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ID PMID Title PublicationDate abstract
19522557 Treating autoimmune disease by targeting CD8(+) T suppressor cells. 2009 Aug Current treatments for autoimmune disease are hampered by the non-specificity of immunomodulatory interventions, having to accept broad suppression of immunoresponsiveness with potentially serious side effects, such as infection or malignancy. The development of antigen-specific approaches, downregulating pathogenic immune responses while maintaining protective immunity, would be a major step forward. One possible approach involves the targeting of physiological regulatory mechanisms, such as inhibitory CD8 T cells that are now recognized to fine-tune many aspects of immune responses. CD8 T suppressor (Ts) cells may directly inhibit other T cells or condition antigen-presenting cells in such a way that immune amplification steps are dampened. The promise of CD8 Ts cells lies in their potential to disrupt host-injurious immune responses in a targeted fashion. For therapeutic purposes, such CD8 Ts cells could either be generated in vitro and transferred into the host or their numbers and activity could be modulated by treating the patient with established or novel immunomodulators. Emerging evidence shows that several subsets of CD8 Ts cells exist. While there is still considerable uncertainty about the molecular mechanisms through which CD8 Ts cells can reset immune responses to protect the host, their potential diagnostic and therapeutic use is intriguing and has generated renewed interest.
20634240 Autoimmune disease incidence among women prenatally exposed to diethylstilbestrol. 2010 Oct OBJECTIVE: Animal studies have suggested that prenatal diethylstilbestrol (DES) exposure may alter immune system development and function including antigen self-recognition. A cohort study was conducted to investigate whether prenatal DES exposure might influence the incidence of at least some specific autoimmune diseases in women. METHODS: A group of women who were and were not prenatally exposed to DES have been followed for more than 25 years for numerous health outcomes including autoimmune disease. To verify diagnoses, medical records or physician abstracts were requested for all women who reported a diagnosis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), optic neuritis (ON), and idiopathic thrombocytopenic purpura (ITP). Incidence rates of these autoimmune diseases were compared between women who were and who were not prenatally DES-exposed. RESULTS: Overall, there was no increase in verified autoimmune disease among DES-exposed women relative to those who were not exposed (RR 1.2; 95% CI 0.7, 2.1). There was, however, a positive association between prenatal DES exposure and RA among women younger than 45 years (RR 4.9; 95% CI 1.1, 21.6) and an inverse association among women who were 45 years and older (RR 0.1; 95% CI 0.01, 0.7). CONCLUSION: Overall, these data provide little support for an association between prenatal DES exposure and development of autoimmune disease. The implication that such exposure may be related to RA in an unusual age-related manner is based on small numbers of cases and warrants further study.
19578932 Prediction of DAS28-ESR remission at 6 months by baseline variables in patients with rheum 2009 We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX.
19904767 Activating NK-cell receptors co-stimulate CD4(+)CD28(-) T cells in patients with rheumatoi 2010 Feb Effector T-cell responses can be modulated by competing positive or negative signals transduced by NK-cell receptors (NKR). In the CD4(+) T-cell population, the expression of NKR is primarily found in the CD4(+)CD28(-) T-cell subset, also known as CD28(null) T cells. These T cells are frequently found in rheumatoid arthritis (RA) and other inflammatory disorders, suggesting that signaling through NKR may play a role in the autoimmune reaction. Here we aimed to dissect the phenotype and function of NKR-expressing CD4(+)CD28(-) T cells in patients with RA. By analyzing a broad array of NKR on CD4(+)CD28(-) T cells we found a significant expression of the co-activating receptors 2B4 (CD244), DNAM-1 (CD226), and CRACC. Pair-wise ligations of 2B4 with DNAM-1 and/or NKG2D lead to increased effector functions of primary CD4(+)CD28(-) T cells to suboptimal levels of anti-CD3 stimulation. Using multi-parameter flow cytometry, we demonstrate that such co-ligation led to an increased magnitude in overall responsiveness without changing qualitative aspects of the response. Altogether these results demonstrate a pattern of additive effects in NKR-mediated functional modulation of CD4(+)CD28(-) T cells in RA. This may have consequences for the inflammatory responses imposed by these cells, thus influencing disease manifestations.
