The rheumatoid arthritis patient in the clinic: comparing more than 1300 consecutive DMARD courses

D. Aletaha and J. S. Smolen1,

Division of Rheumatology, Department of Internal Medicine III, University of Vienna and
1 Second Department of Medicine, Lainz Hospital, Vienna, Austria


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Therapy of rheumatoid arthritis (RA) is typically characterized by the sequential use of disease-modifying anti-rheumatic drugs (DMARDs). This study aimed to reveal treatment patterns with traditional DMARDs and their changes during the two decades before the recent introduction of new DMARDs.

Methods. A total of 593 RA patients were followed from their first presentation to our clinic throughout the course of their disease; 222 patients received their first DMARD therapy while under our care. More than 2300 patient years of therapy were analysed for the efficacy [using C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) as surrogates] and duration of drug therapy of consecutive DMARDs.

Results. Before 1985, 65–90% of initial DMARDs were gold compounds, but their use decreased continuously thereafter. Antimalarial (AM) drugs were important initial DMARDs in new patients at all times, whereas sulphasalazine (SSZ) and methotrexate (MTX) gained increasing significance after 1985 (the first DMARD was MTX in up to 29% of new patients). Penicillamine (DPA), azathioprine (AZP), cyclosporin (CyA) and combination therapies were not usually employed initially, but were reserved for the later course of the disease. Gender, age and rheumatoid factor were not different between patients receiving different DMARDs. The baseline acute-phase response was higher in patients treated with MTX (mean CRP 3.5 mg/dl) than in those treated with SSZ (CRP 2.4 mg/dl; P < 0.05) or AM (CRP 2.1 mg/dl; P < 0.05), suggesting that MTX was used preferentially in patients with high disease activity. On the other hand, once AM or SSZ had been discontinued, MTX was the most common subsequent DMARD (in 31 and 56% respectively). Comparison of first DMARDs with subsequent ones revealed that first DMARDs were more effective: the acute-phase response decreased most prominently during first therapies (CRP reduction was 1.28 mg/dl during first courses and 0.35 mg/dl during fourth or later courses; P < 0.01); and retention rates were significantly longer for first compared with subsequent therapies (median of 24.5 months for first and 18.6 months for fourth or subsequent therapies; P < 0.001).

Conclusion. MTX was the most commonly employed DMARD therapy for RA and was used increasingly as first therapy in newly diagnosed RA. Patients with high disease activity were given MTX therapy more often than other DMARDs, while those with low activity were more likely to receive SSZ or AM, and MTX on failure of these drugs. First DMARDs in new patients were retained longer than subsequent DMARDs, apparently because they are more effective.

KEY WORDS: Rheumatoid arthritis, First DMARD, Consecutive DMARD, Efficacy.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Therapy of rheumatoid arthritis (RA) focuses on the retardation and, ideally, halting of the natural course of the disease using disease-modifying anti-rheumatic drugs (DMARDs) [13]. However, insufficient efficacy of DMARDs and a significant degree of toxicity lead to relatively low retention rates for these drugs [46]. As a consequence, RA patients are likely to receive several compounds consecutively during the course of their chronic disease.

The objective of this study was to reveal the effect of serial DMARD therapies on the effectiveness, safety and treatment duration of consecutive DMARDs. We also describe the pattern of initial DMARDs employed in new patients over the past two decades. We also explored the preferred DMARDs when preceding ones had failed. Finally, our data may provide a basis for expectations and future measures of success of traditional as well as the new, recently approved DMARDs [710].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Files of RA patients from the out-patient clinics of two rheumatology centres, the Department of Rheumatology at the Vienna General Hospital (n=362) and the Centre for Rheumatic Diseases at the Lainz Hospital, Vienna (n=231), both of which are specialized referral centres, were analysed. The prerequisite for this analysis was the presence of RA [10] and the administration of at least one course of disease-modifying therapy. The influence of selection bias on the identified patients is considered very low, as data were extracted from the files in 1999 but files of all RA patients, including those with long-standing RA, who were seen in the out-patient clinics at least once after 1993, are kept in the archives. Therefore, charts of patients who were lost to follow-up or had died since 1993 were also available, and the only charts that were not available for analysis were those for patients who had no visit after 1993. To determine the potential presence and degree of bias, we analysed disease duration for therapies and reasons for treatment discontinuation before and after 1993, and found no significant difference.

