Quantitative heritability of anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis

Objective

The majority of genetic risk factors for rheumatoid arthritis (RA) are associated with anti–citrullinated protein antibody (ACPA)–positive RA, while far fewer genetic risk factors have been identified for ACPA‐negative RA. This study was undertaken to quantify the contribution of genetic risk factors in general, and of the predisposing HLA–DRB1 shared epitope (SE) alleles in particular, to the ACPA‐positive and ACPA‐negative subsets of RA, by computing their heritability and assessing the contribution of the HLA SE alleles.

Methods

One hundred forty‐eight RA twin pairs, in which at least 1 twin of each pair had RA, were tested for ACPAs and typed for HLA–DRB1 genotypes. Heritability was assessed in a logistic regression model including a bivariate, normally distributed random effect, representing the contribution of unobserved genetic factors to RA susceptibility, with the correlation of the random effects fixed according to twin zygosity. The contribution of the HLA SE alleles to genetic variance was assessed using a similar model, except that estimates were based on genotype‐specific population prevalences.

Results

The heritability of RA among the twin pairs was 66% (95% confidence interval [95% CI] 44–75%). For ACPA‐positive RA, the heritability was 68% (95% CI 55–79%), and for ACPA‐negative RA it was 66% (95% CI 21–82%). Presence of the HLA SE alleles explained 18% (95% CI 16–19%) of the genetic variance of ACPA‐positive RA but only 2.4% (95% CI 1.6–10%) of the genetic variance of ACPA‐negative RA.

Conclusion

The heritability of ACPA‐positive RA is comparable with that of ACPA‐negative RA. These data indicate that genetic predisposition plays an important role in the pathogenesis of ACPA‐negative RA, for which most individual genetic risk factors remain to be identified.

     

Human platelet antigens – 2013

To date, 33 human platelet alloantigens (HPAs) have been identified on six functionally important platelet glycoprotein (GP) complexes and have been implicated in alloimmune platelet disorders including foetal and neonatal alloimmune thrombocytopenia (FNAIT), posttransfusion purpura (PTP) and multitransfusion platelet refractoriness (MPR). The greatest number of recognized HPA (20 of 33) resides on the GPIIb/IIIa complex, which serves as the receptor for ligands important in mediating haemostasis and inflammation. These include HPA‐1a, the most commonly implicated HPA in FNAIT and PTP in Caucasian populations. Other platelet GP complexes, GPIb/V/IX, GPIa/IIa and CD109, express the remaining 13 HPAs. Of the recognized HPAs, 12 occur as six serologically and genetically defined biallelic ‘systems’ where the –a form designates the higher frequency allele and the –b form, the lower. Twenty‐one other HPAs are low‐frequency or rare antigens for which postulated higher frequency –a alleles have not yet been identified as antibody specificities. In addition to the HPA markers, platelets also express ABO and human leucocyte antigen (HLA) antigens; antibodies directed at the former are occasionally important in FNAIT, and to the latter, in MPR.     

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.

     

Opposing effects of HLA–DRB1*13 alleles on the risk of developing anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis

Objective

The effect of non–shared epitope HLA–DRB1 alleles on rheumatoid arthritis (RA) is poorly understood. This study was undertaken to investigate the effects of several HLA–DRB1 alleles, independent of the shared epitope, on the risk of developing anti–citrullinated protein antibody (ACPA)–positive or ACPA‐negative RA in a large case–control study.

Methods

HLA typing for the DRB1 gene was performed in 1,352 patients with RA and 922 controls from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. Relative risks (RRs) and 95% confidence intervals (95% CIs) were calculated.

Results

DRB1*13 was found to protect against ACPA‐positive RA when stratifying for the shared epitope and using a dominant genetic model (RR 0.41 [95% CI 0.26–0.64]). Furthermore, DRB1*13 neutralized the effect of the shared epitope in ACPA‐positive RA (RR 3.91 [95% CI 3.04–5.02] in patients who had the shared epitope but not DRB1*13, and RR 1.22 [95% CI 0.81–1.83] in patients with both the shared epitope and DRB1*13, as compared with patients negative for both the shared epitope and DRB1*13). However, we did not replicate the previous published risk of ACPA‐negative RA conferred by DRB1*03 when a dominant genetic model was used (RR 1.29 [95% CI 0.91–1.82]). Similarly, no significant effect of DRB1*03 on RR for ACPA‐negative RA was seen using the recessive genetic model (RR 1.18 [95% CI 0.6–2.4]). In contrast, the combination of DRB1*03 and DRB1*13 was significantly associated with increased risk of developing ACPA‐negative RA (RR 2.07 [95% CI 1.17–3.67]).