20143079 Two-stage total infected knee arthroplasty treatment with articulating cement spacer. 2010 Jun INTRODUCTION: The treatment of infected total knee arthroplasty (TKA) is controversial and various. Two-stage prolonged reimplantation and 6-week systemic antibiotics use have been a gold standard of treatment in recent years. PATIENTS: Seventeen knees of 17 patients, who underwent primary TKA and subsequently developed infections, were implanted articulating antibiotic-loaded cement spacer through two-stage reimplantation. In the postoperative period, parenteral antibiotic treatment targeting the specific microorganism detected in each patient was started and continued with oral administration. The mean total (parenteral and oral) antibiotic treatment time was 6.8 weeks (6-10). The spacer remained in its location until complete soft tissue recovery and normal values for laboratory parameters were achieved. The mean time interval between spacer implantation and reimplantation was 4.2 months (3-6). RESULTS: In the last follow-up examinations of the patients, conditions requiring reoperation were detected in 3 patients (17.6%). In 2 of these patients (11.7%), infection developed after a mean 1-year interval. The joint motion ranges of the patients were measured in the preoperative period, during spacer use, and following reimplantation. The mean joint motion range of the patients was 58 degrees (12-90) in the preoperative period; in the presence of spacer between the two stages, 69 degrees (15-100); and in the last follow-up examination after reimplantation, 95 degrees (10-120). CONCLUSION: Use of articulating cement spacer in the treatment of infected TKA is efficient and reliable.
19729497 Ultrasonographic features of the hand and wrist in systemic sclerosis. 2009 Nov OBJECTIVES: To investigate ultrasonographic hand and wrist features in patients with SSc and their correlation with clinical and X-ray examinations. METHODS: All the patients and controls underwent clinical examination, X-ray and ultrasonography (US) evaluations of the hands and wrists. Forty-five SSc patients all of whom satisfied the ACR criteria and 45 controls-15 patients with RA, 15 patients with FM syndrome and 15 healthy subjects were assessed. US was performed by a General Electric Logiq-5 PRO using a 7-12 MHz linear array transducer. RESULTS: Joint effusion was found in 22 (49%) SSc patients; synovial proliferation in 19 (42%), which was associated with a power Doppler signal in 11 of them; marginal bone erosions in 5 (11%); joint space narrowing in 8 (18%); periarticular calcinosis in 12 (27%); and osteophytosis in 26 (59%). In SSc patients, the prevalence of synovitis as detected by US (i.e. effusion and/or synovial proliferation) was found to be significantly higher than that found by clinical examination (i.e. tenderness and/or swelling) (26 vs 15 out of 45 cases; P = 0.03). US indicated a significantly higher number of joints with osteophytes than X-rays (59 vs 27%; P < 0.005). CONCLUSIONS: Our study depicts the main sonographic abnormalities of the SSc hand. Using US, we found an unexpectedly high prevalence of joint pathology in SSc without clinically involved hands. The clinical usefulness of US in the assessment of SSc articular involvement either in clinical practice or in therapeutic trials is yet to be defined.
20649954 Robust test method for time-course microarray experiments. 2010 Jul 22 BACKGROUND: In a time-course microarray experiment, the expression level for each gene is observed across a number of time-points in order to characterize the temporal trajectories of the gene-expression profiles. For many of these experiments, the scientific aim is the identification of genes for which the trajectories depend on an experimental or phenotypic factor. There is an extensive recent body of literature on statistical methodology for addressing this analytical problem. Most of the existing methods are based on estimating the time-course trajectories using parametric or non-parametric mean regression methods. The sensitivity of these regression methods to outliers, an issue that is well documented in the statistical literature, should be of concern when analyzing microarray data. RESULTS: In this paper, we propose a robust testing method for identifying genes whose expression time profiles depend on a factor. Furthermore, we propose a multiple testing procedure to adjust for multiplicity. CONCLUSIONS: Through an extensive simulation study, we will illustrate the performance of our method. Finally, we will report the results from applying our method to a case study and discussing potential extensions.
