Oral contraception, parity, breast feeding, and severity of rheumatoid arthritis.

OBJECTIVE: To investigate the influence of breast feeding, use of the oral contraceptive pill (OCP), and parity on rheumatoid arthritis (RA). METHODS: One hundred and seventy six women with RA were compared with 145 control subjects; all had at least one child. RA patients were classified as having severe (n = 82) or mild disease (n = 89) according to clinical joint evaluation, radiological score, biological inflammation, and the presence of HLA-DR1 or -DR4 alleles. RESULTS: The mean age of RA patients was 58 years, and the mean age at the time of diagnosis of RA was 46 years. The mean time between onset of RA and the first birth was 23.6 (SD 3.8) years. The OCP user rates were 33% in the RA group and 47.6% in the control group (p < 0.02). OCP use was related to the mother's year of birth. The relative risk for developing RA was 0.598 (95% confidence interval (CI) 0.33 to 1.1) in women who had used OCP for more than five years compared with those who had never used OCPs. In contrast, the age at which the first pregnancy occurred, the number of children breast fed, and the duration of breast feeding were comparable in RA patients and healthy subjects. Among the RA patients, parity, duration of breast feeding, and the number of breast fed children were significantly increased in those with severe disease. Having more than three children increased the risk of developing severe disease 4.8-fold when adjusted for age and OCP use. Forty six percent of women with severe RA had a history of breast feeding duration greater than six months before disease onset, compared with 26% of patients with mild disease (p < 0.008). Having more than three breast fed children increased the risk of poor disease prognosis 3.7-fold. In contrast, OCP use had a protective role in the course of RA (44% of RA patients with mild disease were OCP users, compared with 21.7% of those with severe RA; p < 0.001). Among those using OCP for more than five years, the relative risk of developing severe disease was 0.1 (95% CI 0.01 to 0.6), after adjustment for age, parity, and breast feeding. CONCLUSION: Our results suggest that parity, and to a lesser extent breast feeding, before RA onset worsened RA prognosis, whereas OCP use had a protective role. Prolactin and oestrogen may have a role in these effects.     

The microbiome and rheumatoid arthritis

Rheumatoid Arthritis (RA) is a severe, chronic autoimmune disease that affects 1% of the world's population. Familial risk contributes 50% of the risk of seropositive RA, with strongest risks seen in first-degree relatives. Smoking increases the risk of developing anti-citrullinated peptide antibody (ACPA)⁺ RA, particularly in individuals with high-risk RA-susceptibility alleles. Other contributory environmental risks including particulate exposure, periodontal disease, bronchiectasis, diet, obesity and the oral contraceptive impact respiratory, oral, intestinal and genital tract mucosal sites. Furthermore, the first signs of autoimmunity may appear at mucosal sites e.g. sputum ACPA-IgA and IgG. While oral and faecal dysbiosis are well described, there is no consistent single bacterial species that appears to drive RA. Animal and human data suggest a model in which multiple environmental influences impact mucosal immune function through the host genetics through enhanced mucosal permeability and the traffic of pro-inflammatory PAMPs and the amplification of autoimmune responses. In some cases, autoimmunity may be driven by cross-reactivity, or mimicry, to pathogen-specific antigens, particularly where the host immune system fails to support their rapid control and elimination.     

Rheumatoid arthritis, the contraceptive pill, and androgens.

Evidence is accumulating that low androgen concentrations are a cause of rheumatoid arthritis. This would explain a number of established features of the epidemiology of the disease. These include: (a) the variation of disease activity with pregnancy; (b) the variation of age at onset by sex; (c) the variation by sex with HLA-B15; (d) the association with bone mineral density; and (e) the differing time trends in incidence rates by sex. It is argued, moreover, that if one makes a plausible assumption--namely, that women who choose oral contraceptives have high androgen concentrations at the time they first make this choice--then an explanation becomes available for the confusion about the relation between rheumatoid arthritis and oral contraception. Grounds are adduced for that assumption. If this line of reasoning is substantially correct it also has implications for the relations between rheumatoid arthritis and smoking and consumption of alcohol.     

HLA antigens in palindromic rheumatism, nonerosive rheumatoid arthritis and classical rheumatoid arthritis

The frequency of HLA antigens has been investigated in patients with definite rheumatoid arthritis (RA) who lacked characteristic erosive radiographic changes that we called nonerosive rheumatoid arthritis ( NERA ). The frequency of HLA-DR4 in patients with NERA was significantly lower than that in classical, erosive RA. A normal frequency of HLA antigens was also found in patients with palindromic rheumatism (PR). Those of the PR patients who however, developed RA during followup, carried HLA-DR4. The patients with PR, NERA and RA who had familial RA demonstrated increased frequency of HLA-DR4.     

