Contribution of Genetic Factors to Lower DHEAS in Patients with Rheumatoid Arthritis.

OBJECTIVE: Lower production of adrenal androgens has been confirmed in females with rheumatoid arthritis (RA); however, the mechanisms of this finding are not completely understood. The aim of our study was to assess the contribution of genetic factors associated with variability of dehydroepiandrosterone sulfate (DHEAS) levels to lower DHEAS in female RA patients. METHODS: 448 RA and 648 healthy controls were genotyped for single-nucleotide polymorphisms (SNPs) in genes ZKSCAN5 (rs11761528), SULT2A1 (rs2637125), HHEX (rs2497306), and ARPC1A (rs740160). Serum DHEAS concentrations were measured in 112 RA patients and 91 healthy women. RESULTS: The allele frequencies in DHEAS-related loci were similar in RA and controls. RA patients had significantly lower serum DHEAS concentrations compared to healthy women. The cumulative number of alleles associated with lower DHEAS within genes ZKSCAN5, SULT2A1, HHEX, and ARPC1A present in each individual negatively correlated with DHEAS levels in RA patients, but not in controls. Linear regression analysis showed significant effect of polymorphisms in genes ZKSCAN5 and ARPC1A on serum DHEAS levels in female RA patients but not in the control group. CONCLUSION: Our findings suggest that complex interactions exist between genotype and adrenal androgen hypofunction in RA.

A framework for remission in SLE: consensus findings from a large international task force on definitions of remission in SLE (DORIS).

OBJECTIVES: Treat-to-target recommendations have identified 'remission' as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE. METHODS: An international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%. RESULTS: The task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life. CONCLUSIONS: The work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.

A 12-week randomized, double-blind, placebo-controlled multicenter study of choline-stabilized orthosilicic acid in patients with symptomatic knee osteoarthritis.

BACKGROUND: The aim of this study was to assess the efficacy of choline-stabilized orthosilicic acid (ch-OSA) in patients with symptomatic knee osteoarthritis (OA). METHODS: In a multicenter, double-blind, placebo-controlled study, 211 patients with knee OA (Kellgren and Lawrence grade II or III) and moderate to moderately severe pain were randomly allocated to ch-OSA or placebo for 12 weeks. The primary outcome was the change in the WOMAC pain subscale from baseline to week 12. Secondary outcomes were changes from baseline to week 12 in WOMAC total, WOMAC stiffness, WOMAC physical function, Subject Global Assessment and levels of cartilage degradation biomarkers C-terminal telopeptide of collagen type II (CTX-II) and cartilage oligomeric matrix protein (COMP). Pre-specified subgroup analyses included the effect of gender. RESULTS: A total of 166 (120 women, 46 men) patients were included in the analysis (87 and 79 in the ch-OSA and placebo group, respectively). In the total study population, no differences were observed between the two treatment groups for the different outcomes but significant treatment x gender interactions were found. In men taking ch-OSA, a significant improvement in WOMAC total, WOMAC stiffness and WOMAC physical function as well as a lower increase in biomarker levels of cartilage degradation was observed, but not in women. The change in WOMAC pain showed a similar positive trend in men taking ch-OSA. CONCLUSION: After 12 weeks of treatment, no effect was found of ch-OSA in the total study population on clinical parameters and biomarkers, but a gender interaction was observed. In men, ch-OSA was found effective in reducing symptoms of knee OA, which was associated with a slight but significant reduction of biomarkers that are related to cartilage degradation. TRIAL REGISTRATION: The study was registered retrospectively: ISRCTN88583133 . Registration date: 2015-10-07.

Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1): an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study to investigate the effect of once daily nitisinone on 24-h urinary homogentisic acid excretion in patients with alkaptonuria after 4 weeks of treatment.

BACKGROUND: Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. METHODS: Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4 weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8 mg of nitisinone. FINDINGS: A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4 weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15 mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8 mg doses, respectively. For the most efficacious dose, 8 mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4 weeks of nitisinone therapy. CONCLUSIONS: In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.

