Contribution of the IL-17 Pathway to Psoriasis and Psoriatic Arthritis.

Investigators have accrued compelling evidence that the IL-17 pathway is central to the pathogenesis of psoriasis and psoriatic arthritis. The evidence comprises genome-wide association studies (GWAS), data from experimental murine models and findings from in vitro studies on patients' cells or tissue biopsies. More recently, the success of drugs blocking the IL-17 pathway in treating both psoriasis (PsO) and psoriatic arthritis (PsA) confirms that IL-17 is a clinically relevant therapeutic target. However, there remain many unanswered questions: is PsA simply an extension of PsO from the skin to the synovial tissue or are there differences in the underlying pathogenesis of these diseases? Which cell type represents the primary source of IL-17 in PsO and PsA? And how are these cells regulated? This review outlines the IL-17 pathway, summarises the evidence supporting its role in PsO and PsA and discusses recent data that may help to address these yet unresolved questions.

Comparison of three screening tools to detect psoriatic arthritis in patients with psoriasis (CONTEST study).

BACKGROUND: Multiple questionnaires to screen for psoriatic arthritis (PsA) have been developed but the optimal screening questionnaire is unknown. OBJECTIVES: To compare three PsA screening questionnaires in a head-to-head study using CASPAR (the Classification Criteria for Psoriatic Arthritis) as the gold standard. METHODS: This study recruited from 10 U.K. secondary care dermatology clinics. Patients with a diagnosis of psoriasis, not previously diagnosed with PsA, were given all three questionnaires. All patients who were positive on any questionnaire were invited for a rheumatological assessment. Receiver operating characteristic (ROC) curves were used to compare the sensitivity, specificity and area under the curve of the three questionnaires according to CASPAR criteria. RESULTS: In total, 938 patients with psoriasis were invited to participate and 657 (70%) patients returned the questionnaires. One or more questionnaires were positive in 314 patients (48%) and 195 (62%) of these patients attended for assessment. Of these, 47 patients (24%) were diagnosed with PsA according to the CASPAR criteria. The proportion of patients with PsA increased with the number of positive questionnaires (one questionnaire, 19·1%; two, 34·0%; three, 46·8%). Sensitivities and specificities for the three questionnaires, and areas under the ROC curve were, respectively: Psoriatic Arthritis Screening Evaluation (PASE), 74·5%, 38·5%, 0·594; Psoriasis Epidemiology Screening Tool (PEST), 76·6%, 37·2%, 0·610; Toronto Psoriatic Arthritis Screen (ToPAS), 76·6%, 29·7%, 0·554. The majority of patients with a false positive response had degenerative or osteoarthritis. CONCLUSION: Although the PEST and ToPAS questionnaires performed slightly better than the PASE questionnaire at identifying PsA, there is little difference between these instruments. These screening tools identify many cases of musculoskeletal disease other than PsA.

Evaluating the use of the interferon-γ response to Mycobacterium tuberculosis-specific antigens in patients with psoriasis prior to antitumour necrosis factor-α therapy: a prospective head-to-head cross-sectional study.

BACKGROUND: Targeted biological therapies have transformed the treatment of chronic inflammatory disease. However, reactivation of latent tuberculosis infection (LTBI) is a significant risk with the use of antitumour necrosis factor (anti-TNF)-α therapy and screening is mandatory prior to treatment. The tuberculin skin test (TST) may be difficult to interpret in patients with inflammatory disease or receiving immunosuppressive therapies. OBJECTIVES: The aim of this study was to evaluate and compare the QuantiFERON(®) -TB Gold In-Tube (QFR) and T-SPOT.TB (TSTB) interferon-γ-release assays (IGRA) against the TST in a cohort of patients commencing anti-TNF-α therapies for chronic inflammatory disease. METHODS: A prospective cross-sectional study was undertaken at a London tertiary referral centre. Demographic data collected included TB risk factors. TST, QFR and TSTB were performed in all patients. RESULTS: Seventy patients with chronic plaque psoriasis were included in the study. Agreement between QFR and TSTB, excluding indeterminate results, was 89% (κ = 0.567), between QFR and TST 85% (κ= 0.313) and 81% (κ = 0.244) between TSTB and TST. There was no significant association with concomitant immunosuppression and either TST or IGRA results. Seven patients received chemoprophylaxis for LTBI diagnosed after clinical risk assessment together with positive TST and/or IGRA. Three patients had positive results in all three tests. CONCLUSIONS: While there was moderate overall agreement between QFR and TSTB and fair correlation between TST, QFR and TSTB, there were a number of discordant results, suggesting that a three-pronged approach using TST, QFR and TSTB may be of additional benefit.

