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ID PMID Title PublicationDate abstract
21516380 Clinical pharmacokinetics of ketoprofen enantiomers in wild type of Cyp 2c8 and Cyp 2c9 pa 2011 Sep Pharmacokinetics of ketoprofen (KTP) enantiomers has been studied in patients with rheumatoid arthritis (RA) following administration of a single oral dose of 100 mg rac-KTP during multidrug therapy taking into consideration the genotype of RA patients Concentrations of (-)-R and (+)-S enantiomers of KTP in plasma, urine and synovial fluid samples were determined using a validated HPCE method. The genotype of the patients was analyzed using PCR-RFLP method to determine the polymorphic variants of genes coding CYP2C8 and CYP2C9 isoenzymes. The levels of KTP enantiomers in synovial fluid at 4 h following administration were insignificantly greater [(-)-R = 1.34 ± 0.91 mg/L; (+)-S = 1.38 ± 0.91 mg/L] than in plasma [(-)-R = 1.15 ± 0.95 mg/L; (+)-S = 1.22 ± 0.95 mg/L]. The values of AUC(0-∞) were 11.89 ± 5.00 and 10.92 ± 4.10 mg h/L for (-)-R and (+)-S enantiomer, respectively, and were lower compared with data obtained in healthy volunteers following administration of the same dose of rac-KTP. But, no statistically significant differences were observed also for C (max), Cl, V (d), t (0.5) and MRT of KTP enantiomers. The total percentage of unchanged KTP eliminated with urine of RA patients was in the range of 30-50% of the administered dose. Though RA patients represented the same wild genotype, quite significant variabilities (Cl((-)-R ) = 2.37-13.50 L/h and Cl((+)-S ) = 2.44-9.90 L/h) existed in the pharmacokinetics parameters of KTP. We concluded that KTP data obtained from healthy volunteers cannot be sufficient to predict disposition of KTP enantiomers in RA patients, especially when undergoing long-term multidrug therapy.
21172929 Retinal vascular calibre is altered in patients with rheumatoid arthritis: a biomarker of 2011 May OBJECTIVES: Alterations in retinal vascular calibre, particularly wider venular calibre, have been independently associated with elevated markers of inflammation and cardiovascular risk in the general population. We hypothesized that retinal vascular calibre would be altered in patients with RA, who are known to have both elevated cardiovascular risk and chronic, systemic inflammation. METHODS: Retinal vascular calibre was measured from digital retinal photographs using computerized methods in 51 RA patients and 51 age- and gender-matched controls. Retinal vascular calibre was compared between RA and control patients with adjustment for relevant variables including cardiovascular risk factors and companion vessel calibre. The relationship between retinal venular calibre and inflammation was assessed by comparing controls and RA patients with high and lower disease activity. RESULTS: Retinal venular calibre [mean (s.d.)] was significantly wider in RA patients than in controls [235.9 (24.6) vs. 211.6 (21.0) µm, P < 0.001]. After adjustment for all relevant variables, mean venular calibre remained 20.3 µm (95% CI 10.4, 30.3) wider in RA patients compared with controls. Retinal venular calibre [mean (s.d.)] also increased with increasing levels of systemic inflammation: 211.6 (21.0) µm in controls, 232.3 (22.4) µm in RA patients with moderate or lower disease activity and 255.5 (28.3) µm in RA patients with high disease activity (P for trend < 0.0001). CONCLUSIONS: This study demonstrates that RA patients have dilated retinal venular calibre, reflecting systemic inflammation and possibly increased cardiovascular risk. Longitudinal studies correlating retinal vascular calibre with subsequent cardiovascular events will clarify the clinical utility of this test in patients with RA.