N-cadherin promoter polymorphisms and risk of osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis. It is characterized by cartilage destruction and bone remodeling, mediated in part by synovial fibroblasts (SFs). Given the functional significance of cadherins in these cells, we aimed at determining the role of genetic variants of N-cadherin (CDH2) in OA of the knee and hip. Six single-nucleotide polymorphisms in the genomic region of the CDH2 gene were genotyped in 312 patients with OA and 259 healthy control subjects. Gene expression of CDH2 was analyzed by qRT-PCR. Liquid chromatography-mass spectrometry was used to identify a transcription factor isolated by DNA pulldown. Its potential for binding to gene variants was examined by electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, and chromatin immunoprecipitation. Genetic analysis identified a polymorphism located in the CDH2 promoter region to be associated with risk of OA. The minor allele of rs11564299 had a protective effect against OA. Compared to carriers of the major allele, carriers of the minor allele of rs11564299 displayed increased N-cadherin levels in SFs. Based on in silico analysis, the minor allele was predicted to generate a novel transcription factor binding site, Direct-binding assays and mass spectrometric analysis identified hnRNP K as binding selectively to the minor allele. In summary, a CDH2 promoter polymorphism influences the risk of OA, and hnRNP K was found to be involved in the regulation of elevated N-cadherin expression in patients with OA carrying the minor allele of rs11564299.

Carboxybetaine Modified Interface for Electrochemical Glycoprofiling of Antibodies Isolated from Human Serum.

Impedimetric lectin biosensors capable of recognizing two different carbohydrates (galactose and sialic acid) in glycans attached to antibodies isolated from human serum were prepared. The first step entailed the modification of a gold surface by a self-assembled monolayer (SAM) deposited from a solution containing a carboxybetaine-terminated thiol applied to the subsequent covalent immobilization of lectins and to resist nonspecific protein adsorption. In the next step, Sambucus nigra agglutinin (SNA) or Ricinus communis agglutinin (RCA) was covalently attached to the SAM, and the whole process of building a bioreceptive layer was optimized and characterized using a diverse range of techniques including electrochemical impedance spectroscopy, cyclic voltammetry, quartz crystal microbalance, contact angle measurements, zeta-potential assays, X-ray photoelectron spectroscopy, and atomic force microscopy. In addition, the application of the SNA-based lectin biosensor in the glycoprofiling of antibodies isolated from the human sera of healthy individuals and of patients suffering from rheumatoid arthritis (RA) was successfully validated using an SNA-based lectin microarray. The results showed that the SNA lectin, in particular, is capable of discriminating between the antibodies isolated from healthy individuals and those from RA patients based on changes in the amount of sialic acid present in the antibodies. In addition, the results obtained by the application of RCA and SNA biosensors indicate that the abundance of galactose and sialic acid in antibodies isolated from healthy individuals is age-related.

Treat-to-target in systemic lupus erythematosus: recommendations from an international task force.

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012-2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that 'treating-to-target' can and will be applicable to the care of patients with SLE.

Increased production of IL-6 and IL-17 in lipopolysaccharide-stimulated peripheral mononuclears from patients with rheumatoid arthritis.

TLR4-mediated inflammatory responses are important for innate immune functions, thus their alterations may participate in the pathogenesis of rheumatoid arthritis (RA). Cortisol is one of the most potent immunomodulatory hormones involved in control of inflammation. In this study, we analyzed TLR4-mediated responses and cortisol effects on the process in peripheral blood mononuclear cells (PBMC) from RA patients. Lipopolysaccharide-stimulated PBMC from 23 female patients and 15 healthy controls were cultured in the presence or absence of cortisol (1 µM) for 24 h. A panel of 17 inflammatory cytokines was analyzed in the cell culture supernatants. Higher (p < 0.05) concentrations of IL-6, IL-17 and MCP-1 were found in lipopolysaccharide-stimulated PBMC from RA patients compared to controls. After normalization of stimulated cytokine secretion to unstimulated cells, a significantly higher (p < 0.05) IL-6 and G-CSF production was found in RA PBMC. Cortisol induced stronger (p < 0.05) suppression of lipopolysaccharide-stimulated secretion of IL-1ß, IL-6, IL-17 and G-CSF in RA group compared to controls. The observed higher production of the key inflammatory cytokines by RA PBMC to lipopolysaccharide stimulation supports involvement of TLR4-mediated processes in RA pathogenesis. The higher sensitivity of LPS-stimulated RA PBMC to immunosuppressive effects of cortisol may reflect adaptive processes to chronic inflammation.

Rituximab in psoriatic arthritis: an exploratory evaluation.

