Disease-modifying anti-rheumatic drug use according to the `sawtooth' treatment strategy improves the functional outcome in rheumatoid arthritis: results of a long-term follow-up study with review of the literature

T. Sokka, T. Möttönen1 and P. Hannonen

Department of Medicine, Jyväskylä Central Hospital, Jyväskylä and
1 Turku University Central Hospital, Turku, Finland

Correspondence to: T. Sokka, Department of Medicine, Central Hospital, FIN-40620 Jyväskylä, Finland.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To investigate long-term functional outcomes of early rheumatoid arthritis (RA) patients treated actively with disease-modifying anti-rheumatic drugs (DMARDs) from diagnosis, according to the `sawtooth' principle, and to compare the results to historical data.

Methods. The surviving 46 and 65 patients from two early RA cohorts were examined on average 13.0 (cohort 1) and 8.5 (cohort 2) yr, respectively, after onset of disease. Functional outcome was measured by the Health Assessment Questionnaire (HAQ) and compared with the HAQ scores of 57 RA patient cohorts found through a Medline computer search.

Results. The respective cross-sectional mean HAQ scores of cohorts 1 and 2 were 0.75 and 0.55, and were more favourable than the mean HAQ scores of 1.27 (27 cohorts, disease duration >10 yr) and 1.13 (13 cohorts, disease duration 5–10 yr) of the comparator cohorts. The median time that our patients were treated with DMARDs out of the total follow-up period was 88%, while in the majority of comparator cohorts the use of DMARDs was less extensive or poorly described.

Conclusions. The observation of better preserved function in patients with RA over 13 and 8.5 yr, compared to earlier reports which indicated more severe declines, is a hopeful sign for the rheumatology community.

KEY WORDS: Rheumatoid arthritis, Functional capacity, Health Assessment Questionnaire, Early RA, Long-term outcome


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Preservation of function is a major goal of treatment in rheumatoid arthritis (RA) as patients generally experience functional declines from the beginning of the disease and throughout the disease course [19].

One approach to preservation of function is the `sawtooth' strategy proposed by Fries [10], which includes early disease-modifying anti-rheumatic drug (DMARD) therapy with continual and serial use of one or multiple DMARDs. It would be optimal to analyse this strategy according to a randomized, controlled (double-blind) clinical trial. However, such a trial is not feasible over the many years required to measure possible effects of sustained DMARD therapy on long-term outcomes of RA, and effectiveness must be analysed through longitudinal observational studies [11].

Self-report questionnaires provide a formal, highly valid and reliable method to assess patients' functional status. Pincus et al. [12], and Hawley and Wolfe [13], have demonstrated that the Stanford Health Assessment Questionnaire (HAQ) [14] is more effective than any other available method in documenting functional decline over 5–10 yr in RA.

In the present paper, we report cross-sectional HAQ scores of 46 and 65 early RA patients at 13 and 8.5 yr after disease onset, treated with DMARDs continually and serially from the diagnosis, later designated by Fries as the `sawtooth' strategy. We also compare our results to historical data.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The study included a total of 135 newly diagnosed RA patients initially recruited to two separate cohorts [15, 16] monitored from the first visit <24 months after disease onset at Jyväskylä Central Hospital. The first cohort of 58 early RA patients was assembled in 1983–85 to study early erosiveness in recent-onset RA (cohort 1). The second cohort of 78 patients was started in the beginning of 1988 as a case–control study to investigate the efficacy and tolerability of sulphasalazine (SASP) in the treatment of early RA (cohort 2). At enrolment of these early RA cases, all met the American Rheumatism Association (ARA) 1958 criteria [17] for definite or classical RA. One initially enrolled patient was later diagnosed as suffering from reactive arthritis and was excluded.

Demographic and clinical characteristics of the patients at outset are shown in Table 1Go. Only one patient was lost to follow-up 1 yr after the diagnosis; demographic and clinical variables of this patient are not included in Table 1Go.


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TABLE 1.  Comparison of mean (range) demographic and clinical variables between the cohort groups at baseline (seropositivity during the follow-up)
 
All patients were enrolled in a prospective, longitudinal study to evaluate the `sawtooth' strategy. In cohort 1, DMARD therapy with i.m. gold was started immediately after the diagnosis, whereas in cohort 2 patients were initially treated with SASP or placebo. In spite of the lag period due to the study setting, the mean symptomatic period before the first genuine DMARD initiation was compatible in both cohorts (8.4 vs 7.5 months for cohorts 1 and 2, respectively). Only one patient has never needed DMARDs due to a self-remitting disease.

All new starts of individual DMARDs or their combinations, as well as the proportion of time the patients were on DMARDs out of the total follow-up time, were recorded.

A total of 23 (17%) patients died during the observation period. At baseline, those who subsequently died were older, and their disease was more active (Table 1Go). The most common cause of death was cardiovascular disease.

