Mortality trends in rheumatoid arthritis: the role of rheumatoid factor

OBJECTIVE: We previously demonstrated a widening in the mortality gap between subjects with rheumatoid arthritis (RA) and the general population. We examined the contribution of rheumatoid factor (RF) positivity on overall mortality trends and cause-specific mortality. METHODS: A population-based RA incidence cohort (1955-1995, and aged >or= 18 yrs) was followed longitudinally until death or January 1, 2006. The underlying cause of death as coded from national mortality statistics and grouped according to ICD-9/10 chapters was used to define cause-specific mortality. Expected cause-specific mortality rates were estimated by applying the age-, sex-, and calendar-year-specific mortality rates from the general population to the RA cohort. Poisson regression was used to model the observed overall and cause-specific mortality rates according to RF status, accounting for age, sex, disease duration, and calendar year. RESULTS: A cohort of 603 subjects (73% female; mean age 58 yrs) with RA was followed for a mean of 16 years, during which 398 died. Estimated survival at 30 years after RA incidence was 26.0% in RF+ RA subjects compared to 36.0% expected (p < 0.001), while in RF- RA subjects, estimated survival was 29.1% compared to 28.3% expected (p = 0.9). The difference between the observed and the expected mortality in the RF+ RA subjects increased over time, resulting in a widening of the mortality gap, while among RF- RA subjects, observed mortality was very similar to the expected mortality over the entire time period. Among RF+ RA subjects, cause-specific mortality was higher than expected for cardiovascular [relative risk (RR) 1.50; 95% confidence interval (CI) 1.22, 1.83] and respiratory diseases [RR 3.49; 95% CI 2.51, 4.72]. Among RF- RA subjects, no significant differences were found between observed and expected cause-specific mortality. CONCLUSION: The widening in the mortality gap between RA subjects and the general population is confined to RF+ RA subjects and largely driven by cardiovascular and respiratory deaths.     

The inflammatory reflex and risk for rheumatoid arthritis: a case-control study of human vagotomy

Recent data suggest remarkable effects of vagus stimulation (reduction) and vagotomy (exacerbation) on acute inflammation in rats, the so-called "inflammatory reflex". Its role in humans remains unknown. Therefore, the aim was to explore whether surgical vagotomy in humans would affect the risk of a prototype inflammatory disease, rheumatoid arthritis. This was a case-control study. Assessment of the relative risk (RR) of developing rheumatoid arthritis after surgical vagotomy during 1964-2001 in 63,092 prevalent rheumatoid arthritis cases versus 125,404 matched controls from the general population and in 2548 incident rheumatoid arthritis cases versus 24,357 matched controls from the general population, respectively, was done. For comparison, we assessed RRs for hospitalisation for gastric disorders not including vagotomy. Data on exposures and rheumatoid arthritis were retrieved from population-based and prospectively recorded Swedish registers. A pre-rheumatoid arthritis vagotomy was not significantly associated with an increased risk for rheumatoid arthritis (RR = 1.17, 95% CI 0.97 to 1.40). RRs in the same range were observed for several other pre-rheumatoid arthritis gastric conditions that do not include vagotomy (eg, gastric ulcer RR = 1.21, 95% 1.11 to 1.33). Vagotomy has no specific effect on the risk of developing rheumatoid arthritis in humans. Gastroduodenal ulcers occur more often than expected even before the occurrence of rheumatoid arthritis.     

Independent association of rheumatoid factor and the HLA-DRB1 shared epitope with radiographic outcome in rheumatoid arthritis

