not by T lymphocytes. Macroscopic appearance at arthroscopy did not predict microscopic features. CONCLUSION Most microscopic measures of inflammation in synovial tissue samples obtained blindly from the SPP were similar to those determined in samples selected at arthroscopy. However, measurements in samples from the SPP may underestimate the intensity of macrophage infiltration in areas more adjacent to cartilage. These observations have important implications for future study of macrophage function in synovial tissue.

Synovial tissue hypoxia and inflammation in vivo

Introduction Hypoxia is a microenvironmental feature in the inflamed joint, which promotes survival advantage for cells. The aim of this study was to examine the relationship of partial oxygen pressure in the synovial tissue (tPO2) in patients with inflammatory arthritis with macroscopic/microscopic inflammation and local levels of proinflammatory mediators. Methods Patients with inflammatory arthritis underwent full clinical assessment and video arthroscopy to quantify macroscopic synovitis and measure synovial tPO2 under direct visualisation. Cell specific markers (CD3 (T cells), CD68 (macrophages), Ki67 (cell proliferation) and terminal deoxynucleotidyl transferase dUTP nick end labelling (cell apoptosis)) were quantified by immunohistology. In vitro migration was assessed in primary and normal synoviocytes (synovial fibroblast cells (SFCs)) using a wound repair scratch assay. Levels of tumour necrosis factor α (TNFα), interleukin 1β (IL1β), interferon γ (IFNγ), IL6, macrophage inflammatory protein 3α (MIP3α) and IL8 were quantified, in matched serum and synovial fluid, by multiplex cytokine assay and ELISA. Results The tPO2 was 22.5 (range 3.2–54.1) mm Hg and correlated inversely with macroscopic synovitis (r=−0.421, p=0.02), sublining CD3 cells (−0.611, p<0.01) and sublining CD68 cells (r=−0.615, p<0.001). No relationship with cell proliferation or apoptosis was found. Primary and normal SFCs exposed to 1% and 3% oxygen (reflecting the median tPO2 in vivo) induced cell migration. This was coupled with significantly higher levels of synovial fluid tumour necrosis factor α (TNFα), IL1β, IFNγ and MIP3α in patients with tPO2 <20 mm Hg (all p values <0.05). Conclusions This is the first study to show a direct in vivo correlation between synovial tPO2, inflammation and cell migration, thus it is proposed that hypoxia is a possible primary driver of inflammatory processes in the arthritic joint.

Human rheumatoid arthritis tissue production of IL-17A drives matrix and cartilage degradation: synergy with tumour necrosis factor-α, Oncostatin M and response to biologic therapies

IntroductionThe aim of this study was to examine IL-17A in patients, following anti-TNF-α therapy and the effect of IL-17A on matrix turnover and cartilage degradation.MethodsIL-17A expression was examined by ELISA and immunohistology in the rheumatoid arthritis (RA) joints. RA whole synovial tissue explant (RA ST), primary synovial fibroblasts (RASFC), human cartilage and chondrocyte cultures were stimulated with IL-17A +/- TNF-α and Oncostatin M (OSM). Matrix metalloproteinase (MMP) and tissue inhibitor (TIMP-1) were assessed by ELISA and zymography. Cartilage proteoglycan release was assessed histologically by Safranin-O staining. Clinical parameters, IL-17A, MMP/TIMP were assessed in patients pre/post biologic therapy.ResultsIL-17A levels were higher in RA vs osteoarthritis (OA)/normal joints (P < 0.05). IL-17A up-regulated MMP-1, -2, -9, and -13 in RA ST, RASFC, cartilage and chondrocyte cultures (P < 0.05). In combination with TNF-α and OSM, IL-17A shifted the MMP:TIMP-1 ratio in favor of matrix degradation (all P < 0.05). Cartilage proteoglycan depletion in response to IL-17A was mild; however, in combination with TNF-α or OSM showed almost complete proteoglycan depletion. Serum IL-17A was detected in 28% of patients commencing biologic therapy. IL-17A negative patients demonstrated reductions post therapy in serum MMP1/TIMP4, MMP3/TIMP1 and MMP3/TIMP4 ratios and an increase in CS846 (all P < 0.05). No significant changes were observed in IL-17A positive patients.ConclusionsIL-17A is produced locally in the inflamed RA joint. IL-17A promotes matrix turnover and cartilage destruction, especially in the presence of other cytokines, mimicking the joint environment. IL-17A levels are modulated in vivo, following anti-TNF therapy, and may reflect changes in matrix turnover.

Matrix metalloproteinase 9, apoptosis, and vascular morphology in early arthritis.

OBJECTIVE To examine matrix metalloproteinase 9 (MMP-9) in the synovial fluid (SF) and synovial membrane (SM) in relation to vascular endothelial cell (EC) apoptosis, vascular endothelial growth factor (VEGF), and SM vascular pattern. METHODS Thirty-four patients underwent needle arthroscopy of the knee joint; 12 had early rheumatoid arthritis (RA), 12 had early psoriatic arthritis (PsA), and 10 had osteoarthritis (OA). The early RA and early PsA patients were matched for disease activity. SF levels of MMP-9 and VEGF were measured by an enzyme-linked immunosorbent assay, and EC apoptosis was measured by TUNEL assay. MMP-9 expression was examined in SM by immunohistochemistry. Synovial tissue explants were stimulated with VEGF, and MMP-9 levels were measured in the supernatants. The synovial vascular pattern was recorded. RESULTS SF MMP-9 levels were significantly higher in early PsA patients than in early RA patients; OA patients had minimal levels. MMP-9 levels correlated with blood vessel morphology and SF VEGF levels. MMP-9 expression was greater in early PsA SM than in early RA SM, but the difference was not significant. In contrast however, EC apoptosis was greater in early RA SM than in early PsA SM. MMP-9 levels increased 2-fold and 9-fold, respectively, in SM explant culture supernatants on day 7 in response to stimulation with 25 ng/ml and 50 ng/ml of VEGF. CONCLUSION SF MMP-9 levels correlate with the pattern of SM neovascularization and SF VEGF levels in early inflammatory arthritis, and VEGF increases MMP-9 production by SM. Endothelial cell apoptosis, however, appears to be more prevalent in early RA. This combination of factors may explain the pattern of differential angiogenesis in these arthritides.