The patients were clinically assessed every 3 months for the first 2 yr, and at least yearly thereafter. In January 1997, the surviving 46 and 65 patients were re-examined, when the mean (range) disease duration from the onset of symptoms was 13.0 (11.7–15.3) and 8.5 (7.2–9.6) yr, respectively.

In this paper, we refer to the cross-sectional findings of the 111 examined cohort patients with special emphasis on the patients' functional outcome and the factors related to it. The examination included assessment of the number of tender and swollen joints, a blood test for erythrocyte sedimentation rate (ESR), radiographs of hands and feet, as well as patients' self-assessed pain, general well-being (GH) and functional status.

The patients' functional capacity was assessed by the Stanford HAQ, scoring from 0 to 3 [14]. The current disease activity was measured by the 28-joint-based Disease Activity Score [DAS=0.56xSQRT (tender joint count)+0.28xSQRT (swollen joint count)+ 0.70xln (ESR)+0.014xGH], ranging from 0 to 10 [18]. The method described by Larsen et al. [19] was used to grade radiographic damage. Indices for the wrists were multiplied by five. These and the indices for the I–V PIP as well as MCP joints of the hands and the IP joints of the big toes, and the I–V MTP joints, were added together to form an index from 0 to 210. Pain and GH were assessed by the patient-completed 100 mm horizontal visual analogue scales (VAS) [14]. Arthritis was judged seropositive if rheumatoid factor was positive at any time during the observation period.

The data were entered into a microcomputer and analysed by using the Statistical Package for the Social Sciences (SPSS) [20]. Patients with mild disability (HAQ<=1) were compared to other patients (HAQ>1) with regard to other clinical variables. Statistical significance of differences was determined using the Mann–Whitney test for continuous measures and the {chi}2 test for dichotomous variables.

A Medline computer search was performed to identify reports which included HAQ or modified HAQ (MHAQ) (scales 1–4 changed to 0–3) scores of cohorts of patients with RA who had had disease for longer than 5 yr, published in English after 1988. Our results were compared with these historical data.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The present cohort
The mean (median) HAQ scores were 0.75 (0.63) for cohort 1 and 0.55 (0.25) for cohort 2 after an average duration of disease of 13.0 and 8.5 yr. A total of 39 (35.1%) patients had an HAQ score of 0, while 86 (77.5%), 21 (18.9%) and 4 (3.6%) patients scored between 0 and 1.0, 1.01–2.0 and 2.01–3.0, representing mild, moderate and severe functional impairment, respectively (Fig. 1Go).



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FIG. 1.  Percentage distribution of the cohort patients in HAQ score groups.

 
Patients with mild functional disability (HAQ<=1) differed statistically significantly from other patients (HAQ>1) according to disease activity, age, pain score VAS, Larsen score, number of DMARD starts and joint replacement. No significant differences were seen between the groups in seropositivity, gender and extra-articular disease (Table 2Go).


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TABLE 2.  Comparison of the patients with mild functional disability and the other patients
 
The median time that our patients were treated with DMARDs out of the total follow-up time was 88%, and the mean (range) counts of new starts of individual DMARDs or combinations of DMARDs were 6.5 (1–16) and 3.5 (0–12) for the patients in cohorts 1 and 2, respectively. Figure 2Go details the distribution of the proportion of cohort patients on individual DMARDs 1–10 yr after the diagnosis. The proportion of DMARD non-recipients, as well as the proportion of those who used combinations, increased over time. At the final visit, a total of 21 patients did not use DMARDs due to a long-lasting remission.



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FIG. 2.  Proportion of patients on individual DMARDs or combinations of DMARDs 1–10 yr after the diagnosis. Year, with the number of patients, is shown on the horizontal axis. DMARD, disease-modifying anti-rheumatic drug; MYO, i.m. gold; HCQ, hydroxychloroquine; SASP, sulphasalazine; DPA, D-penicillamine; AZA, azathioprine; AURA, auranofin; CPH82, podophyllotoxin derivatives; MTX, methotrexate; COMBO, combination of DMARDs.

 
Historical control cohorts
Table 3Go summarizes the characteristics and the HAQ or the MHAQ scores of 57 RA cohorts including a total of 13 591 patients with >5 yr disease duration that we were able to find in 30 reports published in English after 1988 [5, 2149]. Most of the studies were cross-sectional, and the patient recruitment had varied from advertisement calls to clinical in-patients. Several studies consisted of subgroups classified according to status at outset, therapy and care given or the subsequent outcome of the patients, as detailed in Table 3Go. Only three studies consisted of patients with early RA and a follow-up period of several years [26, 30, 36]. Indeed, the cohorts and the patients included were very heterogeneous. Furthermore, the MHAQ scores are recognized to be somewhat lower than the HAQ scores, and thus are not entirely comparable with each other.


