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ID PMID Title PublicationDate abstract
19473560 Monoarticular corticosteroid injection versus systemic administration in the treatment of 2009 Mar OBJECTIVE: To compare the efficacy and safety of intraarticular glucocorticoid injection to its systemic use for treatment of knee synovitis in rheumatoid patients. METHODS: A randomized double-blind controlled study was conducted including 60 patients with RA. Patients were randomized to receive either a single intraarticular knee injection with triamcinolone hexacetonide 60 mg (3 ml) and xylocaine chloride 2% (1 ml) associated to a single intramuscular injection of 1 ml of xylocaine chloride 2% (IAI group) or 1 ml of xylocaine chloride 2% by intraarticular injection and a intramuscular injection of triamcinolone acetonide 60 mg (3 ml) and xylocaine chloride 2% (1 ml) (IM group). All patients were blindfolded for the procedure. Evaluations were performed at baseline and 1, 4, 8 and 12 weeks post-intervention. The following instruments were used: VAS for knee pain, as primary outcome, VAS for knee morning stiffness and edema; the ACR 20, 50 and 70% improvement criteria; knee circumference and goniometry; Likert's scale of improvement; daily use of oral glucocorticoid and NSAIDs, blood pressure and adverse effects. RESULTS: Patients in the IAI group had significantly better results for VAS for knee pain, edema and morning stiffness as well as for improvement evaluation after intervention according to the patient (p<0.001) and physician (p=0.02). CONCLUSION: Our results demonstrate that intraarticular injection with glucocorticoids is superior to its systemic use for the management of monoarticular synovitis in rheumatoid patients. The intraarticular approach showed better results in terms of local inflammatory variables and improvement evaluation by the patient and physician.
20934399 Total knee arthroplasty in severe valgus deformity: interest of combining a lateral approa 2010 Nov INTRODUCTION: Among the patients requiring total knee arthroplasty (TKA), approximately 10-15% presents with a valgus deformity (VD). Severely deformed valgus knees represent a surgical challenge. The purpose of this study is to evaluate the results of TKA in grade II and III valgus knee deformities (Ranawat classification), focusing on axis correction, by using a lateral parapatellar capsulotomy combined with tibial tubercle osteotomy. HYPOTHESIS: The lateral approach in combination with a tibial tuberosity osteotomy is highly beneficial in the treatment of severe valgus knees in patients undergoing primary TKA, for correction of anatomical axis. PATIENTS AND METHODS: Between January 1995 and December 2001, 33 patients with severe VD, grade II and III, were treated with TKA by one surgeon. Twenty-six patients (19 male, seven female) with mean age of 72 years (57-79) were dealt with a resurfacing posterior stabilized design; whereas in seven cases, a constrained type implant was used. These seven patients were excluded from the study. Two more patients were lost for follow-up and were also excluded. The axis deviation of the remaining 24 patients ranged from 15 to 35 degrees, (average 23°). A lateral parapatellar arthrotomy, in combination with tibial tubercle osteotomy was used. Patients' clinical evaluation - using the International Knee Society (IKS) score - with simultaneous radiological assessment was performed yearly after the operation; and for a mean follow-up time of 11.5 years (8 to 15 years). RESULTS: The mean IKS score improved from 44 points (34 to 52) preoperatively, to 91 points (68 to 100) postoperatively, at the last follow-up. In terms of alignment parameter, only two knees had a residual valgus deviation greater than 7° (ideal range : 3-7°). One knee exhibited a 9° valgus, and another one 10°, according to anatomical axis measurments. In one case, there was a 5mm proximal migration of the osteotomised tuberosity fragment, due to breakage of the screw. However, the final outcome was not affected. There were no cases of tibial tubercle's non-union; neither of delayed instability. CONCLUSION: The lateral approach is a useful approach in the treatment of severe valgus knee deformity in patients undergoing primary TKA. Anatomical axis restoration is facilitated, as the contracted structures are easily accessed and, in severe cases, the patellar alignment may be achieved by displacing the osteotomised tubercle. However, careful fixation of the tuberosity is mandatory. LEVEL OF EVIDENCE: Level IV, prospective study of case series.
