Juvenile idiopathic arthritis classified by the ILAR criteria: HLA associations in UK patients.

OBJECTIVE: To determine the HLA associations with juvenile idiopathic arthritis (JIA) and its subgroups as defined by the International League of Associations for Rheumatology (ILAR) classification criteria. METHODS: Five hundred and twenty-one UK Caucasian JIA patients and 537 UK Caucasian controls were typed for HLA class II alleles. Phenotype and haplotype frequencies were compared between all JIA cases and controls and between the seven ILAR-defined JIA subgroups. RESULTS: Three haplotypes (DRB1*08-DQA1*0401-DQB1*0402; DRB1*11-DQA1*05-DQB1*03; DRB1*1301-DQA1*01-DQB1*06) were associated with increased risk and one (DRB1*04-DQA1*03-DQB1*03) with decreased risk of JIA. However, in each case the frequencies also varied between JIA subgroups. CONCLUSION: This study categorically demonstrates that there are multiple HLA class II associations with JIA. It has also, for the first time, defined these associations in the seven different ILAR subgroups in UK JIA cases. Although there are a number of common associations, each ILAR subgroup exhibits different patterns of HLA associations, suggesting that the ILAR classification system does define genetically distinct groups of patients.

HLA-DRB1 and disease outcome in multiple sclerosis.

The association between susceptibility to multiple sclerosis (MS) and the class II MHC allele HLA-DRB1*15 is well established although a possible relationship between this allele and outcome in MS is less clear. HLA-DRB1 typing was performed on 375 unrelated white patients with clinically definite MS and on 367 healthy controls. Putative associations of the gene with outcome were examined by dividing patients into two groups: those with an EDSS of 0-5.5 (mild/moderate disease) and those with an EDSS of 6-10 (severe disease). In order to minimise the effects of disease variability patients with a disease duration of at least 10 years or 15 years were examined. As subsidiary HLA-DRB1*03 and HLA-DRB1*04 associations have been previously reported, the effect of these alleles was also examined. As expected, HLA-DRB1*15 was found more frequently in patients than in controls (P < 0.000001). HLA-DRB1*15 positive patients had a significantly earlier age at onset than HLA-DRB1*15 negative patients. No significant associations were noted between HLA-DRB1*15 and outcome in the total patient group or in patients with a disease duration of 10 years or longer. In patients with a disease duration of at least 15 years HLA-DRB1*15 negative status was associated with a worse prognosis, although this did not remain significant after correction for multiple testing. It is thus likely that the contribution of HLA in MS is primarily towards onset and initial triggering mechanisms rather than influencing disease progression, chronicity and severity.

Cytokine gene polymorphisms and susceptibility to juvenile idiopathic arthritis. British Paediatric Rheumatology Study Group.

OBJECTIVE: To investigate the involvement of candidate cytokine genes in the pathogenesis of juvenile idiopathic arthritis (JIA). METHODS: Single nucleotide polymorphisms and intragenic microsatellite markers within 8 candidate cytokine genes (interleukin-1alpha [IL-1alpha], IL-2, IL-4, IL-6, IL-10, interferon-alpha1 [IFNA1], interferon-gamma [IFNG], and interferon regulatory factor 1 [IRF-1]) were investigated in 417 Caucasian patients with clinically characterized JIA and a panel of 276 unrelated, healthy Caucasian controls, all from the United Kingdom. RESULTS: A novel 3'-untranslated region (3'UTR) polymorphism in IRF-1 was found to be associated with susceptibility to JIA (corrected P = 0.002). No significant association with IL-1alpha, IL-2, IL-4, IL-6, IL-10, IFNA1, or IFNG was observed. CONCLUSION: An association between JIA and a previously unreported 3'UTR polymorphism of IRF-1 was observed. This association was not found to be specific to any particular JIA subgroup. This suggests that IRF-1 may contribute to a common pathogenesis shared by all JIA patients, regardless of clinical phenotype. This is most likely to be a genetic contribution to the chronic inflammatory process that underlies JIA pathology.

ICC/PCR detection of enteroviruses and hepatitis A virus in environmental samples.

