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PMID	Title	PublicationDate	abstract
15247886	Human sera with precipitating antibodies to human soluble immune complexes. A brief commun	2004 May	INTRODUCTION: Previous numerous papers by the senior author dealt with the human serum factor referred to as anti-antibody which is specifically directed against IgG antibodies that underwent molecular transformation in the course of the reactions with their corresponding antigens. The reactions of this serum factor could be conveniently detected by means of agglutination of Rh-positive erythrocytes sensitized by anti Rh antibodies. No precipitation tests could be developed. MATERIAL AND METHODS: Most studies were conducted by means of double diffusion in gel precipitation. RESULTS: A rheumatoid arthritis serum, G, was noted that produced a strong reaction of double diffusion in gel precipitation with serum samples of a renal graft recipient, T. Further screening detected one more rheumatoid arthritis serum reacting with T; of 28 sera from renal graft recipients, 6 reacted in a similar way to T, but the reactions were considerably weaker and poorly reproducible. Evidence was presented that the precipitin in the two rheumatoid arthritis sera under study had properties of previously described anti-antibody. CONCLUSIONS: Sera with precipitating anti-antibodies may serve as exquisite reagents for detection of soluble immune complexes in human sera.
12090562	Clinical and immunogenetic characterization of Mexican patients with 'rhupus'.	2002	The coexistence of systemic lupus erythematosus and rheumatoid arthritis (rhupus), is a rare clinical condition. To date, 50 cases of rhupus have been described worldwide; however, the lack of clinical criteria for this rheumatic condition has created confusion in the characterization of this disorder. Nevertheless, in this paper we describe a comprehensive clinical and serological characterization of a cohort of 22 Mexican patients with rhupus, supported by generic HLA-DR phenotyping. We found that rhupus patients have a special clinical behavior. In this setting, the signs and symptoms of rheumatoid arthritis prevail, little organic damage associated with systemic lupus erythematosus (SLE) exists and none of the cases present thrombosis or morbidity during pregnancy in spite of presenting a high frequency of anticardiolipin antibodies. We also found an increased frequency of HLA-DR1 and HLA-DR2 alleles compared to healthy ethnically matched controls, systemic lupus erythematosus and rheumatoid arthritis patients.
14558078	Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the deve	2003 Oct	OBJECTIVE: To evaluate the prevalence and predictive value of anti-cyclic citrullinated peptide (anti-CCP) antibodies in individuals who subsequently developed rheumatoid arthritis (RA) and to determine the relationship to rheumatoid factor (RF) of any isotype. METHODS: A case-control study was nested within the Northern Sweden Health and Disease Study and the Maternity cohorts of Northern Sweden. Patients with RA were identified among blood donors whose samples had been taken years before the onset of symptoms. Control subjects matched for age, sex, date of sampling, and residential area were selected randomly from the same cohorts. Anti-CCP antibody and RFs were determined using enzyme immunoassays. RESULTS: Eighty-three individuals with RA were identified as having donated blood before presenting with any symptoms of joint disease (median 2.5 years [interquartile range 1.1-4.7] before RA). In samples obtained before the onset of RA, the prevalence of autoantibodies was 33.7% for anti-CCP, 16.9% for IgG-RF, 19.3% for IgM-RF, and 33.7% for IgA-RF (all highly significant compared with controls). The sensitivities for detecting these autoantibodies >1.5 years and
14760786	The effect of oral contraceptives and estrogen replacement therapy on the risk of rheumato	2004 Feb	OBJECTIVE: Epidemiologic evidence for a protective effect of exogenous female sex hormones on the development of rheumatoid arthritis (RA) is contradictory. We examined whether exposure to either oral contraceptives (OC) or postmenopausal estrogen replacement therapy (ERT) is associated with the development of RA in women. METHODS: We separately examined the relationship between use of OC and ERT on the risk of RA in a population based case-control study. Case patients, including all female residents of Rochester, Minnesota, > or = 18 years of age, who first fulfilled 1987 American College of Rheumatology criteria for RA between 1955 and 1994 (n = 445), were compared with age matched female controls from the community. Multivariable conditional logistic regression models were used to determine whether OC or ERT exposure had an effect on RA development after controlling for potential confounders. RESULTS: We observed an inverse association between ever-use of OC and the risk of RA, which persisted after adjusting for potential confounders in multivariate analyses (OR 0.56, 95% CI 0.34, 0.92). Earlier calendar-year of first exposure to OC was associated with lower OR for RA. We found no evidence of a significant association of ERT with RA risk (adjusted OR 1.11, 95% CI 0.69, 1.78). CONCLUSION: Exposure to OC, but not ERT, significantly reduces the risk of development of RA. The risk of developing RA is lower when OC exposure occurred in earlier years, which suggests that the higher doses of estrogens and progestins contained in earlier OC preparations may have a stronger protective effect against developing RA. While this protective effect is strong, it only explains a small portion of the observed decrease in RA incidence over the past few decades because the proportion of Rochester women exposed to OC is quite small.