Five hundred and ninety-three patients were identified in the two clinics and were followed throughout their DMARD therapies until the last evaluation in 1999. The ratio of women to men was 4:1. Testing for rheumatoid factor at the time of first presentation at the clinics was positive in 379 patients (63.9%) and negative in 214 (36.1%). The patients' mean age (±S.D.) at the time of study was 59.1±13.6 yr and the mean disease duration was 12.1±9.3 yr. These patients received a total of 1319 courses of DMARDs. The number of DMARD courses prescribed to an individual RA patient ranged from 1 to 10 (median 2). A total of 2376 patient-years (p.y.) of DMARD therapy were analysed and involved the following therapies (numbers of p.y. are rounded): auranofin (OG; n=68, 131 p.y.), azathioprine (AZP; n=25, 56 p.y.), antimalarials (AM; n=285, 536 p.y.), cyclosporin A (CyA; n=31, 27 p.y.), D-penicillamine (DPA; n=65, 164 p.y.), methotrexate (MTX; n=389, 751 p.y.), parenteral gold compounds (PG; n=109, 218 p.y.), sulphasalazine (SSZ; n=267, 428 p.y.) and combination therapies (Comb.; n=80, 67 p.y.).

For each therapy, the dosage, duration and reason for discontinuation (if applicable) were registered. As surrogate measures of disease activity [1117], baseline values of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) at the beginning of each therapy were compared with values obtained at the end of the respective therapies or, for ongoing therapies, at the time of last evaluation; the acute-phase response correlates well with disease activity as well as with radiographic and functional outcome [1117].

A distinction was made between patients who received their first DMARD therapy at one of the study hospitals (n=222) and those who had received DMARDs before presenting to one of our centres (n=371). The 222 patients with first ever DMARDs were used to determine the pattern of prescription of initial DMARDs in new RA patients and to show changes in this pattern throughout the 1980s and 1990s. All other evaluations of consecutive DMARD therapies in this study were performed using all 593 patients. Statistics were performed using version 10.0 of the Statistical Package for the Social Sciences (SPSS; SPSS, Chicago, IL, USA) for the microcomputer.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Distribution of DMARD therapies
During the whole observation period, the 593 patients received 1319 consecutive DMARD therapies. Eight different regimens were used. Figure 1Go illustrates the DMARD courses of all study patients over the time they were seen at our clinics. MTX was a very frequently employed DMARD at any point in time, accounting for 23–42% of consecutive DMARD courses. SSZ was also used commonly throughout the first four courses (range 19–25%, less frequently later), while chloroquine (CQ) was a typical first drug, accounting for 34% of first, 16% of second and 12% of third courses. In contrast, combination therapies, CyA and AZP were employed in later stages of the disease when other drugs had failed (all three together accounting for 2% of first courses, but almost 50% of courses beyond the fifth).



View larger version (46K):
[in this window]
[in a new window]
 
FIG. 1. Distribution of DMARD therapies in relation to treatment courses (593 patients, 1319 courses, 2376 patient years). The data show individual DMARDs as a proportion of all DMARD courses for first to fifth and subsequent DMARDs (total 100%).

 

Change of DMARD preference over time
Preferences for particular DMARDs changed through the years. To analyse this further, therapies were related to the year of their application (Fig. 2Go). More traditional therapies, such as PG and DPA, dropped from >40% use in earlier to <5% in more recent years. OG had its peak of application in 1987 and decreased consistently thereafter. After its reintroduction [18, 19], MTX soon became an important DMARD and is the most preferred drug at present (30–40% of therapies) (Fig. 2Go). This is in line with a survey which we performed among European rheumatologists in the late 1990s (data not shown).