This study applied the integrated cell culture/polymerase chain reaction methodology (ICC/PCR) for rapid and specific detection of both cytopathogenic and noncytopathogenic viruses. Results of this study showed that the use of direct RT-PCR or conventional cell culture alone may yield erroneous results with the analysis of environmental samples. The purpose of this study was to compare cultural, molecular, and combined assays for the most effective method of virus detection in variable environmental samples. Using ICC/PCR, stock enterovirus inocula of > or =10 PFU were PCR positive in at least 4/5 replicate flasks after only 5 h of incubation in cell culture, and in all flasks after > or =10 h. An inoculum of one PFU was detected by PCR after 20 h of cell culture incubation while for concentrations of virus below one PFU, 25 h of incubation was sufficient. Similarly, hepatitis A virus (HAV) inocula of 100 MPN/flask, produced indeterminate CPE in cell culture, but were clearly detected by ICC/PCR following 48 h of incubation. Lower levels of HAV, 1 and 10 MPN, were detected by ICC/PCR after 96 to 72 h of incubation, respectively. Cell culture lysates from 11 environmental sample concentrates of sewage, marine water, and surface drinking water sources, were positive for enteroviruses by ICC/PCR compared to 3 positive by direct RT-PCR alone. Results from ICC/PCR eventually agreed with cell culture but required < or =48 h of incubation, compared to as long as 3 weeks for CPE following incubation with BGM and FRhK cells.

Health status of Persian Gulf War veterans: self-reported symptoms, environmental exposures and the effect of stress.

BACKGROUND: Most US troops returned home from the Persian Gulf War (PGW) by Spring 1991 and many began reporting increased health symptoms and medical problems soon after. This investigation examines the relationships between several Gulf-service environmental exposures and health symptom reporting, and the role of traumatic psychological stress on the exposure-health symptom relationships. METHODS: Stratified, random samples of two cohorts of PGW veterans, from the New England area (n = 220) and from the New Orleans area (n = 71), were selected from larger cohorts being followed longitudinally since arrival home from the Gulf. A group of PGW-era veterans deployed to Germany (n = 50) served as a comparison group. The study protocol included questionnaires, a neuropsychological test battery, an environmental interview, and psychological diagnostic interviews. This report focuses on self-reported health symptoms and exposures of participants who completed a 52-item health symptom checklist and a checklist of environmental exposures. RESULTS: The prevalence of reported symptoms was greater in both Persian Gulf-deployed cohorts compared to the Germany cohort. Analyses of the body-system symptom scores (BSS), weighted to account for sampling design, and adjusted by age, sex, and education, indicated that Persian Gulf-deployed veterans were more likely to report neurological, pulmonary, gastrointestinal, cardiac, dermatological, musculoskeletal, psychological and neuropsychological system symptoms than Germany veterans. Using a priori hypotheses about the toxicant effects of exposure to specific toxicants, the relationships between self-reported exposures and body-system symptom groupings were examined through multiple regression analyses, controlling for war-zone exposure and post-traumatic stress disorder (PTSD). Self-reported exposures to pesticides, debris from Scuds, chemical and biological warfare (CBW) agents, and smoke from tent heaters each were significantly related to increased reporting of specific predicted BSS groupings. CONCLUSIONS: Veterans deployed to the Persian Gulf have higher self-reported prevalence of health symptoms compared to PGW veterans who were deployed only as far as Germany. Several Gulf-service environmental exposures are associated with increased health symptom reporting involving predicted body-systems, after adjusting for war-zone stressor exposures and PTSD.

Tumour necrosis factor c2 microsatellite allele is associated with the rate of HIV disease progression.

