Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial.

OBJECTIVE: To evaluate whether treating patients with very early inflammatory polyarthritis (IP) with a 3-week course of intramuscular (IM) methylprednisolone acetate may postpone the need for disease-modifying antirheumatic drugs (DMARDs) and prevent IP from evolving into rheumatoid arthritis (RA). METHODS: Patients with very early IP (4-10 weeks' duration) were randomised to receive three injections of either 80 mg IM methylprednisolone acetate or placebo, given at weekly intervals. Assessments were monthly until 6 months after the first injection, and then concluded at 12 months. The primary outcome was the need to start DMARDs by the 6-month assessment. Secondary outcomes included disease activity and final clinical diagnosis by the rheumatologist at 12 months. RESULTS: Patients in the placebo group (76%) were more likely to need DMARDs during the first 6 months of the trial than patients in the glucocorticoid group (61%) (adjusted OR = 2.11, 95% CI 1.16 to 3.85, p = 0.015). Disease activity did not differ between the two groups at 12 months, probably because many patients in the placebo group started DMARDs early in the study. After 12 months, the arthritis had resolved without the need for DMARDs in 9.9% (11/111) of the patients in the placebo group and in 19.8% (22/111) in the glucocorticoid-treated group (adjusted OR = 0.42, 95% CI 0.18 to 0.99, p = 0.048). CONCLUSION: Treatment of patients with very early IP with IM methylprednisolone acetate appears to postpone the prescription of DMARDs and prevent one in 10 patients from progressing into RA.

Adverse reactions to disease-modifying anti-rheumatic drugs in clinical practice.

We analysed computerized records of disease-modifying anti-rheumatic drug (DMARD) monotherapy to determine how long rheumatoid arthritis (RA) patients continued on five commonly prescribed DMARDs, and the incidence and time-course of adverse drug reactions (ADRs) they experienced. We studied the records for 3923 courses of DMARDs given to a cohort of 2170 patients monitored for a total of 9378 treatment-years. Methotrexate (MTX) was the DMARD most likely to be continued long-term; <45% of patients had discontinued the drug after 96 months. For the other DMARDs, the time until 50% discontinued due to ADRs or inefficacy was 43.3 months for sulphasalazine (SAS), 33.9 months for D-penicillamine (DPN) and 26 months for myocrisin. Most monitored ADRs requiring drug discontinuation were seen early in therapy, with a median time to onset of <6 months; the important exceptions to this were haematological ADRs to MTX, where the median delay to neutropenia was 16.9 months, and that to thrombocytopenia was 9.4 months. Monitored ADRs (identified by blood or urine tests) were seen least frequently with SAS (one ADR in every 35 patient-years of monitoring) but this apparent advantage was offset by a high incidence of gastrointestinal ADRs and inefficacy. Overall, one toxicity reaction requiring drug discontinuation was identified for every 15.9 patient-years of monitoring.

Development and preliminary assessment of a simple measure of overall status in rheumatoid arthritis (OSRA) for routine clinical use.

We describe the development and initial assessment of a simple measure of overall status in rheumatoid arthritis (OSRA) for use in the routine clinical setting. The measure is constructed in four parts: demographic details, activity score, damage score and treatment category. It requires no laboratory tests and uses details collected routinely during a clinic visit. It was validated in a series of 488 patients. The measure proved acceptable and demonstrated face, content, construct and discriminant validity. OSRA will be useful as an audit tool in the serial follow-up of RA patients and in describing the characteristics of a population of such patients.

How does the short form 36 health questionnaire (SF-36) in rheumatoid arthritis (RA) relate to RA outcome measures and SF-36 population values? A cross-sectional study.

The aim of the study was to show that the SF-36 is a practical tool for use on outpatients with RA, to examine the relationship between the SF-36 and indices of outcome in RA, and to compare the results with population norms and other disease states. Eighty-six consecutive RA patients attending the Haywood Hospital in Stoke-on-Trent and starting or changing second-line therapy were enrolled. Disease outcome was assessed using the American College of Rheumatology core set and all subjects completed the SF-36 health questionnaire. The cohort had moderately active disease (median ESR 46) and appreciable disability (median HAQ 1.875). Impairment of health status was moderate to marked by the SF-36, with significant differences from population norms and chronic disease states such as low back pain. Good correlations were observed between HAQ and physical function (r>0.75, p<10(-6)) and HAQ and social function (r>0.61, p<10(-6)). In contrast, SF-36 scales for physical and emotional role showed no association with activity measures. We concluded that, SF-36 is a practical tool for use in patients with RA. HAQ is associated with its physical and social function scales. Other SF-36 scales, such as physical and emotional role, are not associated with activity core set measures; this suggests different information is involved. RA has a considerable impact on health status compared to other diseases.

