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Tom W J Huizinga

Publications and source records attributed to Tom W J Huizinga.

At least 37 records · Page 2Linked to original sources
PubMed2006

Aspects of early arthritis. Definition of disease states in early arthritis: remission versus minimal disease activity.

With regard to rheumatoid arthritis, remission as currently used in the literature can have two meanings: either a state with persistent absence of clinical and radiological signs of disease activity without being treated for a specific time period, or it may point to a disease state with minimal disease activity during antirheumatic treatment. A risk factor for the first is absence of autoantibodies, with the anti-CCP-antibodies as best predictors, whereas risk factors for achieving a drug-induced state of minimal disease activity are not well defined. These definitions of remission refer to different disease states; therefore, we propose that the term remission is reserved for patients that are not treated with antirheumatic drugs.

Arthritis↗
PubMed2006

Transition of healthy to diseased synovial tissue in rheumatoid arthritis is associated with gain of mesenchymal/fibrotic characteristics.

The healthy synovial lining layer consists of a single cell layer that regulates the transport between the joint cavity and the surrounding tissue. It has been suggested that abnormalities such as somatic mutations in the p53 tumor-suppressor gene contribute to synovial hyperplasia and invasion in rheumatoid arthritis (RA). In this study, expression of epithelial markers on healthy and diseased synovial lining tissue was examined. In addition, we investigated whether a regulated process, resembling epithelial to mesenchymal transition (EMT)/fibrosis, could be responsible for the altered phenotype of the synovial lining layer in RA. Synovial tissue from healthy subjects and RA patients was obtained during arthroscopy. To detect signs of EMT, expression of E-cadherin (epithelial marker), collagen type IV (indicator of the presence of a basement membrane) and alpha-smooth muscle actin (alpha-sma; a myofibroblast marker) was investigated on frozen tissue sections using immunohistochemistry. Fibroblast-like synoviocytes (FLSs) from healthy subjects were isolated and subjected to stimulation with synovial fluid (SF) from two RA patients and to transforming growth factor (TGF)-beta. To detect whether EMT/fibrotic markers were increased, expression of collagen type I, alpha-sma and telopeptide lysylhydroxylase (TLH) was measured by real time PCR. Expression of E-cadherin and collagen type IV was found in healthy and arthritic synovial tissue. Expression of alpha-sma was only found in the synovial lining layer of RA patients. Stimulation of healthy FLSs with SF resulted in an upregulation of alpha-sma and TLH mRNA. Collagen type I and TLH mRNA were upregulated after stimulation with TGF-beta. Addition of bone morphogenetic protein (BMP)-7 to healthy FLS stimulated with SF inhibited the expression of alpha-sma mRNA. The finding that E-cadherin and collagen type IV are expressed in the lining layer of healthy and arthritic synovium indicates that these lining cells display an epithelial-like phenotype. In addition, the presence of alpha-sma in the synovial lining layer of RA patients and induction of fibrotic markers in healthy FLSs by SF from RA patients indicate that a regulated process comparable to EMT might cause the alteration in phenotype of RA FLSs. Therefore, BMP-7 may represent a promising agent to counteract the transition imposed on synoviocytes in the RA joint.

Actins↗
PubMed2006

Selective involvement of the amygdala in systemic lupus erythematosus.