BACKGROUND: The rate of immunological deterioration and progression to AIDS differs markedly between HIV-positive individuals, and may be influenced by cofactors, HIV phenotype and host T-cell response. Tumour necrosis factor (TNF)-alpha and lymphotoxin stimulate HIV replication and may induce apoptosis of HIV-infected and uninfected lymphocytes in vitro, thus accelerating disease progression and CD4 depletion. Variability in TNF production between individuals is to a degree genetically determined and may be predicted from polymorphisms of microsatellite regions surrounding the human TNF gene locus. METHODS: We examined TNf microsatellite polymorphisms in 24 HIV-positive patients with slower disease progression (CD4 count > 400 x 10(6)/l at > or = 6 years), 20 HIV-positive patients with faster progression (CD4 count < 200 x 10(6)/l within 5 years) and 109 healthy controls resident in north-west England. Typing was performed by polymerase chain reaction amplification of TNF a, b, c and d microsatellites and alleles were defined using fluorescence-based semi-automated microsatellite mapping techniques. RESULTS: No significant differences in TNF a, b and d allele frequencies were observed between faster and slower progressors, or with healthy controls. The frequency of the TNF c2 allele was significantly different between HIV-positive slower (60.9%) and faster (15%) progressors (P = 0.002) with an odds ratio of 0.1 (95% confidence interval, 0-0.6). TNF c2 was also less frequent in faster progressors than in healthy controls (45.9%, P = 0.006) with an odds ratio of 0.2 (95% confidence interval 0-0.8). CONCLUSIONS: This is the first report demonstrating a strong association between the TNF c2 allele and the rate of HIV progression. Although it is possible that this finding may have arisen as a result of linkage disequilibrium with other alleles within the major histocompatibility complex that exert a more powerful effect upon progression, evidence is mounting to suggest that both TNF-alpha and lymphotoxin are closely involved in HIV disease progression and CD4 depletion. Our results serve to highlight the potential importance of genetic polymorphism, particularly of the TNF locus, in influencing the progression of HIV infection.

Patients who develop inflammatory polyarthritis (IP) after immunization are clinically indistinguishable from other patients with IP.

Musculoskeletal symptoms may occur following various types of immunization, and it has also been suggested that, like infection, immunization may act as a trigger for rheumatoid arthritis (RA). A total of 48 of 898 (5.3%) patients with early inflammatory polyarthritis (IP) referred to the Norfolk Arthritis Register reported an immunization in the 6 weeks prior to symptom onset. There were no important clinical or demographic differences between the 48 immunized patients and 185 consecutive patients who did not report prior immunization. In addition, the frequencies of HLA-DRB1*01. *04 and the shared epitope in 33 of the immunized patients were similar to those in the 185 non-immunized patients and to those in 136 healthy controls. Further results from a case-control study suggest that the rate of immunization is higher amongst cases (5.5%) than age- and sex-matched controls (2.8%). In a small number of susceptible individuals, immunization may thus act as a trigger for RA.

HLA class II profile: a weak determinant of factor VIII inhibitor development in severe haemophilia A. UKHCDO Inhibitor Working Party.

The risk of developing factor VIII inhibitor antibodies in haemophilia A may relate both to factor VIII genotype and genes within the HLA complex known to influence immune response. We investigated a cohort of 176 patients with severe haemophilia A and with either high-level inhibitors (> 10BU/ml) or with no history of an inhibitor, stratified according to the presence or absence of the factor VIII gene intron 22 inversion. HLA DRB1, DQA1 and DQB1 polymorphisms were determined by PCR. HLA frequencies form 137 United Kingdom controls were used for comparison. HLA phenotype frequency differences, expressed as odds ratios with 95% confidence intervals were as follows: HLA-DRB*1501, DQB1*0602 and DQA1*0102 were all increased in frequency in patients with inhibitors, only DQA1*0102 reaching statistical significance (OR 2.7, 1.2-5.9). These alleles form part of an established HLA haplotype. The frequencies of HLA-DRB1*1501, DQB1*0602 and DQA1*0102 were particularly raised in patients with inhibitors and a factor VIII gene intron 22 inversion, although again only DQA1*0102 achieved significance (OR 3.1, 1.0-10.1). The frequency of DRB1*01, DQB1*0501, DQA1*0101 were also increased in inhibitor patients lacking the intron 22 inversion although this failed to achieve statistical significance. This data suggests that HLA class II profile constitutes a weak risk factor for developing inhibitor antibodies to factor VIII. This may be more pronounced in patients with an intron 22 inversion.

Polymyalgia rheumatica is associated with both HLA-DRB1*0401 and DRB1*0404.

