1Rheumatology and Rehabilitation Research Unit, University of Leeds and 2St Lukes Hospital, Bradford, UK.
Correspondence to:
P. Helliwell, Rheumatology and Rehabilitation Research Unit, University of Leeds, 36 Clarendon Road, Leeds LS2 9NZ, UK. E-mail: p.helliwell{at}leeds.ac.uk
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Abstract |
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Methods. Retrospective data were obtained from the inception of a clinical database in August 1993 to July 2001 using DMARD as the main search item; a total of 5479 DMARD prescriptions were represented in the data. A subset of the data so obtained was cross-checked against the patient records. Inaccuracies in start and stop dates prior to January 1997, together with other reasons (such as incomplete data), resulted in a final data set of 2356 drugs. The drugs had been given to 1391 patients. Overwhelmingly, the two main ethnic groups were North European (1191 patients) and South Asian (193 patients).
Results. The final data set was based on the following drugs: azathioprine (179); antimalarials (chloroquine and hydroxychloroquine) (407); corticosteroids (648); D-penicillamine (61); methotrexate (459); sulphasalazine (493); and sodium aurothiomalate (96). Survival analysis showed that age and drug type were important variables influencing the duration of time spent on a drug before discontinuation. For age, drug survival was better for the older age group [log rank test, 2(3) = 29.1, P < 0.0001]. For drug, survival was best for steroids, followed in decreasing order by sulphasalazine, methotrexate, sodium aurothiomalate, azathioprine, antimalarials and D-penicillamine [
2(6) = 99.3, P < 0.00001). For all drugs, the main ethnic groups differed, with a 12-month survival rate of drugs in the North European group of 0.742 (95% confidence interval 0.6930.791) and the South Asian group of 0.665 (95% confidence interval 0.6450.684) [log rank test,
2(1) = 18.19, P < 0.00001]. As the two main ethnic groups differed with respect to age and drug type, further survival analysis adjusting for these variables confirmed a significant difference between the two ethnic groups. The main reasons for terminating the DMARD differed between the groups: people of South Asian origin were more likely to discontinue the drug because of rashes, lack of efficacy and worry about the potential side-effects of the drug.
Conclusions. People of South Asian ethnic status terminate DMARD therapy sooner than North Europeans. The reasons for this difference are not clear but may concern problems with effective communication, cultural differences in attitudes to chronic illness or genetic polymorphisms in drug metabolism.
KEY WORDS: Ethnicity, Rheumatic disease, Disease-modifying anti-rheumatic drugs, Culture.
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Introduction |
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The treatment of inflammatory arthritis (mostly RA) requires the expertise of specialists (both medical and non-medical) providing long-term multidisciplinary support for these chronic, painful and disabling disorders. Patient education and self-efficacy provide a significant contribution to the management of these disorders in areas such as drug therapy, rest, exercise and everyday living. Effective communication is seen as essential in maintaining the well-being of people with the illness. Difficulties in effective communication may impair the consultation and implementation of effective therapy, including education about the disease and the drugs used in the treatment process (increased drug compliance may be the main beneficial effect of patient education [4]).
In Birmingham, South Asian patients with RA have more pain and disability than patients of North European origin [5], and similar differences are perceived in Bradford. Additionally, people of South Asian origin appear to be less tolerant of disease-modifying anti-rheumatic drugs (DMARDs). Although a number of factors may explain the greater pain and disability in South Asian patients, including the way culture may influence the individual response to illness, there could be a communication problem preventing effective education about the disease and the drugs used to treat it. For this reason it was hypothesized that South Asian people would have less tolerance of DMARDs compared with people of North European origin, and that this would be reflected in the duration of use of DMARDs. A computerized database that has been in use in Bradford since 1993 enabled this hypothesis to be tested using a retrospective study of all DMARDs prescribed since that date.
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Methods |
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The initial search was for all drugs within the DMARD (second-line) category from inception of the database to July 2001. A total of 5479 such drugs were recorded, together with appropriate demographic and disease details. A number of these cases were excluded (942) because of either incomplete data (41) or because they had the same start and stop date (901) for the drug.
A subsample of the remaining 4537 entries was checked against the written patient record to test the veracity of the database entries. A unique identifier (hospital number) was used to select 100 cases randomly in SPSS v8.0 (SPSS, Chicago, IL, USA). The results showed poor correspondence of start and stop date for cases with a drug start date between 1993 and 1996 inclusive. This was due to the constraints on the data imposed by the databasedrug start date was identified as the date the drug was entered in the database, not the actual start date. Therefore, for the first few years after the database was installed many drug start dates were inaccurate, as existing clinic patients were entered; after 1996 the majority of drug start dates reflected the true starting date. Retaining cases with a drug start date of 1 January 1997 or later further reduced the number of cases to 2653.