14672888	Endothelial dysfunction in young patients with rheumatoid arthritis and low disease activi	2004 Jan	BACKGROUND: Rheumatoid arthritis (RA) is associated with an increased risk of cardiovascular disease. Endothelial dysfunction represents the earliest stage of atherosclerosis. OBJECTIVE: To evaluate the influence of chronic inflammatory state on endothelial function in patients with RA by measuring endothelial reactivity in young patients with RA with low disease activity and without traditional cardiovascular risk factors. METHODS: Brachial flow mediated vasodilatation (FMV), assessed by non-invasive ultrasound, was evaluated in 32 young to middle aged patients with RA (age /=4 determinations multiplied by the disease duration (r = -0.40, p<0.05). In a multivariate regression model, a lower brachial flow mediated vasodilatation was independently predicted by low density lipoprotein cholesterol (beta = -0.40, p<0.05), average CRP levels multiplied by the disease duration (beta = -0.44, p<0.05), and brachial artery diameter (beta = -0.28, p<0.05). CONCLUSIONS: Young to middle aged patients with RA with low disease activity, free from cardiovascular risk factors and overt cardiovascular disease, have an altered endothelial reactivity that seems to be primarily related to the disease associated chronic inflammatory condition.
11915862	Pulmonary nocardiosis in a patient treated with corticosteroid therapy.	2002 Mar	We report a case of pulmonary nocardiosis in a 69-year-old man with rheumatoid arthritis who was receiving corticosteroid treatment. The patient received prednisolone for rheumatoid arthritis and antibiotics for his fever and pneumonia in another hospital, but the response to the therapy was poor. After admission to our hospital, he improved following treatment with imipenem/cilastatin for Nocardia asteroides. Pulmonary nocardiosis is difficult to diagnose and should be considered in the differential diagnosis, especially in an immunocompromised host.
11843171	Pulmonary tuberculosis in patients with rheumatoid arthritis (four case reports).	2002 Jan	Pulmonary involvement is one of the most common extra-articular manifestations of rheumatoid arthritis (RA). We studied four smear-positivepulmonary tuberculosis patients who had had RA for 2.5-12 years. Three of them were using corticosteroids at the time of diagnosis. The clinical, radiological and bacteriological features of all the patients were examined. We conclude that when patients with RA have symptoms related to pulmonary involvement, tuberculosis should be considered, particularly in developing countries.
14982943	Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory response	2004 Jun	We report that mitochondrial DNA (mtDNA) is inflammatogenic in vitro and in vivo as a result of the presence of unmethylated CpG sequences and its oxidative status. Purified human and murine mtDNAs induced arthritis when injected intra-articularly (i.a.) in mice. Importantly, oligodeoxynucleotide that contained a single oxidatively damaged base also induced arthritis when injected i.a. in mice. In contrast, neither human nor murine nuclear DNA induced inflammation. mtDNA-induced arthritis was neither B cell- nor T cell-dependent but was mediated by monocytes/macrophages. mtDNA-induced nuclear factor-kappaB stimulation resulted in the production of tumor necrosis factor alpha, a potent, arthritogenic factor. Finally, extracellular mtDNA was detected in the synovial fluids of rheumatoid arthritis patients but not of control subjects. We conclude that endogenous mtDNA displays inflammatogenic properties as a result of its content of unmethylated CpG motifs and oxidatively damaged adducts.