Arthroscopic estimation of the extent of chondropathy.

INTRODUCTION: Arthroscopy has been used to evaluate articular cartilage (AC) pathology in osteoarthritis (OA) for outcome measurement and validation of non-invasive imaging. However, many fundamental aspects of arthroscopic assessment remain un-validated. OBJECTIVES: This study evaluated arthroscopic estimates of extent of chondropathy. METHODS: Serial arthroscopic assessments were performed in a group of 15 sheep before and after bilateral stifle medial meniscectomy (MMx). Post-mortem assessments were performed in un-MMx sheep and 4 and 16 weeks post-MMx. Arthroscopic assessments of the extent of each grade of chondropathy were compared with a non-arthroscopic hybrid assessment that incorporated biomechanical, thickness and macroscopic assessments. RESULTS: Arthroscopy evaluated only 36% of AC and missed significant pathological changes, softening and chondro-osteophyte, occurring in peripheral regions. The patterns of change in arthroscopic assessments were similar to those of the non-arthroscopic assessment but there was a very strong tendency to over-estimate the extent of softened AC after MMx. In spite of these limitations arthroscopic assessments were responsive to change. Estimates of the extent of normal and softened AC were most responsive to change over time followed by estimates of superficial and deep fibrillation. Arthroscopy was as an excellent discriminator between normal and OA. Assessments of chondro-osteophyte and exposed bone were not responsive to change. CONCLUSIONS: Arthroscopic estimates of extent of chondropathy are prone to substantial error. While experience and training may reduce these errors other approaches may more effectively improve performance.

Arthroscopy -- a potential "gold standard" for the diagnosis of the chondropathy of early osteoarthritis.

OBJECTIVES: The aims of this study were to: 1. Evaluate the performance of arthroscopy for the diagnosis of chondropathy and to compare it to that of direct non-arthroscopic assessments; 2. Determine intra-observer reliability of arthroscopic assessments; 3. Evaluate the effects of the arthroscopic video quality and probing upon diagnostic performance. DESIGN: The ovine medial meniscectomy (MMx) model of early osteoarthritis (OA) was used assuming that pre-MMx articular cartilage (AC) was "normal" and post-MMx AC "chondropathic". Video recordings of arthroscopic assessments of each stifle compartment were evaluated. Scores were given for the quality of the video and the amount of probing. The diagnostic performances of dynamic shear modulus (G), light microscopic assessment and superficial zone collagen birefringence assessments were evaluated and compared to that of arthroscopy. Intra-observer reliability of arthroscopic assessments was also evaluated. RESULTS: Arthroscopic assessments had high sensitivity (91-100%), specificity (62-88%) and accuracy (75-93%) for the diagnosis of chondropathy 16 weeks after MMx. Arthroscopy compared favourably with the direct non-arthroscopic assessments in the lateral compartment and was found to have extremely high intra-observer reliability (kappa 0.78-1.00). The quality of arthroscopic video recordings and the amount of probing did not significantly influence accuracy or reliability. CONCLUSIONS: Arthroscopy performs as well as direct non-arthroscopic assessments of AC for diagnosis of early OA. These results suggest that arthroscopy can be used as a "gold standard" for the validation of non-invasive assessments like magnetic resonance imaging and that arthroscopic diagnosis can be based on small amounts of video footage without AC probing.

Effects of a PEGylated soluble TNF receptor type 1 (PEG sTNF-RI) on cytokine expression in adjuvant arthritis.