20887640 The increased cardiovascular risk in rheumatoid arthritis: when does it start? 2010 Established rheumatoid arthritis (RA) is associated with a doubled cardiovascular risk. However, data about the cardiovascular risk in early RA are scarce. Preclinical atherosclerosis can be reliably assessed with the carotid intima media thickness (cIMT), and the cIMT is a well-validated predictor of cardiovascular events. The cIMT was therefore used in a recent controlled, prospective study in patients with early RA. Surprisingly, an increased cardiovascular risk at baseline could not be demonstrated whereas cIMT progression appeared to be comparable with the general population. Obviously, this study underscores the need for further large-scale investigations to solve the emerging discrepancy with the existing literature.
20067328 Associations between the C677T and A1298C polymorphisms of MTHFR and the efficacy and toxi 2010 BACKGROUND AND OBJECTIVE: The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene have been reported to be associated with the toxicity and efficacy of methotrexate in rheumatoid arthritis (RA), although the results of previous studies have been inconsistent. The aim of this study was to explore whether the C677T and A1298C polymorphisms of MTHFR play a role in the toxicity and efficacy of methotrexate in RA. METHODS: The authors identified and evaluated studies conducted on the association between the C677T and A1298C polymorphisms of MTHFR and on the toxicity and efficacy of methotrexate in RA. A meta-analysis was then conducted to compare the toxicity and efficacy of methotrexate with respect to the 677CC and 677CT/TT genotypes and the 1298AA and 1298AC/CC genotypes. RESULTS: Eight studies, which included a total of 1514 patients with RA, were included in this meta-analysis. Meta-analysis did not show any association between the C677T and A1298C polymorphisms of MTHFR and the toxicity of methotrexate in RA in all patients or in Asian patients. The odds ratios (ORs) for adverse effects with 677CC versus 677CT/TT in all patients and in Asian patients were 0.633 (95% CI 0.325, 1.234; p = 0.180) and 0.621 (95% CI 0.233, 1.655; p = 0.341), respectively. The ORs for adverse effects with 1298AA versus 1298AC/CC in all patients and in Asian patients were 0.942 (95% CI 0.479, 1.851; p = 0.861) and 0.978 (95% CI 0.569, 1.681; p = 0.936), respectively. Heterogeneities were evident among the included studies. In addition, no association was found between the C677T and A1298C polymorphisms and the efficacy of methotrexate in RA in all patients. CONCLUSIONS: Our meta-analysis including 1514 patients with RA found no association between the C677T and A1298C polymorphisms of MTHFR and the toxicity and efficacy of methotrexate in RA. Because of the paucity of pharmacogenetic data, further studies are needed to determine the role of MTHFR polymorphisms in the toxicity and efficacy of methotrexate.
21365950 [Nodular changes in lungs in a patient with rheumatoid arthritis. Diagnostic and therapeut 2010 Rheumatoid arthritis is a systemic inflammatory disease characterized by destructive synovitis and systemic extra-articular involvement exemplified by rheumatoid nodules occurring in the skin, lungs, and other parenchymatous organs. Antirheumatic drugs like methotrexate and leflunomide are known to predispose to the development of pulmonary rheumatoid nodules. We report the case of a 60-year-old male with rheumatoid arthritis previously treated with methotrexate and cyclosporin, in whom multiple pulmonary nodules were disclosed. The patient was extensively diagnosed to exclude any malignancy. Pulmonary rheumatoid nodules were recognized, methotrexate was withdrawn, and cyclophosphamide pulses were started. The size of the nodules decreased and the patient was started on cyclosporin.