BACKGROUND/OBJECTIVE: Current therapies for psoriatic arthritis (PsA) comprise synthetic drugs and tumour necrosis factor inhibitors. In contrast, other biologicals including rituximab (RTX) are available for treating rheumatoid arthritis (RA). RTX is effective in autoantibody positive RA patients, although some efficacy has been reported in seronegative individuals. RTX has not yet been assessed in PsA. Therefore, an open label study of RTX in PsA was performed. PATIENTS AND METHODS: Nine patients with PsA and 14 with RA received RTX at 1000 mg twice within 14 days and were evaluated over 6 months. RESULTS: A PsA response criteria response was attained in 56% of patients. DAS28 improved from 6.2 to 4.9 (medians) in PsA and 6.4 to 5.2 in RA, and Health Assessment Questionnaire from 1.5 to 1.0 and from 2.1 to 1.4, respectively (all p≤0.05). Disease Activity index for PSoriatic Arthritis changed from 52.0 to 32.5 (p<0.05); C reactive protein and Psoriasis Area and Severity Index did not change significantly. RTX was tolerated well. CONCLUSIONS: In this exploratory open study, RTX exhibited significant efficacy in PsA patients with long-standing disease. Thus, RTX may have efficacy in PsA warranting a randomised controlled clinical trial.

Autonomic nervous system function in rheumatoid arthritis.

The sympathoneural and the adrenomedullary systems are involved in regulation of immune processes. Their impairment has been suggested in patients with rheumatoid arthritis (RA). In this study, sympathetic response to orthostasis was evaluated in 22 RA females with <40 years of age and in 15 matched healthy controls. The testing consisted of stabilization period in supine position, legs-up position, 10 min of orthostasis and again supine position. In each of the body position blood samples were drawn, blood pressure and electrocardiogram was recorded. Plasma levels of epinephrine (EPI) and norepinephrine (NE) were measured and sympathoneural activity was evaluated by analysis of heart rate variability (HRV). During the testing, RA patients had similar EPI and NE concentrations compared to controls. Baseline diastolic blood pressure tended to be higher in RA patients compared to controls; however, blood pressure response to orthostasis was comparable between the groups. The RA and control groups did not differ in heart rate and HRV parameters. This study showed normal reactivity of the sympathoneural and the adrenomedullary systems during orthostatic challenge in RA patients younger than 40 years.

[Structure and function of lymphatic capillaries in synovial joint]. / K struktúre a funkcii lymfatických kapilár v synoviálnom klbe.

The review article focuses on the structure and function of lymphatic capillaries in connective tissues of skin, muscles and synovial membrane. Lymphatic capillaries (initial lymphatics) are formed from endothelial cells mutually arranged so that their intercellular junctions have different structure. In one of the different types of intercellular junctions the distal ends of endothelial cells overlap one another in the form of projections. Desmosomes are missing between the cell membranes of the internal and external projection without presence of any other junctional complexes. The external projection of the endothelial cell is tightly attached to the surrounding connective tissue with the help of anchoring filaments. The internal projection of the neighbouring endothelial cell may tilt over to the lumen of the lymphatic capillary and this may result in a several micrometers wide communication between the interstitium and the lumen with efflux of tissue fluid and leukocytes from the interstitium in to the lumen of the capillary. Lymphologists call the above mentioned openable intercellular junctions in their works also endothelial microvalves or primary valves. These primary valves in cooperation with classical (secondary) intralymphatic valves enable one way lymph flow during spontaneous contractions of the initial lymphatics. It is supposed that primary valves in lymphatic capillaries have an important role in the drainage of the connective tissues affected by inflammation also in the synovial joint.

[Relapsing polychondritis]. / Relabujúca polychondritída.