OBJECTIVE: Findings of a recent study suggested that HLA-DRB1 alleles encoding the rheumatoid arthritis (RA) "shared epitope" (SE) were not predictive of erosive damage at 2 years in patients with early inflammatory arthritis who were rheumatoid factor (RF) positive, but were predictive in those who were RF negative. The present study was undertaken to determine whether RF status was also important in the association between the SE and radiographic outcome in patients with longstanding RA. METHODS: The association between radiographic outcome, HLA-DRBI, and RF status was examined in 299 RA patients with established disease (5-30 years). Radiographic outcome was measured by scoring radiographs of the hands and feet using the standard radiographs of Larsen. HLA-DRB1 typing was performed using polymerase chain reaction methodology. Results were stratified by RF status and analyzed by multiple regression. RESULTS: An association between radiographic severity and the SE was found in RF-, but not RF+, patients. RF- patients carrying an SE allele had higher Larsen scores than RF- patients lacking the SE, although there was no association with SE dosage. The mean Larsen score was significantly higher in RF+ patients than in RF- patients, but there were no differences between RF+ patients with 0, 1, or 2 SE alleles. Multiple regression analysis confirmed independent associations of RF and SE positivity with radiographic outcome. No significant associations were found between RF and the SE, or RF and individual SE alleles. CONCLUSION: Our data indicate that RF and the SE are independently associated with radiographic outcome in RA. In RF+ patients with longstanding RA, there is no apparent association between the presence of the SE and radiographic damage. However, in RF-patients, although radiographic outcome is generally less severe, there is an association between severity and presence of the SE.     

Socioeconomic and occupational risk factors for rheumatoid arthritis: a nationwide study based on hospitalizations in Sweden

OBJECTIVE: To investigate possible associations between socioeconomic status, occupation, and hospitalization for rheumatoid arthritis (RA). METHODS: A nationwide database was constructed by linking the Swedish Census to the Hospital Discharge Register in order to obtain data on all first hospitalizations for RA in Sweden during the study period 1964 to 2004. Standardized incidence ratios (SIR) and 95% confidence intervals were calculated by socioeconomic status (education level) and occupation for men and women aged 30 years and older. Three cohorts were defined based on occupational titles recorded in Swedish census data in 1960, 1970, and 1980. RESULTS: A total of 13,820 male and 14,509 female hospitalizations for RA were identified during the study period. Men and women with an education level > 12 years had significantly decreased SIR. Among men, significantly increased SIR were present in all 3 cohorts among farmers, miners and quarry workers, electrical workers, other construction workers, and engine and motor operators. Among women, assistant nurses and religious, juridical, and other social-science-related workers had significantly increased SIR in all 3 cohorts. CONCLUSION: Socioeconomic status and occupation sometimes carry a significantly increased risk of hospitalization for RA. Future studies could investigate specific agents in the occupations for which increased risks are identified.     

Orthopaedic surgery of the lower limbs in 49,802 rheumatoid arthritis patients: results from the Swedish National Inpatient Registry during 1987 to 2001

OBJECTIVES: To analyse changes in the rates of hospital admission and use of orthopaedic surgery to the lower limbs in Swedish patients with rheumatoid arthritis between 1987 and 2001. METHODS: Data for all rheumatoid patients admitted to hospital between 1987 and 2001 were abstracted from the Swedish National Hospital Discharge Register (SNHDR). The data in the register are collected prospectively, recording all inpatient admissions throughout Sweden. The SNHDR uses the codes for diagnoses at discharge and surgical procedures according to the Swedish version of the International Classification of Diseases (ICD). RESULTS: In all, 49,802 individual patients with rheumatoid arthritis were identified, accounting for 159,888 inpatient visits. Hospital admissions for rheumatoid arthritis decreased by 42% (p<0.001) during the period 1987 to 2001. Twelve per cent of all admissions were for a rheumatoid arthritis related surgical procedure to the lower limbs; those admissions decreased markedly (by 16%) between 1987 and 1996, and by 12% between 1997 and 2001, as did the overall number of rheumatoid arthritis related surgical procedures to the lower limbs during both time periods. Between 1997 and 2001, 47% of all rheumatoid arthritis related surgical procedures were total joint arthroplasties. There was an overall trend towards reduced length of hospital stay after orthopaedic surgery to the lower limbs during the study period. CONCLUSIONS: Rates of hospital admission and rheumatoid arthritis related surgical procedures to the lower limbs in Swedish patients with rheumatoid arthritis decreased between 1987 and 2001. This may reflect trends in disease severity, management, and health outcomes of this disease in Sweden.     

Incidence of rheumatoid arthritis in Finland during 1980-1990.