14583566	Estimation of inflammation by Doppler ultrasound: quantitative changes after intra-articul	2003 Nov	OBJECTIVE: To evaluate the use of ultrasound, including quantitative Doppler analysis of synovial vascularisation, before and after intra-articular treatment with glucocorticosteroids in patients with rheumatoid arthritis (RA). METHODS: 51 patients with RA were followed prospectively after an intra-articular glucocorticosteroid injection. Disease modifying antirheumatic drug treatment was kept unchanged and no further injections given in this observation period. At baseline, disease activity was estimated clinically by target join pain on a 100 mm visual analogue scale, on which the target joint was scored 0-3 for swelling and tenderness, and by ultrasound measurements of grey scale pixels, colour Doppler pixels, and the spectral Doppler resistive index (RI) as indicators of synovial swelling and inflammation. After four weeks, the measurements were repeated on the same joint. An observer unaware of the sequence and patient number evaluated the ultrasound images. RESULTS: At one month follow up after the glucocorticosteroid injection, a marked decrease in the fraction of colour pixels was seen in 41/51 patients (Student's t test p<0.001). Correspondingly, the RI increased indicating a diminished flow to the synovium (Student's t test p<0.01). Both the fraction of colour pixels and the RI values corresponded with the clinical evaluation and with the subjective effect of the treatment. The synovial membrane volume estimated by total amount of pixels showed a significant decrease by 31% after treatment. CONCLUSION: Ultrasound-Doppler seems to be a promising tool for the estimation of synovial activity in arthritis. After intra-articular glucocorticosteroid, changes in RI and fraction of colour pixels may both be used as quantitative measurements of the blood flow.
15552526	Tuberculosis and opportunistic infections: relevance to biologic agents.	2004 Sep	With the expanding use of biologic agents, in particular TNF inhibitors, tuberculosis and other opportunistic infections have become an important and growing concern in rheumatology. Clinicians using these therapies should have an understanding of the scope of the problem, the underlying scientific rationale, as well as the optimal approaches to screening, monitoring and treatment.
15593102	Accuracy of Veterans Administration databases for a diagnosis of rheumatoid arthritis.	2004 Dec 15	OBJECTIVE: To determine the accuracy of International Classification of Diseases (ICD) code 714 for rheumatoid arthritis (RA) diagnosis in a Veterans Administration (VA) hospital database and to examine the effects of adding laboratory and pharmacy data to ICD code 714 on accuracy of RA diagnosis. METHODS: We drew a random sample of patients from all Minneapolis VA rheumatology clinic patients who had at least 1 rheumatology clinic visit between January 2001 and July 2002. Charts of 184 patients were reviewed. The gold standard for RA diagnosis was chart documentation of RA diagnosis by a rheumatologist on > or =2 visits >6 weeks apart. The data definitions of RA diagnosis included presence of ICD code 714 alone or various combinations of ICD code 714, a positive rheumatoid factor (RF), and prescription for a disease-modifying antirheumatic drug (DMARD). Accuracy of data definitions of RA was assessed by calculating sensitivity, specificity, positive and negative predictive values, and area under the receiver operator characteristics curve. RESULTS: Diagnosis by ICD code 714 had 100% sensitivity, but specificity was only 55% because of a false-positive rate of 34%. The addition of a positive RF and/or a DMARD prescription to ICD code 714 dramatically improved specificity to 83-97% and positive predictive value to 81-97%; however, sensitivity decreased to 76-88%. Diagnosis by ICD 714 alone had the highest negative predicative value of 100%. The area under the curve was the greatest when both ICD code 714 and a positive RF were included, and the least when ICD code alone was used. CONCLUSION: ICD code 714 in the VA administrative database is a very sensitive screening tool for identifying patients with RA in the rheumatology clinic population. Addition of the presence of a DMARD prescription and/or a positive RF to selection criteria improves specificity of the diagnosis.
14613267	Inflammation and bone resorption as independent factors of accelerated arterial wall thick	2003 Nov	OBJECTIVE: We recently reported that rheumatoid arthritis (RA) patients had increased intima-media thickness (IMT) of the common carotid artery (CCA). The present longitudinal study was performed to determine whether the change in arterial thickness was accelerated in RA patients and to determine which factor was important in the progression of arterial wall changes. METHODS: We studied 62 female RA patients with stable disease activity and 63 healthy female controls. IMT of the CCA was measured twice by high-resolution B-mode ultrasonography. The second examination was performed 18-36 months after the first, and changes were expressed as millimeters of increase per year. Baseline examinations included blood markers of inflammation and urinary calcium excretion (expressed as the calcium-to-creatinine ratio). RESULTS: RA patients showed a significantly greater increase in IMT of the CCA compared with controls. In univariate analyses of the RA patient data, the C-reactive protein (CRP) level correlated with the increase in CCA IMT. Other markers of inflammation (the erythrocyte sedimentation rate and white blood cell and platelet counts) also showed significant positive associations with the annual increase in CCA IMT in multiple regression models when adjusted for age, smoking status, blood pressure, and serum cholesterol level. The urinary calcium-to-creatinine ratio was also significantly associated with an increase in CCA IMT. Moreover, both the CRP level and the urinary calcium-to-creatinine ratio were significantly and independently associated with the increase in IMT of the CCA. CONCLUSION: Patients with RA have a higher rate of increase in thickening of the arterial wall. Inflammation and calcium mobilization are factors closely associated with the accelerated arterial wall changes.