The frequency of HLA-DRB1 alleles was determined in 68 Caucasoid patients with polymyalgia rheumatica (PMR) and 140 controls using polymerase chain reaction (PCR) sequence-specific oligonucleotide typing. In keeping with previous studies, an increased frequency of DRB1*04 was observed in patients [55.9% vs 35.0%, odds ratio (OR) 2.4, 95% confidence interval (CI) 1.3-4.4]. HLA-DRB1*0101 frequency was also increased in patients, although less confidence could be placed on this association (19.1% vs 14.3%, OR 1.4, 95% CI 0.6-3.3). HLA-DRB1*04 subtyping indicated that the frequencies of both DRB1*0401 (38.2% vs 22.1%, OR 2.2, 95% CI 1.0-4.3) and DRB1*0404 (16.2% vs 5.0%, OR 3.7, 95% CI 1.2-11.1) were specifically raised. An increased frequency of the RA shared epitope (QKRAA/QRRAA) was also observed in this group (75.0% vs 44.2%, OR 3.8, 95% CI 1.9-7.6). When the analysis was restricted to only DRB1*04-negative patients and controls, the frequencies of DRB1*0301, *11 and *08 were marginally raised. However, no obvious relationship appeared to exist between PMR susceptibility and DRB1 alleles carrying the DYF conserved epitope in the second hypervariable region. Autoantibodies to thyroid antigens were present in 23% of patients. An increased frequency of DRB1*0301 was observed in patients with thyroid microsomal antibodies compared to those without (54.5% vs 24.6%, OR 3.7, 95% CI 0.8-17.0). This increase was not observed in patients with thyroglobulin autoantibodies. These data indicate that both DRB1*0401 and *0404 are associated with PMR, and that this may extend to include DRB1*0101. The immunogenetic profile of susceptibility markers in this condition appears to be similar to that in rheumatoid arthritis.

Antinuclear antibodies in early onset pauciarticular juvenile chronic arthritis (JCA) are associated with HLA-DQB1*0603: a possible JCA-associated human leucocyte antigen haplotype.

A panel of 43 early onset pauciarticular (EOPA) juvenile chronic arthritis (JCA) patients have been typed for human leucocyte antigens (HLA) DRB1, DPB1, DQA1 alleles, and DQB1*0603 status using molecular-based methods. Increased frequencies of DRB1*08 [odds ratio (OR) 7.7, 95% confidence interval (CI) 2.6-22.3], DRB1*11 (OR 3.1, 95% CI 1.2-8.1), DRB1*1301 (OR 7.7, 95% CI 2.6-22.3), DPB1*0201 (OR 3.5, 95% CI 1.6-8.0), DQA1*0103 (OR 4.4, 95% CI 1.5-13.3), DQA1*0501 (OR 2.9, 95% CI 1.3-6.6), DQA1*0601 (OR 30, 95% CI 3.6-241) and DQB1*0603 (OR 7.3, 95% CI 3.0-17.6) were found in the EOPA-JCA group compared with Caucasoid controls. Stratification of the EOPA-JCA group into antinuclear antibody (ANA) positive (n = 18) and ANA negative (n = 25) individuals revealed that ANA positivity was only associated with DRB1*1301 (OR 4.2, 95% CI 1.0-17.3), DPB1*0201 (OR 4.0, 95% CI 1.0-15.7) and DQB1*0603 (OR 11.5, 95% CI 2.5-53.4). Further analysis of the relative contributions of HLA antigens to ANA status revealed that DQB1*0603 determined the primary HLA effect. No apparent interaction between DQB1*0603 and DRB1*1301 or between DQB1*0603 and DPB1*0201 was found to contribute to the association with ANA. We suggest that those ANA positive individuals with a restricted HLA background, (DQB1*0603 positive), defines a group of EOPA-JCA patients which will be especially valuable in the characterization of the ANA associated with EOPA-JCA.

Lack of influence of non-inherited maternal HLA-DR alleles on susceptibility to rheumatoid arthritis.

OBJECTIVE: To reproduce findings from previous reports that non-inherited maternal HLA class II antigens might contribute to rheumatoid arthritis (RA) susceptibility in the offspring. METHODS: Families were recruited from the Arthritis and Rheumatism Council's National Repository of RA families and HLA-DRB1 alleles were examined in these individuals and their first degree relatives using DNA typing methods. RESULTS: There was no evidence of an increase in either non-inherited maternal HLA-DR4 or the HLA-DRB1 shared epitope as a whole compared with the frequency expected using the non-inherited paternal antigens as controls. CONCLUSIONS: The numbers of probands who were shared epitope negative were small, but we are unable to confirm in these families the findings that non-inherited maternal HLA contributes an additional susceptibility factor to rheumatoid arthritis.