OBJECTIVE: To obtain information on the incidence of rheumatoid arthritis and on its recent trends in Finland. METHODS: The study covered those subjects entitled to receive specially reimbursed medication for rheumatoid arthritis under the nationwide sickness insurance scheme in five out of 21 central hospital districts in Finland (population basis about one million adults) during three years: 1980, 1985, and 1990. RESULTS: The annual incidence of rheumatoid arthritis in 1980 and 1985, satisfying the American Rheumatism Association 1987 classification criteria, was 39/100,000 of the population > or = 16 years of age. The combined incidence of rheumatoid factor (RF) positive arthritis and RF negative polyarthritis was 46/100,000. A decline of approximately 40% occurred in the number of RF negative rheumatoid arthritis cases in 1990 compared with the earlier years. The declining trend was statistically significant (P = 0.008). CONCLUSION: The decline in incidence of RF negative rheumatoid arthritis in Finland may reflect changes in the environment specifically affecting the risk of RF negative disease.     

Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study

OBJECTIVE: To study the association between silica exposure and rheumatoid arthritis and how it is modified by cigarette smoking. METHODS: Data were analysed from 276 male cases and 276 male controls aged 18 to 70 years, included in a Swedish population based study between May 1996 and June 2001. A case was defined as a person recently diagnosed with rheumatoid arthritis according to the ACR criteria. Controls were selected from the study base as a stratified random sample accounting for age, sex, and residency. Men with a self reported history of work with rock drilling, stone crushing, or exposure to stone dust in general were defined as silica exposed. Rheumatoid factor (RF) status among cases was recorded. RESULTS: Silica exposed men had increased risk of rheumatoid arthritis, with an odds ratio (OR), adjusted for age, residential area, and smoking, of 2.2 (95% confidence interval, 1.2 to 3.9) among men aged 18 to 70 years, and 2.7 (1.2 to 5.8) among those aged 50 to 70 years. Men who had worked with rock drilling or stone crushing (regarded as highly exposed) had a slightly greater increase in risk of rheumatoid arthritis than silica exposed men in general, with an OR of 3.0 (1.2 to 7.6). The joint effects of silica exposure and smoking were compatible with synergy between these two exposures in the development of rheumatoid arthritis but this was not conclusive. CONCLUSIONS: Silica exposure is associated with increased risk of developing rheumatoid arthritis. This association is not explained by smoking habits.     

Clinical utility of the anti-CCP assay in patients with rheumatic diseases

OBJECTIVES: To determine the frequency of antibodies to cyclic citrullinated peptides (CCP) in a group of patients with a diversity of rheumatic diseases. METHODS: 249 consecutive sera from an arthritis clinic sent for rheumatology testing were selected for testing with the anti-CCP2 assays and for the presence of rheumatoid factor (RF). Patient charts were reviewed for demographic information, clinical diagnosis, radiographic information, and other laboratory data. RESULTS: The sensitivity and specificity of anti-CCP reactivity for the diagnosis of rheumatoid arthritis (RA) were 66.0% and 90.4%, respectively. This compared with the sensitivity and specificity of RF for RA at 71.6% and 80.3%. Furthermore, 10/29 (34%) RF- patients with RA demonstrated reactivity to CCP. The presence of either anti-CCP or RF increased testing sensitivity for diagnosis of RA to 81.4%; the presence of both RF and anti-CCP demonstrated a testing specificity similar to that of anti-CCP reactivity alone for the diagnosis of RA (91.1%). CONCLUSIONS: The detection of anti-CCP is useful for the diagnosis of RA, in fact even more so than RF, because of its higher specificity.     

Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006

Abstract. Holmqvist ME, Wedrén S, Jacobsson LTH, Klareskog L, Nyberg F, Rantapää‐Dahlqvist S, Alfredsson L, Askling J (Institute of Environmental Medicine, Karolinska Institutet, Stockholm; Karolinska Institutet/Karolinska Hospital, Stockholm; Malmö University Hospital, Malmö; AstraZeneca R&D, Mölndal; and Umeå University Hospital, Umeå, Sweden) Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006. J Intern Med 2010; 268 : 578–585. The risk of ischaemic heart disease (IHD), and in particular myocardial infarction (MI), is increased amongst patients with established rheumatoid arthritis (RA). Few studies have included contemporary patients with RA. We recently reported that the risk of IHD is not elevated before the onset of RA symptoms. However, when, in relation to RA diagnosis, the risk is increased is unknown. Objective. To assess the risk of MI and other IHD events amongst patients diagnosed with RA during the last decade and within 18 months following RA symptom onset, compared to the general population, by time since RA diagnosis, year of RA diagnosis and by rheumatoid factor (RF) status. Methods and patients. A Swedish inception cohort of RA (n = 7469) diagnosed between 1995 and 2006 and a matched general population comparator cohort (n = 37 024), was identified and linked to national registers of morbidity and mortality from IHD. Relative risks (RRs) of MI and other IHD events were estimated using Cox regression. Results. During follow‐up, 233 patients with RA and 701 controls developed a first MI, corresponding to an overall RR of MI of 1.6 (95% confidence interval 1.4, 1.9). Increased risks of MI were already detected within 1–4 years following RA diagnosis, as well as in patients diagnosed with RA during the last 5 years, in RF‐negative patients and for transmural as well as nontransmural MIs. Conclusions. MI risk increases rapidly following RA diagnosis, suggesting the importance of additional mechanisms other than atherosclerosis. The elevated short‐term risk is present amongst patients diagnosed in recent years, underscoring the importance of MI prevention from the time of RA diagnosis.     