20881757 Inadequate therapy behavior is associated to disease flares in patients with rheumatoid ar 2010 Oct OBJECTIVES: (1) To determine 6-month follow-up adherence and persistence with disease-modifying antirheumatic drugs in patients with early rheumatoid arthritis with disease under control. (2) To compare disease flares across adherent, nonadherent, persistent and nonpersistent patients. (3) To identify differences in adherent and persistent rates among therapeutic regimens. (4) To identify baseline prognosticators of poor compliance. METHODS: Ninety-three patients (86% female) had 4 consecutive 2-month apart evaluations during which the 28-joint disease activity score and the Health Assessment Questionnaire were scored, comorbidities and treatment recorded and a compliance questionnaire and a drug record registry applied. Descriptive statistics, Student t and χ tests and logistic regression analysis were used. RESULTS: At the study entry, patients had mean ± standard deviation age of 40.8 ± 13.9 years, the 28-joint disease activity score of 2.1 ± 1.1, the Health Assessment Questionnaire of 0.09 ± 0.2, and 68 of them (73.1%) had remission. During follow-up, 47 patients (50.5%) were adherent and 51 (54.8%) persistent; 14 of 68 patients (20.6%) who achieved remission had a disease flare. Incidence rate and individual risk of a disease flare were significantly greater in nonadherent and nonpersistent patients. Compared with methotrexate monotherapy, therapeutic regimens with >3 disease-modifying antirheumatic drugs had increased risk of nonadherence and nonpersistence (P ≤ 0.02). Higher previous serial erythrocyte sedimentation rate was associated to nonadherence (as was a shorter follow-up at the Clinic) and to nonpersistence (odds ratio: 1.03; 95% confidence interval: 1.01-1.05 for both, P = 0.05 and P = 0.001, respectively). CONCLUSIONS: Therapy behavior of patients with rheumatoid arthritis with mild/no disease activity and disability was poor and translated into disease flares. Higher serologic activity was associated to poor compliance with therapy.
19284577 Serum levels of soluble receptor for advanced glycation end products and of S100 proteins 2009 INTRODUCTION: The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface receptor molecules. High concentrations of three of its putative proinflammatory ligands, S100A8/A9 complex (calprotectin), S100A8, and S100A12, are found in rheumatoid arthritis (RA) serum and synovial fluid. In contrast, soluble RAGE (sRAGE) may prevent proinflammatory effects by acting as a decoy. This study evaluated the serum levels of S100A9, S100A8, S100A12 and sRAGE in RA patients, to determine their relationship to inflammation and joint and vascular damage. METHODS: Serum sRAGE, S100A9, S100A8 and S100A12 levels from 138 patients with established RA and 44 healthy controls were measured by ELISA and compared by unpaired t test. In RA patients, associations with disease activity and severity variables were analyzed by simple and multiple linear regressions. RESULTS: Serum S100A9, S100A8 and S100A12 levels were correlated in RA patients. S100A9 levels were associated with body mass index (BMI), and with serum levels of S100A8 and S100A12. S100A8 levels were associated with serum levels of S100A9, presence of anti-citrullinated peptide antibodies (ACPA), and rheumatoid factor (RF). S100A12 levels were associated with presence of ACPA, history of diabetes, and serum S100A9 levels. sRAGE levels were negatively associated with serum levels of C-reactive protein (CRP) and high-density lipoprotein (HDL), history of vasculitis, and the presence of the RAGE 82Ser polymorphism. CONCLUSIONS: sRAGE and S100 proteins were associated not just with RA inflammation and autoantibody production, but also with classical vascular risk factors for end-organ damage. Consistent with its role as a RAGE decoy molecule, sRAGE had the opposite effects to S100 proteins in that S100 proteins were associated with autoantibodies and vascular risk, whereas sRAGE was associated with protection against joint and vascular damage. These data suggest that RAGE activity influences co-development of joint and vascular disease in rheumatoid arthritis patients.
