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A J MacGregor

Publications and source records attributed to A J MacGregor.

At least 19 recordsLinked to original sources

Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins.

OBJECTIVE: To test the hypothesis that cigarette smoking is associated with susceptibility to rheumatoid arthritis (RA) by comparing smoking history between twins with RA and their unaffected co-twins. METHODS: Interview questionnaires on smoking history were administered to 79 identical (monozygotic [MZ]) and 71 same-sex nonidentical (dizygotic, [DZ]) twin pairs who were discordant for RA, recruited from the Arthritis and Rheumatism Council Twin Study. Results were expressed as odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: Although most twin pairs were concordant for smoking history, there was a strong association between ever smoking and RA in the MZ pairs (OR 12.0, 95% CI 1.78-513), with a similar trend observed in the DZ pairs (OR 2.5, 95% CI 0.92-7.87). CONCLUSION: The discordance in cigarette smoking history for individuals who are at presumed identical genetic risk for RA supports other data suggesting the role of smoking in disease susceptibility.

Arthritis, Rheumatoid

Unexpected HLA haplotype sharing in dizygotic twin pairs discordant for rheumatoid arthritis.

Dizygotic twins are generally believed to be no more genetically similar than sibs born from separate pregnancies. In the present study, a panel of 93 dizygotic twin pairs discordant for rheumatoid arthritis were typed for HLA-A, -B, -Cw, and -DR antigens. HLA haplotype sharing identical by descent between the twins showed a trend towards increased sharing of both HLA haplotypes; this increased sharing was statistically significant when the female/female twin pairs were considered separately. In contrast, the pattern of HLA haplotype sharing in sib pairs (n = 128) was consistent with a 1:2:1 ratio of 2, 1, or 0 haplotypes shared. An analysis of 16 normal dizygotic twin pairs was consistent with these results raising the possibility that dizygotic twins in general are genetically more similar at the HLA complex than sibs born from separate pregnancies.

Arthritis, Rheumatoid

Classification criteria for rheumatoid arthritis.

The development of classification schemes for RA in the last 40 years has followed the increasingly precise understanding of the nature of the clinical disease and the recognition of the different requirements of classification methods in clinic and population settings. In published studies of RA in clinic patients the most widely used criteria sets have been the 1958 ARA (ACR) criteria and its 1961 adaptation (the Rome (active) criteria). These sets classified disease as 'classical', 'definite', 'probable' and 'possible' RA based on criteria comprising clinical, serological, radiological and histological features (the latter were dropped from the Rome criteria set because of their impracticality). More recently, a new criteria set (the 1987 ARA criteria) has been developed using statistical techniques. This set was derived using RA cases and controls attending hospital clinics. It is based on the earlier criteria sets but accommodates the characteristic pattern of joint involvement in RA more precisely. The criteria recognize only the single disease category of 'rheumatoid arthritis'. In validation studies, the 1987 criteria set has been found to have enhanced specificity over earlier schemes in clinic-based studies of RA. The sensitivity may, however, be reduced, in particular in studies of early disease. The application of classification criteria for case recognition in the population and family studies of RA has proved more problematic. In these settings, there is the additional requirement to recognize individuals with remitted and inactive disease as RA cases. The 1966 New York criteria were developed for this specific purpose, however their format proved cumbersome and they have not been widely adopted. The 1987 criteria set is insufficiently sensitive to recognize inactive disease if the criteria are applied exactly as they have been defined. The sensitivity of the 1987 criteria set is, however, substantially enhanced if the criteria are adapted to incorporate features of past disease activity, for example by allowing deformity to substitute for swelling and by incorporating data on the past occurrence of rheumatoid factor and rheumatoid nodules. Developments in the immunology and genetics of RA may in the future provide more accurate tools for classification and may lead to recognition of more precise disease subsets. At present, however, the 1987 ARA criteria provide the most appropriate basis for case recognition in both clinic and population-based studies.

Arthritis, Rheumatoid

Heterogeneity of disease phenotype in monozygotic twins concordant for rheumatoid arthritis.