BACKGROUND: Antibodies specifically affect the amygdala in a mouse model of systemic lupus erythematosus (SLE). The aim of our study was to investigate whether there is also specific involvement of the amygdala in human SLE. METHODS AND FINDINGS: We analyzed a group of 37 patients with neuropsychiatric SLE (NP-SLE), 21 patients with SLE, and a group of 12 healthy control participants with diffusion weighted imaging (DWI). In addition, in a subset of eight patients, plasma was available to determine their anti-NMDAR antibody status. From the structural magnetic resonance imaging data, the amygdala and the hippocampus were segmented, as well as the white and gray matter, and the apparent diffusion coefficient (ADC) was retrieved. ADC values between controls, patients with SLE, and patients with NP-SLE were tested using analysis of variance with post-hoc Bonferroni correction. No differences were found in the gray or white matter segments. The average ADC in the amygdala of patients with NP-SLE and SLE (940 x 10(-6) mm2/s; p = 0.006 and 949 x 10(-6) mm2/s; p = 0.019, respectively) was lower than in healthy control participants (1152 x 10(-6) mm2/s). Mann-Whitney analysis revealed that the average ADC in the amygdala of patients with anti-NMDAR antibodies (n = 4; 802 x 10(-6) mm2/s) was lower (p = 0.029) than the average ADC of patients without anti-NMDAR antibodies (n = 4; 979 x 10(-6) mm2/s) and also lower (p = 0.001) than in healthy control participants. CONCLUSIONS: This is the first study to our knowledge to observe damage in the amygdala in patients with SLE. Patients with SLE with anti-NMDAR antibodies had more severe damage in the amygdala compared to SLE patients without anti-NMDAR antibodies.

Adult↗
PubMed2006

Drug evaluation: apratastat, a novel TACE/MMP inhibitor for rheumatoid arthritis.

Wyeth Research was developing apratastat (TMI-005), one in a series of dual TNFalpha-converting enzyme and matrix metalloprotease-13 inhibitors, for the potential treatment of inflammation, especially rheumatoid arthritis. By January 2005, apratastat had entered a phase II clinical trial; however, in October 2006, Wyeth reported that it had terminated development of the drug because of lack of efficacy in this trial.

ADAM Proteins↗
PubMed2005

The devil in the details: the emerging role of anticitrulline autoimmunity in rheumatoid arthritis.

Rheumatoid arthritis is a chronic inflammatory autoimmune disease of unknown cause. The immune response against citrullinated Ags has recently become the prime suspect for disease pathogenesis. Immunity against citrullinated Ags is thought to play a pivotal role in the disease for several reasons: 1) citrullinated Ags are expressed in the target organ, the inflamed joint; 2) anti-citrullinated protein Abs are present before the disease becomes manifest; and 3) these Abs are highly specific for rheumatoid arthritis. In this review, data from clinical, genetic, biochemical, and animal studies is combined to create a profile of this remarkable autoantibody response. Moreover, a model is proposed of how the anti-citrullinated proteins response is generated and how it could eventually lead to chronic inflammation.

Antigen-Antibody Complex↗
PubMed2005

Redefining the HLA and RA association: to be or not to be anti-CCP positive.

Rheumatoid Arthritis (RA) is the most common chronic inflammatory joint disease. The overall prevalence is 1% and in people older than 60 it is more than 2%. RA has auto-immune features: auto-antibodies against the Fc part of IgG, so-called Rheumatoid Factor (RF) are found more often in RA patients and more recently RA-specific auto-antibodies directed against Cyclic Citrunilated Peptides (CCP) have been discovered. Based on twin studies the contribution of genetic factors to the pathogenesis has been estimated to be about 60%. The main genetic contribution (about 40%) comes from the HLA complex. An association between HLA-DR4 and RA was already documented almost 30 years ago. This association was more prominent for severe forms of the disease. Because more HLA-DRB1 alleles appeared to be associated with RA and the products of these alleles shared a 5AA sequence in a peptide-binding pocket the so-called Shared Epitope (SE) hypothesis was formulated, the prediction being that these DRB1 molecules would bind an RA inducing peptide(s). Thus far however such (a) peptides remain elusive. Because the risk for RA associated with different but SE-identical DRB1 alleles varies considerably this SE can also not be the whole explanation for the HLA contribution to RA susceptibility/severity. A modified SE has been postulated and a role for DQ has been postulated. There is also evidence for a contribution of non-class II genes to susceptibility. About 5 years ago we have reported that certain HLA-DRB1 alleles are associated with protection from (severe) RA. The products of these alleles carry instead of the SE sequence another peptide anchor region consisting of the amino acid DERAA. In a large prospective cohort study we showed recently that these alleles indeed confer (dominant) protection both against developing RA and a severe course of the disease. This protection was observed both in the presence and the absence of SE susceptibility alleles. We are presently exploring the hypothesis that this protection is mediated by regulatory T cells reactive with the DERAA epitope. An obvious way to unravel the apparently complex association between HLA and RA is to reduce the heterogeneity of this multifactorial disease. Recently, we have discovered that SE positive DRB1 alleles are exclusively associated with CCP positive RA. The previously reported association with RF positive RA appeared to be secondary to the association with anti-CCP pos. RA. This was the case both for the association found for susceptibility and severity. Interestingly, DRB1*03 was exclusively associated with anti-CCP neg. RA. Because recent evidence puts the immune response against citrunilated proteins (CCP) as prime suspect for disease induction and progression in this subgroup of RA these observations are a big leap forwards in solving the HLA-RA puzzle.