19671817 Reducing invasiveness, duration, and cost of magnetic resonance imaging in rheumatoid arth 2009 Aug OBJECTIVE: Gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) provides highly sensitive assessment of inflammatory and destructive changes in rheumatoid arthritis (RA) joints, but intravenous (IV) Gd injection prolongs examination time and increases cost, invasiveness, and patient discomfort. We explored to what extent RA joint pathologies in wrists and metacarpophalangeal (MCP) joints can be reliably assessed by unenhanced MRI images compared with Gd-enhanced MRI as the reference method. METHODS: MRI data sets from 2 RA substudies were scored according to preliminary OMERACT RA MRI scoring system (RAMRIS): Substudy A included 1.0 T/1.5 T MR images from 40 RA patients, which were scored twice by 2 experienced readers. Substudy B included 0.2 T dedicated extremity MRI (E-MRI) images from 55 patients, scored twice by one experienced reader. The first reading included only unenhanced images, whereas complete image sets were available for the second reading. RESULTS: Gd contrast injection appeared unimportant to MRI scores of bone erosions and bone edema in RA wrist and MCP joints. However, when post-Gd MRI was considered the standard reference, MRI without Gd provided only moderate to high agreement concerning assessment of synovitis, and omitting the post-Gd acquisitions increased the interreader variation on synovitis scores. Low-field (0.2 T) E-MRI in these exercises provided a lower sensitivity of unenhanced imaging for synovitis than MRI using higher-field strengths. CONCLUSION: Omitting IV contrast injection did not change scores of bone erosions and bone edema, but decreased the reliability of synovitis scores. However, this disadvantage may for some purposes be outweighed by the possibility to assess more joints and/or greater feasibility.
18722728 Computer-assisted quantification of interstitial lung disease associated with rheumatoid a 2009 Nov PURPOSE: To validate a threshold-based prototype software application (MeVis PULMO 3D) for quantification of chronic interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) using variable threshold settings for segmentation of diseased lung areas. METHODS: Twenty-two patients with rheumatoid arthritis were included and underwent thin-section CT (4x1.25mm collimation). CT scans were assessed by two observers for extent of ILD (EoILD), and twice by MeVis PULMO 3D for each protocol. MeVis PULMO 3D used four segmentation threshold (ST) settings (ST=-740, -780, -800 and -840HU). Pulmonary function tests were obtained in all patients. Statistical evaluation used 95% limits of agreement (LoA) and linear regression analysis. RESULTS: There was total concordance between the software measurements. Interobserver agreement was good (LoA=-28.36 to 17.58%). EoILD by readers correlated strongly with DL(CO) (r=-0.702, p<0.0001) and moderately with FVC (r=-0.523, p=0.018). There was close correlation between readers and MeVis PULMO 3D with best results for ST <780HU (EoILD vs. MeVis PULMO 3D: r=0.650 for ST=-800 and -840HU, respectively; p=0.002). MeVis PULMO 3D correlated best with DL(CO) at ST of -800HU (r=-0.44, -0.49, -0.58 and -0.57 for ST=-740, -780, -800 and -840, respectively; p=0.007-0.05) and moderately with FVC (r=-0.44, -0.51, -0.59 and -0.45 for ST=-740, -780, -800 and -840), respectively; p=0.007-0.05). CONCLUSION: The MeVis PULMO 3D system used holds promise to become a valuable instrument for quantification of chronic ILD in patients with RA when using the threshold value of -800HU, with evidence of the closest correlations, both with human observers and physiologic impairment.
20798997 Effects of different medical treatments on serum copper, selenium and zinc levels in patie 2011 Sep The aim of the present study was to measure the changes in serum selenium, zinc, and copper in patients being treated for rheumatoid arthritis. Thirty-two patients and 52 healthy controls were included in the study. The copper level was higher and those of selenium and zinc were lower in the patients relative to controls. Treatment with methotrexate elevated the zinc levels, but not zinc and selenium. Treatments with salazopyrin, corticosteroids, chloroquine, and non-steroidal anti-inflammatory drugs did not change the levels of any of the elements studied. The decrease in zinc and selenium levels and elevation in copper levels observed in the patients probably resulted from the defense response of organism and are mediated by inflammatory-like substances.
