Notch signalling pathways mediate synovial angiogenesis in response to vascular endothelial growth factor and angiopoietin 2.

OBJECTIVE: Notch signalling pathways are critical for angiogenesis and endothelial cell (EC) fate; however the mechanisms regulating these processes in the inflamed joint remain to be elucidated. Here, we examine whether Notch signalling mediates vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2)-induced vascular function. METHODS: Notch-1 intracellular domain (Notch-1 IC), Notch-4 IC, Delta-like-ligand 4, Hes-related transcriptional repressors-1 and 2 (Hrt-1, Hrt-2) mRNA and/or protein expression was measured by Real-time PCR and/or western blot. VEGF/Ang2 induced EC function was assessed using transwell invasion chambers, matrigel tube formation assays and wound repair scratch assays±Notch-1 siRNA or an γ-secretase inhibitor N-(N-(3,5-Difluorophenacetyl-L-alanly))-S-phenylglycine-t-Butyl Ester (DAPT) in RA synovial explants or human microvascular EC. Interleukin (IL)-6 and IL-8 were measured by ELISA and MMP2 and 9 by gelatine zymography. RESULTS: Notch-1 IC and Notch-4 IC protein expressions were demonstrated in RA and psoriatic arthritis synovial biopsies, with minimal expression observed in Osteoarthritis (OA). VEGF and Ang2 induced Notch-1 IC/ Notch-4 IC protein expression in synovial explant cultures and human microvascular EC levels were further potentiated by VEGF/Ang2 stimulation in combination. Notch-1, Delta-like-ligand 4, and Hrt-2 mRNA expression were significantly induced by VEGF and Ang2 alone and in combination. Furthermore VEGF/Ang2-induced EC invasion, angiogenesis and migration were inhibited by Notch-1 siRNA or DAPT. Conditioned media from VEGF/Ang2 stimulated RA synovial explants induced EC tube formation, an effect that was inhibited by DAPT. Finally, DAPT significantly decreased VEGF/Ang2 induced IL-6, IL-8, MMP2 and 9 expressions in RA synovial explants. CONCLUSIONS: Notch-1 mediates VEGF/Ang2-induced angiogenesis and EC invasion in inflammatory arthritis.

Kikuchi-Fujimoto disease--an unusual mimicker?

We describe the case of a 27-year-old Chinese female diagnosed with Kikuchi-Fujimoto disease in Ireland. It principally occurs in Asian populations, but is being increasingly reported in non-Asian populations. This rare, benign disease may potentially be misdiagnosed as lymphoma, and has an association with the subsequent development of systemic lupus erythematosus. Clinicians and pathologists need to be aware of the clinical and histological features of this rare disorder to avoid misdiagnosis.

How do people with knee osteoarthritis use osteoarthritis pain medications and does this change over time? Data from the Osteoarthritis Initiative.

INTRODUCTION: The aim of this analysis was to describe comprehensively the cross-sectional and longitudinal patterns of analgesic and nutraceutical medication use for knee osteoarthritis (OA) in a contemporary US cohort and to investigate associated demographic and clinical factors. METHODS: Baseline, 12, 24 and 36 month data were obtained retrospectively from the National Institutes of Health Osteoarthritis Initiative. Participants had symptomatic radiographic knee OA. Multiple binary logistic regression models identified characteristics independently associated with the use of analgesics or nutraceuticals. RESULTS: We included 987 subjects (55.9% female, mean age 61.5 years, 71.0% white). At baseline, 68.2% reported frequent use of a conventional analgesic or nutraceutical for joint pain (for more than half of the previous month). Non-prescription non-steroidal anti-inflammatory drugs (NSAIDs) were the most frequently reported medications (26.8%), even in those more than 75-years old. Multiple conventional analgesics were used by 11.9%. Frequent analgesic use was more likely in women (odds ratio (OR) 1.8 (95% confidence interval (CI) 1.3 to 2.3)) and people with more pain (moderate 1.7 (1.2 to 2.4); severe 3.1 (2.1 to 4.7)); nutraceutical use was less likely in non-whites (0.4 (0.3 to 0.6)), those more than 74-years old (0.6 (0.3 to 0.9)) and those with comorbidities (0.6 (0.5 to 0.9)) and more likely in people with Kellgren-Lawrence (KL) grade 4 (2.2 (1.5 to 3.3)). Overall there was no change in the proportion of participants frequently using prescription or over the counter (OTC) analgesics at 36 months, although most people had changed medication type; of those using a traditional analgesic at baseline approximately one third were still using the same type at 36 months (ranging from 26.2% of baseline prescription NSAID users to 40.6% of baseline acetaminophen users). All participants reporting baseline analgesic use also reported 36 month analgesic use. Female participants (OR 95% CI 1.2 to 3.2, P = 0.009), those with high body mass index (1.2 to 4.8, P = 0.010) and those with moderate (1.6 to 2.6, P = 0.090) or severe (1.8 to 12.0, P = 0.002) baseline pain were more likely to use pain medication during the 36 month follow-up period; participants more than 75-years old were less likely (0.2 to 1.0, P = 0.053). CONCLUSIONS: Most people with knee OA used pharmacological therapies frequently, and use appeared to be according to American College of Rheumatology recommendations. Change in medication type used was common. Persistent non-prescription NSAID use in older people is an area of concern.