Carboxyhemoglobin levels in patients with cocaine-related chest pain.

Carboxyhemoglobin (COHb) levels were measured in patients who came to an emergency department complaining of acute chest pain. For subjects not receiving prior oxygen therapy, those with cocaine-related chest pain (n = 10) had a higher mean COHb level than a comparison group (n = 28) with nonischemic chest pain (4.50 +/- 2.40 vs 2.73 +/- 0.66; p < 0.05). Four of the seven (57 percent) who smoked crack had COHb levels greater than 4.5 percent, while only one of six (17 percent) smokers of only tobacco had such a level. These findings suggest an additional mechanism, the formation of COHb, which could aggravate cocaine-induced cardiotoxicity.

Absence of an association between HLA-DRB1*04 and rheumatoid arthritis in newly diagnosed cases from the community.

OBJECTIVES: To determine HLA-DR4 and DR1 allele frequencies in a series of patients with newly diagnosed early inflammatory arthritis. METHODS: HLA-DR1 and DR4 frequencies were determined by oligonucleotide typing of 208 patients classified as having either rheumatoid arthritis (RA) or undifferentiated inflammatory polyarthritis. RESULTS: The frequency of occurrence of DR4 in these patients with RA did not differ significantly from that in controls in the United Kingdom (42 v 37%). HLA-DR1 was increased in the group with inflammatory polyarthritis (25 v 18%). CONCLUSIONS: The frequency of DR4 is not increased in newly diagnosed community based patients with RA. This supports the hypothesis that DR4 is less important as a marker for susceptibility to RA than it is for disease persistence or severity.

Absence of rheumatoid arthritis in a rural Nigerian population.

A 2-stage population screening survey of 2,000 inhabitants of 2 rural townships in southern Nigeria was undertaken. No case of rheumatoid arthritis (RA) was discovered in those responding, although 3 cases of inflammatory polyarthritis were found. One of these individuals satisfied the modification of the American College of Rheumatology classification tree criteria that allows for missing radiographic data. Simultaneous monitoring, during a 4-month period, of the local health clinic serving the townships also failed to reveal a case of RA. Three (5.5%) of 55 individuals tested were positive for rheumatoid factor, a rate lower than in previous surveys of rural West African populations. Further immunogenetic investigation of that subsample from this population, using HLA oligonucleotide typing, suggested that HLA-DR4 was rare (1/55). Further, although HLA-DR1 was present in 7 (13%), 6 had the DRB1*0102 variant seen in black populations and not thought to be associated with RA. Our study confirmed the findings of others that rural African groups have extremely low rates of RA. In addition HLA genes containing the RA associated "shared epitope" are also relatively infrequent and might explain this reduction in RA prevalence.

Longitudinal study of astronaut health: mortality in the years 1959-1991.

We conducted a historical cohort study of mortality among 195 astronauts who were exposed to space and medical sources of radiation between 1959 and 1991. Cumulative occupational and medical radiation exposures were obtained from the astronaut radiation exposure history data base. Causes of death were obtained from obligatory death certificates and autopsy reports that were on file in the medical records. There was a total of 20 deaths that occurred during the 32-year follow-up period of which 16 were due to accidents. The all-cause standardized mortality ratio (SMR) was 181 (95% confidence interval 110, 279). There was 1 cancer death in the buccal cavity and pharyngeal ICD-9 rubric whose occurrence was significantly beyond expectation. Mortality for coronary disease was 53% lower than expected (2 deaths; SMR = 47; 95% confidence limits 5, 168). The crude death rate for 12 occupationally related accidents was 445 deaths per 100,000 person-years and was an order of magnitude greater than accidental death rates in the mining industries. The SMR of 1346 for fatal accidents was significantly beyond expectation (16 deaths; 95% confidence limits 769, 2168) and was similar to SMRs for accidents among aerial pesticide applicators. The 10-year cumulative risk of occupational fatalities based on the exponential, Weibull, Gompertz, and linear-exponential distributions was 10%. Mortality from motor vehicle accidents was slightly higher than expected, but was not significant (1 death; SMR = 165; 95% confidence limits 2,922). Radiation exposures from medical procedures accounted for a majority of cumulative dose when compared with space radiation exposures. Overall, it was found that astronauts are at a health disadvantage as a result of catastrophic accidents.