Relapsing polychondritis (RP) is an unusually rare disease involving multiple organs. It has an episodic course, occasionally also progressing. Typically, inflammation of cartilaginous tissues and tissues rich in glycosaminoglycans is present. Clinical symptoms are concentrated in auricula, nose, larynx, upper respiratory tract, joints, heart, blood vessels, inner ear, cornea and sclera. Manifestations include: (1) chondritis of auricular, nasal, laryngotracheal, costal and joint cartilages, (2) inflammation of the eyes and inner ear, (3) collapse of laryngotracheal structures and structures in the subglottic area resulting in increased susceptibility to upper respiratory tract infections, (4) diversity of clinical manifestations, of the disease course and also of the treatment response. Concurrent systemic vasculitis or glomerulonephritis may contribute to higher morbidity and premature mortality. In about 30% of cases the RP is secondary, accompanied by other systemic connective tissue disorders as RA, SLE, Sjögren's syndrome, thyroiditis, ulcerative colitis, psoriasis and Behcet's syndrome. Diagnosis is based on 1986 diagnostic criteria from Minnesota and RP has to be suspected when the inflammatory bouts involve at least two of the typical sites - auricular, nasal, laryngotracheal or one of the typical sites and two other--ocular, statoacoustic disturbances (hearing loss and/or vertigo) and arthritis. In the treatment are, apart from corticoids and nonsteroidal anti-inflammatory drugs, also corticoids combined with immunosuppressive therapy (cyclophosphamide, azathioprine, chlorambucil, cyclosporine) used. More recently, also biologic therapy is used in RP (infliximab, adalimumab, ethanercept, tocilizumab, rituximab). It is necessary to underscore that biologic therapy for RP is only a research modality used in very severe refractory forms of RP. Preliminary results suggest that biologic therapy will have its place in severe refractory relapsing forms of RP.

Radiological evolution of spinal disease in alkaptonuria and the effect of nitisinone.

OBJECTIVES: Ochronotic spondyloarthropathy represents one of the main clinical manifestations of alkaptonuria (AKU); however, prospective data and description of the effect of nitisinone treatment are lacking. METHODS: Patients with AKU aged 25 years or older were randomly assigned to receive either oral nitisinone 10 mg/day (N=69) or no treatment (N=69). Spine radiographs were recorded yearly at baseline, 12, 24, 36 and 48 months, and the images were scored for the presence of intervertebral space narrowing, soft tissue calcifications, vacuum phenomena, osteophytes/hyperostosis and spinal fusion in the cervical, thoracic and lumbosacral segment at each of the time points. RESULTS: At baseline, narrowing of the intervertebral spaces, the presence of osteophytes/hyperostosis and calcifications were the three most frequent radiographic features in AKU. The rate of progression of the five main features during the 4 years, ranked from the highest to lowest was as follows: intervertebral spaces narrowing, calcifications, vacuum phenomena, osteophytes/hyperostosis and fusions. The rate of progression did not differ between the treated and untreated groups in any of the five radiographic parameters except for a slower rate of progression (sum of all five features) in the treatment group compared with the control group (0.45 (1.11) nitisinone vs 0.74 (1.11) controls, p=0.049) in the thoracic segment. CONCLUSION: The present study shows a relatively slow but significant worsening of radiographic features in patients with AKU over 4 years. Our results demonstrate a modest beneficial effect of 10 mg/day of nitisinone on the slowly progressing spondylosis in AKU during the relatively limited follow-up time. TRIAL REGISTRATION NUMBER: NCT01916382.

Adalimumab with or without methotrexate in juvenile rheumatoid arthritis.

BACKGROUND: Tumor necrosis factor (TNF) has a pathogenic role in juvenile rheumatoid arthritis. We evaluated the efficacy and safety of adalimumab, a fully human monoclonal anti-TNF antibody, in children with polyarticular-course juvenile rheumatoid arthritis. METHODS: Patients 4 to 17 years of age with active juvenile rheumatoid arthritis who had previously received treatment with nonsteroidal antiinflammatory drugs underwent stratification according to methotrexate use and received 24 mg of adalimumab per square meter of body-surface area (maximum dose, 40 mg) subcutaneously every other week for 16 weeks. We randomly assigned patients with an American College of Rheumatology Pediatric 30% (ACR Pedi 30) response at week 16 to receive adalimumab or placebo in a double-blind fashion every other week for up to 32 weeks. RESULTS: Seventy-four percent of patients not receiving methotrexate (64 of 86) and 94% of those receiving methotrexate (80 of 85) had an ACR Pedi 30 response at week 16 and were eligible for double-blind treatment. Among patients not receiving methotrexate, disease flares (the primary outcome) occurred in 43% of those receiving adalimumab and 71% of those receiving placebo (P=0.03). Among patients receiving methotrexate, flares occurred in 37% of those receiving adalimumab and 65% of those receiving placebo (P=0.02). At 48 weeks, the percentages of patients treated with methotrexate who had ACR Pedi 30, 50, 70, or 90 responses were significantly greater for those receiving adalimumab than for those receiving placebo; the differences between patients not treated with methotrexate who received adalimumab and those who received placebo were not significant. Response rates were sustained after 104 weeks of treatment. Serious adverse events possibly related to adalimumab occurred in 14 patients. CONCLUSIONS: Adalimumab therapy seems to be an efficacious option for the treatment of children with juvenile rheumatoid arthritis. (ClinicalTrials.gov number, NCT00048542.)