22302417 Abatacept in subjects who switch from intravenous to subcutaneous therapy: results from th 2012 Jun OBJECTIVE: To assess safety, immunogenicity and efficacy in rheumatoid arthritis (RA) patients switched from long-term intravenous to subcutaneous (SC) abatacept. METHODS: In this phase IIIb, open-label, single-arm trial, patients who completed ≥4 years of intravenous abatacept (in long-term extensions of two phase III studies) were enrolled to receive SC abatacept (125 mg/week). The primary objective was safety during the first 3 months after switching from intravenous therapy. RESULTS: 123 patients entered the study (mean Disease Activity Score 28 (based on C reactive protein) and HAQ-DI of 3.4 and 0.94, respectively). At month 3, 120 (97.6%) patients were continuing to receive SC abatacept; no patients discontinued due to lack of efficacy. Adverse events (AEs) were reported in 49 (39.8%) patients through month 3. One patient (0.8%) discontinued due to an AE and one patient (0.8%) experienced a serious AE. Two (1.6%) patients had SC injection site reactions (erythema, pain), both with mild intensity. Clinical efficacy was maintained throughout. Limited impact on immunogenicity was observed when switching routes of administration. CONCLUSION: These data demonstrate that patients can switch from long-term monthly intravenous abatacept to a weekly fixed dose of 125 mg SC abatacept with no increased safety concerns. This study further supports SC abatacept as an alternative treatment option for patients with RA.
21186172 The power Doppler ultrasonography score from 24 synovial sites or 6 simplified synovial si 2011 May OBJECTIVE: We evaluated the significance of the power Doppler ultrasonography (PDUS) score by comparing it with serum biomarkers and clinical disease activity. METHODS: We measured the PDUS scores of 24 synovial sites in 12 joints in 22 RA patients. For convenience, the PDUS scores of six synovial sites in six joints were also examined. Each joint was scored for a power Doppler (PD) signal on a scale from 0 to 3. The PDUS scores are the sums of the PD signal scores for the 24 synovial sites or the 6 synovial sites. On the same day, serum variables as well as clinical disease activity were evaluated. RESULTS: The PDUS scores from the 24 joint sites were significantly positively correlated with DAS of 28 joints (DAS-28), simplified disease activity index (SDAI), clinical disease activity index (CDAI) and serum biomarkers including MMP-3, VEGF and tissue inhibitor of metalloproteinases-1 (TIMP-1). Accordingly, the PDUS scores from the six synovial sites greatly correlated with those from the 24 joint sites. Clinical disease activities as well as serum variables were also clearly correlated with the PDUS scores from the six synovial sites. CONCLUSION: The standard as well as the simplified PDUS scores well reflected clinical disease activity and serum variables, including angiogenic factors. Our data reaffirm the utility of ultrasonography for monitoring disease activity in patients with RA.
23124653 Vitamin K2 administration is associated with decreased disease activity in patients with r 2013 Sep OBJECTIVES: Vitamin K2 (VitK2) is reported to induce not only bone mineralization of human osteoblasts and apoptosis of osteoclasts, but also apoptosis of rheumatoid arthritis (RA) synovial cells, while its clinical effect on disease activity of RA remains unknown. METHODS: 158 female RA patients (mean age 62.5 years) who had not been treated with warfarin, biologics, or teriparatide were enrolled in this study. VitK2 (45 mg/day) was administered in 70 patients with a serum undercarboxylated osteocalcin level of >4.5 ng/ml or with decreased bone mineral density in spite of the treatment with other anti-osteoporosis medications, regardless of RA disease activity. A longitudinal study was conducted in 52 patients who were additionally treated with VitK2 without changing their other medications for three months. RESULTS: In the cross-sectional study, as compared to the VitK2-naïve group (n = 88), the VitK2-treated group (n = 70) showed lower serum CRP (1.7 ± 0.2 vs. 0.5 ± 0.1 mg/dl; P < 0.001), MMP-3 (220.4 ± 21.9 vs. 118.0 ± 14.4 ng/ml; P < 0.001), and DAS28-CRP (2.9 ± 0.1 vs. 2.4 ± 0.1; P < 0.05). In the longitudinal study, patients who were additionally treated with VitK2 showed significant decreases in serum CRP (1.1 ± 0.2 to 0.6 ± 0.2 mg/dl; P < 0.001), MMP-3 (160.1 ± 25.6 to 125.0 ± 17.8 ng/ml; P < 0.05), and DAS28-CRP (3.1 ± 0.2 to 2.4 ± 0.1; P < 0.001). CONCLUSIONS: VitK2 may have the potential to improve disease activity besides osteoporosis in RA.