Arthritis, Rheumatoid↗
PubMed2005

CTLA4 is differentially associated with autoimmune diseases in the Dutch population.

Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) is an important negative regulator of T-cell response and its genetic association with type 1 diabetes (T1D) has recently been demonstrated. The frequent co-association of autoimmune diseases (AID) and the implication from multiple genome scans that the CTLA4 gene region is a general autoimmune region, led us to study the role of CTLA4 in independent cohorts of T1D, coeliac disease (CD) and rheumatoid arthritis (RA) patients. We present independent data that confirm the association of CTLA4 in Dutch patients with juvenile onset T1D and show differential association of CTLA4 with CD and RA. The CTLA4 gene polymorphisms were tested for association in 350 T1D, 310 CD, 520 RA patients and 900 controls. In addition, 218 families were tested by the transmission disequilibrium test (TDT). T1D patients showed the highest association with the MH30*G: -1147*C: +49*G: CT60*G: JO37_3*G (haplotype 2) in both a case/control cohort (P=0.002, OR=1.42) and by TDT (P=0.02, OR=1.43). In contrast, this haplotype showed no association in the RA and CD cohorts. However, we observed an increased frequency of the MH30*G: -1147*T: +49*A: CT60*G: JO37_3*A (haplotype 3) in the CD patients diagnosed at a young age (OR=1.6, P=0.026, P (c)=0.052). Furthermore, when T1D and CD patients were stratified based on the HLA risk, the T1D susceptible CTLA4 haplotype 2 was over-represented in the high HLA-risk T1D and CD groups. In conclusion, we confirmed association between CTLA4 haplotype 2 and T1D in the Dutch population. Association with another CTLA4 haplotype (haplotype 3) was confirmed for CD, but only in those patients who had an early age of expression. No effect was found between RA and CTLA4. The association of the CTLA4 haplotype 2 with the high-risk HLA genotype in T1D and CD, which share DQ2 as the one of high-risk alleles, might provide a clue to understanding the common genetic background of AID.

Adolescent↗
PubMed2005

Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis.