Experience of six years of a regional peer review scheme in rheumatology.

OBJECTIVE: Following discussions on peer review by the British Society for Rheumatology, the West Midlands Rheumatology Service and Training Committee established a peer review scheme for the West Midlands in 1998. We report our initial 6 yr of experience, during which all 14 units have been visited. METHODS: A rotating programme of visits was organized. Following this first cycle of peer review, questionnaires were sent to all consultants and senior allied health professionals in each visited unit and to all members of each visiting team to evaluate the process. RESULTS: There was clear consensus amongst staff from both visited units and visiting teams that a peer review visit is worthwhile and constructive. It is a good opportunity for education and exchange of ideas between staff and to promote the multidisciplinary team in rheumatology. Most recommendations from the reports were considered necessary. The most frequent recommendations were for an increase in consultants and therapy staff. Appointing further consultants has been successful. Opinion was only divided on whether the reports were viewed seriously by Trusts, whether peer review should be regional or national, and how to accurately assess the quality, as well as the quantity, of care provided. Staff would support further cycles of peer review visits. CONCLUSIONS: This has been a successful initiative and a positive learning experience for all staff involved. Specifically, it helped to obtain more staff and secure facilities. We recommend developing this scheme and promoting it to other regions.

The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions.

OBJECTIVE: To identify the proportion of patients with inflammatory arthritis who remain on methotrexate in the medium to long term and the incidence of side-effects in clinical practice. METHOD: The study population comprised all patients with inflammatory arthritis treated with methotrexate and monitored in clinics under the auspices of Staffordshire Rheumatology Centre. Two clinical auditors collected data retrospectively from the computer database used to support monitoring of patients on disease-modifying anti-rheumatic drugs. Information was collected on duration of treatments and reasons for stopping treatment. For patients identified as having potentially serious side-effects or who died whilst taking methotrexate, further information on their outcome was collected from patients' medical notes and where applicable post mortem reports and death registers. RESULTS: Between 1986 and 1999, 673 patients were treated with methotrexate, of whom 551 had a diagnosis of rheumatoid arthritis. From the Kaplan-Meier analysis, the probability of patients remaining on treatment 5 yr after starting methotrexate was 0.74. Three hundred and sixteen patients stopped methotrexate between 1986 and 1999. In 117 patients, the methotrexate was restarted. Seventy-two patients (10.7% of all patients) stopped because of inefficacy or patient choice or situation. Thirty-seven patients (5.5%) stopped methotrexate due to abnormal haematology (usually low neutrophils). Thirty-seven patients (5.5%) stopped methotrexate due to abnormalities in liver function tests. Life-threatening side-effects were identified in 12 patients (1.8%). These included six pneumonitis, five cytopenias and one disseminated varicella zoster. Two of these patients (0.3%) died, one from pneumonitis and one from disseminated varicella zoster. A total of 25 patients (3.7%) died while taking methotrexate and four died (0.6%) within 3 months of stopping methotrexate. One death (0.15%) was directly attributable to methotrexate (methotrexate pneumonitis). CONCLUSION: This study has shown that methotrexate is well tolerated in clinical practice in the medium to long term. It has produced accurate data on the incidence of adverse effects of methotrexate in a local population in a non-research setting. It has identified the incidence of life-threatening side-effects to be 1.7% with one death (0.15%) directly due to methotrexate. This information should prove useful when recommending such treatment to patients with inflammatory arthritis.

Assessment of specialist registrars in rheumatology: experience of an objective structured clinical examination (OSCE).