19545624 Intra-articular drug delivery systems for the treatment of rheumatic diseases: a review of 2009 Oct Osteoarthritis and rheumatoid arthritis are rheumatic diseases for which a curative treatment does not currently exist. Their management is directed towards pain relief achieved with different classes of drugs among which non-steroidal and steroidal anti-inflammatory substances are the most frequently used agents. Nevertheless, the oral or systemic administration of such drugs is hindered by numerous side effects, which could be overcome by their intra-articular (i-a.) administration as dosage forms capable of gradually releasing the active substance. The present review article summarises the research done in the field of drug delivery systems for i-a. injection vs. current management of osteoarthritis or rheumatoid arthritis. Aspects such as the influence of size, shape, polymer matrix or targeted drug on the i-a. retention time, phagocytosis and biological activity will be discussed. Finally, we will comment on the need for adapted delivery systems for the novel and very potent anti-inflammatory drugs, such as inhibitors of the p38 mitogen-activated protein kinase or the IL-1beta conversion enzyme, which to date cannot be properly used due to the severe side effects associated with their systemic administration.
19481004 Infectious complications of biologic agents. 2009 Feb Infection is a frequent complication in rheumatoid arthritis (RA) and other autoimmune diseases. Since 2000, the spectrum of therapeutic possibilities (ie, biologic agents) for treating RA has expanded rapidly and many safety reports of patients treated with these drugs have been published. In most studies, biologics are associated with an increased incidence of infections with the use of tumor necrosis factor antagonists. Reported risks for developing infection differ among studies. This article provides an overview of which studies the authors consider the most relevant.
21149495 Nationwide prevalence of rheumatoid arthritis and penetration of disease-modifying drugs i 2011 Apr OBJECTIVE: To provide Swedish nationwide data on the prevalence of rheumatoid arthritis (RA), including variations by age, sex, geography, demography and education level, and assess antirheumatic treatment penetration. METHODS: Patients ≥16 years assigned an RA diagnosis were identified from inpatient (n=96 560; 1964-2007) and specialist outpatient care (n=56 336; 2001-2007) in the Swedish National Patient Register, and the Swedish Rheumatology Quality Register (n=21 242; 1995-2007). Data on prescriptions, demography, vital status and educational level were retrieved from national registers. RESULTS: A total of 58 102 individuals (mean age 66 years; 73% women) assigned an RA diagnosis were alive in Sweden in 2008, corresponding to a cumulative prevalence of 0.77% (women 1.11%, men 0.43%). The 2001-2007 period prevalence was 0.70%. Restriction to patients with ≥2 visits or diagnosis from a rheumatologist/internist reduced the overall cumulative prevalence to 0.68%. Whereas urban/rural differences (crude 0.65-1.00%) were explained by age differences, the age/sex-adjusted prevalence remained higher in patients with ≤9 years education (0.86%) than for those with 10-12 years (0.82%) and >12 years (0.65%). Treatment exposures (76% any disease-modifying antirheumatic drugs (DMARDs) or steroids, 64% any DMARD, 15% biological agents) varied with age; use of biological agents decreased from 22% in 16-59 years olds to 3% in ≥80 years olds. Any DMARD use correspondingly decreased from 71% to 43%. Applying age cut-off points from previous northern European and North American prevalence studies reduced or eliminated between-study differences. CONCLUSION: This nationwide approach yielded a prevalence of RA similar to previous regional assessments. While displaying only modest geographical variation and no urban/rural gradient, prevalence was associated with educational level. Although most patients received antirheumatic drugs, age was a strong treatment determinant.