Antibodies to citrullinated proteins (anti-cyclic-citrullinated peptide [anti-CCP] antibodies) are highly specific for rheumatoid arthritis (RA) and precede the onset of disease symptoms, indicating a pathogenetic role for these antibodies in RA. We recently showed that distinct genetic risk factors are associated with either anti-CCP-positive disease or anti-CCP-negative disease. These data are important as they indicate that distinct pathogenic mechanisms are underlying anti-CCP-positive disease or anti-CCP-negative disease. Likewise, these observations raise the question of whether anti-CCP-positive RA and anti-CCP-negative RA are clinically different disease entities. We therefore investigated whether RA patients with anti-CCP antibodies have a different clinical presentation and disease course compared with patients without these autoantibodies. In a cohort of 454 incident patients with RA, 228 patients were anti-CCP-positive and 226 patients were anti-CCP-negative. The early symptoms, tender and swollen joint count, and C-reactive protein level at inclusion, as well as the swollen joint count and radiological destruction during 4 years of follow-up, were compared for the two groups. There were no differences in morning stiffness, type, location and distribution of early symptoms, patients' rated disease activity and C-reactive protein at inclusion between RA patients with and without anti-CCP antibodies. The mean tender and swollen joint count for the different joints at inclusion was similar. At follow-up, patients with anti-CCP antibodies had more swollen joints and more severe radiological destruction. Nevertheless, the distribution of affected joints, for swelling, bone erosions and joint space narrowing, was similar. In conclusion, the phenotype of RA patients with or without anti-CCP antibodies is similar with respect to clinical presentation but differs with respect to disease course.

Adult↗
PubMed2005

Gene transfer of tissue inhibitor of metalloproteinases-3 reverses the inhibitory effects of TNF-alpha on Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts.

Apart from counteracting matrix metalloproteinases, tissue inhibitor of metalloproteinases-3 (TIMP-3) has proapoptotic properties. These features have been attributed to the inhibition of metalloproteinases involved in the shedding of cell surface receptors such as the TNFR. However, little is known about effects of TIMP-3 in cells that are not susceptible to apoptosis by TNF-alpha. In this study, we report that gene transfer of TIMP-3 into human rheumatoid arthritis synovial fibroblasts and MRC-5 human fetal lung fibroblasts facilitates apoptosis and completely reverses the apoptosis-inhibiting effects of TNF-alpha. Although TNF-alpha inhibits Fas/CD95-induced apoptosis in untransfected and mock-transfected cells, fibroblasts ectopically expressing TIMP-3 are sensitized most strongly to Fas/CD95-mediated cell death by TNF-alpha. Neither synthetic MMP inhibitors nor glycosylated bioactive TIMP-3 are able to achieve these effects. Gene transfer of TIMP-3 inhibits the TNF-alpha-induced activation of NF-kappaB in rheumatoid arthritis synovial fibroblasts and reduces the up-regulation of soluble Fas/CD95 by TNF-alpha, but has no effects on the cell surface expression of Fas. Collectively, our data demonstrate that intracellularly produced TIMP-3 not only induces apoptosis, but also modulates the apoptosis-inhibiting effects of TNF-alpha in human rheumatoid arthritis synovial fibroblast-like cells. Thus, our findings may stimulate further studies on the therapeutic potential of gene transfer strategies with TIMP-3.

Adenoviruses, Human↗
PubMed2005

IL-10 and toll-like receptor-4 polymorphisms and the in vivo and ex vivo response to endotoxin.