View larger version (25K):
[in this window]
[in a new window]
 
FIG. 2. Changes in the use of DMARDs for RA during 1970–1999 (593 patients, 1319 courses, 2376 patient years).

 

Continuation and switching of DMARD therapies
In most patients, DMARD therapies were not maintained, and many patients subsequently used up to 10 other DMARD courses. Of the 1319 therapies analysed, 911 (69%) were terminated before closure of the database. Approximately 50–60% of all individual DMARD courses were followed by another DMARD course (grey sections of columns in Fig. 3Go). The proportions of patients who were on 1st, 2nd, 3rd, 4th and 5th DMARDs at the time of evaluation ranged from 25 to 40% (white sections of columns in Fig. 3Go). Around 6–15% of the patients were lost to follow-up during each of the DMARD courses (black sections of columns in Fig. 3Go).



View larger version (42K):
[in this window]
[in a new window]
 
FIG. 3. Continuation and switching of DMARD courses. The first column represents all patients who received an initial DMARD (i.e. 100% of patients); the percentages above the 2nd to 5th columns show the proportions of patients who later received a 2nd, 3rd, 4th or 5th DMARD. The grey sections at the bottom of the columns represent the proportion of patients receiving a particular DMARD course (1st to 5th) who later received a different DMARD course. Black sections represent the proportion of patients lost to follow-up for courses 1–5. White sections represent the proportion of patients who were still receiving a particular DMARD (1st to 5th) at the time of evaluation.

 
Patients whose therapies were sustained for >6 or >9 yr and patients who stayed on their first DMARD for longer than 3 yr did not differ significantly from the remainder in gender, age or rheumatoid factor status (data not shown). Baseline values of neither CRP nor ESR were predictors of duration of therapy (data not shown). The leading causes for discontinuation were adverse events (42%) and inefficacy (37%).

Alternatives when drugs fail
To analyse which drugs were preferred when other drugs had failed, we looked at the individual patients' DMARD history. Over all courses of therapy, MTX, SSZ and CQ were the most commonly used DMARDs (Fig. 1Go). In patients in whom these drugs were employed as first, second or third courses while under our care, the previous and following therapies were explored (Table 1Go). Among patients receiving MTX, the proportion of those who did not receive a subsequent DMARD was higher compared with those receiving SSZ or CQ ({chi}2 test, P<0.001). This may have been due partly to the more frequent prescription of MTX in recent years, but is also an indicator of the better retention of this drug. Most MTX therapies were preceded by SSZ and CQ. Frequently, patients on SSZ had received MTX or CQ previously, and those on CQ had received PG and MTX. CQ and SSZ were the most frequently used first DMARDs (Table 2Go).


View this table:
[in this window]
[in a new window]
 
TABLE 1. Common alternatives in DMARD therapy

 

View this table:
[in this window]
[in a new window]
 
TABLE 2. DMARD prescription in new patients (n=222)

 
The data reveal that CQ, SSZ and MTX were used to a similar extent in the early phase of therapy. Certain characteristics of the patients or their disease must have led to the choice of either one of these drugs, as the efficacy/toxicity trade-offs are similar for these drugs [20]. In fact, the acute-phase response at treatment initiation was significantly higher in patients on MTX than in those who were beginning CQ (P<0.01) or SSZ (P<0.05) (Table 3Go), suggesting that mild disease was treated differently from more active disease.


View this table:
[in this window]
[in a new window]
 
TABLE 3. CRP and ESR at treatment initiation

 

Acute-phase response
Another aim was to assess the reduction of the acute-phase response during DMARD therapies and to compare this change between consecutive courses. Disease activity is usually assessed using composite indices [2124]. However, detailed joint counts were not routinely performed prospectively in our clinics in the earlier years and were therefore unavailable for all time points. In contrast, laboratory variables, such as ESR and CRP, were available for most patients. Because, with all limitations in mind, CRP and ESR constitute surrogates of disease activity [1117], they were used here to estimate the efficacy of DMARD therapies. Therefore, mean changes between values at the beginning and end of each therapy (or the end of observation for ongoing therapies) were calculated. The results summarized in Fig. 4AGo reveal that the biggest reduction in the acute-phase response occurred during first courses (P<0.01) and suggest decreasing efficacy of later therapies (t-test, P<0.01).