Seronegative rheumatoid arthritis, rheumatoid factor cross reactive idiotype expression, and hidden rheumatoid factors.

The major rheumatoid factor cross reactive idiotype (RCRI), defined by prototypic monoclonal rheumatoid factors (RFs), is expressed as a dominant idiotype by pokeweed mitogen induced plasma cells obtained from seropositive (RF+) patients with rheumatoid arthritis (RA). Some patients who meet clinical diagnostic criteria for RA set by the American Rheumatism Association fail to express RFs at any time during their clinical course. To determine if seronegative (RF-) patients with RA, so designated by the latex fixation, Rose-Waaler classic binding assays, or a RF enzyme linked immunosorbent assay (ELISA), express the RCRI in the absence of detectable RFs we examined pokeweed mitogen plasma cells from these patients by indirect immunofluorescence. In addition, we used an inhibition ELISA to detect RCRI bearing molecules in the sera of RF- patients with RA. Five of 10 RF- patients with RA had a high prevalence of RCRI+ plasma cells (16-49% of total pokeweed mitogen plasma cells in culture). Six of 20 RF- patients with RA had high serum concentrations of molecules marked by the RCRI, equivalent to 21-110 micrograms/ml of RCRI+ reference monoclonal IgM RF. Four of five patients who expressed the RCRI in high prevalence in pokeweed mitogen plasma cells, also demonstrated high concentrations of RCRI in their sera detected by inhibition ELISA. There was significant concordance of RCRI expression determined by the two different assays. Four RF- patients with RA who expressed RCRI in their whole sera had hidden RFs detected in their 19S and, in one case, 7S serum fraction. Detection of RF related molecules in whole sera by the expression of RCRI in RF- patients with RA identifies a subgroup of RF- patients with RA who possess hidden RFs. Some RF- patients with RA can express the major RCRI in pokeweed mitogen plasma cells and in their sera and therefore are related to patients with prototypic Waldenstrom's macroglobulinaemia, who produce RCRI+ 19S IgM monoclonal RFs.     

Mortality risk associated with rheumatoid arthritis in a prospective cohort of older women: results from the Iowa Women's Health Study

OBJECTIVE: To determine whether rheumatoid arthritis (RA) is associated with excess mortality among older women. METHODS: RA associated mortality was examined in a prospective cohort study that was started in 1986, and included 31 336 women aged 55-69 years without a history of RA at baseline. Up to 1997, 158 cases of RA were identified and validated against medical records. The relative risk (RR) and 95% confidence interval (CI) were calculated as measures of association between RA onset and subsequent mortality (overall and cause-specific) using Cox proportional hazards regression. RESULTS: Compared with non-cases, women developing RA during follow up had a significantly increased mortality risk (RR=1.52; 95% CI 1.05 to 2.20). Mortality was higher among rheumatoid factor (RF) positive cases (RR=1.90; 95% CI 1.24 to 2.92) than among RF negative cases (RR=1.00; 95% CI 0.45 to 1.99). There were trends towards increased proportions of RA related deaths from infection (RR=3.61; 95% CI 0.89-14.69) and circulatory disease (RR=1.46; 95% CI 0.76 to 2.81) but not malignancy (RR=0.97; 95% CI 0.46 to 2.04). CONCLUSIONS: RA was associated with significantly increased mortality in a cohort of older women, and the association appeared to be restricted to those with RF positive disease.     