To determine to what extent lipopolysaccharide-induced IL-10 production capacity is determined by polymorphisms in toll-like receptor-4 (TLR4) and the IL-10 promoter region, we measured in vivo IL-10 and TNF-alpha production in patients undergoing elective cardiopulmonary bypass surgery, a major surgical trauma associated with ischemia-reperfusion injury that triggers an endotoxemia and profound inflammatory response in most patients. Ex vivo the IL-10 and TNF-alpha production was measured in a whole blood stimulation assay, using 3 LPS concentrations. Positive correlations were found between TNF-alpha and IL-10 production ex vivo, upon stimulation with each of the LPS concentrations. Also, the estimated TNF-alpha and IL-10 EC50, and TNF-alpha(max) and IL-10max were positively correlated (r = 0.203; p = 0.023 and r = 0.287; p = 0.001, respectively), indicating that these parameters describing LPS sensitivity and maximal production capacity, respectively, can be estimated by measuring either TNF-alpha or IL-10. Interleukin-10 concentrations in patients experiencing endotoxemia in vivo negatively correlated with the IL-10 levels produced upon stimulation with 1000 ng/mL LPS as well as the estimated IL-10max ex vivo. In vivo, a positive correlation between the TNF-alpha concentration at time-point 2 and the IL-10 concentration at time-point 3 was found, consistent with an important contribution of the magnitude of TNF-alpha release upon the subsequent IL-10 production. Carriers of the IL-10 promoter -1330G, -1082A, -819T, -592A (GATA) haplotype had lower IL-10 production ex vivo upon stimulation with 10 and 100 ng/mL LPS and higher EC50 values (the estimated LPS concentration at which 50% of the maximal IL-10 response is reached) as compared to carriers of the other haplotypes combined, indicating decreased LPS sensitivity ex vivo. These individuals did not differ from the others in interleukin-10 production capacity upon stimulation with a high LPS concentration (i.e., 1000 ng/mL) and the estimated IL-10(max) values, were similar, indicating unimpaired maximal IL-10 production capacity ex vivo. Carriers of the IL-10 promoter AGCC haplotype had lower EC50 values as compared to carriers of the other haplotypes combined, indicating increased LPS sensitivity ex vivo. In accordance with this finding, carriers of the AGCC haplotype had higher circulating IL-10 levels in vivo. The common TLR4 polymorphisms (Asp299Gly and Thr399Ile) were associated with slightly higher IL-10 production capacity ex vivo and in vivo, however, this was not statistically significant. Our results indicate that polymorphisms in the proximal IL-10 promoter region are associated with in vivo and ex vivo LPS sensitivity. The contribution to the inter-individual variation, however, is limited since the variation between individuals in LPS sensitivity and IL-10 production capacity can only partly be attributed to these IL-10 promoter polymorphisms.

Endotoxins↗
PubMed2005

The type of collagen cross-link determines the reversibility of experimental skin fibrosis.

Fibrotic processes in humans are characterised by an excessive accumulation of collagen containing increased levels of hydroxyallysine-derived cross-links. The occurrence of these cross-links appears to be an important criterion in assessing the irreversibility of fibrosis. We hypothesise that increased hydroxyallysine cross-linking results in a collagenous matrix that is less susceptible to proteolytic degradation and therefore the collagen deposition is no longer reversible. In this report, we show that collagen matrices with increased hydroxyallysine cross-link levels were less susceptible to matrix metalloproteinase 1 degradation than are collagen matrices containing low hydroxyallysine levels. These data indicate that the type of collagen cross-link influences collagen catabolism. In vivo evidence for the importance of the cross-linking type in determining the reversibility of the fibrotic process was found using the bleomycin-induced skin fibrosis mouse model. The analysis of the accumulated collagen in the fibrotic skin of bleomycin-treated mice did not reveal an increase in hydroxyallysine cross-link levels. In concurrence with our hypothesis, the collagen accumulation resolved in time when the mice were no longer receiving bleomycin treatment, showing the reversibility of the fibrosis. In conclusion, our data indicate that the type of collagen cross-linking is an important factor in determining whether the outcome of the fibrotic process is reversible or not.

2-Aminoadipic Acid↗
PubMed2005

Fibroblast-like synoviocytes derived from patients with rheumatoid arthritis show the imprint of synovial tissue heterogeneity: evidence of a link between an increased myofibroblast-like phenotype and high-inflammation synovitis.

