A survey of British rheumatologists’ DMARD preferences for rheumatoid arthritis

P. Jobanputra1,2, J. Wilson1, K. Douglas2 and A. Burls1

1Department of Public Health and Epidemiology, University of Birmingham, Edgbaston, Birmingham and 2Department of Rheumatology, Selly Oak Hospital, University Hospital Birmingham NHS Trust, Raddlebarn Road, Birmingham B29 6JD, UK.

Correspondence to: P. Jobanputra. E-mail: P.Jobanputra{at}bham.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. To determine the current disease-modifying anti-rheumatic drug (DMARD) preferences of UK consultant rheumatologists.

Methods. A questionnaire was sent in May 2002. We asked which DMARD(s) was most frequently preferred first and sought the most typical sequence of DMARDs, including DMARD combinations. Also we determined the extent to which prognostic and other factors influenced treatment choices. Comments were invited, written responses abstracted and key themes identified.

Results. After two mailings, 331 (of 460; 72%) suitable questionnaires were returned. Ninety-five per cent (315/331) preferred methotrexate (154, 46.5%) or sulphasalazine (144, 43.5%) or either of these two (17, 5%) as first-choice agent. Of those who chose methotrexate first, 80% (123/154) ranked sulphasalazine second, 45% (55/123) combined sulphasalazine and methotrexate and 49% (27/55) then added hydroxychloroquine to this combination, in active disease. Of those who chose sulphasalazine first, 95% (137/144) ranked methotrexate second, 75% (113/150) preferring methotrexate monotherapy and 12% (18/150) the combination with sulphasalazine. Rheumatologists who preferred sulphasalazine first more commonly used subsequent DMARDs singly than those who started with methotrexate (P < 0.0001). Leflunomide was more commonly preferred than intramuscular gold as third choice (52/145 vs 29/145; P < 0.003). The most popular sequence of DMARDs was methotrexate or sulphasalazine, singly or in combination, leflunomide, intramuscular gold and anti-tumour necrosis factor therapy. Poor prognostic factors influenced DMARD choice, but patient occupation and drug costs did not.

Conclusion. Methotrexate has displaced other DMARDs, especially sulphasalazine, as agent of first choice and newer agents have displaced older DMARDs. Whether the expressed preference for particular DMARDs accurately reflects actual use, and is optimal in rheumatoid arthritis, remains to be determined.

KEY WORDS: Survey, DMARD, Prescribing preference, Rheumatologists, Rheumatoid arthritis.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Little is known about the current disease-modifying anti-rheumatic drug (DMARD) preferences of British rheumatologists. Sulphasalazine was the agent of first choice for British rheumatologists in a previous UK survey [1], but currently methotrexate is widely regarded as the standard against which other DMARDs should be compared. Several recent surveys, from North America, have shown that combinations of DMARDs are preferred in contemporary practice [2, 3]. Since DMARDs are now used earlier in disease and with the availability of several new DMARDs recently, we set out to investigate current prescribing preferences in the UK. Our motive in doing so was a need to inform and develop an economic model for the treatments of rheumatoid arthritis [4, 5].


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Questionnaire
A postal survey of consultant rheumatologists working in the UK was undertaken in May 2002. The British Society for Rheumatology ordinary member's list from the 2001 directory was used to identify practising specialists. Trainees and those in paediatric practice were excluded from this survey because only the practice of established specialists with significant experience of treating adults was of interest. The questionnaire was developed by detailed discussion with colleagues and piloted locally. The final questionnaire examined three main areas: DMARD(s) of first choice from a given list but with an option to name a preferred DMARD under ‘other’ (minocycline, cyclophosphamide and anakinra were not listed, the latter as it was not licensed at the time of the survey); typical DMARD sequence in a patient who fails to respond or has an adverse effect to a DMARD; and factors that might influence choice of DMARD. Rheumatologists were told that the survey sought a ‘snapshot’ of current practice and that their responses should reflect practice within ‘current constraints, rather than what you would consider ideal treatment’.

Rheumatologists were asked, in a series of questions, what factors influenced treatment patterns. These were: rheumatoid factor status, presence of erosions at diagnosis, number of joints involved, episodic vs persistent disease, need for rapid symptom control (e.g. due to patient distress, job context, social role), manual vs sedentary occupation, drug cost, a high acute-phase reaction, side-effect profile of drug and age of patient. Respondents were asked to indicate whether they strongly agreed, agreed, were neutral, disagreed or strongly disagreed that these factors influenced their DMARD choice. If they agreed comments were invited. Respondents were also asked to suggest any other factors that might influence choice and were asked to give their year of graduation.