The objective of the study was to investigate the genetic contribution to the clinical expression of rheumatoid arthritis (RA) by comparison of disease features in RA-concordant monozygotic (MZ) twin pairs. Fourteen RA-concordant MZ twin pairs recruited from a nation-wide study were examined to determine the degree of similarity in: (a) age of disease onset; (b) pattern of joint involvement; (c) pattern of extra-articular disease; (d) toxic reactions to drugs; (e) disease course; and (f) serology for rheumatoid factor (RF) and antinuclear antibody. There was considerable within-pair diversity in the variables studied. Some similarity within twin pairs was observed for the ages at disease onset (R = 0.63), presence of erosive changes (kappa = 0.61) and the presence of IgM RF (R = 0.87). No important similarity was seen, however, in the pattern of joint involvement, the occurrence of extra-articular disease, adverse drugs reactions, clinical disease course and reported disability level. There is heterogeneity in the genetic contribution to the clinical expression of RA. The overall lack of similarity for the majority of clinical variables indicates the importance of non-genetic factors on the expression of disease.

Age Factors

Rheumatoid factor isotypes in monozygotic and dizygotic twins discordant for rheumatoid arthritis.

OBJECTIVE: To examine the influence of genetic factors in determining the occurrence of rheumatoid factor (RF) isotypes. We investigated the hypothesis that, in twin pairs discordant for rheumatoid arthritis (RA), a genetic influence would be indicated by a higher rate of occurrence of RF among the unaffected monozygotic (MZ) when compared with the unaffected dizygotic (DZ) co-twins of seropositive affected twins. METHODS: IgM, IgA, and IgG RF were measured by ELISA in 70 MZ and 84 DZ disease discordant pairs using a cutoff for seropositivity defined using a normal control population. The risk of seropositivity in the unaffected twins of MZ when compared with DZ seropositive index twins was examined using odds ratios (OR). RESULTS: For all 3 RF isotypes, levels in the unaffected twins of seropositive index twins were higher than in the control population. MZ unaffected twins showed an increased risk for seropositivity for IgM and IgG RF when compared with DZ unaffected twins: IgM OR = 2.2 (95% CI 0.9-5.4), IgG OR = 2.4 (95% CI 0.9-6.6). The greatest excess risk for seropositivity occurred for IgM RF amongst the unaffected twin of an index twin with past or current documented evidence of RF seropositivity, OR = 3.4 (95% CI 1.4-8.5). For IgA RF, seropositivity risk in MZ unaffected twins was not increased, OR = 1.0 (0.3-3.1). The seropositivity risk for all 3 isotypes was independent of the age of the pair, the age of disease onset in the index twin, and the sex, HLA-DRB1*01 and DRB1*04 status of the unaffected twin. CONCLUSION: Genetic factors are important in determining the level of IgM and IgG RF. A genetic contribution to RA seropositivity exists that is independent of HLA-DR.

Adult

"Homozygosity" for the HLA-DR shared epitope contributes the highest risk for rheumatoid arthritis concordance in identical twins.

OBJECTIVE: To assess the contribution of HLA-DRB1 alleles in determining rheumatoid arthritis (RA) concordance in monozygotic twins. METHODS: Ninety-one monozygotic twins pairs in which at least 1 twin was affected were typed for HLA-DRB1 using both serologic methods and polymerase chain reaction amplification with sequence-specific oligonucleotide hybridization. The role of DR4 and of the shared epitope in disease concordance was investigated. Relative risks (RR) with 95% confidence intervals were determined. RESULTS: Increased concordance for RA was observed in both DR4 positive and shared epitope positive pairs (RR 3.4 and 3.7, respectively). A 5-fold risk for RA concordance was seen in twins who were "homozygous" for the shared epitope, compared with those negative for the shared epitope. CONCLUSION: In the absence of the shared epitope, RA concordance in monozygotic twins is rare. In contrast, "homozygosity" for the shared epitope is the most important factor in determining RA concordance.

Arthritis, Rheumatoid

Influence of previous exposure to human parvovirus B19 infection in explaining susceptibility to rheumatoid arthritis: an analysis of disease discordant twin pairs.