OBJECTIVE: Given the heterogeneity of gene expression patterns and cellular distribution between rheumatoid arthritis (RA) synovial tissues, we sought to determine whether this variability was also reflected at the level of the fibroblast-like synoviocyte (FLS) cultured from RA synovial tissues. METHODS: Gene expression profiles in FLS cultured from synovial tissues obtained from 19 RA patients were analyzed using complementary DNA microarrays and hierarchical cluster analysis. To validate the subclassification, we performed prediction analysis and principal components analysis. Genes that differed significantly in their expression between FLS cultures were selected using Statistical Analysis of Microarrays software. Real-time quantitative polymerase chain reaction was performed to validate the microarray data. Immunocytochemistry was applied to study the expression of the genes of interest in FLS and synovial tissues. RESULTS: Hierarchical clustering identified 2 main groups of FLS characterized by distinctive gene expression profiles. FLS from high-inflammation synovial tissues revealed increased expression of a transforming growth factor beta/activin A-inducible gene profile that is characteristic of myofibroblasts, a cell type considered to be involved in wound healing, whereas increased production of growth factor (insulin-like growth factor 2/insulin-like growth factor binding protein 5) appeared to constitute a characteristic feature of FLS derived from low-inflammation synovial tissues. The molecular feature that defines the myofibroblast-like phenotype was reflected as an increased proportion of myofibroblast-like cells in the heterogeneous FLS population. Myofibroblast-like cells were also found upon immunohistochemical analysis of synovial tissue. CONCLUSION: Our findings support the notion that heterogeneity between synovial tissues is reflected in FLS as a stable trait, and provide evidence of a possible link between the behavior of FLS and the inflammation status of RA synovium.

Arthritis, Rheumatoid↗
PubMed2005

Association of the risk of osteoarthritis with high innate production of interleukin-1beta and low innate production of interleukin-10 ex vivo, upon lipopolysaccharide stimulation.

OBJECTIVE: In a sibpair study of osteoarthritis (OA) patients, we investigated whether, upon stimulation with lipopolysaccharide (LPS), variations in the innate ex vivo production of interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), IL-10, and tumor necrosis factor alpha (TNFalpha) in whole-blood assays contribute to the risk of OA. METHODS: Data from 305 patients with OA at multiple sites (hand, knee, hip, and spine), whose median age was 60 years (range 43-79 years), were compared with those from 137 controls. OA was defined in accordance with the American College of Rheumatology criteria. Whole-blood samples were stimulated with LPS (10 ng/ml). In the supernatants, cytokines were measured by enzyme-linked immunosorbent assay. Odds ratios (ORs) were used as measures of the relative risk of OA in relation to quartiles of IL-1beta, IL-1Ra, TNFalpha, and IL-10 production. The ORs were adjusted for sex and age, and 95% confidence intervals (95% CIs) were computed using robust standard errors to take into account the intrafamily effect. RESULTS: Subjects in the highest quartile of IL-1beta and IL-1Ra had an increased risk of OA (OR 3.3, 95% CI 1.4-7.9 and OR 8.0, 95% CI 3.7-17.4, respectively), while subjects in the lowest quartile of IL-10 had a 3-fold increased risk of OA (OR 3.1, 95% CI 1.5-6.5). High innate ex vivo production of TNFalpha was not associated with an increased risk of OA. CONCLUSION: Subjects with a high innate ex vivo production of IL-1beta and IL-1Ra and low innate ex vivo production of IL-10 have an increased risk of OA. These results suggest that a proportion of the genetic susceptibility to OA may be encoded for by variations in innate cytokine activity.

Adult↗
PubMed2005

Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is characterized by inflammation and destruction of synovial joints. Fibroblast-like synoviocytes (FLS) harvested from synovial tissue of patients with RA can invade normal human cartilage in severe combined immunodeficient (SCID) mice and Matrigel basement membrane matrix in vitro. This study was undertaken to investigate the association of these in vitro characteristics with disease characteristics in patients with RA. METHODS: Synovial tissue samples from 72 RA and 49 osteoarthritis (OA) patients were obtained. Samples of different joints were collected from 7 patients with RA. The FLS invasiveness in Matrigel was studied, and the intraindividual and interindividual differences were compared. From the patients with FLS who exhibited the most extreme differences in in vitro ingrowth (most and least invasive FLS), radiographs of the hands and feet were collected and scored according to the Sharp/van der Heijde method to determine the relationship between in vitro invasion data and estimated yearly joint damage progression. RESULTS: FLS from patients with RA were more invasive than FLS from patients with OA (P < 0.001). The mean intraindividual variation in FLS invasion was much less than the mean interindividual variation (mean +/- SD 1,067 +/- 926 and 3,845 +/- 2,367 for intraindividual and interindividual variation, respectively; P = 0.035), which shows that the level of FLS invasion is a patient characteristic. The mean +/- SEM Sharp score on radiographs of the hands or feet divided by the disease duration was 4.4 +/- 1.1 units per year of disease duration in patients with the least invasive FLS (n = 9), which was much lower compared with the 21.8 +/- 3.1 units per year of disease duration in patients with the most invasive FLS (n = 9) (P < 0.001). CONCLUSION: The ex vivo invasive behavior of FLS from RA patients is associated with the rate of joint destruction and is a patient characteristic, given the much smaller intraindividual than interindividual FLS variation.