23077926 [Prospective study of the efficiency and safety of adalimumab in treatment of active estab 2012 Apr Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by synovial pannus formation leading to cartilage destruction, bone erosion, and disability. AIM: To evaluate the efficiency and safety of adalimumab (ADA) in association with one or more classic remissive drugs in active established RA. MATERIAL AND METHODS: Prospective observational 12 months study in 33 consecutive active RA treated with ADA. Patients were assessed according to a complex protocol including both individual parameters (clinical, biological) and composite disease activity scores (DAS28, CDAI, SDAI), while response to therapy was evaluated based on EULAR and ACR response criteria. RESULTS: Statistical significant improvement has been demonstrated in all patients under ADA (p < 0.05); after 3 months of treatment 51.5% RA fulfilled ACR20, 39.3% ACR50 and 9% ACR70 criteria; after 6 months of treatment 66.6% of patients and 33.3% fulfilled ACR20 and, respectively, ACR50 criteria. Moreover, 30.3% of all patients had good response after 6 months, 66.6% moderate response and only 3.03% displayed no response in the same period. 24.2% and 45.4% of RA achieved remission (DAS28 < or = 2.6) after 9 and 12 months of ADA, while 39.3% and 21.2% had moderate activity. Rate and type of adverse events demonstrated the safety and good tolerance of ADA. CONCLUSIONS: Our data support the efficacy and safety of ADA in active established RA in the settings of the real-life clinical practice.
22302136 Clinical and radiographic results from a 2-year comparison of once-weekly versus twice-wee 2012 Nov OBJECTIVES: The twice-weekly administration of 25 mg of etanercept (TW) has been shown to be effective in patients with rheumatoid arthritis (RA). However, the once-weekly administration of 25 mg of etanercept (OW) was tried in order to address the economic burden of anti-rheumatic biologics. We evaluated the clinical and radiographic results from a 2-year follow-up study of patients receiving OW or TW. METHODS: Sixty-three biologics-naive patients with RA were randomly assigned to receive either OW (n = 42) or TW (n = 21). RESULTS: From baseline to year 2, rates of clinical remission,according to the Disease Activity Score of 28 joints(DAS-28) (based on C-reactive protein; CRP)–with clinical remission being regarded as a DAS-28 (CRP) score of2.3–were significantly improved in the OW group (from 1.6 to 39.0%) and in the TW group (from 9.5 to 47.6%),but no significant between-group difference was observed at year 2. Radiographic joint damage, quantified with the modified Sharp score, was significantly progressive in the OW group in contrast to findings in the TW group. Thus,among patients receiving TW therapy, the progression of joint damage may have been inhibited or may have shown remission. CONCLUSIONS: These results suggest that, in terms of DAS-28 remission, OW therapy can efficiently substitute for TW therapy in biologics-naive patients with RA. However, TW therapy was indispensable in preventing the worsening of joint damage.
22260742 Tocilizumab improves cardiac disease in a hemodialysis patient with AA amyloidosis seconda 2012 Mar A 58-year-old Japanese woman on hemodialysis (HD) was admitted for intractable rheumatoid arthritis. Even after HD was started due to end-stage renal failure in 2004, her arthropathy worsened. A soluble tumor necrosis factor receptor inhibitor (etanercept at 25 mg twice weekly), tacrolimus (2 mg daily), and prednisolone (10 mg daily) had been administered since 2005, but high disease activity had persisted. She was admitted to our hospital in July 2007. C-reactive protein (CRP) was 6.8 mg/dL, and the DAS-CRP score was calculated to be 8.3. The cardiothoracic ratio (CTR) was 62% on a chest radiograph, but dialysis hypotension was remarkable. Left ventricular mass (LVM) was calculated as 320 g using echocardiography. Endoscopic biopsy of the stomach and duodenum revealed heavy deposition of AA amyloid. Etanercept was discontinued and tocilizumab was started at a dose of 320 mg (8 mg/kg) monthly. Even after predonisolone and tacrolimus were tapered gradually and discontinued because of her good response, CRP and DAS-CRP became 0.0 mg/dL and 1.5, respectively. In September 2011, re-evaluation was performed. CTR was reduced to 51% and LVM was decreased to 180 g. Endoscopic biopsy of the stomach and duodenum revealed disappearance of AA amyloid. Although AA amyloidosis of the gastrointestinal tract has already been reported to be improved by tocilizumab, this is the first report on improvement of myocardial hypertrophy as well as dialysis hypotension.