基质金属蛋白酶及组织金属蛋白酶抑制剂与类风湿性关节炎

基质金属蛋白酶(MMPs)是降解细胞外基质(ECM)的一种重要的蛋白酶,对类风湿性关节炎的发生、发展有重要作用.组织金属蛋白酶抑制剂(TIMPs)是MMPs的天然抑制物,MMPs/TIMPs两者比例可作为反映疾病活动程度及预后的重要指标.     

Immunosenescence,autoimmunity, and rheumatoid arthritis

Current disease models of autoimmune syndromes, such as rheumatoid arthritis, propose that chronic inflammation is caused by 'forbidden T-cell clones' that recognize disease-inducing antigens and drive tissue-injurious immune reactions. Reappraisal of disease incidence data, however, emphasizes that rheumatoid arthritis is a syndrome of the elderly that occurs with highest likelihood in individuals in whom the processes of T-cell generation and T-cell repertoire formation are compromised. Thymic T-cell production declines rapidly with advancing age. Multiple mechanisms, including antigen-driven clonal expansion and homeostasis-driven autoproliferation of post-thymic T cells, impose replicative stress on T cells and induce the biological program of cellular senescence. T-cell immunosenescence is associated with profound changes in T-cell functional profile and leads to accumulation of CD4+ T cells that have lost CD28 but have gained killer immunoglobulin-like receptors and cytolytic capability and produce large amounts of interferon-gamma. In patients with rheumatoid arthritis, T-cell immunosenescence occurs prematurely, probably due to a deficiency in the ability to generate sufficient numbers of novel T cells. We propose that autoimmunity in rheumatoid arthritis is a consequence of immunodegeneration that is associated with age-inappropriate remodeling of the T-cell pool.     

Dissatisfaction,disability, and rheumatoid arthritis

Objectives. To investigate dissatisfaction with function in patients with rheumatoid arthritis [RA], and to see if dissatisfaction can be adequately explained by level of function. Methods. Fifty patients with RA were assessed for disease activity, psychological status, disability, expectation of future disability, and satisfaction with both global function and individual activities of daily living [ADL]. Results. Fifty percent of patients expressed dissatisfaction with global function, which correlated more strongly with pain (r = 0.474) and psychological status than with function (r = 0.398). Only 10% predicted improvement in global function. Seventy-two percent expressed dissatisfaction with performing at least one ADL. Conclusions. Patient dissatisfaction with both global function and individual ADL function is high and cannot adequately be explained by disability alone. Correlation with pain and psychological status implies that modifying these variables (perhaps through education programs about pain relief or relaxation) could reduce dissatisfaction.     

Metalloproteinases, inflammation, and rheumatoid arthritis

Ideally, the inflammatory response occurs rapidly to terminate infection. It also must halt in a timely manner to stop this reaction from inflicting self damage. Such a highly regulated process results from altering balances in pro- and anti-inflammatory signals orchestrated by multiple cell types and factors within the tissue microenvironment. The discovery of new substrates of metalloproteinases within this microenvironment has disclosed a new function in inflammation. The role of these proteases now extends beyond extracellular matrix remodelling enzymes to that of mediators of inflammatory signals involving various chemokines and cytokines. As natural inhibitors of these metalloproteinases, TIMPs have the potential of regulating the inflammatory response and affecting diseases such as rheumatoid arthritis. TIMP-3, in particular, stands out as an important regulator of inflammation with its ability to specifically inhibit proinflammatory cytokines and tissue destruction in the joint.     

The mortality of rheumatoid arthritis

Objective. To determine the risk and causes of death and to quantify mortality predictors in patients with rheumatoid arthritis (RA). Methods. RA patients (n = 3,501) from 4 centers (Saskatoon n = 905, Wichita n = 1,405, Stanford n = 886, and Santa Clara n = 305) were followed for up to 35 years; 922 patients died. Results. The overall standardized mortality ratio (SMR) was 2.26 (Saskatoon 2.24, Wichita 1.98, Stanford 3.08, Santa Clara 2.18) and increased with time. Mortality was strikingly increased for specific causes: infection, lymphoproliferative malignancy, gastroenterologic, and RA. In addition, as an effect of the SMR of 2.26, the expected number of deaths was increased nonspecifically across all causes (except cancer), with a large excess of deaths attributable to cardiovascular and cerebrovascular diseases. Independent predictors of mortality included age, education, male sex, function, rheumatoid factor, nodules, erythrocyte sedimentation rate, joint count, and prednisone use.