MHC2TA promoter polymorphism (-168*G/A, rs3087456) is not associated with susceptibility to rheumatoid arthritis in British Caucasian rheumatoid arthritis patients

OBJECTIVE: To investigate the association of a single-nucleotide polymorphism (SNP) in the promoter region of MHC2TA gene (-168*G/A, rs3087456), which has previously been described in a Swedish rheumatoid arthritis (RA) cohort, in British Caucasian RA patients. METHODS: We genotyped 733 RA patients and 613 healthy controls for MHC2TA -168*G/A SNP by amplification-refractory mutation system (ARMS). Data were analysed using SPSS version 13.0 software and the chi-square test was applied where appropriate. RESULTS: The MHC2TA -168*G/A SNP was not associated with increased susceptibility to RA in our patients. Stratifying the patients according to the presence or absence of rheumatoid factor (RF) showed the SNP to be more common in RF negative patients, but this did not reach statistical significance. CONCLUSION: We did not confirm the previously reported association of this MHC2TA polymorphism with RA in our UK population despite its ethnic similarities with the Swedish population in which it was first described.     

Cigarette smoking and the risk of rheumatoid arthritis among postmenopausal women: results from the Iowa Women's Health Study

PURPOSE: To determine whether cigarette smoking increases the risk of rheumatoid arthritis among postmenopausal women. SUBJECTS AND METHODS: We followed a cohort of 31 336 women in Iowa who were aged 55 to 69 years in 1986 and who had no history of rheumatoid arthritis. Through 1997, 158 cases of rheumatoid arthritis were identified and validated based on review of medical records and supplementary information provided by physicians. Multivariable Cox proportional hazards regression was used to derive rate ratios (RRs) and 95% confidence intervals (CIs) for the association between cigarette smoking and rheumatoid arthritis. RESULTS: Compared with women who had never smoked, women who were current smokers (RR = 2.0; 95% CI: 1.3 to 2.9) or who had quit 10 years or less before study baseline (RR = 1.8; 95% CI: 1.1 to 3.1) were at increased risk of rheumatoid arthritis, but women who had quit more than 10 years before baseline were not at increased risk (RR = 0.9; 95% CI: 0.5 to 2.6). Both the duration and intensity of smoking were associated with rheumatoid arthritis. Multivariable adjustments for age, marital status, occupation, body mass index, age at menopause, oral contraceptive use, hormone replacement therapy, alcohol use, and coffee consumption did not alter these results. CONCLUSION: These results suggest that abstinence from smoking may reduce the risk of rheumatoid arthritis among postmenopausal women.     

Evaluation of revised International League of Associations for Rheumatology classification criteria for juvenile idiopathic arthritis in Spanish children (Edmonton 2001)

OBJECTIVE: To evaluate the revised (Edmonton 2001) International League of Associations for Rheumatology (ILAR) classification criteria for Juvenile Idiopathic Arthritis (JIA) in a cohort of Spanish children. METHODS: One hundred twenty-five patients with chronic arthritis categorized according to traditional criteria and to the first revision of ILAR JIA criteria (Durban 1997) were reclassified according to the second JIA criteria revision (Edmonton 2001). RESULTS: Edmonton criteria allocated 92% of the patients classified by traditional criteria in their corresponding ILAR categories. Most patients with systemic (94%), pauciarticular (91%) and polyarticular (88%) juvenile chronic arthritis as well as those with juvenile spondyloarthropathy (94%) were reclassified in the corresponding ILAR categories. Two children with probable psoriatic arthritis (PsA) were reclassified in the rheumatoid factor-negative (RF-) polyarthritis category, whereas only one of 2 children with definite PsA could be allocated to the ILAR PsA class. Ten patients (8%) constituted the undifferentiated arthritis group, 8 because of psoriasis in a first-degree relative, one because of the presence of RF in a girl with oligoarthritis, and another because of psoriasis in a boy who was HLA-B27-positive. In comparison with the Durban JIA criteria the Edmonton revision decreased the number of patients whose arthritis fulfilled criteria in no category or in 2 or more categories (from 19 to 10), and delineated better the population included in the RF- polyarthritis category. CONCLUSION: The Edmonton criteria made the ILAR classification more transparent and easy to apply. Family history of psoriasis was responsible for most allocations to the undifferentiated arthritis category (8/10).     