Contribution of a risk factor clinic to lipid management in patients with coronary artery disease.

The progress of a cohort of 145 patients seen between June 1986 and June 1989 was reviewed. These patients had treatment prescribed by the clinic and had data recorded over serial visits; they allowed us to determine the contribution of the risk factor clinic. Eighty-six percent had coronary artery disease. Patients were given nutritional advice, partly in groups. In addition 61% were treated with drug therapy. Seventy-four percent had modified their diet before the clinic visit but only 32% received less than 30% of energy from fat; the number rose to 67% by discharge. Sixty-four percent had a body mass index of 25 or greater, falling to 53% at discharge. Mean total cholesterol of the 145 patients was 7.9, HDL cholesterol 1.06, and total:HDL cholesterol ratio 7.7 mmol/L. Changes with clinic management were: total cholesterol -19%, HDL cholesterol +11%, total:HDL cholesterol ratio -25%, LDL cholesterol -21%. Despite these changes, levels were less than optimal for patients with coronary arterial disease in at least 50% of patients at the time of discharge. Improved results can be achieved only with a more aggressive approach to drug therapy. Recent studies in patients with coronary disease provide strong support for such a change in management.

Effect of repeated occupational exposure to lead, cessation of exposure, and chelation on levels of lead in bone.

A sensitive K-X-ray fluorescence (K-XRF) instrument was used to measure lead levels in the tibia and patella on a series of twelve subjects who had relatively well-documented histories of lead exposure and blood lead levels. For some subjects, K-XRF measurements were taken at multiple points in time, and before and after chelation with EDTA (ethylenediamine tetraacetic acid). Results confirm that K-XRF measured bone lead levels correspond to cumulative blood lead indices and not to current blood lead levels. Moreover, the data suggest that bone lead levels; (1) correspond to urinary lead following the EDTA mobilization test unless previous chelation has occurred; (2) rise initially after lead exposure ceases and blood lead levels decrease, probably from redistribution from soft tissue, and then fall; and (3) do not decrease with a 3- to 5-day course of therapeutic EDTA chelation. K-XRF levels in the patella were noted to decrease more rapidly than levels in the tibia after cessation of lead exposure, a finding that probably reflects the greater turnover of lead in trabecular bone than in cortical bone.

Clinical experiences: development of a medical surveillance protocol for hazardous waste workers.

Medical surveillance of hazardous waste workers is essential for the health of these workers, who have unique, complex exposures. In order for this preventive tool to be effective, the supervising and/or examining physician must be educated about the specific health risks of hazardous waste workers and also must perform a comprehensive examination. Results of testing should be evaluated both for remarkable abnormalities as well as longitudinal subtle changes in individuals, and also for trends in workers with similar exposures. Fitness for duty determinations should be then made with appropriate communication of abnormalities and follow-up recommendations to both employers and employees. To date, clinical and research findings from clinical centers performing surveillance examinations on hazardous waste workers have not revealed remarkable abnormalities related to their potential exposures. The possible causes for these results include: (1) the workers have been well protected; (2) the current diagnostic methodologies are not sensitive enough to detect pathophysiologic changes; and (3) disease may not yet be manifest due to latency or cumulative effects of long-term low-dose exposure. In addition, one must keep in mind that previous clinical and research data were collected from test results of workers who were mainly involved in feasibility, as opposed to remediation, activities. With the prospective change of more clean-up involvement of hazardous waste workers, their potential for exposure may increase. Therefore, periodic collaborative evaluation of existing surveillance programs' results (e.g., every 5 years) is advised. This would allow determination of the efficacy of the current diagnostic methods in detecting disease, as well as the possible inclusion of more sensitive and/or specific newer technologies for use on a more routine basis.(ABSTRACT TRUNCATED AT 250 WORDS)