21803751 Rheumatoid arthritis near remission: clinical rather than laboratory inflammation is assoc 2011 Nov BACKGROUND: Disease activity in rheumatoid arthritis (RA) can be measured clinically (eg, swollen joint count (SJC)) or systemically (eg, C reactive protein (CRP)). In general, both contribute to the progression of joint damage, but the relevance of residual inflammation in patients near remission is unclear. OBJECTIVE: To determine the independent contribution of SJC and CRP to progression of joint damage in patients near remission. METHODS: Data from methotrexate monotherapy arms of the ASPIRE, ERA, Leflunomide, PREMIER and TEMPO trials (n=1184) were pooled and the average SJC and CRP values from visits at 6, 9 and 12 months were determined. The two variables were then dichotomised into active and inactive, where inactive was defined as a mean. Radiographic outcomes were assessed according to these definitions. RESULTS: The greatest progression was seen in patients in whom both SJC and CRP were active and the smallest in those in whom both were inactive. If SJC was inactive, radiographic progression was not different between those with inactive or active CRP (0.7 ± 4.3/year and 0.8 ± 5.4/year, respectively, p=0.19). However, if CRP was inactive (<1 mg/dl), SJC status still determined radiographic progression (0.7 ± 4.3/year and 1.8 ± 5.6/year, for inactive and active SJC, respectively, p=0.004). The importance of SJC in patients with inactive CRP was also shown in a linear model (p=0.019), while CRP was not significantly different in patients with inactive SJC (p=0.40). CONCLUSION: In patients with RA who are near remission, the amount of joint swelling appears to be more predictive of radiographic progression than the amount of CRP.
21619490 Cystatin C concentration is correlated with disease activity in rheumatoid arthritis patie 2011 OBJECTIVES: Rheumatoid arthritis (RA) is a systemic, inflammatory disease. Renal involvement worsens the course of RA and increases mortality. It is suggested that chronic inflammatory processes may contribute to renal impairment. The aim of this study was to investigate the impact of chronic inflammation and RA activity on glomerular filtration rate (GFR). METHODS: The study population consisted of 140 RA patients. High disease activity was observed in 42 patients (30%), and long-term RA (duration ≥ 10 years) in 64 (45.7%). Measures of renal function included: serum cystatin C, serum creatinine (SCr), and creatinine-based estimated GFR (eGFR) calculated by Cockcroft and Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulas. RESULTS: The mean (SD) cystatin C concentration was 0.77 (0.2) mg/L, SCr 0.71 (0.23) mg/dL, eGFR(CG) 110.5 (37.8) mL/min/1.73 m², and eGFR(MDRD) 109.5 (34.5) mL/min/1.73 m². Cystatin C levels correlated positively with creatinine, and negatively with eGFR(CG) and eGFR(MDRD). Cystatin C concentration was significantly higher in patients with high disease activity, long-term RA, and hypertension, and in males. Patients currently being treated with biologics had non-significantly lower cystatin C levels than those treated with conventional modifying drugs. Cystatin C levels were significantly associated with markers of clinical, functional disease activity, and markers of inflammation. By contrast, there were no such correlations with other parameters of renal function. CONCLUSIONS: In patients with RA, cystatin C may be not only an indicator of GFR but also a marker of intensity of chronic inflammatory processes.
