Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells.

Pathogenic T cells in individuals with rheumatoid arthritis (RA) infiltrate non-lymphoid tissue sites, maneuver through extracellular matrix and form lasting inflammatory microstructures. Here we found that RA T cells abundantly express the podosome scaffolding protein TKS5, which enables them to form tissue-invasive membrane structures. TKS5 overexpression was regulated by the intracellular metabolic environment of RA T cells-specifically, by reduced glycolytic flux that led to deficiencies in ATP and pyruvate. ATPlopyruvatelo conditions triggered fatty acid biosynthesis and the formation of cytoplasmic lipid droplets. Restoration of pyruvate production or inhibition of fatty acid synthesis corrected the tissue-invasiveness of RA T cells in vivo and reversed their proarthritogenic behavior. Thus, metabolic control of T cell locomotion provides new opportunities to interfere with T cell invasion into specific tissue sites.

Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation.

OBJECTIVES: Accelerated atherosclerotic disease typically complicates rheumatoid arthritis (RA), leading to premature cardiovascular death. Inflammatory macrophages are key effector cells in both rheumatoid synovitis and the plaques of coronary artery disease (CAD). Whether both diseases share macrophage-dependent pathogenic mechanisms is unknown. METHODS: Patients with RA or CAD (at least one myocardial infarction) and healthy age-matched controls were recruited into the study. Peripheral blood CD14+ monocytes were differentiated into macrophages. Metabolic profiles were assessed by Seahorse Analyzer, intracellular ATP concentrations were quantified and mitochondrial protein localisation was determined by confocal image analysis. RESULTS: In macrophages from patients with RA or CAD, mitochondria consumed more oxygen, generated more ATP and built tight interorganelle connections with the endoplasmic reticulum, forming mitochondria-associated membranes (MAM). Calcium transfer through MAM sites sustained mitochondrial hyperactivity and was dependent on inactivation of glycogen synthase kinase 3b (GSK3b), a serine/threonine kinase functioning as a metabolic switch. In patient-derived macrophages, inactivated pGSK3b-Ser9 co-precipitated with the mitochondrial fraction. Immunostaining of atherosclerotic plaques and synovial lesions confirmed that most macrophages had inactivated GSK3b. MAM formation and GSK3b inactivation sustained production of the collagenase cathepsin K, a macrophage effector function closely correlated with clinical disease activity in RA and CAD. CONCLUSIONS: Re-organisation of the macrophage metabolism in patients with RA and CAD drives unopposed oxygen consumption and ultimately, excessive production of tissue-destructive enzymes. The underlying molecular defect relates to the deactivation of GSK3b, which controls mitochondrial fuel influx and as such represents a potential therapeutic target for anti-inflammatory therapy.

Efficacy of intranasal corticosteroids for the ocular symptoms of allergic rhinitis: A systematic review.

Current treatment options for allergic rhinoconjunctivitis include topical antihistamines, vasoconstrictors, mast cell stabilizers, intranasal corticosteroids (INCS), and nonsteroidal anti-inflammatory drugs that are generally used as a supplement to oral or intranasal therapies, necessitating the use of multiple treatments for the different symptoms of allergic rhinitis (AR). To assess the efficacy of INCS for ocular symptoms (OS) of AR. A search was performed of clinical trials (n = 32) from 1973 to 2009 of English articles (Medline, Embase, and PubMed) using "intranasal corticosteroid," "allergic rhinitis," "ocular symptoms," "allergic conjunctivitis," and "rhinoconjunctivitis" as key words. Quality assessment for the 32 eligible studies was performed using the Jadad score. Statistical analysis for continuous data was done by weighted mean difference or standardized mean difference. Thirty-two trials were included and separated into three different groups. The overall weighted mean was obtained from the Jadad score and came out to 9.29 (95% CI, 8.7-9.88). For meta-analysis for total OS scores and individual symptoms (10 parallel studies) the weighted mean was 10.17 (95% CI, 9.34-11). In the parallel studies, meta-analysis of individual symptoms (nine studies) gave a weighted mean of 10.09 (95% CI, 9.55-10.63). For eye symptoms but no individual symptoms (13 studies), the weighted mean was 8.56 (95% CI, 7.66-9.46). To date, clinical studies conducted statistically showed the efficacy of INCS on the OS of AR as evidenced by the meta-analysis results for the studies reporting total OSs.

Association Between Immunosuppression and Outcomes in Oral Cavity Squamous Cell Carcinoma.

OBJECTIVE: To assess the effect of immunosuppression on recurrence and mortality outcomes in oral cavity squamous cell carcinoma (SCC) after initial surgical treatment. STUDY DESIGN: Retrospective cohort study. SETTING: A single academic tertiary referral center. METHODS: Patients with oral cavity SCC treated with initial surgery were included. Immunosuppressed versus nonimmunosuppressed groups were compared. Primary end points were 5-year overall recurrence and all-cause mortality. Secondary end points were recurrence subtypes (local, regional, and distant) and disease-specific mortality. RESULTS: Of 803 patients with oral cavity SCC, 71 (9%) were immunosuppressed from therapeutic drug use (n = 48) or systemic disease (n = 23). The immunosuppressed group consisted of patients with a history of transplant (21%), autoimmune or pulmonary disorder (45%), hematologic malignancy or myeloproliferative disorder (30%), and HIV infection (3%). After adjusting for baseline variables of age, sex, comorbidities, pathologic tumor characteristics, and adjuvant treatment, all recurrence and mortality outcomes were worse in the immunosuppressed group. The multivariate-adjusted hazard ratio for overall recurrence was 2.16 (95% CI, 1.50-3.12; P < .01), and all-cause mortality was 1.79 (95% CI, 1.15-2.78; P < .01) in Cox regression analysis. The 2 groups were then matched in a 1:5 ratio according to the same baseline variables. All end points apart from disease-specific mortality were significantly worse in the immunosuppressed group after matching. CONCLUSION: This study demonstrates that immunosuppression is associated with poor outcomes in oral cavity SCC, with an approximate 2-fold increase in rates of recurrence and mortality. Future studies are needed to assess the risks and benefits of adjusting therapeutic immunosuppression in this population.

