Ethnic differences in responses to disease modifying drugs

P. S. Helliwell1,2 and G. Ibrahim2

1Rheumatology and Rehabilitation Research Unit, University of Leeds and 2St Luke’s 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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conflict of interest
 References
 
Background and objective. The UK has a growing South Asian population. In the South Asian population of Bradford people appear to be less tolerant of disease-modifying anti-rheumatic drugs (DMARDs). One reason for this may be poor communication during patient education, which is generally designed for white North European people. Our objective was to obtain information on DMARDs that were used, the duration of their use and reasons for their discontinuation between ethnic groups.

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, {chi}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 [{chi}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 0.693–0.791) and the South Asian group of 0.665 (95% confidence interval 0.645–0.684) [log rank test, {chi}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.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conflict of interest
 References
 
The UK now has a South Asian population of approximately 1.5 million, with a well-maintained cultural and ethnic identity. In Bradford, 17% of the 486 000 community is South Asian, mostly originating from a small area to the north-west of the region called Miapur (http://www.bradford.gov.uk). The prevalence of rheumatoid arthritis (RA) amongst South Asians living in London is higher than that in Karachi, although it is still somewhat less than the prevalence of RA in the white UK population [1, 2]. Generalized musculoskeletal complaints are probably more common in South Asian females living in the UK than in white UK residents [3].

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.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conflict of interest
 References
 
Patient data were recorded in Harris (North East Software, Edinburgh, UK), a database based on Dataflex software used for data storage, audit and, in linkage with a word-processing package, letter generation [6]. When a DMARD is started or stopped, the system automatically logs the date and reason for stopping. A summary of DMARDs, past and present, is supplied on every document, together with the reasons for stopping the drug. The database can be searched by drug type and this data can be downloaded, together with demographic and other disease-related information, into a file delimited by tabs or commas. Ethnic origin was identified by name and by personal knowledge of the people attending the clinics. This process was facilitated by the homogeneity of the South Asian population in Bradford.

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 database—drug 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.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conflict of interest
 References
 
The data set consisted of 2356 separate drugs. These drugs had been given to 1391 patients, an average of 1.69 drugs per patient. The patient group consisted of 947 females and 444 males with a mean age of 59.6 yr (range 16.1–93.7). The ethnic distribution of this group was 1191 North European, 193 South Asian, 4 Afro-Caribbean and 3 Chinese. As the latter two groups were small in comparison, these patients were excluded from the analysis. 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).

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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TABLE 1. Drug, time on drug (months) and proportional survival of drugs

 
Figure 1 shows the survival curve for all drugs according to ethnic group. The statistics from these curves reveal a 12-month ‘survival’ rate of drugs in the North European group of 0.742 [95% confidence interval (CI) 0.693–0.791] and in the South Asian group of 0.665 (95% CI 0.645–0.684). The log rank test between the two curves was significant [{chi}2(1) = 18.19, P < 0.00001].



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FIG. 1. Survival curves for all drugs for both major ethnic groups. The numbers still at risk at 10, 20, 30, 40 and 50 months were as follows: South Asian 220, 147, 87, 42 and 20; North European 1220, 872, 570, 350 and 117. Cum survival, cumulative survival.

 
Drug, age and gender were examined independently as possible confounders. Age was transformed into a categorical variable of four equal groups for this part of the analysis. Univariate statistics revealed significant differences between ethnic groups for age [{chi}2(3) = 263.2, P < 0.0001], drug [{chi}2(6) = 44.6, P < 0.0001] and gender [{chi}2(1) = 12.4, P < 0.0001]. The contrast between ethnic groups for these variables is shown in Table 2. Survival analysis showed that age and drug were important variables influencing the duration of time spent on a drug before discontinuation (log rank statistics). For age, drug survival was better for the older age group [log rank test, {chi}2(3) = 29.1, P < 0.0001]. For drug, survival was best for steroids and worst for D-penicillamine, as indicated in Table 1 [{chi}2(6) = 99.3, P < 0.00001].


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TABLE 2. Differences between ethnic groups according to gender, age and drug

 
To allow for inequalities between the groups with respect to drug, and age, these other variables were entered as strata, separately, within the log rank analysis. The effect of this adjustment was reflected in the log rank test with the following {chi}2 values for ethnic status: drug, 13.35, degrees of freedom (d.f.) 1, P < 0.0003; age, 8.97, d.f. 1, P = 0.003. The results therefore indicate a significant difference in drug survival between the two ethnic groups with adjustment for these confounding variables.

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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TABLE 3. Differences between ethnic groups according to reason for discontinuing drug

 

    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conflict of interest
 References
 
This study has found that South Asian patients, compared with patients from Northern Europe, terminate DMARD therapy sooner and are more likely to stop the DMARD because of dermatological reactions, inefficacy or because they are unhappy about the drug generally. The study hypothesis was therefore supported.

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.


    Conflict of interest
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conflict of interest
 References
 
The authors did not declare any conflicts of interest.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conflict of interest
 References
 

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Submitted 3 July 2002; Accepted 3 March 2003