OBJECTIVES: Assessment of higher medical trainees (specialist registrars) in rheumatology is an important challenge facing the rheumatology community, particularly with the advent of the implemention of the changes recommended by the Calman Report in the UK. So far there has been remarkably little work in this area. Our aim was to implement and evaluate an objective structured clinical examination (OSCE) for rheumatology specialist registrars (SpRs). METHODS: Twelve SpRs completed a 12-station OSCE designed to assess core rheumatological clinical skills. The OSCE was designed and manned by consultant members of the West Midlands Rheumatology Services and Training Committee. The OSCE was evaluated by the SpRs, the participating consultant supervisors and the patients, by means of questionnaires. RESULTS: We present the details of the OSCE stations and the scores for each station. In terms of evaluation, 11 out of 12 SpRs felt that it was a very worthwhile exercise. Participating patients found it interesting, if tiring. All would be happy to participate in such an examination again. All participating consultants found it interesting and useful in terms of establishing the level of competence among trainees. CONCLUSION: The OSCE represents one practical approach to assessing clinical skills in rheumatology SpRs. It has potential in both formative and summative assessment. The broader issues around the assessment of rheumatology trainees are discussed.

Identification of T-cell stimulatory antigens of Chlamydia trachomatis using synovial fluid-derived T-cell clones.

Chlamydia trachomatis is a major cause of sexually transmitted disease, infertility and reactive arthritis in the Western world, and of trachoma in the developing world. There is evidence that the chronic inflammatory reaction seen in diseases associated with chlamydiae represents a delayed-type hypersensitivity response to chlamydial antigens. Little is known about which chlamydial antigens elicit T-cell responses yet such information could have important implications in terms of both immunopathological understanding of these diseases and immunoprophylaxis design. In this study, 61 chlamydia-specific T-cell clones have been produced from the synovial fluid of an individual with sexually acquired reactive arthritis (SARA). Ten clones have been characterized in detail and used to identify T-cell stimulatory antigens of chlamydiae by means of T-cell immunoblotting. Two distinct antigenic fractions have been identified, one recognized by three of the clones (molecular weight 18,000), the other recognized by six of the clones (molecular weight 30,000). The fractions are distinct from the major outer membrane protein, the 57,000 MW stress protein and the 60,000 MW cysteine-rich membrane protein of chlamydiae. The major histocompatibility complex (MHC) restriction of the response to these antigens differed: clones recognizing the 18,000 MW antigen required antigen-presenting cells expressing DR1 subtype DRB1*0101 or DRB1*0102 which only differ at amino acids 85 and 86 on the DR beta-chain; by contrast clones recognizing the 30,000 MW antigen were presented to only by antigen-presenting cells from DRB1*0101 individuals, reflecting extreme sensitivity of these clones to the polymorphism at positions 85 and 86 on the DR beta-chain.

A longitudinal study of peripheral blood mononuclear cell proliferative responses to bacterial antigens in reactive arthritis.

Reactive arthritis (ReA) is a sterile inflammatory arthritis which usually occurs after an enteric or genitourinary infection. In recent years it has been recognized that synovial fluid mononuclear cells from an affected joint demonstrate marked proliferative responses if incubated with preparations of the organism triggering the arthritis; peripheral blood mononuclear cell (PBMC) responses are typically much smaller. One interpretation of this finding is that recognition of the triggering organism is enhanced within the joint compared to peripheral blood, but it could also be argued that the PBMC responses are actually depressed during acute arthritis. We have examined this possibility in a longitudinal study of PBMC proliferative responses in patients with ReA. In this study we have demonstrated that PBMC proliferative responses to the triggering organism were indeed depressed during acute ReA, and showed a significant increase after recovery from the arthritis. These findings also applied to PBMC recognition of the recall antigen PPD, and to the response to IL-2.

Control perceptions in patients with rheumatoid arthritis: the role of social support.

OBJECTIVE: To identify factors that patients perceive as influencing control in living with rheumatoid arthritis. METHOD: A sample of 40 patients with rheumatoid arthritis were randomly recruited from an outpatient population and partook in an in depth, qualitative interview by one researcher to identify control perceptions. The data were analysed utilizing Colaizzi's procedural steps. RESULTS: Four major categories were identified that positively influenced control perceptions: The reduction of physical symptoms. Social support matching perceived need. The provision of information. The nature of the clinical consultation. Three components were identified in relation to social support: Remaining involved in family activities. Ongoing support from family members. Achieving a balance between support needs and support provision. CONCLUSION: The categories identified can be influenced by practitioners enabling patients with RA to obtain perceived control over their condition.