View larger version (28K):
[in this window]
[in a new window]
 
FIG. 4. (A) Reduction in CRP and ESR during DMARD therapy. Statistical analysis was with the t-test. Comparison of first with later therapies: P <= 0.001 for duration of therapy and P <= 0.01 for CRP and ESR reduction. Comparison of consecutive therapies: P < 0.05 for duration of 1st vs 2nd therapy; other differences were not significant. (B) Treatment duration for consecutive DMARD therapies.

 

DMARD retention rates
In general, there was a tendency to decreasing treatment duration with increasing number of consecutive DMARD therapies (Fig. 4BGo). This was particularly evident for the first DMARDs (mean 24.5 months), which were sustained significantly longer than second (20.4 months; P<0.05) or subsequent DMARDs (19.2 months; P<0.001).

First ever DMARDs and consecutive therapies
For 222 of the 593 study patients (37.4%), data were available for the first ever DMARD therapy employed between 1971 and 1999. (In the remaining patients at least one DMARD therapy had been applied before referral to our centres, either at the private practice of a general practitioner or rheumatologist or at another hospital, with no records available for further analysis.) In Table 2Go, the first DMARDs of all new patients are related to all their subsequent therapies. The ratio of first ever to subsequent individual DMARDs was >=1 for CQ, PG, SSZ and OG, suggesting frequent clinical use of these drugs as first DMARDs during recent decades. Drugs more commonly used later in the course of the disease (ratio < 1) were DPA, MTX, AZP and CyA; however, the last two were never used as initial DMARDs. Not surprisingly, combination therapies were also employed late in the disease course. These conclusions can also be drawn from the average number of DMARDs before application of a particular regimen (Table 2Go).

When the use of first ever DMARDs was analysed over time, antimalarials were clearly leading in the 1970s and 1980s, while SSZ and MTX took the lead in the late 1990s (Fig. 5Go). When the effects of first ever DMARDs on the acute-phase response were analysed, the data shown in Fig. 4Go were fully confirmed: CRP levels fell from 28.8±29.8 mg/l before therapy to 15.6±19.1 mg/l at the end, and ESR levels were 44.9±30.0 mm/h before and 29.4±25.4 mm/h at the end of first DMARD therapies (P < 0.001 for both variables). These results strengthen the conclusion from the data described above and in Fig. 4AGo that earlier DMARD courses were more effective than later ones.



View larger version (26K):
[in this window]
[in a new window]
 
FIG. 5. Initial DMARDs for RA during 1974–1999 (222 patients, 469 courses, 671 patient years). The data show the changes in frequency of application of gold compounds, chloroquine, methotrexate and sulphasalazine as first DMARDs.

 


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Therapeutic approaches change over time as a consequence of increasing information on efficacy and safety, and of the emergence of new therapies. For many years, no new DMARDs for treating RA have been developed. Changes in the use of traditional DMARDs have reflected the increasing evidence about their efficacy and/or toxicity.

There are many determinants of drug choice in RA patient care. The choice of a certain drug is the result of a decision process that usually includes disease activity and certain physician or patient characteristics. Furthermore, actual trends, such as new drugs and intention to treat early [25], are influencing this decision process. Also, the previous therapy (and the reason for its discontinuation) may be considered before starting a new therapy. Finally, there will be considerable intra-individual variation in drug prescription between rheumatologists [26].

Of the three most commonly applied DMARDs in the 1970s and 1980s, DPA, PG and CQ, only the last continued to be a standard therapy in the late 1990s. CQ was always considered the least toxic DMARD [20] and was therefore a preferred drug, prescribed early in the disease process. However, the approach to the therapy of RA has changed during the past 10–15 yr to give priority to more effective agents [13, 25, 27]. Because the efficacy/toxicity trade-offs for MTX and SSZ are similar to those of antimalarials [20], these drugs have been used more and more frequently in newly diagnosed RA during the last decade (Fig. 2Go). In our patient series, drugs like AZP and CyA were not used as first DMARDs at all, which might partly reflect the lack of opportunity for them to be employed as first DMARDs in earlier years and the fear of increased toxicity from these agents.