The survey was mailed in May 2002 with a covering letter on headed paper from the Birmingham University Department of Public Health and Epidemiology. A pre-paid envelope for reply was attached. Those not responding were sent a reminder 1 month later. Questionnaires were numbered to allow identification of non-responders and to facilitate a second mailing, but responses and analysis were entirely anonymous. No payment was offered. All data entries were checked for accuracy by a second person.

Analysis
Drug preferences and choices were compared using a frequency distribution histogram. Sequences were determined by plotting a pathway starting with the most commonly cited first-choice drug in the sequence. Proportions were compared with a {chi}2-test. Hand-written comments were abstracted by a medical secretary and cross-checked for accuracy. Key themes were identified from a sample of responses and applied to all remaining responses with modifications, if appropriate. Themes were agreed between researchers by consensus.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Response rate
From the 463 surveys sent, 340 (73%) were returned. Six replies were discounted (three people were not working as consultant rheumatologists, two were paediatric rheumatologists and one had retired). A further two questionnaires were returned because the recipient had moved or was unknown at the address. One person refused to complete the survey, giving 331 (72%) completed questionnaires of 460 individuals treating adults.

First-choice DMARD
Rheumatologists ranked, in order of preference, the DMARD they would give as first agent to a generic patient who had not previously received a DMARD, from a given list. Methotrexate was ranked first by 154 (47%) respondents and sulphasalazine by 144 (44%). Methotrexate and sulphasalazine were ranked jointly first by 5% (17/331; Fig. 1). Of those who ranked methotrexate as first choice, 80% (123/154) ranked sulphasalazine second. Methotrexate was ranked second by 95% (137/144) of those who ranked sulphasalazine first. Out of those who ranked methotrexate or sulphasalazine as first choice, 76 and 74%, respectively, estimated that over half of their patients received these drugs. Injectable methotrexate was ranked first by a small proportion of respondents and was particularly popular at third rank (Fig. 1) .



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FIG. 1. Ranking of DMARDs in initial treatment. Data shown are from a question that asked: ‘What DMARD are you most likely to give as first-line therapy?’ from a list. Data show the ranks given to DMARDs from this list and indicates the percentage of rheumatologists choosing a particular DMARD according to rank order.

 
DMARD sequences and preferred combinations
The most typical sequences of DMARDs preferred for patients who fail to respond to initial therapy are illustrated in Fig. 2. Data shown are for unambiguous responses to a second question asking specifically about sequences (therefore numbers shown do not correspond directly to those shown above). Leflunomide was more commonly preferred, after methotrexate or sulphasalazine, than intramuscular gold as third-choice agent (52/145 preferences compared with 29/145; P < 0.003).



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FIG. 2. Typical sequences of preferred DMARDs. Data shown are from a question that asked: ‘Patients often fail several DMARDs, please can you tell us a typical DMARD sequence you might use?’ MTX, methotrexate; SAS, sulphasalazine; MYO, intramuscular gold (sodium aurothiomalate); LEF, leflunomide; anti-TNF implies infliximab or etanercept; AZA, azathioprine; HCQ, hydroxychloroquine.

 
Of those who chose methotrexate first, 80% (123/154) ranked sulphasalazine second, 45% (55/123) combined sulphasalazine and methotrexate and 49% (27/55) then added hydroxychloroquine to this combination, in active disease. Rheumatologists who chose methotrexate first, and who preferred monotherapy, most commonly chose methotrexate, sulphasalazine, leflunomide (34%, 18/52) and anti-tumour necrosis factor (anti-TNF) therapy (38%, 7/18) in succession.

Of those who chose sulphasalazine first, 95% (137/144) ranked methotrexate second, 75% (113/150) preferred methotrexate monotherapy and 12% (18/150) the combination, in active disease.

Rheumatologists who preferred sulphasalazine first more commonly chose monotherapy for successive DMARDs than those who started with methotrexate (P < 0.0001). The most popular sequence was sulphasalazine, methotrexate, leflunomide (30%, 34/113) and either intramuscular gold (50%, 17/34) or anti-TNF (29%, 10/34) in succession.