Conclusion

Our findings indicate that the DRB1*13 allele plays a dual role in the development of RA, by protecting against ACPA‐positive RA but, in combination with DRB1*03, increasing the risk of ACPA‐negative RA.

     

Regulation of the hypothalamo–pituitary–adrenal axis by cytokines

Many of the pro-inflammatory cytokines which are released in response to immune/inflammatory insults exert marked stimulatory influences on the hypothalamo-pituitary-adrenocortical (HPA) axis; they thus provoke the release of glucocorticoids which, in turn, temper the ensuing immune-inflammatory response and thereby complete a homeostatic neuroendocrine-immune regulatory loop. This article reviews the putative mechanisms by which cytokines, released acutely in response to such insults, activate the HPA axis, placing particular emphasis on the actions and interactions of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and interleukin-6 (IL-6) and on the counter-regulatory mechanisms that are in place.     

Differences in synovial tissue infiltrates between anti–cyclic citrullinated peptide–positive rheumatoid arthritis and anti–cyclic citrullinated peptide–negative rheumatoid arthritis

Objective

To compare synovial tissue infiltrates from patients with anti–cyclic citrullinated peptide (anti‐CCP)–positive rheumatoid arthritis (RA) with those from patients with anti‐CCP–negative RA.

Methods

Synovial tissue samples were obtained arthroscopically from the inflamed knee joints of 57 patients with RA (34 of whom were anti‐CCP positive) and examined for several histologic features along with immunohistologic expression of cell markers. Joint damage was assessed using the Kellgren/Lawrence (K/L) scale (range 0–4) on standard anteroposterior radiographs. In 31 patients (18 of whom were anti‐CCP positive), synovial tissue was available from an earlier time point, allowing analysis of temporal changes.

Results

Synovial tissue from anti‐CCP–positive patients was characterized by a higher mean number of infiltrating lymphocytes (61.6 versus 31.4/high‐power field [hpf] [400×]; P = 0.01), less extensive fibrosis (mean score of 1.2 versus 2.0; P = 0.04), and a thinner synovial lining layer (mean score of 2.1 versus 3.3; P = 0.002) compared with synovial tissue from anti‐CCP–negative patients. Anti‐CCP–positive patients expressed more CD3, CD8, CD45RO, and CXCL12. More anti‐CCP–positive patients had a K/L score >1 compared with anti‐CCP–negative patients. The difference in the mean lymphocyte counts was already present a mean of 3.8 years before the index biopsy (76.7 lymphocytes/hpf and 26.7 lymphocytes/hpf in anti‐CCP–positive patients and anti‐CCP–negative patients, respectively; P = 0.008) and was independent of disease duration and K/L score.

Conclusion

Synovitis in patients with anti‐CCP–positive RA differs from that in patients with anti‐CCP– negative RA, notably with respect to infiltrating lymphocytes, and is associated with a higher rate of local joint destruction.

     

Association between body mass index and anti–citrullinated protein antibody–positive and anti–citrullinated protein antibody–negative rheumatoid arthritis: Results from a population‐based case–control study

Objective

Being overweight or obese is associated with many chronic diseases, but previous studies of the association with rheumatoid arthritis (RA) have shown inconsistent results. The aim of this study was to investigate the association between body mass index (BMI) and the risk of developing the 2 main subtypes of RA.

Methods

At inclusion, cases and controls answered questions about their weight and height and donated blood samples. The presence of antibodies to citrullinated protein antigens (ACPAs) was analyzed among 2,748 cases and 3,444 controls (28% men). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using conditional logistic regression.