Genetic structure of the population with rheumatoid arthritis in north east England: a genetic approach to define different subtypes.

Clinically and immunologically rheumatoid arthritis (RA) is possibly a heterogeneous disorder. Despite numerous efforts clearer definition of this heterogeneity has been of limited success. Measurements of rheumatoid factor (RF) and antinuclear antibodies (ANA) by conventional methods define subpopulations of patients with RA and in a few recent studies an association of human leucocyte antigens (HLA) undoubtedly indicates the immunogenetic differences in the susceptibility of RA patients with different status of autoantibodies. The studies on a few isolated non-HLA genetic markers in RA are controversial. To understand the role of genetic factors in susceptibility 24 single gene characters other than HLA were investigated in 225 patients with RA classified by humoral status (presence or absence of RF and ANA) into three groups and in 104 healthy control individuals from the north east of England. Locus by locus comparison suggested associations of MN, Lewis, and Bf system with RF positive patients. Although the associations with MN and Lewis blood groups require further investigations, the involvement of the Bf locus is in agreement with the immunological component of the disease suggested by HLA associations and it could be due to the phenomenon of linkage disequilibrium. Measures of genetic distance applied to the subpopulations of patients with RA, divided according to the presence or absence of humoral factors, suggest that RF+ ANA+, RF- ANA-, and RF+ ANA- subgroups are distinct genetic diseases, each affecting a different subsection of the population which is genetically distinct. Such genetic heterogeneity may suggest a different pathogenetic mechanism for each of these subpopulations of rheumatoid arthritis.     

Increased absence due to sickness among employees with fibromyalgia

BACKGROUND: Little is known about the effect of fibromyalgia on absence due to sickness in working populations. OBJECTIVE: To examine the risk of absence due to sickness among employees with fibromyalgia. METHODS: A prospective cohort study with 1-year follow-up of recorded and certified absence due to sickness after a survey of chronic diseases among 34 100 Finnish public sector employees (27 360 women and 6740 men) aged 17-65 years at baseline in 2000-2. RESULTS: 20 224 days of absence due to sickness for the 644 employees with fibromyalgia and 454 816 days for others were documented. Of those with fibromyalgia, 67% had co-occurring chronic conditions such as osteoarthritis, rheumatoid arthritis, depression or other psychiatric disorders. Compared with employees with none of these chronic conditions, the hazard ratio (HR) adjusted for age, sex and occupational status was 1.85-fold (95% confidence interval (CI) 1.53 to 2.18) for people with fibromyalgia alone and 2.63-fold (95% CI 2.34 to 2.96) for employees with fibromyalgia with coexisting conditions. The excess rate of absence due to sickness was 61 episodes/100 person-years among people with fibromyalgia alone. Among employees with musculoskeletal and psychiatric disorders, secondary fibromyalgia was associated with a 1.4-1.5-fold increase in risk of absence. CONCLUSION: Fibromyalgia is associated with a substantially increased risk of medically certified absence due to sickness that is not accounted for by coexisting osteoarthritis, rheumatoid arthritis or psychiatric disorders.     

Life on the edge: patterns of formal and informal help to older adults in the United States and Sweden

OBJECTIVE: Our objective in this study was to compare assistance received by individuals in the United States and Sweden with characteristics associated with low, moderate, or high 1-year placement risk in the United States. METHODS: We used longitudinal nationally representative data from 4,579 participants aged 75 years and older in the 1992 and 1993 waves of the Medicare Current Beneficiary Survey (MCBS) and cross-sectional data from 1,379 individuals aged 75 years and older in the Swedish Aging at Home (AH) national survey for comparative purposes. We developed a logistic regression equation using U.S. data to identify individuals with 3 levels (low, moderate, or high) of predicted 1-year institutional placement risk. Groups with the same characteristics were identified in the Swedish sample and compared on formal and informal assistance received. RESULTS: Formal service utilization was higher in Swedish sample, whereas informal service use is lower overall. Individuals with characteristics associated with high placement risk received more formal and less informal assistance in Sweden relative to the United States. DISCUSSION: Differences suggest formal services supplement informal support in the United States and that formal and informal services are complementary in Sweden.     