20213808 Adipocytokines, insulin resistance, and coronary atherosclerosis in rheumatoid arthritis. 2010 May OBJECTIVE: The prevalence of subclinical coronary atherosclerosis is increased in patients with rheumatoid arthritis (RA), and the increased risk is associated with insulin resistance. Adipocytokines have been linked to obesity, insulin resistance, inflammation, and coronary heart disease in the general population. This study was undertaken to examine the hypothesis that adipocytokines affect insulin resistance and coronary atherosclerosis among patients with RA. METHODS: The coronary calcium score, homeostatic model assessment for insulin resistance (HOMA-IR) index, and serum adipocytokine (leptin, adiponectin, resistin, and visfatin) concentrations were determined in 169 patients with RA. The independent effect of each adipocytokine on insulin resistance according to the HOMA-IR index and on coronary artery calcification determined by electron beam computed tomography was assessed in models adjusted for age, race, sex, body mass index (BMI), traditional cardiovascular risk factors, and inflammation mediators. In addition, an interaction analysis was performed to evaluate whether the effect of the HOMA-IR index on the coronary calcium score is moderated by adipocytokines. RESULTS: Increased concentrations of leptin were associated with a higher HOMA-IR index, even after adjustment for age, race, sex, BMI, traditional cardiovascular risk factors, and inflammation mediators (P < 0.001), but concentrations of visfatin (P = 0.06), adiponectin (P = 0.55), and resistin (P = 0.98) showed no association with the HOMA-IR index. None of the adipocytokines was independently associated with the coronary calcium score (all P > 0.05). Serum leptin concentrations showed a significant interaction with the HOMA-IR index (P for multivariate interaction = 0.02). Increasing leptin concentrations attenuated the increased risk of coronary calcification related to insulin resistance. Serum concentrations of the other adipocytokines showed no significant interactions with the HOMA-IR index (each P > 0.05). CONCLUSION: Leptin is associated with insulin resistance in patients with RA but, paradoxically, attenuates the effects of insulin resistance on coronary calcification.
21193990 A PTPN22 promoter polymorphism -1123G>C is associated with RA pathogenesis in Chinese. 2012 Mar The minor allele of the non-synonymous single nucleotide polymorphism (SNP) +1858C>T within the PTPN22 gene has now been unequivocally confirmed as conferring susceptibility to RA in population from Europe and America, but not in population from Asia. The aim of this study was to jointly address and integrate these separate findings to further elucidate the association between the PTPN22 gene and RA in Chinese Hans of Guangdong province. Four hundred and ninety-four cases with RA and 496 healthy controls were randomly selected, their SNPs at position -1123G>C (rs2488457), +1858C>T (rs2476601), +788G>A (rs33996649), and rs1310182 were genotyped using PCR-RFLP, followed by agarose gel electrophoresis. +1858C>T (rs2476601) and +788G>A (rs33996649) are not polymorphic in Chinese Hans. Meanwhile, our result reveals that the degree of association between the promoter polymorphism, -1123G>C and RA, was analogous to that observed in Japanese reports (odds ratio [OR] = 1.517, 95% CI = [1.154-1.995], P = 0.003). Expression study also indicated a tendency for association between -1123G>C and PTPN22 gene expression. Our study underpins that the promoter polymorphism, -1123G/C, may be a causal SNP for RA in Asian.
19046922 NF-kappaB modulators in osteolytic bone diseases. 2009 Feb Osteoclasts are responsible for bone resorption and play a pivotal role in the pathogenesis of osteolytic disorders. NF-kappaB is a set of nuclear factors that bind to consensus DNA sequences called kappaB sites, and is essential for osteoclast formation and survival. NF-kappaB signalling pathways are strictly regulated to maintain bone homeostasis by cytokines such as RANKL, TNF-alpha and IL-1, which differentially regulate classical and/or alternative NF-kappaB pathways in osteoclastic cells. These pathways are also modulated by NF-kappaB mediators, including TRAF6, aPKC, p62/SQSTM1 and deubiquitinating enzyme CYLD that are involved in the ubiquitin-proteasome system during RANK-mediated osteoclastogenesis. Abnormal activation of NF-kappaB signalling in osteoclasts has been associated with excessive osteoclastic activity, and frequently observed in osteolytic conditions, including periprosthetic osteolysis, arthritis, Paget's disease of bone, and periodontitis. NF-kappaB modulators such as parthenolide and NEMO-binding domain peptide demonstrate therapeutic effects on inflammation-induced bone destruction in mouse models. Unravelling the structure and function of NF-kappaB pathways in osteoclasts and other cell types will be important in developing new strategies for treatments of bone diseases.