OBJECTIVE: To investigate the effects of TNF blocking therapy on synovial immune activity in rat adjuvant arthritis (AA) by measuring mRNA expression of key macrophage and T cell cytokines during PEG sTNF-RI treatment (10mg/kg) on days 8, 10 and 12. METHODS: Paw volume was assessed every 3-4 days. Ankles were removed for quantitative radiology and histology and synovial membrane removed to determine cytokine mRNA expression using semi-quantitative RT-PCR. T cells in joints were quantified by immunohistochemistry. RESULTS: Paw volume was significantly decreased in rats treated with PEG STNF-RI from days 12 to 17. Histology scores and synovial T cell numbers were reduced on days 13 and 17 and radiology scores significantly reduced on day 13. Expression of synovial TNF, IFN-gamma, IL-17, IL-2 and IL-4 mRNA was unchanged in treated rats and TGF-beta expression was significantly increased at day 13. CONCLUSIONS: PEG sTNF-RI attenuates AA and disease recurs after treatment ceases, similar to human rheumatoid arthritis. Continued TNF production and/or ongoing T cell activity, may explain the recrudescence of disease once treatment is stopped.

Poor accuracy and interobserver reliability of knee arthroscopy measurements are improved by the use of variable angle elongated probes.

OBJECTIVES: (a)To determine the accuracy and reliability of arthroscopic measurements of cartilage lesion diameter in an artificial right knee model; (b) to determine whether the use of a set of variable angle elongated probes improves performance; and (c) to identify other sources of variability. METHODS: Ovoid "lesions" were drawn on the five cartilage surfaces of four plastic knees models. Two observers assessed these 20 lesions arthroscopically, measuring two diameters in orientations parallel and orthogonal to the probe. Observer 1 (orthopaedic surgeon) and observer 2 (arthroscopic rheumatologist) made two sets of measurements, firstly with the conventional probe and five months later with the variable angle elongated (VAE) probes. The knees were disarticulated to determine true lesion diameter. RESULTS: Observer 1 had negligible bias and good accuracy regardless of orientation or probe type. Observer 2 demonstrated both bias and poor accuracy using the conventional probe. Both improved using VAE probes. Poor interobserver reliability with conventional probes also improved using VAE probes. Major sources of variability could be traced to the probe type, the characteristics of the operator, and the orientation of the lesion in relation to the probe; the lesion location itself did not cause variability. CONCLUSIONS: Variation in accuracy and poor interobserver reliability of measurements with conventional methods of cartilage lesion diameter measurement improved when specially designed measurement probes were used. Arthroscopic measurements performed as well as most clinical and radiographic measures. These findings have important implications for the use of arthroscopy as an outcome in multicentre trials where arthroscopists have different levels of experience.

The in vivo effects of tumour necrosis factor blockade on the early cell mediated immune events and syndrome expression in rat adjuvant arthritis.

Anti-TNF therapy is effective in rheumatoid arthritis (RA); however, its mechanisms of action are incompletely understood. T cell-driven mechanisms are thought to play an important role in RA and the effects of TNF blockade on these mechanisms are unclear. Adjuvant arthritis (AA) is a T cell dependent model of inflammatory arthritis. The aims of this study were to investigate the effects of TNF blockade on in vivo T cell cytokine expression and to clarify the role of TNF in the inguinal lymph nodes (ILN) in early arthritis. AA was induced in male DA rats. Rats received either 3 mg/kg or 10 mg/kg PEG sTNF-RI at days 0, 2 and 4 postinduction or 10 mg/kg anti-TNF antibody on day of arthritis induction. Control rats received either saline or normal sheep serum. Paw volume was assessed every 3-4 days. Rats were sacrificed on days 0, 6, 13 and 21 postinduction. Ankles were removed for quantitative radiology and histology. Synovium and ILN were removed for cell culture and to determine mRNA expression of cytokines using semiquantitative RT-PCR. TNF and IFN-gamma protein production was measured using a bioassay and an ELISA. TNF blockade did not suppress mRNA expression of T cell cytokines in the ILN of rats in the early phase of AA, suggesting ongoing T cell activity. TNF protein production by ILN cells in culture was reduced in PEG sTNF-RI treated rats, although mRNA expression was increased in the ILN prior to culture. Early administration of PEG sTNF-RI did not attenuate AA, in contrast to an anti-TNF antibody, which suppressed disease. A shorter half-life for the PEG sTNF-RI compared with the anti-TNF antibody or the development of anti-PEG sTNF-RI antibodies may account for these results.