12209505	Comparison of synovial tissues from the knee joints and the small joints of rheumatoid art	2002 Aug	OBJECTIVE: Serial synovial biopsy samples are increasingly being used for the evaluation of novel therapies for rheumatoid arthritis (RA). Most studies have used tissues from knee biopsies, but technical improvements have made serial small joint arthroscopy feasible as well. Theoretically, there could be differences in the features of synovial inflammation between various joints as a result of mechanical factors, differences in innervation, and other factors. We therefore undertook this study to compare the cell infiltrate in paired synovial biopsy samples from inflamed knee joints and paired inflamed small joints of patients with RA. METHODS: Nine RA patients with both an inflamed knee joint and an inflamed small joint (wrist or metacarpophalangeal joint) underwent an arthroscopic synovial biopsy of both joints on the same day. Multiple biopsy specimens were collected and stained for macrophages, T cells, plasma cells, fibroblast-like synoviocytes, and interleukin-6 (IL-6) by immunohistochemistry. Sections were evaluated by digital image analysis. RESULTS: There were no significant differences in mean cell numbers for all markers investigated in samples from the knee joint compared with samples from the small joints. We detected statistically significant correlations for the numbers of sublining macrophages, T cells, and plasma cells, as well as for IL-6 expression, between the knee joint and the small joints. However, there was no significant correlation between different joints for the numbers of intimal macrophages or fibroblast-like synoviocytes. CONCLUSION: The results of this study show that the inflammation in one inflamed joint is generally representative of that in other inflamed joints. Therefore, it is possible to use serial samples from the same joint, selecting either large or small joints, for the evaluation of antirheumatic therapies.
15172047	Cytotoxic T-lymphocyte antigen 4-immunoglobulin in rheumatoid arthritis.	2004 May	It is apparent that the potential to significantly affect the immune response exists through artificial modulation of a system of molecules on the surface of T cells that has been designed to specifically provide on-off switches to support or abrogate the activation of T cells. This approach holds considerable promise because it avoids toxicities associated with cell lysis, while theoretically specifically affecting only those T cells, which are being continuously stimulated to become activated. Although there is presently a paucity of studies in humans on the clinical effects of cytotoxic T-lymphocyte antigen 4-immunoglobulin in patients who have rheumatoid arthritis, the existing studies indicate a clear therapeutic value with this approach.
15188353	Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritis synovium.	2004 Jun	OBJECTIVE: Microsomal prostaglandin E synthase 1 (mPGES-1) catalyzes the formation of PGE(2) from cyclooxygenase-derived PGH(2). Microsomal PGES-1 is induced by proinflammatory cytokines and is strongly linked to conditions that result in high PGE(2) biosynthesis. PGE(2) contributes to the pathogenesis of rheumatoid arthritis (RA), acting as a mediator of inflammation and promoting bone destruction. Induction of mPGES-1 in rheumatoid synoviocytes by proinflammatory cytokines has been demonstrated in vitro, indicating an important role in RA pathogenesis. Recent studies using mPGES-1-deficient mice demonstrated the importance of this gene in chronic inflammation. The aim of this study was to investigate the expression and localization of mPGES-1 in synovial biopsy specimens obtained from patients with RA. METHODS: Synovial tissue samples from 24 patients with RA were obtained, and immunohistologic analysis was performed using polyclonal antibodies against mPGES-1. Double immunofluorescence staining was performed with antibodies to CD3, CD19, CD20, CD68, CD163, and prolyl 4-hydroxylase. RESULTS: Intracellular mPGES-1 staining was observed in synovial membranes from all of the RA patients studied. Specifically, strong expression of mPGES-1 was detected in synovial lining cells. In sublining mononuclear and fibroblast-like cells, the extent of mPGES-1 staining was less than that in the synovial lining cells. In some patients, positive staining was observed in endothelial cells. With the double immunofluorescence technique, mPGES-1 production was detected in synovial macrophages and fibroblasts, while mPGES-1 expression was not observed in lymphocytes. CONCLUSION: The demonstration of mPGES-1 expression in synovial tissues from patients with RA suggests a role for mPGES-1 in the RA disease process. Microsomal PGES-1 might be a potential new target for treatment strategies to control PGE(2) synthesis in patients with RA, without the systemic side effects associated with cyclooxygenase inhibitors.