21196130 Rituximab in rheumatoid arthritis and the risk of malignancies: report from a French cohor 2011 Oct OBJECTIVE: To determine in real-life conditions the safety of treatment with rituximab (RTX) in patients with rheumatoid arthritis (RA) regarding malignancies. METHODS: Analysis of safety data from a cohort of RA patients who received at least one course of RTX. RA patients with previous malignancies were followed-up and compared to the group of patients with no history of malignancy. RESULTS: One hundred and eighty-six RA patients, 33 (17.7%) males, the mean age and disease duration were 55.8 ± 13.0 and 14.5 ± 11.1 years, respectively. The mean follow-up was 22.3 ± 15.1 months, corresponding to a follow-up of 346 pt-years of RTX exposure. Among these, 24 (12.9%) patients had a history of a prior malignancy. Five cancers were diagnosed during follow-up with four new malignancies (1 prostate, 1 breast, 1 colon and 1 cervical cancers) and one recurrence of a known breast cancer. The overall cancer rate was 1.45/100 pt-years (95%CI: 0.19 to 2.70), which is comparable to previously studied DMARD-treated cohorts. No new hematopoietic neoplasms were reported and the six lymphomas that have been in remission prior to RTX-therapy remained under follow-up. The baseline demographic and disease characteristics and the cancer-risk of the 24 patients who presented with a prior malignancy were similar to those with no cancer history (162 patients). CONCLUSIONS: Although based on a modest number of observed cancers, and despite selection bias (12.9% of prior malignancies in our RTX treated RA), this observational study suggests that RTX does not increase the cancer risk in RA patients.
23223694 Disability and quality-of-life are not influenced by the prevalence of autoantibodies in e 2012 Dec INTRODUCTION: Although many studies have suggested that the presence of autoantibodies, such as rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (anti-CCP) in rheumatoid arthritis (RA) are predictors of joint damage, the association with disability and quality of life questionnaires are not known. OBJECTIVES: To evaluate the correlation between the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) scores with serological markers, such as RF, anti-CCP, and anti-citrullinated vimentin (anti-Sa). PATIENTS AND METHODS: Sixty five patients with early RA (ERA) from the Brasília Cohort of ERA were evaluated. Serology tests (ELISA) for RF (IgM, IgG, and IgA), anti-CCP (CCP2, CCP3, and CCP3.1), and anti-Sa were performed, with the application of the HAQ and SF-36 questionnaires in the initial evaluation. RESULTS: The mean age was 45 years, with a female predominance (86%). At the initial evaluation, RF was positive in 32 individuals (49.23%), anti-CCP in 34 (52.3%), and anti-Sa in nine (13.8%). The initial HAQ score was 1.8. The SF-36 scores were as follow: role-emotional, 19.3; social functioning, 43.1; bodily pain, 25.43; general health, 57.6; mental health, 48.1; vitality, 49.5; role-physical, 4.6; and physical functioning, 24.7. The HAQ and SF-36 scores did not vary with autoantibody levels. CONCLUSION: In many patients, ERA has a major impact on physical ability and health-related quality of life. Although RF and anti-CCP tests have been related with joint destruction and worse clinical prognosis, there is no correlation with the results of questionnaires of quality of life and disability.
21346237 Interplay between TNF and regulatory T cells in a TNF-driven murine model of arthritis. 2011 Apr 1 CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are involved in several autoimmune diseases, including rheumatoid arthritis. TNF-α blockers induce therapeutic benefits in rheumatoid arthritis via a variety of mechanisms. We aimed to characterize the impact on Treg of TNF-α overexpression in vivo and of TNF-α inhibiting treatments. We used human TNF-α transgenic mice as a model of strictly TNF-α-dependent arthritis. Our study showed that initial Treg frequency was lower in TNF-α transgenic mice than in wild-type mice. However, the course of arthritis was marked by elevation of Treg frequency and a dramatic increase in expression of TNFR2. Antagonizing TNF-α with either the anti-human TNF-α Ab (infliximab) or active immunotherapy (TNF-kinoid) increased the Treg frequency and upregulated CTLA-4, leading to enhancement of suppressor activity. Moreover, both anti-TNF-α strategies promoted the differentiation of a CD62L(-) Treg population. In conclusion, in an in vivo model of TNF-α-driven arthritis, Treg frequency increased with inflammation but failed to control the inflammatory process. Both passive and active TNF-α-inhibiting strategies restored the suppressor activity of Treg and induced the differentiation of a CD62L(-) Treg population.