Influences of clinical factors on treatment preferences
A majority of respondents agreed, or strongly agreed, that the presence of erosions at diagnosis (80%), drug side-effects (78%), high acute-phase reaction (66%), episodic vs persistent disease (66%), and the number of involved joints (68%) affected DMARD choice (Table 1). Forty-nine per cent agreed or strongly agreed that rheumatoid factor (RF) status affected DMARD choice, but 22% disagreed or strongly disagreed. Rheumatologists were generally not influenced by patient occupation or drug costs. The year in which rheumatologists qualified did not influence whether methotrexate or sulphasalazine was chosen first.


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TABLE 1. Agreement on whether specific clinical factors influenced DMARD preferences

 
Analysis of written comments
Influence of prognostic factors. Early use of DMARDs was cited in 56 comments in relation to adverse prognostic factors such as a positive RF or polyarticular disease. Many (347 comments) referred to ‘aggressive’ therapy and methotrexate was frequently perceived as the drug of choice for aggressive therapy (>100 comments). Combination therapy, with sulphasalazine and methotrexate, was favoured over these drugs singly in this setting (66 comments). ‘Aggressive therapy’ was also perceived as potentially more hazardous, for example in reference to anti-TNF therapies, ‘ . . . more aggressive use of more toxic agents—introduce anti-TNF earlier’. Episodic disease was regarded as having a good prognosis and hydroxychloroquine (61 comments) and sulphasalazine were commonly preferred. Four respondents mentioned the use of intermittent steroids with episodic disease. A variety of other comments referred to more general factors, for example ‘clinical findings influence me most’, or ‘x-ray erosions are very misleading’ or missed opportunities in erosive disease (‘missed the boat’).

Role of social factors. Occupation did not generally influence DMARD choice, but some recommended a more ‘aggressive’ approach or use of more rapidly acting agents for those with manual occupations: ‘more likely to lose job therefore quick acting drug’. Another approach was ‘work advice and probably retraining’. Few respondents agreed that occupation influenced DMARD choice and comments were invited only if respondents agreed. Twenty spontaneous comments were made about caution in relation to childbearing and fertility. Comments indicated avoidance of methotrexate and preference for sulphasalazine or azathioprine. Some rheumatologists indicated that the goals of therapy were different when treating elderly patients, and also suggested logistic difficulties with elderly or infirm patients: ‘long-term benefits less important . . . ’ or ‘elderly/infirm . . . difficulty with bloods would choose sulphasalazine, as monitoring less frequent once established’.

Influence of drug toxicity and comorbidity. Potential adverse effects of DMARDs influenced choice, for example, ‘higher threshold for use, i.e. disease needs to be more active to justify’. Similarly comorbidity, smoking habit and alcohol use also affected preferences, ‘avoid methotrexate in lung disease’, or ‘reluctant to stop alcohol would not prescribe methotrexate—choice would be intramuscular gold’. Some indicated that sulphasalazine was avoided in liver disease and if patients were antinuclear antibody positive. Comments also reflected the complexity of clinical choices, ‘difficult to answer without writing an essay’.

Influence of drug costs and administration and departmental infrastructure. Consultants were, by and large, uninfluenced by drug costs, but a wider perspective was taken in some comments. For example, ‘not just cost of drugs, other facilities especially clinical nurse specialist, time and facilities to use TNF blockers and to teach/train patients (is) not available’ or, ‘mode of administration (IV, e.g. infliximab) more difficult than self-administered drugs’. Safety monitoring of DMARDs was also a consideration in choosing agents, as was the support of nurse specialists, ‘convenience of monitoring, co-operation by GP, availability of clinical nurse specialist’.

Influence of patient preferences. There were 43 comments about the patient's point of view. Some emphasized the importance of patient acceptance of therapies and others reflected patient empowerment through various sources of information. For example, ‘most important is patient acceptance after education’, or ‘patient preference—some patients are very adamant about their treatment preferences . . . ’. A few comments indicated a negotiation with patients, ‘patients sometimes come with their own ideas—I take that into consideration’ or, ‘patient preference having discussed pros and cons of various options’.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Our survey shares a number of limitations with other recent surveys [6]. A response rate of 73%, found in our survey, is slightly better than that reported in a Canadian survey and is regarded as a good rate for postal surveys [6, 7]. Although 1 in 4 rheumatologists did not respond we believe that the 331 suitable responses received reliably represent DMARD preferences of UK rheumatologists in mid-2002. Direct comparison of our findings with previous surveys, and with surveys in other countries, cannot readily be made because of differences in the purpose and methods of previous surveys, international variations in availability and licensing of DMARDs over time, and the influence of individual health-care systems. For example, several previous surveys have focused on drug doses and drug safety monitoring practices [1, 6].