OBJECTIVES: To assess the association between exposure to parvovirus B19 and susceptibility to rheumatoid arthritis (RA). METHODS: One hundred and fifty five twin pairs (76 monozygotic (MZ) and 79 dizygotic (DZ)), discordant for RA, were tested for the presence of IgG antiparvovirus antibodies using ELISA. The data obtained were analysed using conditional logistic regression, from which odds ratios and 95% confidence intervals were calculated. RESULTS: Overall, there was no association between exposure to parvovirus and RA (OR = 1.2, 95% CI: 0.7-1.7). However, in two subgroups there was a suggestion of an association. These were: (1) pairs where the affected twin was rheumatoid factor (RF) seronegative (OR = 2.0, 95% CI: 0.9-12.4) and (2) in opposite-sexed twin pairs where the affected twin was female (OR = 3.0, 95% CI: 0.9-11.6). CONCLUSION: Previous exposure to parvovirus infection did not explain disease susceptibility in both MZ and DZ discordant pairs with rheumatoid arthritis. This infection, however, might be relevant in some subgroups.

Antibodies, Viral

Low prevalence of rheumatoid arthritis in black-Caribbeans compared with whites in inner city Manchester.

OBJECTIVE: To compare the prevalence of rheumatoid arthritis (RA) in Black-Caribbeans and Whites living in the same urban area. METHODS: Cases of inflammatory joint disease were ascertained initially from a postal screening survey of 1851 Black and 1829 age and sex-matched non-Blacks identified from general practice age-sex registers of seven general practices in the Moss Side and Hulme districts of Manchester. The ethnicity of respondents was confirmed using data from a postal screening questionnaire. Those reporting joint swelling or a history of arthritis were reviewed by a rheumatologist at surgeries held in each practice. The clinical records of the questionnaire non-responders and questionnaire-positive non-attenders at surgery were reviewed. RESULTS: In an adjusted denominator population of 1046 Black-Caribbeans and 997 Whites, the cumulative prevalence of RA was 2.9/1000 in Black-Caribbeans and 8/1000 in Whites, representing a prevalence in Black-Caribbeans of 0.36 times that found in Whites (95% confidence interval 0.1-1.3). CONCLUSIONS: Rheumatoid arthritis occurs less commonly in Black-Caribbeans than in Whites. The findings are consistent with published studies showing a low RA prevalence in rural African Black populations.

Adult

A comparison of the performance of different methods of disease classification for rheumatoid arthritis. Results of an analysis from a nationwide twin study.

OBJECTIVE: We have assessed the importance of the distinction between classification criteria for rheumatoid arthritis (RA) that recognize the presence of currently active disease from those that, in addition, incorporate evidence of past disease activity in ascertaining disease occurrence. We applied 7 classification schemes to a population of twins with inflammatory arthritis to determine (a) the number of individuals classified as RA positive by each scheme and hence the effect on the estimate of disease concordance in the twins and (b) their performance in correctly assigning a diagnosis compared with a physician's opinion. METHODS: The schemes assessed were the 1958 ARA (Rome) criteria which detect active disease, the 1966 New York (using both the 2/4 and 3/4 published cutoffs) which detect "ever" disease and 4 variants of the 1987 ARA criteria. These were the 4/7 and decision tree approaches applied on the basis of the relevant features (1) being present at the time of the study and (2) being present ever and allowing current joint deformity to substitute for absent joint swelling. RESULTS: In all, 283 individuals with a history of joint swelling were assessed, 255 of whom were considered to have RA by their physician. Criteria used to recognize "current" RA identified only about 70% of those which recognized RA ever. These differences in ascertainment level produced a marked effect on the monozygotic twin RA concordance estimates with percentages ranging from 10 to 18%. The results from receiver operating curves confirmed that criteria used to assess only current RA were too insensitive to be of value. Of the criteria that recognized RA status ever the 1987 ARA performed best overall. CONCLUSION: The use of classification methods that incorporate past as well as current evidence of disease activity is essential to avoid important misclassification in epidemiological and family studies. The 1987 criteria, applied retrospectively and allowing joint deformity to substitute for swelling, are of enhanced value over other existing schemes.

Adult

Twin concordance rates for rheumatoid arthritis: results from a nationwide study.