Why not use OSRA? A comparison of Overall Status in Rheumatoid Arthritis (RA) with ACR core set and other indices of disease activity in RA.

OBJECTIVE: The Overall Status in Rheumatoid Arthritis (OSRA) is a recently validated measure designed for routine immediate clinical use in patients with rheumatoid arthritis (RA). It is composed of demographic data, activity score (activity total), damage score (damage total), and drug treatment. We tested the hypothesis that this tool relates to existing measures and pooled indices of disease activity, including the SF-36. METHODS: Demographic information, OSRA, SF-36, and the ACR core set [inflammatory indicators (ESR, CRP), tender and swollen joints, visual analog scale for pain, Patient and Physician Global Assessment, and Health Assessment Questionnaire (HAQ)] were collected for 86 consecutive outpatients with RA who were starting or changing second-line therapy and again at 6 months. OSRA measures were examined for their relationship to all core set variables (SF-36, HAQ, Stoke Index, Disease Activity Score, and Mallya-Mace) using Spearman's rank correlation. OSRA was used to audit 246 consecutive outpatients with RA to determine its clinical utility. RESULTS: The median age was 58 years (range 29-82); median disease duration 63 mo (range 3-384); OSRA disease activity (mean 3.8, range 0-8) and damage (mean 2.7, range 0-7) scores were strongly associated with specific ACR core set and SF-36 measures, and all pooled indices examined. OSRA disease activity was significantly higher in outpatients in whom second-line therapy was changed. CONCLUSION: (1) The OSRA was highly correlated with HAQ and core set measures of disease activity: (2) the OSRA damage total was strongly associated with HAQ and correlated strongly with both duration and Larsen score; (3) OSRA scores also correlated well with specific SF-36 measures (activity total with Physical Functioning and Bodily Pain; damage total with Physical and Social Functioning); (4) OSRA shows good correlation with pooled indices that cannot be performed immediately in clinic; and (5) the OSRA activity score shows a strong association with clinical decisions made in the outpatient department.

Interaction between tumor necrosis factor microsatellite polymorphisms and the HLA-DRB1 shared epitope in rheumatoid arthritis: influence on disease outcome.

OBJECTIVE: To investigate whether interactions between tumor necrosis factor (TNF) microsatellite polymorphisms and the HLA-DRB1 shared epitope (SE) are associated with disease severity in rheumatoid arthritis (RA), and to determine if such associations are the same in male and female patients. METHODS: Genotyping for the TNFa microsatellite and HLA-DRB1 was carried out on 157 RA patients with established disease (duration >5 years). Disease severity measures included radiographic damage (the Larsen method), functional assessment by the Health Assessment Questionnaire, history of joint surgery, and global appraisal of outcome by means of a visual analog scale score. The association of severity measures with TNFa microsatellite polymorphisms stratified by SE status, and the interaction between TNFa and the SE, were investigated using stratified analyses and multiple or logistic regression analyses. RESULTS: No significant associations were observed between any single TNFa microsatellite polymorphism and disease severity, although preliminary evidence for an interaction between TNFa6 and TNFa11 was obtained. In the presence of the SE, a significantly worse outcome was associated with individuals carrying TNFa6, and a significant interaction (P = 0.04-0.006) was found between these alleles for all the outcome measures examined except history of joint surgery. In the absence of the SE, the TNFa6 allele was associated with significantly better outcome scores. When examined by sex, significant associations between the TNFa6/SE haplotype and disease outcome measures were found only in females. No statistically significant interactions were found in males, although the TNFa6/SE haplotype was still associated with the worst outcome scores. CONCLUSION: The association of the SE with disease severity in RA is influenced by an interaction with the TNFa6 microsatellite polymorphism. This interaction appears to be acting predominantly in female patients, although the trend is similar in the smaller percentage of males carrying the TNFa6/SE haplotype.

MHC restriction of synovial fluid lymphocyte responses to the triggering organism in reactive arthritis. Absence of a class I-restricted response.