Our purpose was to identify contemporary DMARD preferences in order to refine an economic model of new agents for rheumatoid arthritis (RA) [4, 5]. Principally we were interested in the sequence of DMARDs that rheumatologists prefer in order that we could compare the cost-effectiveness of different sequences and the positioning of newer agents. Prescribing intentions, we believe, are more likely to reflect future use and, although hypothetical, are of greater value for our purpose than historical patterns of actual prescribing. Nevertheless, recent observational data from Europe shows similar actual use of DMARDs to that indicated in our survey [8, 9].

Respondents fell into two broad camps: those preferring to start with sulphasalazine and those starting with methotrexate. Curiously sulphasalazine starters tended to prefer single-use DMARDs whilst methotrexate starters tended to favour combinations. Our survey questioned prescribing intent. We cannot say whether this intent is translated into actual prescribing nor do we report rheumatologists’ ideal DMARD sequences, since we asked for preferences ‘within current constraints’. Furthermore, we did not create a patient vignette, as some surveys have done [10], but simply asked what rheumatologists might do ‘in patients with newly diagnosed RA’. Since early RA is a heterogeneous disorder, differences in prescribing preferences may merely reflect this clinical heterogeneity. Our findings, therefore, do not necessarily imply that rheumatologists practise very differently when faced with similar patients.

Our survey, unsurprisingly, found an increased preference for using methotrexate early in newly diagnosed RA. New treatments such as leflunomide and anti-TNF therapies were preferred to older agents such as gold. Leflunomide, for example, was preferred significantly more often as third-choice DMARD than intramuscular gold. This may reflect perceptions of efficacy or logistic difficulties of administering agents such as intramuscular gold, or both. Sulphasalazine, as reported in an earlier UK survey [1], remained a popular first choice in contrast to recent North American surveys where it was much less favoured than methotrexate [2, 3]. Oral gold, chloroquine and penicillamine were rarely chosen, indicating greatly diminished use in the UK.

Known poor prognostic factors in RA influenced DMARD choice and erosions at diagnosis most strongly influenced DMARD choice. The questions posed were limited and, although comments were invited, reflected physician priorities rather than factors that might influence patients in making therapeutic choices [11]. However, we heartened to note that at least some comments referred to the role of patient preferences in making decisions about DMARDs.

In the face of poor prognostic factors, rheumatologists often invoked ‘aggressive’ DMARD use. Comments suggested that ‘aggressive’ referred to drugs such as methotrexate, anti-TNF agents and combination therapy. There appeared to be a perception, by some respondents, that such therapies were potentially more toxic than other agents and therefore their use was regarded as ‘aggressive therapy’. Observational and randomized studies do not necessarily support these perceptions about greater toxicity [12, 13]. Economic factors can influence DMARD preferences [14] and about a third of our respondents agreed or strongly agreed that cost affected choice. It is likely therefore that the sequences of DMARDs described in our survey might have been quite different if respondents had been asked to disregard cost.

In summary DMARD preference in the UK is broadly similar to current European practice and shows a greater predilection for sulphasalazine compared with the US [2, 810]. A growing preference for early methotrexate use may reflect increasing confidence in this drug and may also be due to the greater likelihood for more prolonged drug use with methotrexate compared with other DMARDs [15]. It is also of interest that compliance with methotrexate seems to be better than with sulphasalazine [16]. Our findings may be of importance to pharmaceutical companies seeking to place newly developed agents. However, with a widening choice of DMARDs including biological agents, informed choices can only be made if head to head comparisons of new agents with older therapies, and perhaps of different sequences, are made.


    Acknowledgments
 
We would like to thank all the rheumatologists who took time to respond to this survey. We are also grateful to C. Harris and S. Wycherley for secretarial support. L. Clark was the survey administrator and C. Leonard assisted with data checking. PJ, JW and AB are members of the West Midlands Health Technology Collaboration (WMHTAC) that is supported by the NHS R&D HTA programme.

Conflict of interest

The authors have declared no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Submitted 14 May 2003; Accepted 7 July 2003