15479890	HLA-DR-DQ haplotypes and genotypes in Finnish patients with rheumatoid arthritis.	2004 Nov	OBJECTIVES: To elucidate the contribution of HLA-DR-DQ haplotypes and their genotypic combinations to susceptibility to rheumatoid arthritis, and to evaluate the various models for HLA associated risk for the disease in a series of Finnish patients. METHODS: 322 Finnish patients with rheumatoid arthritis were typed for common north European HLA-DR-DQ haplotypes and compared with a series of 1244 artificial family based control haplotypes. RESULTS: The association of the so called shared epitope (SE) haplotypes (DRB10401, 0404, 0408, and 01) with rheumatoid arthritis was confirmed. The DRB10401 haplotypes carried a far stronger risk for the disease than the (DRB101/10)-(DQA101)-DQB10501 haplotypes. Seven protective HLA haplotypes--(DRB115)-(DQA101)-DQB10602; (DRB108)-(DQA104)-DQB104; (DRB111/12)-DQA105-DQB10301; (DRB11301)-(DQA101)-DQB10603; (DRB11302)-(DQA101)-DQB10604; (DRB107)-DQA10201-DQB10303; and (DRB116)- (DQA101)-DQB10502--were identified. In accordance with the reshaped shared epitope hypothesis, all the protective DRB1 alleles in these haplotypes share either isoleucine at position 67 or aspartic acid at position 70 in their third hypervariable region motif. However, differences in the disease risk of haplotypes carrying the same DR but different DQ alleles were also found: (DRB107)-DQA10201-DQB10303 was protective, while (DRB107)-DQA10201-DQB1*02 was neutral. The same haplotypes carried different risks for rheumatoid arthritis depending on their combination in genotypes. CONCLUSIONS: When assessing the influence of HLA genes on the susceptibility to rheumatoid arthritis, not only should the HLA-DR or -DQ alleles or haplotypes be unravelled but also the genotype. The effect of HLA class II region genes is more complicated than any of the existing hypotheses can explain.
12375316	The methotrexate therapeutic response in rheumatoid arthritis.	2002 Oct	OBJECTIVE: Methotrexate (MTX) is used frequently as a disease modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA), and patients tend to continue taking this drug for longer periods than alternative single agents. The shape of the therapeutic response beyond one or 2 years, however, has not been fully studied. We examined the properties of the pure MTX "therapeutic segment," that period that begins with start of MTX and terminates when MTX is discontinued or another DMARD is added, by observational study. METHODS: We studied new MTX starts for the period 1988 through 1996 for 437 patients from a parent cohort of 4253 patients. Patients were drawn from 8 Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) data centers: 2 community based populations; 2 private rheumatological practices; 2 university referral practices; and 2 university clinics for underserved minority urban populations. Health Assessment Questionnaire (HAQ) Disability Index scores (0-3) were obtained prospectively each 6 months. RESULTS: At MTX start, patients had relatively long average disease duration of 16.7 years, and had moderately severe disability, with an initial HAQ mean disability score of 1.48. Over the 10 year period examined in the parent cohort of 4253 patients (and thus irrespective of therapy), the prevalence of MTX use rose from 19% to 45%, while mean HAQ disability declined from 1.34 to 1.11. This correspondence is consistent with an accrual of benefits from more frequent use of MTX and other DMARD over this period. The MTX therapeutic segment revealed a distinct shape. HAQ-Disability Index values began at 1.48 at baseline and declined to a maximal improvement of 1.23 at 30 months. This long period to maximum benefit may have been partly driven by a slow titration upward to an optimal dosage. After 42 months, disability for this population began to re-progress and reached 1.39 at 84 months, still below the pretreatment baseline. Re-progression to baseline was about 8 or more years. Cumulative disability averted with MTX treatment for this population was roughly 1.30 disability-unit-years. CONCLUSION: MTX treatment of RA in practice differs substantially from common perception and appears suboptimal by being too little, too late, and too long to treatment change. A modification of the "sawtooth strategy" in which the disease is "ratcheted down" by change of MTX therapy at 3 years or when re-progression has proceeded halfway to baseline, rather than waiting for return to baseline, is suggested by these data. Also suggested is the need for more rapid upward dosage titration and longer maintenance of an optimal or highest tolerated dosage. "Therapeutic segment" data provide insights into strategic approaches to management of RA since they allow estimation of population aggregate properties such as time to maximum benefit and the time to return to baseline.