20868568 Identification of streptococcal proteins reacting with sera from Behçet's disease and rhe 2010 Jul OBJECTIVES: We evaluated the reactivity of sera from Behçet's disease (BD), systemic lupus erythematosus (SLE), dermatomyositis (DM), rheumatoid arthritis (RA), and Takayasu's arteritis (TA) patients against human α-enolase and streptococcal α-enolase, and identified additional streptococcal antigens. METHODS: Enzyme-linked immunosorbent assay (ELISA) and immunoblotting were performed using sera from patients with BD, SLE, DM, RA, and TA and healthy volunteers (control) against human α-enolase and streptococcal α-enolase. Immunoblot analysis and matrix-assisted laser desorption ionisation-time-of-flight mass spectrometry were used to identify and recombine other streptococcal antigens. RESULTS: Specific positive signals against recombinant human α-enolase were detected by IgM ELISA of serum samples from 50% of BD, 14.3% of SLE, 57.1% of DM, 42.9% of RA, and 57.1% of TA patients. Specific positive signals against streptococcal α-enolase were detected from 42.9% of BD, 14.3% of DM, and 14.3% of TA patients. No SLE and RA sera reacted against streptococcal α-enolase antigen. Streptococcal proteins reacting with sera were identified as hypothetical protein (HP) for SLE and DM patients, acid phosphatase (AP) for RA patients, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for TA patients. CONCLUSIONS: We observed that RA patients did not present serum reactivity against either HP or GAPDH though BD, SLE, DM, and TA patients did. Also, AP reacted with sera from BD, SLE, DM, RA, and TA patients.
19323359 Diagnosis and management of Sjögren syndrome. 2009 Mar 15 Sjögren syndrome is a systemic autoimmune disease characterized by dry eyes and dry mouth. Other organ systems are affected in many patients. Sjogren syndrome is classified as primary or secondary. In primary disease, Sjogren syndrome is a solitary process, whereas secondary disease accompanies another autoimmune disease--often rheumatoid arthritis. Sjögren syndrome is a challenging diagnosis, requiring the family physician to coordinate with a team of specialists, including dentists, otolaryngologists, rheumatologists, and ophthalmologists. Pilocarpine and cevimeline can help relieve dry eyes and dry mouth.
19405018 Patient-reported outcomes following biologic therapy in a sample of adults with rheumatoid 2009 May 15 OBJECTIVE: To examine self-reported symptoms and functioning in a community-based sample of persons with rheumatoid arthritis who did and did not initiate treatment with biologic agents. METHODS: Data were from annual telephone interviews (1998-2003) with an observational cohort identified through community rheumatologists. Self-reported function and symptoms of subjects who initiated biologic therapy (etanercept or infliximab) and reported consistent use at 2 annual interviews (continuous use; n = 64) were compared at 1 year prior to initiation of therapy (baseline), and years 1 and 2 of therapy to those with no biologic therapy (n = 183) and those who initiated biologic therapy but discontinued use (n = 42). RESULTS: At baseline, subjects taking biologic agents reported significantly worse function and symptoms on all measures except fatigue and pain severity. After 2 years, significant differences in the Health Assessment Questionnaire scores remained, but there were no other significant differences between the nonuser group and the continuous use group. The discontinued use group exhibited significantly greater pain severity and more painful joints than nonusers. Improvements in the number of painful (33.4% versus 16.2%; P = 0.004), and swollen (38.4% versus 18.7%; P = 0.003) joints, and morning stiffness (27.3% versus 10.4%; P = 0.001) were more frequent in the continuous use group than in the nonuser group. CONCLUSION: Results suggest that biologic treatment was initiated based on severe disease. Over approximately 17 months of treatment, differences in some but not all symptoms between the continuous use group and the nonuser group narrowed to statistical nonsignificance.
20408777 Serum levels of oncostatin M (a gp 130 cytokine): an inflammatory biomarker in periodontal 2010 May OBJECTIVE: Periodontitis is considered to be a risk factor for systemic diseases such as atherosclerosis, diabetes, etc., and cytokines play a key role. The present study was carried out to measure the level of serum oncostatin M (OSM) in patients with chronic periodontitis, and to evaluate the effect of non-surgical periodontal therapy on the serum OSM concentration. MATERIALS AND METHODS: Sixty subjects were divided into three groups (each group n = 20) based on the gingival index (GI), probing pocket depth (PPD) and clinical attachment level (CAL): group I healthy; group II gingivitis; and group III chronic periodontitis. Group III patients were followed for 8 weeks after non-surgical periodontal therapy as the after-treatment group (group IV). Estimation of serum OSM was done using an enzyme-linked immunosorbent assay. RESULTS: The mean OSM concentrations in serum were highest in the chronic periodontitis group (mean 68.05 pg ml(-1)) and decreased following treatment (39.65 pg ml(-1)) while OSM was undetectable in healthy subjects or in patients with gingivitis. CONCLUSION: Increased serum OSM concentration in patients with chronic periodontitis and its positive correlation with PPD and CAL, suggest its role as an inflammatory biomarker in periodontal disease and it may exaggerate other systemic conditions such as atherosclerosis and rheumatoid arthritis.