Synovial fluid mononuclear cells (SFMC) from patients with reactive arthritis (ReA) show marked proliferative responses to preparations of the organism triggering the arthritis. Initial studies with MHC-specific MoAbs have indicated that a significant element of these proliferative responses is mediated by class II MHC-restricted CD4+ T cells. It is imperative to establish the presence or absence of a class I-restricted response, for two reasons. Firstly, the association of ReA with the MHC class I molecule, HLA B27, raises the possibility of there being a B27-restricted response to the triggering organism. Secondly, a number of the organisms associated with ReA are intracellular pathogens, whose antigens might be expected to be presented by class I MHC molecules. In an effort to identify a class I MHC-restricted pathogen-specific response in the SFMC of ReA patients, we have assessed the proliferative responses of SFMC depleted of CD4+ T cells. Responses were grossly diminished by CD4+ T cell depletion. We also investigated Chlamydia-specific cytotoxicity in the SFMC of patients with sexually acquired ReA in a system using productive chlamydial infection to produce both targets and effectors. Significant antigen specific cytotoxicity was not seen. These experiments do not provide evidence to support the existence of pathogen-specific responses by CD8+, class I-restricted synovial fluid T cells in ReA.

The mechanical joint score: a new clinical index of joint damage in rheumatoid arthritis.

OBJECTIVES: To evaluate the mechanical joint score (MJS) in terms of its reliability between observers and over time, its ease of use and its relationship with conventional measures of rheumatoid arthritis (RA) disease activity, severity and functional outcome. METHODS: The MJS was evaluated in 103 patients with reference to the following joints: total proximal interphalangeal (PIP) joints, total metacarpophalangeal (MCP) joints, wrists, elbows, shoulders, hips, knees, ankles and total metatarsophalangeal (MTP) joints. The score was based on the appearance of the joints on a scale of 0-3, 0 representing no abnormality and 3 severe abnormality or previous surgery. The MJS was evaluated in terms of its intra- and inter-observer variability and its content, construct and criterion validities. A subset of 29 patients were re-evaluated after 5 yr to examine change in MJS over time. RESULTS: The MJS performed well in terms of inter-observer and intra-observer reliability. The MJS showed strong correlation with the Larsen X-ray score of hands and feet (Spearman correlation coefficient 0.74) and with the modified Health Assessment Questionnaire (Spearman correlation coefficient 0.56) and only weak correlation with indices of disease activity, such as the Ritchie index and erythrocyte sedimentation rate. The MJS showed highly significant positive change over time. CONCLUSION: The MJS is a reliable clinical index of joint damage and may be a useful new outcome measure in RA.

The relationship between serial measures of disease activity and outcome in rheumatoid arthritis.

Disease activity was measured annually over a median period of 7 years (range 5-9) in a cohort of 127 patients with rheumatoid arthritis. The measurements were plotted, and the area under the resultant curve measured. The relationship of serial measures of disease activity (area under the curve) to outcome (measured radiologically, functionally and by global assessment) was investigated. A significant correlation was found between persistent disease activity and radiographic deterioration. Similar results were found for functional outcome, as measured by Steinbrocker grade, health assessment questionnaire score or global assessment (by analogue score). Single measures of disease activity did not predict outcome. Although imprecise, current methods of measuring disease activity in RA, if measured serially, are valuable in predicting outcome over a 5-10 year period.

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.

Mortality in rheumatoid arthritis: relationship to single and composite measures of disease activity.

BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous disease characterized by a variable course of remissions and relapses. Single measures of disease activity at only one point in time may not reflect the overall control of disease activity. OBJECTIVE: The aim was to determine (i) the predictive value of 20 baseline demographic and disease variables on mortality, and (ii) the relationship between serial measures of the Stoke index (SI; a validated index of disease activity in RA) and mortality in RA. METHODS: Mortality in 309 RA patients followed up for a median of 14 yr was analysed retrospectively. The standardized mortality ratio (SMR) was calculated for all causes of death. The predictive values of baseline and time-integrated variables were assessed using multivariate Cox proportional hazards regression analysis. RESULTS: The SMR was 1.65. At baseline, only nodules, erosions, RA latex titre, white cell count and globulin level were predictive of mortality after correction for age, sex and disease duration. Using a stepwise Cox proportional hazards regression model, the most powerful predictors of mortality were age, nodules and RA latex titre. Individual measures of disease activity and the SI at baseline were not predictive of mortality. However, the mean level of the SI over 12 months was related to mortality (P=0.039). CONCLUSIONS: At baseline, the demographic and disease variables most significantly related to mortality in RA are age, nodules and RA latex titre. Individual measures of disease activity at a single point in time are poor predictors of mortality in RA. However, measurement of the mean level of disease activity over time using the composite SI has a significant relationship with mortality. A high level of sustained inflammation appears to be an important predictor of premature death.