Results

Compared to those with normal weight (BMI <25 kg/m²), the adjusted overall OR for developing ACPA‐negative RA was 1.1 (95% CI 0.9–1.3) for overweight individuals (BMI ≥25 to <30 kg/m²) and 1.4 (95% CI 1.1–1.9) for obese individuals (BMI ≥30 kg/m²). When stratified by sex, the OR for ACPA‐negative RA for obese women was 1.6 (95% CI 1.2–2.2), and there was no association between obesity and ACPA‐negative RA in men (OR 1.1, 95% CI 0.6–1.8). In obese men compared to men with normal weight, the OR for ACPA‐positive RA was 0.6 (95% CI 0.3–0.9), while there was no association between BMI and ACPA‐positive RA among women (OR 1.0, 95% CI 0.8–1.2).

Conclusion

Our findings show that obesity is associated with developing ACPA‐negative RA in women, and indicate an inverse association between BMI and ACPA‐positive RA in men.     

Predictors of neonatal hypothalamic–pituitary–adrenal axis activity at delivery

Objective Clinical and preclinical studies indicate that maternal stress during pregnancy may exert long‐lasting adverse effects on offspring. This investigation sought to identify factors mediating the relationship between maternal and neonatal hypothalamic–pituitary–adrenal (HPA) axes in pregnant women with past or family psychiatric history. Patients Two hundred and five pairs of maternal and umbilical cord blood samples from a clinical population were collected at delivery. Measurements Maternal and neonatal HPA axis activity measures were plasma adrenocorticotrophic hormone (ACTH), total cortisol, free cortisol and cortisol‐binding globulin concentrations. The effects of maternal race, age, body mass index, psychiatric diagnosis (DSM‐IV), birth weight, delivery method and estimated gestational age (EGA) at delivery on both maternal and neonatal HPA axis measures were also examined. Incorporating these independent predictors as covariates where necessary, we evaluated whether neonatal HPA axis activity measures could be predicted by the same maternal measure using linear regression. Results Delivery method was associated with umbilical cord plasma ACTH and both total and free cord cortisol concentrations (T = 10·53–4·21; P < 0·0001–0·010). After accounting for method of delivery and EGA, we found that maternal plasma ACTH concentrations predicted 23·9% of the variance in foetal plasma ACTH concentrations (T = 6·76; P < 0·0001), and maternal free and total plasma cortisol concentrations predicted 39·8% and 32·3% of the variance in foetal plasma free and total cortisol concentrations (T = 5·37–6·90; P < 0·0001), respectively. Conclusion These data suggest that neonatal response is coupled with maternal HPA axis activity at delivery. Future investigations will scrutinize the potential long‐term sequelae for the offspring.     

Strong combined gene–environment effects in anti–cyclic citrullinated peptide–positive rheumatoid arthritis: A nationwide case–control study in Denmark

Objective

To study the role of shared epitope (SE) susceptibility genes, alone and in combination with tobacco smoking and other environmental risk factors, for risk of subtypes of rheumatoid arthritis (RA) defined by the presence or absence of serum antibodies against cyclic citrullinated peptides (CCPs).

Methods

To address these issues, a nationwide case–control study was conducted in Denmark during 2002–2004, comprising incident cases of RA or patients with recently diagnosed RA (309 seropositive and 136 seronegative for IgG antibodies against CCP) and 533 sex‐ and age‐matched population controls. Associations were evaluated by logistic regression analyses, in which odds ratios (ORs) served as measures of relative risk.

Results

Compared with individuals without SE susceptibility genes, SE homozygotes had an elevated risk of anti‐CCP–positive RA (OR 17.8, 95% confidence interval [95% CI] 10.8–29.4) but not anti‐CCP–negative RA (OR 1.07, 95% CI 0.53–2.18). Strong combined gene–environment effects were observed, with markedly increased risks of anti‐CCP–positive RA in SE homozygotes who were heavy smokers (OR 52.6, 95% CI 18.0–154), heavy coffee drinkers (OR 53.3, 95% CI 15.5–183), or oral contraceptive users (OR 44.6, 95% CI 15.2–131) compared with SE noncarriers who were not exposed to these environmental risk factors.

Conclusion

Persons who are homozygous for SE susceptibility genes, notably those who are also exposed to environmental risk factors, have a markedly and selectively increased risk of anti‐CCP–positive RA. A distinction between anti‐CCP–positive RA and anti‐CCP–negative RA seems warranted, because these RA subtypes most likely represent etiologically distinct disease entities.