19292064 [Isoniazid prophylaxis for pulmonary tuberculosis in Chinese patients with rheumatoid arth 2009 Jan OBJECTIVE: To investigate the efficacy and safety of Isoniazid prophylaxis (INHP) for tuberculosis in Chinese patients with rheumatoid arthritis (RA) who receive long-term Methotrexate (MTX) therapy. METHODS: Two hundred and one (201) patients with RA were randomized to initial treatment with either MTX/Isoniazid (INH) [MTX, 0.1-0.3 mg/(kg x week), maximal 20 mg/week; INH, 5 mg/(kg x d), max 300 mg/d] or MTX alone [0.1-0.3 mg/(kg x week), maximal 20 mg/week]. The doses of MTX remained the same after 6-month INH treatment. All patients were followed up for 36 months, the incidence of pulmonary tuberculosis (TB) was investigated, while the toxicity of INH and MTX were assessed. RESULTS: There were 77 patients completed INHP. Two withdrew due to unwilling to participate. Treatment was discontinued in 4 cases (4.9%) owing to toxicity: increasing ALT/AST in two (2.5%), decrease of white blood cell (WBC) in one (1.2%) and anaphylaxis in one (1.2%). In control group, 5 patients withdrew for personal reasons. The incidence of adverse effect due to MTX in this group was 6.2%: Hepatotoxicity appeared in 4 patients (3.5%) and decrease of WBC was seen in 3 (2.7%). Nine patients (8.5%) developed TB in control group, and 1 patient (1.3%) developed TB 14 months after INH treatment. The risk of TB infection in control group was 6 times more than that in INHP group (chi2 = 4.47, P < 0.05). CONCLUSION: INHP is safe and effective to prevent TB in RA patients treated with MTX.
19214672 Bisphosphonate increases risk of gastroduodenal ulcer in rheumatoid arthritis patients on 2009 BACKGROUND: Rheumatoid arthritis (RA) patients are at increased risk of peptic ulcers (PU) induced by nonsteroidal antiinflammatory drugs (NSAIDs). However, the impact of potential drug interactions on the development of PU has yet to be determined in a daily clinical setting. The aim was to estimate the clinical important interactions for PU presented by comedication in Japanese RA outpatients on long-term NSAID treatment. METHODS: This retrospective cohort study enrolled 196 consecutive RA outpatients on NSAID medication for at least 3 months. Potential risk factors for endoscopic PU were analyzed in RA outpatients on longterm NSAID treatment. RESULTS: PU incidence was 31% with bisphosphonate co-therapy and 17% without the co-therapy. PU incidence was only 5% in subjects with proton pump inhibitors (PPI) or prostaglandin E1 analogues (PG) co-therapy, 14% with histamine-H(2) receptor antagonists(H2RA) co-therapy, and 27% without anti-ulcer agents. In multivariate logistic regression analysis, bisphosphonate co-therapy remained a significant risk factor for PU (OR, 2.29; 95% CI, 1.09-4.81). Other risk factors for ulcer development were advanced age (greater than 60 years) and smoking (OR, 2.58; 95% CI, 1.03-6.49 and OR, 2.71; 95% CI, 1.13-5.53, respectively.) Factors that significantly reduced the incidence of PU were H2RA or PPI/PG cotherapies (OR, 0.29; 95% CI, 0.12-0.68.). CONCLUSIONS: Bisphosphonate co-therapy as well as advanced age and smoking was found to be a significant risk factor in PU, while co-therapies of standard-dose H2RA or PPI/PG proved effective in preventing PU in Japanese RA patients on long-term NSAID treatment.
20169297 Co-morbidity and age-related prevalence of psoriasis: Analysis of health insurance data in 2010 Mar Epidemiological studies indicate an increased risk of co-morbidities and an association with other inflammatory diseases in psoriasis. However, most analyses have been performed on small samples of patients. The aim of this study was to evaluate the prevalence of co-morbidities in psoriasis based on a large set of health insurance data. The database of 1.3 million patients in a German nationwide statutory health insurance scheme was analysed. Data-sets of patients with confirmed psoriasis were extracted and analysed for co-morbidities. Of 1,344,071 subjects, 33,981 had a diagnosis of psoriasis (prevalence 2.5%). Metabolic syndrome was 2.9-fold more frequent among these patients. The most common diagnoses were arterial hypertension (35.6% in psoriasis vs. 20.6% in controls) and hyperlipidaemia (29.9% vs. 17.1%). The frequencies of rheumatoid arthritis (prevalence ratio (PR) 3.8), Crohn's disease (PR 2.1) and ulcerative colitis (PR 2.0) were also increased among patients with psoriasis. In conclusion, psoriasis is associated with significant co-morbidities that imply an elevated risk of severe complications.