Prospective evaluation of magnetic resonance imaging and physical examination findings in patients with greater trochanteric pain syndrome.

OBJECTIVE: This study examined patients with greater trochanteric pain syndrome (GTPS) to determine the prevalence of gluteus medius pathology by utilizing magnetic resonance imaging (MRI), and to evaluate the presence of Trendelenburg's sign, pain on resisted hip abduction, and pain on resisted hip internal rotation as predictors of a gluteus medius tear in this group of patients. METHODS: Twenty-four subjects with clinical features consistent with GTPS were recruited. A standard physical assessment was performed at study entry, including assessment of the 3 specific physical signs. Following this initial assessment, MRI of the affected hip was performed. A 1.5T whole body MRI system was utilized, with T1 and T2 fast spin-echo sequences performed in the coronal and axial planes. All MR images were reviewed in random order by a single radiologist. In 12 patients, the 3 physical signs were assessed at study entry and at 2 months by the same observer and the intraobserver reliability for each of the signs was calculated. RESULTS: All subjects were women (median age 58 years, range 36-75 years). The median duration of symptoms was 12 months (range 12-60 months). MRI findings were as follows: 11 patients (45.8%) had a gluteus medius tear, 15 patients (62.5%) had gluteus medius tendinitis (pure tendinitis in 9 patients and tendinitis with a tear in 6 patients), 2 patients had trochanteric bursal distension, and 1 patient had avascular necrosis of the femoral head. Trendelenburg's sign was the most accurate of the 3 physical signs in predicting a tendon tear, with a sensitivity of 72.7% and a specificity of 76.9%. Moreover, Trendelenburg's sign was the most reliable measure, with a calculated intraobserver kappa of 0.676 (95% confidence interval 0.270-1.08). CONCLUSION: The results support the hypothesis that gluteus medius tendon pathology is important in defining GTPS. In this series, trochanteric bursal distension was uncommon and did not occur in the absence of gluteus medius pathology. The physical findings suggest that Trendelenburg's sign is the most sensitive and specific physical sign for the detection of gluteus medius tears, with an acceptable intraobserver reliability. Further delineation with MRI, especially in patients with a positive Trendelenburg's sign, is recommended prior to any consideration of surgery in this group of patients. Finally, with the pathology of this condition defined, the challenge will be to devise and assess, by randomized controlled trial, an appropriate treatment strategy for this group of patients.

The kappa-opioid agonist, asimadoline, alters cytokine gene expression in adjuvant arthritis.

OBJECTIVE: We have previously found that the kappa-opioid agonist, asimadoline, attenuates adjuvant arthritis in a dose-dependent, antagonist-reversible manner. To elucidate possible mechanisms, we investigated the effects of asimadoline (5 mg/kg/day i.p.) or vehicle on in vivo cytokine expression and T-cell recruitment in adjuvant arthritis. METHODS: Arthritis severity was assessed every 3-4 days for 21 days. Rats were killed on days 0, 13 and 21 post-induction and synovial membrane and inguinal lymph nodes were removed for mRNA extraction. Changes in cytokine mRNA expression were measured using reverse transcription-polymerase chain reaction (RT-PCR) and densitometry. T cells in joints were quantified by immunohistochemistry. RESULTS: Asimadoline significantly decreased arthritis severity at day 13, with a concomitant decrease in synovial membrane expression of cytokines interleukin-17 and transforming growth factor-beta (TGF-beta) mRNA at day 13, and no change in T cell numbers in the joints of arthritic rats. By contrast, in the inguinal lymph nodes, expression of tumour necrosis factor was increased at day 13 and TGF-beta mRNA was increased throughout. CONCLUSION: An altered balance, therefore, in the pro- and anti-inflammatory effects of TGF-beta by asimadoline might explain its striking anti-arthritic actions.