We report the concordance rate for RA in a nationwide study of 91 monozygotic (MZ) and 112 dizygotic (DZ) pairs. Twin pairs were recruited from both a national media campaign and a 2-month prospective inquiry of all UK rheumatologists. Disease status was established following a structured clinical and serological appraisal, together with radiological assessment where necessary. Zygosity was confirmed using DNA fingerprinting. In all, 14 (15.4%) of the MZ and four (3.6%) of the DZ pairs were disease concordant (risk ratio: 4.3 95% CI 1.5 to 12.6). There was no difference in the concordance between the media and clinical derived twins. Further the excess MZ concordance persisted after adjusting for age, age at disease onset, sex and rheumatoid factor status. Analysing the data in relation to the timing of disease onset in the first affected twin showed that subsequent disease risk in the initially unaffected co-twins of the MZ affected probands increased with increasing duration of follow-up. We conclude that the overall MZ concordance at 15% is lower than the 30% figure normally quoted from a study some 30 years ago and sets a ceiling at the potential genetic contribution to disease susceptibility.

Adult

Lack of association of increased antibody levels to mycobacterial hsp65 with rheumatoid arthritis: results from a study of disease discordant twin pairs.

OBJECTIVES: To investigate the role of humoral immunity to mycobacterial hsp65 in the aetiology of rheumatoid arthritis. METHODS: Levels of IgG antibodies to recombinant mycobacterial hsp65 were measured by enzyme linked immunosorbent assay (ELISA) in serum samples of 152 twin pairs discordant for RA and in serum samples from 62 normal blood donors. RESULTS: No significant differences between antibody levels in the subjects with RA compared either with their unaffected twins or with a group of normal blood donors was observed. In the monozygotic twins there was a strong but negative association between levels of antibody to hsp65 and disease status. Zygosity, sex, and HLA status did not significantly affect levels of antibody to hsp65. CONCLUSION: Previous reports of an association between hsp65 and RA were not confirmed.

Antibodies, Bacterial

Fasting lipids and anticardiolipin antibodies as risk factors for vascular disease in systemic lupus erythematosus.

Fasting cholesterol, triglyceride, low density lipoprotein cholesterol, high density lipoprotein cholesterol, apoprotein AI, and apoprotein B were measured in 64 patients with systemic lupus erythematosus to assess the risk factors for vascular disease. The relation between the lipid profile, steroid treatment, the presence of anticardiolipin antibodies, and the prevalence of vascular disease was examined. Raised concentrations of triglyceride and apoprotein B were seen in those patients treated with more than the equivalent of 10 mg prednisolone a day in the six months before testing. An increase in vascular disease was found only in the subgroup of patients with increased triglycerides who also expressed anticardiolipin antibodies. This study confirms the association between treatment with high doses of steroids in lupus and the development of an atherogenic plasma lipid profile. The presence of anticardiolipin antibodies compounds the risk of developing vascular disease.

Adult

Analysis of antibody reactivity in the sera of 42 patients with paraproteinaemia.

The clinical expression of disease in patients with conditions in which autoimmunity is thought to contribute to the pathogenesis of disease is the result of an unfortunate combination of predisposing and environmental factors. The presence of autoantibodies showing a variety of antigen specificities in sera from many of these patients has been closely correlated with particular spectra of organ involvement or tissue destruction. Their precise role in the disease process is as yet unclear. Sera from patients with paraproteinaemia also often contain autoantibodies to a variety of cell components, although symptoms of autoimmune disease are rarely found in this group of individuals. In this study of 42 sera from patients with paraproteinaemia we have confirmed the presence of autoantibodies in 33% (13/42) of samples. Amongst the autoantibodies detected were those to human neutrophils (3), U1RNP (8) and cardiolipin (4). In five sera, the immunoglobulin class of autoantibody did not correlate with that of the monoclonal band. This study extends previous reports of the repertoire of autoantibodies present in sera from patients with paraproteinaemia.

Antibodies, Anticardiolipin

Updating practices among Yorkshire general dental practitioners.

Ninety-eight per cent was the response achieved by a June 1989 postal survey to determine how general dental practitioners (GDPs) in Yorkshire Region maintain their professional knowledge. Such a good response adds confidence to the survey's findings which show many GDPs are educationally active and use a variety of media to keep up to date. Nevertheless, there remains a substantial proportion who should be doing more and need encouragement.

Education, Dental, Continuing