21191378 Translational pharmacokinetics and pharmacodynamics of an FcRn-variant anti-CD4 monoclonal 2011 Feb MTRX1011A is a humanized anti-CD4 antibody with an amino acid substitution (N434H) to improve its binding to the neonatal Fc receptor (FcRn). Pharmacokinetic/pharmacodynamic (PK/PD) data in baboons suggest that the increased binding to FcRn reduces the nonspecific elimination rate (K(el)) of MTRX1011A by ~50% but does not affect its PK-PD relationship. The human PK/PD data of MTRX1011A from a phase I study in patients with rheumatoid arthritis (RA) were compared with those previously reported for TRX1, its predecessor antibody, using population PK-PD modeling. The results suggest a comparable PK-PD relationship and no significant difference between the K(el) values of the two antibodies. However, the results may have been confounded by the differences in the clinical populations in which the two antibodies were studied and the presence of preexisting immunoglobulin M (IgM) antibodies in the RA sera that recognize N434H in MTRX1011A. This study highlights the challenges in translating from animal studies to human application the effects of FcRn-directed mutations on the PK of monoclonal antibodies.
20436072 Methotrexate drug interactions in the treatment of rheumatoid arthritis: a systematic revi 2010 Jul OBJECTIVE: Patients with rheumatoid arthritis (RA) often have comorbidities that require multiple medications. Several of these medications may alter the efficacy or increase the toxicity of methotrexate (MTX). The purpose of our study was to determine which drugs used in combination with MTX (excluding disease modifying antirheumatic drugs, folic and folinic acid, corticosteroids, and biologic agents) enhance side effects or toxicity of MTX or lower its efficacy. METHODS: A systematic literature search was performed with Medline, Embase, Cochrane Register and Database, and abstracts from the 2006/2007 annual congresses of the American College of Rheumatology and the European League Against Rheumatism. A manual search of the citation lists of retrieved publications was performed. RESULTS: Of the 1172 articles identified, 67 were included: 21 pharmacokinetics studies, 5 observational studies, and 78 case reports. Most medications do not significantly affect the pharmacokinetics profile of MTX. Among the clinical studies, cytopenia and elevation of liver enzymes were the main reported toxicities. The use of trimethoprim-sulfamethoxazole (TMP-SMX) was mentioned as a risk factor for developing cytopenia in one observational study and in 17 case reports. Thirty case reports of cytopenia were attributed to the use of concomitant nonsteroidal antiinflammatory drugs, including acetylsalicylic acid. Two studies described mild abnormalities of liver enzymes with the use of isoniazid, and one study with the use of high-dose ASA. CONCLUSION: Based on the published literature, MTX has limited drug interactions, with the exception of TMP-SMX and high-dose ASA, which can exacerbate toxicity of MTX. The clinical significance of these interactions has not been substantiated by extensive clinical observations.
19890347 Genome-wide association study of generalized vitiligo in an isolated European founder popu 2010 Mar Generalized vitiligo is a common disorder in which patchy loss of skin and hair pigmentation principally appears to result from autoimmune loss of melanocytes from affected regions. We previously characterized a unique founder population in an isolated Romanian community with elevated prevalence of generalized vitiligo and other autoimmune diseases, including autoimmune thyroid disease, rheumatoid arthritis, and type I diabetes mellitus. Here, we describe a genome-wide association study (GWAS) of generalized vitiligo in 32 distantly related affected patients from this remote village and 50 healthy controls from surrounding villages. Vitiligo was significantly associated with single-nucleotide polymorphisms (SNPs) in a 30-kb LD block on chromosome 6q27, in close vicinity to IDDM8, a linkage and association signal for type I diabetes mellitus and rheumatoid arthritis. The region of association contains only one gene, SMOC2, within which SNP rs13208776 attained genome-wide significance for association with generalized vitiligo (P=8.51x10(-8)) at odds ratio 7.445 (95% confidence interval=3.56-15.53) for the high-risk allele and population attributable risk 28.00. SMOC2 encodes a modular extracellular calcium-binding glycoprotein of unknown function. Our findings indicate that SMOC2 is a risk locus for generalized vitiligo and perhaps other autoimmune diseases.