22910485 Model-based meta-analysis: an important tool for making quantitative decisions during drug 2012 Sep Modeling during drug development is routinely used to integrate subject-level information, evaluate response, and inform clinical trials. Model-based meta-analysis (MBMA) combines aggregate safety and efficacy results from many trials. Because MBMA is based on results from large numbers of subjects, it increases the power to precisely detect small but clinically significant effects, providing a basis for quantitative drug development decisions and reducing time and cost. This Commentary describes an overview of MBMA and its application during drug development.
21717420 NF-AT5 is a critical regulator of inflammatory arthritis. 2011 Jul OBJECTIVE: To investigate the role of NF-AT5, an osmoprotective transcription factor, in synovial hyperplasia and angiogenesis in patients with rheumatoid arthritis (RA). METHODS: The expression of NF-AT5 in synovial tissue and synoviocytes from RA patients was examined by immunohistochemistry and Western blot analysis, respectively. Messenger RNA (mRNA) in RA synoviocytes and human umbilical vein endothelial cells (HUVECs) transfected with dummy small interfering RNA (siRNA) or NF-AT5 siRNA were profiled using microarray technology. Assays to determine synoviocyte apoptosis and proliferation were performed in the presence of NF-AT5 siRNA. VEGF₁₆₅-induced angiogenesis was assessed by measuring the proliferation, tube formation, and wound migration of HUVECs. Experimental arthritis was induced in mice by injection of anti-type II collagen antibody. RESULTS: NF-AT5 was highly expressed in rheumatoid synovium, and its activity was increased by proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor α. The mRNA profiling of synoviocytes and HUVECs transfected with NF-AT5-targeted siRNA revealed 3 major changes in cellular processes associated with the pathogenesis of RA: cell cycle and survival, angiogenesis, and cell migration. Consistent with these results, NF-AT5 knockdown in RA synoviocytes and HUVECs inhibited their proliferation/survival and impeded angiogenic processes in HUVECs. Mice with NF-AT5 haploinsufficiency (NF-AT5(+/-)) developed a very limited degree of synovial proliferation, as seen on histologic analysis, and decreased angiogenesis, and they exhibited a nearly complete suppression of experimentally induced arthritis. CONCLUSION: NF-AT5 regulates synovial proliferation and angiogenesis in chronic arthritis.
21555606 Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. 2011 Sep OBJECTIVE: To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab. DESIGN: Case study. SETTING: Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver. PATIENTS: Four patients developing PML in the setting of rituximab therapy for RA. INTERVENTION: Rituximab therapy. MAIN OUTCOME MEASURES: Clinical and pathological observations. RESULTS: Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease. CONCLUSION: These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low.