Cytokine expression and synovial pathology in the initiation and spontaneous resolution phases of adjuvant arthritis: interleukin-17 expression is upregulated in early disease.

The aim of this study was to understand the immune processes controlling the initiation and spontaneous resolution of adjuvant arthritis (AA). We investigated synovial T-cell recruitment and mRNA expression of IL-17 and other important disease related cytokines, IFN-gamma, IL-2, IL-4, TNF and TGF-beta in inguinal lymph node (ILN) and synovial membrane (SM). Arthritis severity was assessed by a numerical rating score and rats were sacrificed every 3--4 days postadjuvant induction. Further assessment involved quantitative radiology and histology of the ankle joints on each day, and the ILN and SM were removed for RNA extraction. Cytokine mRNA expression was measured using RT-PCR and densitometry. Paraffin sections of rat ankle joints were stained for T-cells (CD3) by immunohistochemistry. In the ILN, there was an increase in IL-17, TNF and IFN-gamma expression in the early stages of disease, with a secondary sustained increase in IFN-gamma expression. In the SM, there was expression of T-cell cytokines in early arthritis (day 13), and prolonged TNF and TGF-beta expression, which reflected disease progression. IL-4 mRNA expression increased in the later stages of AA. Synovial T-cell numbers transiently increased at day 6, and remained high from days 13--28. Increased pro-inflammatory cytokine expression, including IL-17, in the ILN reflects the initiating events in the early stage of disease. IL-17 may therefore play an important role in the pathogenesis of AA. The increase in IL-4 (an anti-inflammatory cytokine) in the SM in the later stages of AA suggests that IL-4 is involved in the spontaneous resolution of AA. The initial increase in IFN-gamma in the ILN may reflect a pro-inflammatory response, while the prolonged secondary increase may indicate activation of regulatory T-cells.

Symmetrical synovial fluid cell cytokine messenger RNA expression in rheumatoid arthritis: analysis by reverse transcription/polymerase chain reaction.

To investigate the complex intra-articular immune activity in rheumatoid arthritis (RA), we analysed the expression of a wide range of cytokine mRNAs in synovial fluid cells from patients with rheumatoid arthritis. To minimize in vitro artefact, mRNA was rapidly extracted from synovial fluid leucocytes taken from single joints of seven patients and simultaneously from both knee joints of four patients. Expression of interleukin (IL) 1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, granulocyte-macrophage colony-stimulating factor, tumour necrosis factor-alpha and interferon-gamma (IFN-gamma) was detected using the reverse transcription/polymerase chain reaction. The expression of cytokines varied between patients. IFN-gamma mRNA was detected in 60% of the patients and IL-4 mRNA in 10%. Cytokine expression in both knees was very similar. These results suggest that T-cell activity in RA is detectable using sensitive techniques and that the intra-articular immunopathology of RA is systemically very similar.

Gold treatment of rheumatoid arthritis decreases synovial expression of the endothelial leukocyte adhesion receptor ELAM-1.

Leukocyte adhesion receptors on endothelial cells play an important role in the evolution of synovitis. We studied sequential synovial biopsies at Weeks 0, 2 and 12 in 11 patients with rheumatoid arthritis beginning parenteral gold therapy either alone or combined with 120 mg intramuscular methylprednisolone acetate at Weeks 0, 4 and 8 of treatment. Expression of endothelial leukocyte adhesion molecule 1 (ELAM-1) decreased on synovial blood vessels after both 2 and 12 weeks treatment (p less than 0.05), while the overall vascularity of the synovium did not change. Neutrophil numbers within the synovial membrane also decreased although this did not reach statistical significance. In contrast, there was no significant change in numbers or subset distribution of T cells or in Class II MHC expression by synovial lining cells, mononuclear cells or endothelial cells. Our results suggest that one of the early effects of intramuscular gold and glucocorticoid therapy may be a downregulation of the acute inflammatory process associated with the endothelial expression of a neutrophil adhesion receptor and the subsequent recruitment of neutrophils into the joint.