20639398 Locus category based analysis of a large genome-wide association study of rheumatoid arthr 2010 Oct 1 To pinpoint true positive single-nucleotide polymorphism (SNP) associations in a genome-wide association study (GWAS) of rheumatoid arthritis (RA), we categorize genetic loci by external knowledge. We test both the 'enrichment of associated loci' in a locus category and the 'combined association' of a locus category. The former is quantified by the odds ratio for the presence of SNP associations at the loci of a category, whereas the latter is quantified by the number of loci in a category that have SNP associations. These measures are compared with their expected values as obtained from the permutation of the affection status. To account for linkage disequilibrium (LD) among SNPs, we view each LD block as a genetic locus. Positional candidates were defined as loci implicated by earlier GWAS results, whereas functional candidates were defined by annotations regarding the molecular roles of genes, such as gene ontology categories. As expected, immune-related categories show the largest enrichment signal, although it is not very strong. The intersection of positional and functional candidate information predicts novel RA loci near the genes TEC/TXK, MBL2 and PIK3R1/CD180. Notably, a combined association signal is not only produced by immune-related categories, but also by most other categories and even randomly defined categories. The unspecific quality of these signals limits the possible conclusions from combined association tests. It also reduces the magnitude of enrichment test results. These unspecific signals might result from common variants of small effect and hardly concentrated in candidate categories, or an inflated size of associated regions from weak LD with infrequent mutations.
20132067 Expression analysis of Notch-related molecules in peripheral blood T helper cells of patie 2010 OBJECTIVE: Expression of Notch homologues in local tissue inflammation in rheumatoid arthritis (RA) and cultured synoviocytes has been reported, but the expression profile of Notch-related molecules in peripheral lymphocytes in RA remains unclear. In this study, we measured the expression of Notch receptors and downstream molecules in peripheral lymphocytes from RA patients. METHODS: Expression of Notch receptors in peripheral lymphocytes of RA patients was assessed by both flow cytometry and real-time polymerase chain reaction (PCR). Expression of the representative Notch target gene HES-1 and the regulatory gene NUMB in purified T helper cells from RA patients was determined by real-time PCR, and expression of Notch intracellular domain (ICD) was determined by immunoblot analysis. RESULTS: There was an increased expression of Notch 2, Notch 3, and Notch 4 in T helper cells from active RA patients, among which increased expression of Notch 3 was mainly by activated T cells. Notably, expression of Notch 3 in T cells decreased in inactive RA patients and the level was similar to that of healthy controls (HC). Notch receptors were rarely observed on B cells and no difference in expression was found between RA patients and HC. T helper cells from RA patients exhibited increased expression of the target gene HES-1 but decreased expression of the negative modulation gene NUMB of Notch signalling. There was also an increased nuclear translocation of Notch-ICD in T helper cells from active RA disease. CONCLUSION: The present study demonstrated that T helper cells from RA patients display a significantly altered expression profile of Notch receptors and enhanced activation of Notch signalling compared with HC.
20351133 A comparative study of the modified Sauvé-Kapandji procedure for rheumatoid wrist with an 2010 Oct We compared the clinical and radiological results of the modified Sauvé-Kapandji procedure for 41 of 86 operated rheumatoid wrists with (n=22) and without (n=19) stabilization of the proximal ulnar stump with a slip of half the extensor carpi ulnaris tendon. Gender, age, and follow-up period were similar in the two groups. We found no difference clinically or on radiographs between the two groups other than better early postoperative pain relief in those stabilized. Stabilization of the proximal ulnar stump may not be necessary in the modified Sauvé-Kapandji procedure for rheumatoid wrists.
19999316 [Referring to an unusual case: pulmonary affection and rheumatoid arthritis]. 2009 Nov 11 We report the case of a 60 year female patient suffering from rheumatoid arthritis for the last 25 years, under TNF-blocker and leflunomide, affected by a recurrent pneumothorax with several subpleural nodules, basal bronchiectasis and apical bullous emphysema. The patient was administered several treatments: aspiration, talc pleurodesis, surgical pleurodesis, pleurodesis induced by tetracycline and autologous blood. To allow the pleural inflammatory reaction necessary to the success of the pleurodesis, we had to interrupt the treatment by TNF-blocker and leflunomide. We then witnessed a partial pleurodesis with persistence of a pneumothorax. The medical situation is improving with disappearance of dyspnea.