Certolizumab pegol for the treatment of rheumatoid arthritis.

INTRODUCTION: Improved understanding of the pathogenesis of rheumatoid arthritis (RA), and subsequent development of targeted therapies, have greatly advanced the management of this chronic inflammatory disease. The aim of treatment is a state of clinical remission. Certolizumab pegol (CZP) is a novel pegylated TNF alpha inhibitor (TNFi) therapy and is the focus of this review. AREAS COVERED: CZP is different from other TNFi as it contains a polyethylene glycol (PEG) moiety, and lacks the constant fragment (Fc) of immunoglobulin; therefore it does not activate complement. In this review in addition to clinical efficacy of CZP, effects on radiographic and patient-reported outcomes, are discussed. Adverse event data from clinical trials and extension studies are also reviewed. EXPERT OPINION: The addition of novel TNFi therapies to treat RA is welcomed. As well as displaying clinical efficacy, there is evidence to suggest that CZP has unique characteristics, including reduced transfer across the placenta and reduced frequency of injection site reactions. Furthermore, randomised controlled trials (RCTs) of CZP have demonstrated rapid improvements in workplace and home productivity in patients contributing to reducing the significant socioeconomic burden of RA.

Differential expression of NK receptors CD94 and NKG2A by T cells in rheumatoid arthritis patients in remission compared to active disease.

OBJECTIVE: TNF inhibitors (TNFi) have revolutionised the treatment of rheumatoid arthritis (RA). Natural killer (NK) cells and Natural Killer Cell Receptor+ T (NKT) cells comprise important effector lymphocytes whose activity is tightly regulated through surface NK receptors (NKRs). Dysregulation of NKRs in patients with autoimmune diseases has been shown, however little is known regarding NKRs expression in patients with TNFi-induced remission and in those who maintain remission vs disease flare following TNFi withdrawal. METHODS: Patients with RA were recruited for this study, (i) RA patients in clinical remission following a minimum of one year of TNFi therapy (n = -15); (2) Active RA patients, not currently or ever receiving TNFi (n = 18); and healthy control volunteers (n = 15). Patients in remission were divided into two groups: those who were maintained on TNFi and those who withdrew from TNFi and maintained on DMARDS. All patients underwent full clinical assessment. Peripheral blood mononuclear cells were isolated and NKR (CD94, NKG2A, CD161, CD69, CD57, CD158a, CD158b) expression on T-(CD3+CD56-), NK-(CD3-CD56+) and NKT-(CD3+CD56+) cells was determined by flow cytometry. RESULTS: Following TNFi withdrawal, percentages and numbers of circulating T cells, NK cells or NKT cell populations were unchanged in patients in remission versus active RA or HCs. Expression of the NKRs CD161, CD57, CD94 and NKG2A was significantly increased on CD3+CD56-T cells from patients in remission compared to active RA (p<0.05). CD3+CD56-T cell expression of CD94 and NKG2A was significantly increased in patients who remained in remission compared with patients whose disease flared (p<0.05), with no differences observed for CD161 and CD57. CD3+CD56- cell expression of NKG2A was inversely related to DAS28 (r = -0.612, p<0.005). CONCLUSION: High CD94/NKG2A expression by T cells was demonstrated in remission patients following TNFi therapy compared to active RA, while low CD94/NKG2A were associated with disease flare following withdrawal of therapy.

Remission in psoriatic arthritis: is it possible and how can it be predicted?

INTRODUCTION: Since remission is now possible in psoriatic arthritis (PsA) we wished to examine remission rates in PsA patients following anti tumour necrosis factor alpha (TNFalpha) therapy and to examine possible predictors of response. METHODS: Analysis of a prospective patient cohort attending a biologic clinic, between November 2004 and March 2008, was performed prior to commencing therapy and at regular intervals. Baseline clinical characteristics including demographics, previous disease-modifying antirheumatic drug (DMARD) response, tender and swollen joint counts, early morning stiffness, pain visual analogue score, patient global assessment, C reactive protein (CRP) and health assessment questionnaire (HAQ) were collected. RESULTS: A total of 473 patients (152 PsA; 321 rheumatoid arthritis (RA)) were analyzed. At 12 months remission, defined according to the disease activity score using 28 joint count and CRP (DAS28-CRP), was achieved in 58% of PsA patients compared to 44% of RA patients, significant improvement in outcome measures were noted in both groups (P<0.05). Analysis of a subgroup of PsA and RA patients matched for DAS28-CRP at baseline also showed higher numbers of PsA patients achieving remission. Linear regression analysis identified the HAQ at baseline as the best predictor of remission in PsA patients (P<0.001). CONCLUSIONS: DAS28 remission is possible in PsA patients at one year following anti-TNF therapy, at higher rates than in RA patients and is predicted by baseline HAQ.