A further reduction in the number of cases was made to include only drugs used for inflammatory arthritis or connective tissue disorders because, on the Harris database, drugs such as allopurinol and amitriptyline are labelled as second line. Finally, drugs with a frequency of fewer than 50 cases were excluded: these included auranofin (2), chlorambucil (7), cyclosporin (45), cyclophosphamide (12), leflunomide (12) and thalidomide (6).
Data were analysed in SPSS v11.1 by univariate statistics and by survival curves using the log rank test for comparison between curves. Within each data set two events were identified. First, if the drug was discontinued for any reason this event was labelled terminal. Secondly, if the person was still taking the drug at the time of the last observation, or if they were withdrawn from observation for other reasons (such as being lost to follow-up), this event was labelled as censored. The log rank test compares survival over the whole period of observation but ignores censored events. A major assumption of this method of analysis is the rate at which drugs are started; this was assumed to remain constant over the study period.
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Results |
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Table 1 gives the duration of time on each of the drugs, including both censored and terminal events. The maximum time approached 55 months because of the time cut-off imposed on the data. The last column in Table 1 gives the proportion of patients still taking the drug at the time the last person discontinued the drug, and relates only to terminal events in the at-risk population at that time.
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Information on the reason for stopping the drug was available in 558/818 (68%) of cases where the drug had been discontinued. The reasons given for discontinuation are given in Table 3 according to ethnic status. The 95% CI values suggest significant differences between ethnic groups with respect to gastrointestinal and respiratory problems (more common in North Europeans) and rashes, lack of effect, and concern about the potential side-effects of the drug (more common in South Asians).
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Discussion |
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A limitation of this study is that it was based on electronic data and was therefore subject to errors of two types: attribution and data entry. However, automatic coding of start and stop dates was reliable for drugs started after 1 January 1997. Veracity of drug use and reason for discontinuation were checked on a subsample and found to be reliable. However, although the problem of attribution remains, discontinuation of a drug because of, for example, rash is a clinical judgement applying equally to all ethnic groups. A full case-note review would have been ideal, if only to gather additional information (such as disease duration, disability, joint counts and inflammatory markers) with which to further evaluate these findings. A prospective study recording these data is in progress.
There are a number of possible explanations for the observed difference. There is clearly a problem with communication in the South Asian group, particularly with first-generation females whose knowledge of written and spoken English is poor. Although interpreters are provided, they may have difficulty translating the nuances of disease education and DMARD therapy to this group. Difficulties in effective communication may impair consultation and the implementation of effective therapy, including education about the disease and the drugs used in the treatment process. In our experience, Pakistani Muslim people rarely attend patient education groups. This may, in part, be a problem with language and partly cultural. Furthermore, patient literature is rarely translated into other languages. Of the patient information leaflets produced by the arc, only one is written in another language (Bengali) and none of the drug information leaflets have been translated.
However, the solution may not be purely one of translating existing material, as language may not be the only barrier to effective communication. Culture may also influence the societal response to illness and to treatment, including drug treatment. Our impression in working with South Asian people in Bradford is that expectations are high. Furthermore, work with minority ethnic groups in the USA has shown that there are cultural differences in how people make sense of pain and express their pain to others [7]. South Asian patients may also present emotional distress in somatic terms when they have such symptoms as pain and loss of function, and may therefore misunderstand the role of DMARD therapy in their treatment [8].
Could the observed differences be due to biological factors? In a recent study of British South Asians living in the West Midlands, 107 patients of North Indian or Pakistani origin with RA were matched for age, sex and disease duration with 107 patients of North European origin [5]. All patients were attending rheumatology clinics in Birmingham. The results showed that, per unit of disease outcome (measured as bone damage on X-ray), South Asian patients expressed greater pain and disability (measured with a visual analogue scale and standardized questionnaire respectively). Of the known prognostic factors for bone damage (rheumatoid factor, HLA status, swollen joints and C-reactive protein concentration), only the genetic component was different, South Asian RA patients having a more favourable profile, with a lower frequency of the conserved third allelic hypervariable region, particularly DRB1*0401.
The increased prevalence of dermatological side-effects may also reflect a genetic difference between ethnic groups, possibly in the prevalence of HLA-DR3 type [9]. However, genetic differences in the distribution of polymorphic traits rather than a unique trait may be more important in this context [10]. Such differences in the functional activity of enzymes concerned with the metabolism of drugs, such as CYP2C, and in the presence of the so-called multi-drug resistance genes coding for P-glycoprotein [11], may be responsible for some of the observed differences, but further work is required to elucidate these possibilities. It is worth acknowledging that racial disparities in clinical trials may have contributed to this problem, thus effectively concealing inter-ethnic differences in responses to these drugs [12].
In conclusion, a clear difference between ethnic groups with respect to the tolerance of DMARDs has been found. Problems with effective communication, cultural differences in expectations and response to illness and genetic differences may explain the observed contrast.
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Conflict of interest |
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References |
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