12784386	Distribution of protein nitrotyrosine in synovial tissues of patients with rheumatoid arth	2003 Jun	OBJECTIVE: Because nitric oxide related species have been found in the inflamed joints of patients with arthritis, we investigated whether protein nitrotyrosine (a marker of tissue exposure to peroxynitrite) is present in their synovial tissues. METHODS: Protein nitrotyrosine was detected immunohistochemically and by Western blot analysis. Synovial tissues removed surgically from 12 patients with rheumatoid arthritis (RA) (mean age 63.7 yrs) and 20 with osteoarthritis (OA) (mean age 66.6 yrs) were studied. RESULTS: Nitrated proteins were detected immunohistochemically in all of 18 tissues examined. Diffuse staining of the stroma was seen in all patients, with more extensive staining in RA than OA (p = 0.008). Intense staining was detected in some lymphocytes, but not in others, even within a single lymphoid aggregate. Neutrophils did not stain for nitrotyrosine. Vascular endothelial cells stained for nitrotyrosine but adjoining smooth muscle cells did not. Both cytoplasmic and nuclear staining was seen in macrophages, endothelial cells, and lymphocytes. Numerous bands of nitrated proteins were detected by Western blot analysis of 15 synovial tissue extracts. Inducible nitric oxide synthase (iNOS) was detected immunohistochemically in endothelial cells, macrophages, vascular smooth muscle cells, and synoviocytes. CONCLUSION: Nitrotyrosine-containing proteins were found in essentially all synovia from RA and OA patients. The most prominent site of nitration in all cases was the stroma. iNOS, the likely source of the nitrating species, was found in a variety of cell types.
12674455	Diagnostic and therapeutic injection of the shoulder region.	2003 Mar 15	The shoulder is the site of multiple injuries and inflammatory conditions that lend themselves to diagnostic and therapeutic injection. Joint injection should be considered after other therapeutic interventions such as nonsteroidal anti-inflammatory drugs, physical therapy, and activity-modification have been tried. Indications for glenohumeral joint injection include osteoarthritis, adhesive capsulitis, and rheumatoid arthritis. For the acromioclavicular joint, injection may be used for diagnosis and treatment of osteoarthritis and distal clavicular osteolysis. Subacromial injections are useful for a range of conditions including adhesive capsulitis, subdeltoid bursitis, impingement syndrome, and rotator cuff tendinosis. Scapulothoracic injections are reserved for inflammation of the involved bursa. Persistent pain related to inflammatory conditions of the long head of the biceps responds well to injection in the region. The proper technique, choice and quantity of pharmaceuticals, and appropriate follow-up are essential for effective outcomes.
14558082	Polymorphisms in the interferon-gamma/interleukin-26 gene region contribute to sex bias in	2003 Oct	OBJECTIVE: To determine whether polymorphisms in the interferon-gamma (IFNgamma)/interleukin-26 (IL-26; formerly, AK155) gene cluster contribute to sex-based differential susceptibility to rheumatoid arthritis (RA). METHODS: Four microsatellite markers, located in a 118-kb interval that contains both the IFNgamma and IL-26 genes on chromosome 12q15, were typed in 251 patients with RA and 198 unrelated healthy controls (all of whom lived in Northern Ireland) by means of polymerase chain reaction-based fragment analysis. RESULTS: Marker D12S2510, which is located 3 kb 3' from the IL-26 gene, was significantly associated with RA in women (corrected P [P(corr)] = 0.008, 2 degrees of freedom [2 df]) but not in men (P = 0.99, 2 df). A 3-marker haplotype, IFNGCA13;D12S25108;D12S2511*9, was inferred that showed significant underrepresentation in women with RA (odds ratio 0.50, 95% confidence interval 0.32-0.78; P = 0.002, P(corr) = 0.03) but not in men with RA. CONCLUSION: Our results demonstrate that common polymorphisms in the IFNgamma/IL-26 gene region may contribute to sex bias in susceptibility to RA, by distorting the propensity of female carriers versus male carriers to contract this disease. These results conform to our recent observations of a role for this gene cluster in sex-based differential susceptibility to another Th1-type inflammatory disease, multiple sclerosis.