21505073 The human AIRE gene at chromosome 21q22 is a genetic determinant for the predisposition to 2011 Jul 1 Rheumatoid arthritis (RA) is a typical complex trait and the major cause of chronic inflammation worldwide. Although multiple genetic loci have been shown for their association with the onset of RA, they cover only a part of its genetic components and are largely ethnicity-specific. To identify novel genetic factors related to the predisposition and prognosis of RA in Japanese, we conducted a large-scale genome-wide association (GWA) study. We performed a GWA analysis by scanning the genome of 1247 RA cases and 1486 controls for 277 420 single nucleotide polymorphisms (SNPs), followed by replication analysis using two independent sample sets consisting of 1865 cases and 1623 controls, and 2303 cases and 3380 controls. We identified two SNPs, rs2075876 and rs760426, in intron of the autoimmune regulator AIRE gene at chromosome 21q22 that showed strong associations with the disease (P= 3.6 × 10(-9) and P= 4.4 × 10(-8), respectively). Rs1800250, in exon7 of AIRE, was in strong linkage disequilibrium (r(2)= 0.94) with rs2075876 and introduced an amino acid alteration (S278R) in the SAND domain of the AIRE protein. In silico analysis showed the decreased transcription of AIRE by the risk allele of rs2075876 compared with the alternative allele (P= 6.8 × 10(-5)). No correlation was observed between the rs2075876 genotype and quantitative traits reflecting the progression of RA. As AIRE is a key molecule which regulates the expression and presentation of self-antigens in thymic negative selection, its downregulation by genetic polymorphisms may result in the survival of auto-reactive T cells to trigger auto-inflammation in RA.
21740352 Function of histone deacetylase inhibitors in inflammation. 2011 Histone deacetylases (HDACs) display multi-faceted roles in coordinating the interaction of intracellular signaling pathways with chromatin remodeling and transcription factor function to finely specify gene alterations and maintenance of gene expression during cellular activation, proliferation, and differentiation. These processes, epigenetic and non-epigenetic, are critical to the development of both the adaptive and innate arms of the mammalian immune system, and the measured initiation and resolution of immune responses. Pharmacological modulators of HDAC activity have demonstrated uniformly potent anti-inflammatory effects in experimental animal models of these diseases, in relevant immune and stromal cell populations from patients, as well as initial successes in the clinic. Recent studies have identified key roles for specific HDACs in regulating immune function, as well as alterations in HDAC expression and function in a number of immune-mediated inflammatory diseases (IMIDs), which may contribute to pathology in these diseases. Here, we review recent advances in our understanding of HDAC function in the immune system, their contribution to IMIDs, and the therapeutic potential of altering HDAC activity in IMIDs.
22324944 Identification of activated cytokine pathways in the blood of systemic lupus erythematosus 2012 Feb AIM: To develop genomic signatures of seven cytokines involved in the pathogenesis of rheumatic diseases such as systemic lupus erythematosus (SLE), dermatomyositis (DM), polymyositis (PM), rheumatoid arthritis (RA), or systemic scleroderma (SSc) that could potentially help identify patients likely to respond to therapies that target these individual cytokines. METHODS: Over-expressed transcripts in the whole blood (WB) were identified from 262 SLE, 44 DM, 33 PM, 38 SSc and 89 RA subjects and compared to 24 healthy subjects using Affymetrix arrays. Cytokine-inducible gene signatures such as type I interferon (IFN), tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, IL-10, IL-13, IL-17, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were assessed in the WB of these subjects to identify subpopulations showing activation of specific cytokine pathways. RESULTS: Significant activation of the type I IFN pathway in a population of five diseases studied was universally observed. The TNF-α and IL-1β pathways were activated in subgroups of PM and RA subjects, respectively, with another subgroup of RA subjects showing activation of the IL-13 pathway. The GM-CSF pathway was activated in a subgroup of SSc subjects and the IL-17 pathway was activated in subgroups of all diseases except SLE. CONCLUSIONS: A novel gene expression measurement of activated cytokines in five different rheumatic diseases is presented. Characterizing the cytokine pathways most activated in specific patient subpopulations has the potential to help target the appropriate patient populations for corresponding anti-cytokine therapies.
20182819 Estrogen and autoimmune disease. 2011 Feb Estrogenic hormones possess both immunostimulating and immunosuppressive properties. In systemic lupus erythematosus (SLE), pregnancy is associated with disease flares. In some situations, exogenous estrogen predisposes to development of new SLE, flares of preexisting SLE, and thromboses in susceptible individuals. In contrast, treatment with exogenous estrogen protects postmenopausal rheumatoid arthritis (RA) patients from active RA and osteoporosis. The search for estrogen-like compounds with anti-inflammatory properties may expand treatment options in RA.