20127131 The diagnostic utility of the anti-CCP antibody test is no better than rheumatoid factor i 2010 Jun To establish the diagnostic utility of the anti-cyclic-citrullinated peptide antibody (aCCP) test in Black South Africans with early rheumatoid arthritis (RA). A cross-sectional study comparing the rheumatoid factor (RF) and aCCP status in RA patients and a control group consisting of healthy subjects, and patients with systemic lupus erythematosus (SLE) and scleroderma. The sensitivity, specificity, positive (PPV) and negative predictive values of the aCCP test alone were 82.5%, 84.9%, 87.6% and 79% versus 81.7%, 90.7%, 92.5% and 78% for RF alone. The best specificity (95.3) and PPV (95.8%) was observed when both aCCP and RF tests were positive. Patients with erosive disease had a significantly higher mean RF titre compared with those with non-erosive disease (p = 0.007). There was a trend towards an association of smoking (OR = 4.1, 95% CI = 0.9-18.6) and functional disability (p = 0.07) with RF-positive status. No similar clinical associations were observed with aCCP. Almost a third of SLE patients were aCCP positive. Despite the best specificity and PPV observed when both the aCCP and RF tests were positive, our findings suggest that testing for aCCP is only cost-effective in the RF-negative patient in whom there is a strong clinical suspicion of RA.
19924719 Improving the signal-to-noise ratio in genome-wide association studies. 2009 Genome-wide association studies employ hundreds of thousands of statistical tests to determine which regions of the genome may likely harbor disease-causing alleles. Such large-scale testing simultaneously requires stringent control over type I error and maintenance of sufficient power to detect true associations. These contradictory goals have led some researchers beyond Bonferroni correction of P-values to an exploration of methods to improve the detection of a few true effects in the presence of many unassociated loci. This article reviews how Genetic Analysis Workshop 16 Group 5 investigators proposed to adjust for multiple tests while simultaneously using information about the structure of the genome to improve the detection of true positives.
20980283 The interferon regulatory factor 5 gene confers susceptibility to rheumatoid arthritis and 2011 Jan BACKGROUND: Increased expression of type I IFN genes, also referred to as an IFN signature, has been detected in various autoimmune diseases including rheumatoid arthritis (RA). Interferon regulatory factors, such as IRF5, coordinate type I IFN expression. Multiple IRF5 variants were suggested as autoimmunity susceptibility factors. OBJECTIVE: As the linkage proof remains important to establish fully any genetic RA susceptibility factor, the authors took advantage of the largest reported European trio family resource dedicated to RA to test for linkage IRF5 and performed a genotype-phenotype analysis. METHODS: 1140 European Caucasian individuals from 380 RA trio families were genotyped for IRF5 rs3757385, rs2004640 and rs10954213 single nucleotide polymorphisms (SNP). RESULTS: Single marker analysis provided linkage evidence for each IRF5 SNP investigated. IRF5 linked to RA with two haplotypes: the CTA risk haplotype 'R' (transmission (T)=60.6%, p=23.1×10(-5)) and the AGG protective haplotype 'P' (T=39.6%, p=0.0015). Linkage was significantly stronger in non-erosive disease for both IRF5 R and P haplotypes (T=73.9%, p=4.20×10(-5) and T=19.6%, p=3.66×10(-5), respectively). Multivariate logistic regression analysis found IRF5 linked to RA independently of the rheumatoid factor status. IRF5 RR and PP haplotypic genotypes were associated with RA, restricted to the non-erosive phenotype: p=1.68×10(-4), OR 4.80, 95% CI 2.06 to 11.19; p=0.003, OR 0.17, 95% CI 0.05 to 0.57, respectively. CONCLUSION: This study provides the 'association and linkage proof' establishing IRF5 as a RA susceptibility gene and the identification of a genetic factor that seems to contribute to the modulation of the erosive phenotype. Further studies are warranted to clarify the role of IRF5 in RA and its subphenotypes.