Arthritis, Rheumatoid↗
PubMed2005

An independent role of protective HLA class II alleles in rheumatoid arthritis severity and susceptibility.

OBJECTIVE: To prospectively investigate the effect of the DERAA-encoding HLA alleles on disease susceptibility and severity in a large cohort of patients with rheumatoid arthritis (RA), and to differentiate protective effects from non-predisposition by comparing subgroups of patients with an equal amount of predisposition alleles. METHODS: HLA class II alleles were determined in 440 patients with early RA and in 423 healthy controls. In order to study the effect of HLA on disease severity, radiographic joint destruction was evaluated, using the modified Sharp/van der Heijde method, during 4 years of followup. RESULTS: The presence of DERAA-encoding HLA-DRB1 alleles conferred a lower risk of developing RA for both the presence and absence of SE alleles (odds ratio 0.6). At all time points, radiographic destruction was significantly less severe in DERAA-positive patients with 1 SE allele compared with DERAA-negative patients with 1 SE allele. Additionally, a protective effect of DERAA was detected in the groups of patients who were prone to having more severe disease because of the presence of anti-cyclic citrullinated peptide antibodies or because of smoking. CONCLUSION: DERAA-encoding HLA-DRB1 alleles independently protect against RA and are associated with less severe disease.

Alleles↗
PubMed2005

Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis.

OBJECTIVE: Recent data have shown that the most prominent and longest known genetic risk factors for rheumatoid arthritis (RA), HLA-DRB1 shared epitope alleles, are only associated with RA that is characterized by the presence of antibodies against cyclic citrullinated peptide (anti-CCP antibodies) and not with anti-CCP-negative RA. We undertook this study to investigate whether anti-CCP-negative RA is associated with other HLA-DRB1 alleles. METHODS: HLA typing was performed for 377 patients from the Leiden Early Arthritis Clinic who were diagnosed as having RA within the first year of followup (206 anti-CCP-positive patients and 171 anti-CCP-negative patients), 235 patients who, after 1 year, had undifferentiated arthritis (UA) (28 anti-CCP-positive patients and 207 anti-CCP-negative patients), and 423 healthy control subjects. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for HLA-DRB1 allele frequencies were determined for all patient groups compared with the healthy control group. RESULTS: HLA-DR3 was more frequently present in the anti-CCP-negative RA group than in the control group (OR 1.84, 95% CI 1.26-2.67). This was not the case for anti-CCP-positive RA (OR 0.92, 95% CI 0.60-1.40). HLA-DR3 was also more frequently present in anti-CCP-negative UA patients (OR 1.59, 95% CI 1.10-2.28), but not in anti-CCP-positive UA patients (OR 0.68, 95% CI 0.17-1.92). CONCLUSION: HLA-DR3 is associated with anti-CCP-negative arthritis and not with anti-CCP-positive arthritis. These data show that distinct genetic risk factors are associated with the presence of anti-CCP antibodies in RA and indicate that different pathogenetic mechanisms underlie anti-CCP-positive and anti-CCP-negative RA.

Adolescent↗