Canakinumab reduces the risk of acute gouty arthritis flares during initiation of allopurinol treatment: results of a double-blind, randomised study.

OBJECTIVE: This study assessed the efficacy and safety of canakinumab, a fully human anti-interleukin 1ß monoclonal antibody, for prophylaxis against acute gouty arthritis flares in patients initiating urate-lowering treatment. METHODS: In this double-blind, double-dummy, dose-ranging study, 432 patients with gouty arthritis initiating allopurinol treatment were randomised 1:1:1:1:1:1:2 to receive: a single dose of canakinumab, 25, 50, 100, 200, or 300 mg subcutaneously; 4×4-weekly doses of canakinumab (50+50+25+25 mg subcutaneously); or daily colchicine 0.5 mg orally for 16 weeks. Patients recorded details of flares in diaries. The study aimed to determine the canakinumab dose having equivalent efficacy to colchicine 0.5 mg at 16 weeks. RESULTS: A dose-response for canakinumab was not apparent with any of the four predefined dose-response models. The estimated canakinumab dose with equivalent efficacy to colchicine was below the range of doses tested. At 16 weeks, there was a 62% to 72% reduction in the mean number of flares per patient for canakinumab doses ≥50 mg versus colchicine based on a negative binomial model (rate ratio: 0.28-0.38, p≤0.0083), and the percentage of patients experiencing ≥1 flare was significantly lower for all canakinumab doses (15% to 27%) versus colchicine (44%, p<0.05). There was a 64% to 72% reduction in the risk of experiencing ≥1 flare for canakinumab doses ≥50 mg versus colchicine at 16 weeks (hazard ratio (HR): 0.28-0.36, p≤0.05). The incidence of adverse events was similar across treatment groups. CONCLUSIONS: Single canakinumab doses ≥50 mg or four 4-weekly doses provided superior prophylaxis against flares compared with daily colchicine 0.5 mg.

The effects of ß-glucan isolated from Pleurotus ostreatus on methotrexate treatment in rats with adjuvant arthritis.

The purpose of this study was to evaluate the effect of ß-(1,3/1,6)-D: -glucan isolated from Pleurotus ostreatus (ß-glucan-PO) on prophylactic treatment of adjuvant arthritis (AA) with methotrexate (MTX) in rats. Groups of rats with AA were treated with methotrexate (1 mg/kg/week), ß-glucan-PO (1 mg/kg every second day) or their combination for the period of 28 days from adjuvant application. Body mass, hind paw swelling, arthrogram scores and a level of serum albumin were measured as markers of inflammation and arthritis. Treatment with low dose of MTX significantly inhibited the markers of both inflammation and arthritis. MTX and its combination with ß-glucan-PO significantly increased body mass of arthritic rats. ß-glucan-PO administered alone significantly decreased both the hind paw swelling and arthritic score. In combination with MTX, ß-glucan-PO markedly potentiated the beneficial effects of MTX, which resulted in a more significant reduction of hind paw swelling and arthritic scores. The concentration of albumin in the serum of arthritic controls was significantly lower than in healthy controls. Both MTX alone and the combination treatment with MTX + ß-glucan-PO significantly inhibited the decrease in serum albumin. ß-Glucan-PO increased the treatment efficacy of basal treatment of AA with MTX.

Low- versus high-baseline epinephrine output shapes opposite innate cytokine profiles: presence of Lewis- and Fischer-like neurohormonal immune phenotypes in humans?