Socioeconomic indicators and mortality for ischemic cardiopathy in the RIFLE population. The RIFLE Group. Risk Factors and Life Expectancy]

The aim of this paper was to evaluate the relationship between socioeconomic indicators (education, occupation and residence) and short-term CHD mortality in an Italian population sample. Socioeconomic indicators and major CHD risk factors (BMI, SBP, DBP, TOT-CH, HDL-CH and TRIG) were measured in 15,315 males aged 40-69 years; mortality data by cause were collected for the next six years. CHD mortality risk ratio (RR) in the different educational and occupational levels and by residence was computed by Cox proportional hazards models. The association between socioeconomic indicators and CHD risk factors was explored by covariance and logistic regression analysis. After six years, 632 men died, 181 of whom because of coronary fatalities. No association with educational level was found for CHD mortality (RR = 1.00 high, 0.69 intermediate, 0.92 low), nor did occupational level show a significant association. Urban vs rural residence (RR = 1.00) showed a RR for CHD mortality of 1.35. Adjustment for bio-behavioral risk factors did not change the above results; only mortality for CHD of urban vs rural residents increased (RR = 1.63, p < 0.003). By considering the interaction between schooling and occupation, it was found that education appropriated to occupational level was a protective factor. The study does not indicate any association between education/occupational level and CHD mortality in male RIFLE population samples. The mean level of major CHD risk factors within different educational/occupational levels supports these results. Status incongruity as well as residence in an urban environment proved to be risk conditions for CHD mortality.     

DNA analysis of HLA-DR, DQ, and DP alleles in children with polyarticular juvenile rheumatoid arthritis.

HLA-DR, DQ and DP alleles were determined by restriction fragment length polymorphism analysis and oligonucleotide probe hybridization of polymerase chain reaction amplified genomic DNA in 94 Caucasian children with polyarticular juvenile rheumatoid arthritis (JRA) [13 rheumatoid factor (RF)+ and 81 RF-] and 100 healthy controls. HLA-DRw8, DQw4, DQA1*0401, DQB1*0402 were increased in frequency in those patients with RF seronegative disease, with highest frequencies seen in patients with young age at onset (< 5 years of age). These findings were similar to what we observed in children with pauciarticular JRA, especially those with young age at onset. DPB1*0301 was also found in increased frequency in the RF- group, and in particular those seronegative for antinuclear antibody. In contrast to what is observed in patients with pauciarticular JRA, the frequency of DPB1*0201 was not increased in any polyarticular JRA patient group. These data suggest that polyarticular JRA shares many genetic features with pauciarticular JRA.     

Regulation of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis: contrasting effects of HLA-DR3 and the shared epitope alleles

OBJECTIVE: To examine the association between HLA-DRB1 alleles and the production of anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF) autoantibodies in patients with rheumatoid arthritis (RA). METHODS: We studied 1,723 Caucasian RA patients enrolled in the North American Rheumatoid Arthritis Consortium (NARAC) family cohort and the Study of New Onset Rheumatoid Arthritis (SONORA) cohort. All patients were tested for anti-CCP antibodies (by enzyme-linked immunosorbent assay), RF (by nephelometry), and HLA-DR genotype (by polymerase chain reaction and sequence-specific oligonucleotide hybridization). RESULTS: When controlled for the presence of RF, anti-CCP positivity was strongly associated with the HLA-DRB1 shared epitope (SE). In RF+ patients, the presence of the SE was very significantly associated with anti-CCP positivity, with an odds ratio (OR) of 5.8 and a 95% confidence interval (95% CI) of 4.1-8.3. This relationship was also seen in RF- patients (OR 3.1 [95% CI 1.8-5.3]). In contrast, RF positivity was not significantly associated with presence of the SE independently of anti-CCP antibodies. Strikingly, HLA-DRB1*03 was strongly associated with reduced anti-CCP titers, even after controlling for the presence of the SE and restricting the analysis to anti-CCP+ patients. HLA-DR3 was also associated with anti-CCP- RA in our population. CONCLUSION: The HLA-DRB1 SE is strongly associated with the production of anti-CCP antibodies, but not RF. In contrast, HLA-DR3 alleles are associated with anti-CCP- disease and with lower levels of anti-CCP antibodies, even when controlling for the SE. These data emphasize the complexity of the genetic effects of the major histocompatibility complex on the RA phenotype.