Management of oral complications of disease-modifying drugs in rheumatoid arthritis.

Stomatitis is a troublesome adverse effect of disease-modifying anti-rheumatic drug (DMARD) therapy in rheumatoid arthritis (RA) patients. This review presents data to examine the incidence, clinical features and consequences of DMARD-related stomatitis, and suggests an algorithm for its clinical management. The specific objectives of the two studies presented here were to determine the incidence of DMARD-related stomatitis and its effect on DMARD continuation, and secondly to identify the clinical and laboratory risk factors. We investigated two cohorts of patients: (i) a retrospective survey of data collected from drug monitoring clinics run for patients on DMARDs from 1987 to 1994 involving 1539 patients and 2394 drug exposures; (ii) a prospective study of 25 consecutive RA patients presenting with DMARD-related stomatitis compared to 29 RA controls with no history of DMARD stomatitis. The retrospective survey showed that 2% of DMARD patients stopped therapy because of stomatitis, but 55% of these were able to resume the same therapy. In the case control study. 24% of patients discontinued temporarily and 8% permanently. Cases of DMARD-related stomatitis differed from controls in that they had a higher incidence of previous mouth ulcers (40% vs 14%), they smoked less (8% vs 31%) and Schirmer's test was more often abnormal (44% vs 21%). There were no differences in RA severity, disease activity or oral hygiene. Haematinic deficiencies were equally common in cases and controls: 30% for iron, 8% for vitamin B12 and 24% for folic acid. Herpes simplex virus was involved in a minority (8%) of cases. In conclusion, the occurrence of stomatitis in RA patients on DMARD should not lead to cessation of drug therapy, but to a careful evaluation so that patients may be maintained on effective treatment.

Influence of polymorphism in the manganese superoxide dismutase locus on disease outcome in rheumatoid arthritis: evidence for interaction with glutathione S-transferase genes.

OBJECTIVE: To determine whether polymorphism in the manganese superoxide dismutase (MnSOD) gene is associated with susceptibility or disease outcome in rheumatoid arthritis (RA). METHODS: We used a case-control approach with 153 RA patients and 218 control subjects to examine for any associations between MnSOD genotypes and susceptibility to RA. We also investigated the influence of genotypes on radiologic outcome, as measured using the Larsen score for radiographs of the hands and feet, and on functional outcome, as assessed by the Health Assessment Questionnaire. MnSOD typing was carried out using polymerase chain reaction-based methods. Results were analyzed using multiple regression analysis, with adjustment for age, sex, and disease duration. In separate analyses, we corrected for rheumatoid factor (RF) status and/or the presence of the HLA-DRB1 "shared epitope" (SE). We also examined whether radiologic outcome was influenced by interactions between MnSOD and glutathione S-transferase (GST) genes. RESULTS: No association between MnSOD genotype and development of RA was found. The MnSOD VV genotype was associated with a significantly higher (P = 0.04) Larsen score (104.4) than MnSOD AA (83.0), while MnSOD AV was associated with an intermediate score (91.8). Correction for RF status had no significant effect on the results of the analysis, but significance was lost (P = 0.09) after correction for the presence of the SE. There was evidence of interaction between the GSTT1 and MnSOD genotypes, with the MnSOD VV/GSTT1-null combination being associated with the highest Larsen score (142.1; P = 0.007 after correction for the SE). CONCLUSION: Polymorphism in the MnSOD gene is not associated with susceptibility to RA. Our data suggest that MnSOD VV is associated with more severe radiologic outcome, although this relationship may not be independent of the effect of the SE. However, interaction between MnSOD and GST genes appears to influence radiologic outcome independently of the SE.