Outcome of active disease in ankylosing spondylitis: a prospective study.

BACKGROUND: People with ankylosing spondylitis (AS) typically experience episodic exacerbations, but the extent to which they subsequently experience a sustained reduction in disease markers below recognized thresholds for active disease is unclear. OBJECTIVE: To investigate changes in, and associations between, disease markers over 18 months in people with active AS. METHODS: Within a cohort of 89 participants with AS, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores of 4 or higher were used to identify those with active disease. Standard assessment tools were used to monitor participants prospectively at four consecutive six-monthly intervals. Participants received standard treatments but none received anti-tumor necrosis factor-alpha (TNFalpha) medication during the study. RESULTS: The median age of the cohort was 50 years (inter-quartile range [IQR] 38.5-55.5), the median age of disease onset was 25 years (IQR 18-33) and the median disease duration was 18 years (IQR 13-27). Forty-seven (53%) participants had a BASDAI score of 4 or higher on the first assessment, of whom 45 (51%) scored 4 or higher on all subsequent assessments. Furthermore, 38 (43%) and 16 (18%) participants scored BASDAI 5 or 6, respectively, or higher, throughout. BASDAI scores correlated strongly with Bath Ankylosing Spondylitis Functional Index (BASFI) scores. Compared with 19 (21%) participants whose BASDAI scores were consistently below 4 throughout, participants with persistently high BASDAI scores showed higher scores for anxiety and depression, and some evidence of functional deterioration during the study period. CONCLUSIONS: In this cohort, disease markers in most people with active AS were sustained above the standard threshold for active disease. This has important implications for planning care pathways and for optimal utilization of anti-TNFalpha treatment.

Disease and psychological status in ankylosing spondylitis.

OBJECTIVES: Psychological factors may be important in the assessment and management of ankylosing spondylitis (AS). Our primary objective was to describe associations between disease and psychological status in AS, using AS-specific assessment tools and questionnaires. Our secondary objectives were to identify patient subgroups based on such associations and to determine the stability of the measures over time. METHODS: A total of 110 patients were assessed at 6-monthly intervals up to four times using tools to measure disease [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI)], psychological [Hospital Anxiety and Depression Questionnaire (HADS), Health Locus of Control-Form C Questionnaire (HLC-C)] and generic health [Short form (SF)-36] status. RESULTS: Eighty-nine participants completed all four assessments. Throughout the study, BASDAI, BASFI and BASMI scores correlated significantly with anxiety, depression, internality and health status, but not with levels of belief in chance or powerful others. Clinically anxious or depressed subgroups had significantly worse BASDAI and BASFI, but not BASMI, scores. BASMI scores were the least closely linked to psychological status. Mean scores for disease, psychological and health status were clinically stable over the 18 months period. CONCLUSIONS: Disease status scores in AS correlated significantly with anxiety, depression, internality and health status. Interpretation of AS disease scores should take an account of psychological status and the choice of measures used. These findings have important potential applications in AS management and monitoring, including the identification of patients for biological therapies.

Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery.

OBJECTIVES: To determine whether continued methotrexate treatment increases the risk of postoperative infections or of surgical complications in patients with rheumatoid arthritis (RA) within one year of elective orthopaedic surgery. DESIGN: A prospective randomised study of postoperative infection or surgical complications occurring within one year of surgery in patients with RA who underwent elective orthopaedic surgery. SUBJECTS: 388 patients with RA who were to undergo elective orthopaedic surgery. Patients who were receiving methotrexate were randomly allocated to groups who either continued methotrexate (group A) or who discontinued methotrexate from two weeks before surgery until two weeks after surgery (group B). Their complication rates were compared with complications occurring in 228 patients with RA (group C) who were not receiving methotrexate and who also underwent elective orthopaedic surgery. MAIN OUTCOME MEASURES: Signs of postoperative infection were recorded, including rubor, discharge, systemic infection, and frequency of wound dehiscence as well as the incidence of any surgical complication requiring a secondary revision procedure that occurred within one year of surgery. The frequencies of flare up activity of RA at six weeks and six months after surgery were also recorded. A flare of rheumatoid disease was defined as an increase in joint pain in two or more joints notified by the patient as well as by an increase in articular index of at least 25% after surgery. RESULTS: Signs of infection or surgical complications occurred in two of 88 procedures in group A (2%), 11 of 72 procedures in group B (15%), and 24 of 228 (10.5%) procedures in group C. The surgical complication or infection frequency in group A was less than that in either group B (p<0.003) or group C (p=0.026). At six weeks after surgery there were no flares in group A, six flares in group B (8%), and six flares in group C (2.6%). Logistic regression analysis of the overall surgical complication rate in all the patients with RA studied showed that methotrexate, whether continued or discontinued before surgery, did not increase the early complication rate in the patients with RA who underwent elective orthopaedic surgery. Other drugs-penicillamine, indometacin, cyclosporin, hydroxychloroquine, chloroquine, and prednisolone-all did significantly increase the risk of infection or surgical complication after elective orthopaedic surgery. The risk of surgery was also increased in the presence of intercurrent chronic diseases-diabetes, hypertension, bronchiectasis, psoriasis, asthma, and ischaemic heart disease. CONCLUSION: Continuation of methotrexate treatment does not increase the risk of either infections or of surgical complications occurring in patients with RA within one year of elective orthopaedic surgery. Thus methotrexate treatment should not be stopped in patients whose disease is controlled by the drug before elective orthopaedic surgery.

Family and twin studies in systemic lupus erythematosus.