Immunogenetic mechanisms operating within the immune system are known to influence cytokine profiles and disease susceptibility. Yet the role of the individual's neurohormonal background in these processes remains undefined. Hormonal imbalances are documented in immune-related diseases, but it is unclear whether this represents a secondary phenomenon or a primary "defect" related to specific neurohormonal immune phenotype(s). We report that in a large subpopulation of healthy humans the baseline epinephrine output (but not cortisol and sex steroid hormones) correlated inversely with proinflammatory and positively with anti-inflammatory cytokine production. Thus, low vs high epinephrine excretors had a 2- to 5-fold higher TNF-alpha and IL-12 production but 2-fold lower IL-10 production induced by LPS ex vivo. In alternative settings, we found low baseline levels and profoundly blunted stress-induced epinephrine responses but high TNF-alpha levels in Lewis vs Fischer inbred rats. Additionally, isoproterenol, a beta adrenoreceptor agonist suppressed LPS-induced TNF-alpha production, with more pronounced effect in Lewis than in Fischer rats. In human monocytes, epinephrine and the beta(2) adrenoreceptor agonist fenoterol potently inhibited LPS-induced TNF-alpha and IL-12, but stimulated IL-10 production. The order of potency for hormones able to inhibit IL-12 production ex vivo was: epinephrine > norepinephrine > or = 1,25-(OH)(2) vitamin D(3) > hydrocortisone. This indicates that baseline epinephrine conditions cytokine responsiveness and through this mechanism intrinsic hypo- or hyperactive adrenal medullas in some individuals may shape opposite cytokine profiles. Since Lewis and Fischer rats have opposite susceptibility to experimental immunological diseases, this suggests that the parallel human phenotypes could be linked to differing responsiveness and susceptibility to infections and immune/inflammatory-related conditions.

Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial.

BACKGROUND: Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit. METHODS: SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). FINDINGS: Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. INTERPRETATION: Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression. FUNDING: European Commission Seventh Framework Programme.

Clinical and laboratory features of the catastrophic antiphospholipid syndrome.

Catastrophic antiphospholipid syndrome (CAPS, Asherson's syndrome) is an unusual form of antiphospholipid syndrome (APS) characterized by multi-organ failure and high mortality. Fortunately, CAPS accounts for less than 1% of APS cases. Due to the rarity of the condition, an international registry of CAPS patients was created in 2000 supported by the European Forum on Antiphospholipid Antibodies held in Taormina, Italy at the Tenth International Congress on Antiphospholipid Antibodies. Clinical and laboratory features are the most important in the criteria for the diagnosis of this syndrome and can affect many organ systems. The majority of patients presented with multiple organ involvement at the time of CAPS. The combination of pulmonary, cardiac, and renal involvement was most commonly seen. The organ systems most commonly involved at the onset include the cardiopulmonary system, primarily characterized by dyspnea and respiratory failure, the central nervous system, and the renal system. Laboratory criteria for the classification of CAPS include the presence of antiphospholipid antibodies-LA and/or aCL and/or beta(2)-GPI antibodies.

Methotrexate treatment ameliorated testicular suppression and anorexia related leptin reduction in rats with adjuvant arthritis.

Methotrexate (MTX) has been frequently used in the treatment of rheumatoid arthritis (RA). However, its action on arthritis associated male hypogonadism, or anorexia related low leptin production has not yet been studied. The well-established model of human RA is rat adjuvant-induced arthritis (AA). In the present series we aimed at the evaluation of the effects of MTX on AA induced inflammatory parameters, testosterone suppression, and anorexia associated lowered leptin release. AA was induced in male Lewis rats by intradermal injection of heat killed Mycobacterium butyricum in incomplete Freund's adjuvant in the base of the tail. Arthritic rats were treated with two doses of MTX: 0.3 and 0.5 mg/kg twice a week orally for the period of 28 days. The evaluated parameters were body mass, hind-paw swelling, arthrogram scores, serum albumin, total testosterone and leptin on days 14, 21 and 28 of AA. MTX treatment ameliorated all parameters studied dose dependently. Higher dose of MTX induced a significant reduction in the hind-paw swelling, arthritic score, and an increase in serum albumin in all examined time intervals of AA. This dose also significantly improved the suppressed testosterone and leptin levels found in arthritic rats. Prophylactic MTX treatment of rats with AA improved all inflammatory and arthritic parameters studied indicating its clear anti-inflammatory effects. The significant improvement of testosterone and leptin shows beneficial effects of MTX on reproduction and anorexia related leptin reduction during chronic AA.