In general, CQ and SSZ were the most commonly used first DMARDs. However, when these drugs failed, MTX followed in most cases. Nevertheless, the administration of MTX as first DMARD to newly diagnosed RA patients has increased considerably throughout the years (Fig. 5Go). MTX became the most popular DMARD in the treatment of RA after it was reintroduced in the mid-1980s [18]. Once MTX is employed, the probability of switching to another DMARD is lower. This is in line with the high retention rate of MTX compared with other agents [6, 28].

CRP and/or ESR values at initiation of therapy were significantly higher for MTX compared with SSZ and CQ. This suggests that patients with more active disease were more likely to be treated with MTX than with other DMARDs, while CQ and SSZ were rather used in patients with low disease activity. Interestingly, the reduction in the acute-phase response was greater for first DMARDs and tended to decrease for consecutive ones. Moreover, the proportion of patients with adverse events was significantly higher during later DMARD courses compared with the first (data not shown). On these two grounds, initial DMARDs were retained significantly longer than later ones. Thus, patients fared significantly better on the first than on subsequent DMARDs, which is in accordance with a recent meta-analysis [29].

Although true remission or cure is still rare, DMARDs are effective and therefore necessary in order to retard the progression of RA [16]. Nevertheless, adverse events emerge or drugs become ineffective. This has been shown clearly here: 50–60% of patients treated with a DMARD required a subsequent course with another drug. Termination of therapy reflects failure of RA treatment.

The common lack of response as well as the failure of RA to respond consistently to DMARD therapy requires a wide range of disease-modifying drugs. Several new DMARDs have been introduced recently [79]. Clinical practice will reveal whether the newly introduced agents, irrespective of their cost, are good alternatives only when other DMARDs have failed, or have the efficacy and the safety necessary for them to be used as initial drugs in the treatment of RA. The clinical trials suggest that these drugs will not be effective in all patients and are accompanied by adverse events. These data, in conjunction with the findings of the present report, emphasize the need for a continued search for more effective and less toxic therapies for the retardation and arrest of disease progression in RA.