We have estimated how much of the total genetic predisposition to SLE may be attributable to genes outside the HLA region by comparing figures for concordance of SLE in monozygotic twins with those for concordance in HLA identical siblings in Australia. None of six dizygotic co-twins of white Australian SLE probands was concordant for SLE. One of four (25%) monozygotic co-twins of white Australian SLE probands was concordant for SLE which when added to previously published figures for Caucasoid populations gives an overall concordance rate for SLE in monozygotic twins of 25%. None of 18 HLA identical, same sex siblings of SLE probands, had definite SLE by the study criteria (i.e. less than 6%). The comparison of these figures shows that most of the genetic predisposition to SLE is attributable to genes outside the HLA region.

Lack of linkage between anti-nuclear antibody or clinical features of systemic lupus erythematosus (SLE) and TCR-A/Vbeta loci in families of subjects with SLE.

The role of the TCR-A and TCR-Vbeta genes in the genetic predisposition to SLE expression and anti-nuclear antibody (ANA) production were examined by linkage analysis in eighteen multiplex and forty-three simplex SLE families. All subjects were Caucasian. A significantly increased prevalence of positive ANAs in first-degree relatives of SLE patients from multiplex families was noticed compared to that of simplex families. Linkage between TCR-A/Vbeta genes and SLE expression and ANA production were analysed by affected sib-pair method. Results showed that the haplotypes identical by descent sharing TCR-A and TCR-Vbeta genes in the affected sib-pairs was not different from that expected (P = 0.93 and P = 0.74, respectively). There was no linkage between ANA positivity and TCR-A and TCR-Vbeta genes in ANA positive sib-pairs from both multiplex and simplex families. This study suggests that germline TCR-A and TCR-Vbeta gene loci confer no susceptibility to ANA and SLE expression.

X-chromosome inactivation in monozygotic twins with systemic lupus erythematosus.

The hypothesis that a low concordance rate in monozygotic (MZ) twins with systemic lupus erythematosus (SLE) may be accounted for by differences in X-chromosome inactivation was examined. Five MZ twin pairs, four discordant and one concordant, were recruited, zygosity confirmed by DNA fingerprinting, and their pattern of X-chromosome inactivation in DNA samples prepared from peripheral blood and buccal cells were examined. X-chromosome inactivation was assessed by the methylation status of the CpG region near trinucleotide repeats in exon 1 of the androgen receptor gene on X-chromosome after digestion with the methylation-sensitive enzyme HpaII or HhaI and PCR amplification. X-chromosome inactivation patterns were found to be the same between affected and non-affected twins in all four discordant twin pairs, with random patterns in two pairs and skewed patterns in the others. The concordant twins demonstrated the same random patterns. X-chromosome inactivation was also examined from buccal smear DNA and shown to have the same pattern as that noted from peripheral blood DNA in one informative twin pair. Differences in X-chromosome inactivation patterns were not observed in these five MZ twin pairs. The results could not support the hypothesis that differences in X-chromosome inactivation is the mechanism accounting for the low concordance rate noted in MZ twins with SLE.

Lack of interaction between flucloxacillin and methotrexate in patients with rheumatoid arthritis.

1. The aim of the study was to examine the potential pharmacokinetic interaction between methotrexate and flucloxacillin. 2. Ten rheumatoid arthritis patients participated in the interaction study. Subjects were allocated to either methotrexate alone (5-15 mg per week) or methotrexate plus flucloxacillin (500 mg four times a day 48 h prior to sampling) in a random order. 3. There was a statistically, but not clinically, significant decrease in methotrexate AUC (1307 +/- 389 vs 1212 +/- 394 micrograms l-1 h) in the presence of flucloxacillin. Cmax and tmax parameters for methotrexate were not significantly altered in the presence of flucloxacillin. 4. Data from an additional 10 rheumatoid arthritis patients, starting on methotrexate, were added to the data from the placebo arm of the interaction study and a model dependent pharmacokinetic analysis was performed. The plasma concentration profiles were best described by a two-compartment model with a mean clearance of 11.9 (+/- 1.7) l h-1 and an initial volume of distribution of 31.2 (+/- 2.6) l. The pronounced intersubject variability in the pharmacokinetic parameters was not related to any of the available covariate information. 5. Our findings suggest that no important clinical interaction occurs between flucloxacillin and methotrexate in patients with rheumatoid arthritis.

TAP2D is associated with HLA-B44 and DR4 and may contribute to rheumatoid arthritis and Felty's syndrome susceptibility.

OBJECTIVES: TAP2 transporter gene polymorphisms have been ascertained in patients with rheumatoid arthritis (RA) and Felty's syndrome (FS) to determine whether particular alleles of this gene are disease associated. METHODS: TAP2 dimorphisms at amino acid positions 379, 565 and 665 were detected using ARMS-PCR in 89 RA patients, 24 FS patients and 64 control subjects. TAP 2 alleles were assigned from these results. RESULTS: The frequency of one particular allele, TAP2D, was increased in both RA (OR 2.6, 95% CI 1.2 - 5.8) and FS (OR 3.9, 95% CI 1.4 - 10.7). When individual amino acid polymorphisms were compared between patients and controls, isoleucine at position 379 (present in TAP2D and TAP2C) was significantly increased, indicating that this dimorphism itself may be associated with RA (OR 5.0, 95% CI 2.4 - 10.2) and FS (OR 5.0, 95% CI 1.91 - 3.2). DISCUSSION: The presence of TAP2D was greatly increased in HLA-B44/DR4 positive RA (83%) and FS (67%) patients. These frequencies were appreciably higher than in the HLA-B44/DR4 controls (11%), suggesting that linkage disequilibrium alone may not explain the increase in TAP2D frequency in patients and that this allele may represent an additional risk factor in these conditions.