Ultrasound evaluation of the hands and wrists in patients with systemic sclerosis: Osteophytosis is a major contributor to tender joints.

OBJECTIVE: To evaluate the prevalence and clinical associations of ultrasound (US) findings of inflammatory arthritis and joint and soft tissue pathology in patients with systemic sclerosis (SSc). METHODS: The hands and wrists of 43 SSc patients and 35 age-balanced controls were evaluated by clinical exam and musculoskeletal US. Synovial and tenosynovial pathology were assessed using semi-quantitative Gray Scale (GS) and Power Doppler (PD) scoring. US evaluation for osteophytes, erosions, ulnar artery occlusion, and median nerve cross-sectional areas was performed. Tender joints (TJ), swollen joints (SJ), modified Rodnan skin score (mRSS), digital ulcers, contractures, and calcinosis were evaluated. Concordance between US and physical exam findings at each joint region were assessed, and associations between their severity were analyzed. RESULTS: TJs and SJs were present in 44.2% and 62.8% of SSc patients, respectively. Inflammatory arthritis, defined as having both GS>0 and PD>0, was observed in 18.6% of SSc patients and no controls. There was a high concordance by joint region between GS synovial hypertrophy and osteophytes (κ=0.88) as well as TJs (κ=0.72). SSc patients had more osteophytes compared to controls (48.8% vs 22.9%, p = 0.018) as well as higher osteophyte severity (p = 0.033). CONCLUSIONS: Despite a high percentage of tender and swollen joints, less than 20% of SSc patients met criteria for inflammatory arthritis on US. The high concordance of osteophytes with GS synovial hypertrophy and tender joints suggest that osteophytosis may be a significant contributor to joint pain in SSc patients.

Accelerated atherosclerosis in patients with chronic inflammatory rheumatologic conditions.

Atherosclerosis is a complex inflammatory disease involving aberrant immune and tissue healing responses, which begins with endothelial dysfunction and ends with plaque development, instability and rupture. The increased risk for coronary artery disease in patients with rheumatologic diseases highlights how aberrancy in the innate and adaptive immune system may be central to development of both disease states and that atherosclerosis may be on a spectrum of immune-mediated conditions. Recognition of the tight association between chronic inflammatory disease and complications of atherosclerosis will impact the understanding of underlying pathogenic mechanisms and change diagnostic and therapeutic approaches in patients with rheumatologic syndromes as well as patients with coronary artery disease. In this review, we provide a summary of the role of the immune system in atherosclerosis, discuss the proposed mechanisms of accelerated atherosclerosis seen in association with rheumatologic diseases, evaluate the effect of immunosuppression on atherosclerosis and provide updates on available risk assessment tools, biomarkers and imaging modalities.

Oralair®: sublingual immunotherapy for the treatment of grass pollen allergic rhinoconjunctivitis.

Oralair(®) is a sublingual grass pollen immunotherapy tablet that was authorized for use in Europe on 26 November 2009 and is currently in Phase III clinical trials in the USA. It is indicated for the management of grass pollen allergic rhinitis with or without conjunctivitis in adults, adolescents and children (above the age of 5) with clinically relevant symptoms, confirmed by a positive cutaneous test and/or a positive titer of the specific IgE to the grass pollen. Treatment is composed of an initiation phase (3-day dose escalation: 100 IR [index of reactivity] on day 1, 200 IR on day 2 and 300 IR on day 3) and a continuation phase at a dosage of 300 IR/day. Treatment is scheduled to start approximately 4 months before the actual start of the pollen season and should be continued throughout the season. The treatment should be prescribed and initiated by an experienced allergy specialist.

Allergy to ophthalmic preservatives.

PURPOSE OF REVIEW: The purpose of the present review is to examine the hypersensitivity reactions to preservatives in topical ophthalmic therapies. RECENT FINDINGS: Ocular hypersensitivity reactions to different types of preservatives in different chemical classes of topical ophthalmic treatments reviewed in the literature include IgE-mast cell mediated, cell mediated and toxic. Quaternary ammoniums (benzalkonium chloride) are most commonly (8% reported cases in OVID and PubMED based searches) associated with irritant toxic reactions whereas the organomercurials (thimerosal) and the alcohols (chlorobutanol) have the highest association (19% of OVID and 14% of PubMED based searches and 20% of OVID and 11% of PubMED searches), respectively, with allergic responses although the term allergy for the 'alcohols' appears to be actually an irritant effect whereas the organomercurials appear to truly interact with the immune system as neoantigens. SUMMARY: A large number of clinical and experimental studies reveal that preservatives in topical ophthalmic medications have been demonstrated to produce effects from inflammation/ hypersensitivity to permanent cytotoxic effects involving all structures of the eye.