    Notes
 
Correspondence to: J. S. Smolen, Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Vienna General Hospital, Waehringer Guertel 18–20, A-1090 Vienna, Austria. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Wilske KR, Healey LA. Remodeling the pyramid—a concept whose time has come. J Rheumatol1989;16:565–7.[ISI][Medline]
  2. Bensen WG, Bensen W, Adachi JD, Tugwell PX. Remodelling the pyramid: the therapeutic target of rheumatoid arthritis. J Rheumatol1990;17:987–9.[ISI][Medline]
  3. Pincus T. Aggressive treatment of early rheumatoid arthritis to prevent joint damage. Bull Rheum Dis1998;47:2–7.
  4. Choy EH, Scott DL. Drug treatment of rheumatic diseases in the 1990s. Achievements and future developments. Drugs1997;53:337–48.[ISI][Medline]
  5. Wijnands MJ, van't Hof MA, van Leeuwen MA, van Rijswijk MH, van De Putte LB, van Riel PL. Long-term second-line treatment: a prospective drug survival study. Br J Rheumatol1992;31:253–8.[ISI][Medline]
  6. Wolfe F, Hawley DJ, Cathey MA. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1017 consecutive starts. J Rheumatol1990;17:994–1002.[ISI][Medline]
  7. Maini R, St Clair EW, Breedveld F et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet1999;354:1932–9.[ISI][Medline]
  8. Smolen JS, Kalden JR, Scott DL et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet1999;353:259–66.[ISI][Medline]
  9. Weinblatt ME, Kremer JM, Bankhurst AD et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med1999;340:253–9.[Abstract/Free Full Text]
  10. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum1988;31:315–24.[ISI][Medline]
  11. Menkes CJ. Effects of disease-modifying anti-rheumatic drugs, steroids and non-steroidal anti-inflammatory drugs on acute-phase proteins in rheumatoid arthritis. Br J Rheumatol 1993;32(Suppl. 3):14–8.
  12. Otterness IG. The value of C-reactive protein measurement in rheumatoid arthritis. Semin Arthritis Rheum1994;24:91–104.[ISI][Medline]
  13. Wolfe F, Michaud K. The clinical and research significance of the erythrocyte sedimentation rate. J Rheumatol1994;21:1227–37.[ISI][Medline]
  14. Wolfe F. Comparative usefulness of C-reactive protein and erythrocyte sedimentation rate in patients with rheumatoid arthritis. J Rheumatol1997;24:1477–85.[ISI][Medline]
  15. Kushner I. C-reactive protein in rheumatology. Arthritis Rheum1991;34:1065–8.[ISI][Medline]
  16. van Leeuwen MA, van Rijswijk MH, van der Heijde DM et al. The acute-phase response in relation to radiographic progression in early rheumatoid arthritis: a prospective study during the first three years of the disease. Br J Rheumatol 1993;32(Suppl. 3):9–13.[Medline]
  17. Devlin J, Gough A, Huissoon A et al. The acute phase and function in early rheumatoid arthritis. C-reactive protein levels correlate with functional outcome. J Rheumatol1997;24:9–13.[ISI][Medline]
  18. Weinblatt ME, Coblyn JS, Fox DA et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med1985;312:818–22.[Abstract]
  19. Weinblatt ME, Maier AL, Fraser PA, Coblyn JS. Longterm prospective study of methotrexate in rheumatoid arthritis: conclusion after 132 months of therapy. J Rheumatol1998;25:238–42.[ISI][Medline]
  20. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum1992;35:1117–25.[ISI][Medline]
  21. Pinals RS, Masi AT, Larsen RA. Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum1981;24:1308–15.[ISI][Medline]
  22. Felson DT, Anderson JJ, Boers M et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. The Committee on Outcome Measures in Rheumatoid Arthritis Clinical Trials. Arthritis Rheum1993;36:729–40.[ISI][Medline]
  23. van Gestel AM, Prevoo ML, van't Hof MA, van Rijswijk MH, van De Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum1996;39:34–40.[Medline]
  24. Paulus HE, Ramos B, Wong WK et al. Equivalence of the acute phase reactants C-reactive protein, plasma viscosity, and Westergren erythrocyte sedimentation rate when used to calculate American College of Rheumatology 20% improvement criteria or the Disease Activity Score in patients with early rheumatoid arthritis. Western Consortium of Practicing Rheumatologists. J Rheumatol1999;26:2324–31.[ISI][Medline]
  25. Irvine S, Munro R, Porter D. Early referral, diagnosis, and treatment of rheumatoid arthritis: evidence for changing medical practice. Ann Rheum Dis1999;58:510–3.[Abstract/Free Full Text]
  26. Suarez-Almazor ME, Soskolne CL, Saunders LD, Russell AS. Use of second line drugs for the treatment of rheumatoid arthritis in Edmonton, Alberta. Patterns of prescription and longterm effectiveness. J Rheumatol1995;22:836–43.[ISI][Medline]
  27. van der Heijde DM, van Riel PL, Nuver-Zwart IH, van De Putte LB. Sulphasalazine versus hydroxychloroquine in rheumatoid arthritis: 3-year follow-up. Lancet1990;335:539.[ISI][Medline]
  28. de la Mata J, Blanco FJ, Gomez-Reino JJ. Survival analysis of disease modifying antirheumatic drugs in Spanish rheumatoid arthritis patients. Ann Rheum Dis1995;54:881–5.[Abstract]
  29. Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors predicting response to treatment in rheumatoid arthritis: the importance of disease duration. Arthritis Rheum2000;43:22–9.[ISI][Medline]
Submitted 19 July 2001; Accepted 13 May 2002