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TABLE 3.  Characteristics and the mean [median] HAQ (MHAQ) scores in the 57 RA patient cohorts with a disease duration of at least 5 yr
 
In the cohorts with disease duration between 5 and 10 yr, the mean (n=13) or median (n=9) HAQs and the mean MHAQs (n=3) ranged from 0.5 to 1.8 or from 1.3 to 2.3 and from 0.5 to 1.0, respectively. The respective corresponding figures in cohorts with disease duration >10 yr were 0.8–2.4 (n=27), 1.8 (n=1) and 0.6–1.3 (n=3). Table 3Go also shows that the median MHAQ of an additional cohort with disease duration >10 yr was 1.4.

A statement regarding DMARD treatment was found in 24 out of the 57 referred cohorts. The mean number of prescribed DMARDs was mentioned in seven [27, 42, 45], the point [24] and period [26, 30, 40, 43] prevalence of DMARD use in two and five, respectively, and the proportion of the follow-up time on DMARDs in two [44] cohorts. In the study by Munro et al. [36], the DMARD was defined to be i.m. gold.

In Fig. 3Go, originally sketched by Fries, we have summarized the HAQs of the historical cohorts found as well as our present results.



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FIG. 3.  `The sawtooth strategy', as illustrated by Fries [10], supplied with mean or median HAQ scores of 50 cohorts as well as the mean HAQ scores of the present study. Each number corresponds to a study in the reference list (and Table 3Go). Permission for the use of the figure was granted by the Journal of Rheumatology and Professor Fries.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The primary observation in the present study was that the functional capacity of 111 patients with RA who were initially seen after <2 yr of disease was well preserved after 13 and 8.5 yr. Scores for our patients were 0.75 after 13 yr and 0.55 after 8.5 yr of disease, in contrast to scores >1 for most studies.

Fries proposed the figure concerning different courses of RA to illustrate the failure of traditional `pyramidal' DMARD use to alter the long-term disability status of RA patients. However, long-term outcome of RA depends on variables beyond therapy given. Since the course of epidemiological RA is more favourable than that of clinical disease [50], one has to know how the patient cohort is assembled and how the disease is defined [51]. The referred cohorts with patients with the poorest outcome seemed to represent clinical cases in whom DMARD therapy had been started with long delays, if not at all [28, 29, 33, 37]. Furthermore, some of the series with conspicuously good functional outcome appeared to consist of `community based inception cohorts' [21, 23, 38, 40, 41, 43, 44].

We regard our patients as representing good examples of population-based clinical RA cohorts. The hospital in Jyväskylä is the only rheumatological centre in the region, which has 260000 inhabitants. Based on the common consensus, all new RA cases are referred to our centre for diagnostic and therapeutic purposes. Our cohorts also have negligible drop-out rates. Indeed, only one male patient in these two cohorts was lost to follow-up.

Those who died may have been severely disabled and could have worsened the final HAQ scores. However, we suppose that this bias does not differ from other reported clinical cohorts.

One may argue that superior long-term outcomes of our patients were the result of less aggressive disease than in comparator studies—some patients in cohorts with early RA patients might not have progressive disease seen in other long-term studies [52]. A conspicuous shortage of most of the referred comparator studies was the absence of clinical data at the outset, which hampers adequate comparisons. Only in three other reports did the cohort patients consist of early RA cases and their clinical data at the baseline could be found [26, 30, 36]. The data are demonstrated in Table 4Go. In comparison to our results, the most striking differences were the remarkably higher HAQ outcome scores and very modest use of DMARDs in two of them [26, 30]. While all but one of our patients have been treated with DMARDs with a median coverage of 88% of the total follow-up time, only 65 and 55%, respectively, of the patients in the studies by Fex et al. [30] and Corbett et al. [26] had ever been treated with DMARDs.


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TABLE 4.  Cohorts of early RA patients. Comparison of demographic data, ESR and joint damage scores at onset, the use of DMARDs and HAQ scores at the latest visit
 
Some reports of beneficial results of early DMARD initiation on relatively long-term outcome of RA have been published. Egsmose et al. [53] demonstrated that RA cases who had been treated early with DMARDs had a statistically significantly better 5 yr HAQ score than the other group with delayed DMARD initiation. The 6 yr HAQ of the patients of Möttönen et al. [54] (46 patients of that cohort are also included in the present study) was 0.64. Also, these patients had been treated with DMARDs from diagnosis, according to the `sawtooth' strategy. A beneficial effect of early DMARD initiation could not be excluded either when the good functional outcome of 128 Canadian RA patients was considered [40]. In a recent report by Munro et al. [36], early i.m. gold therapy indicated long-lasting (at least for 5 yr) better functional capacity compared to delayed i.m. gold initiation, although the benefits were only modest when compared to other studies (Fig. 3Go).

The beneficial impact of sustained DMARD therapy on maintenance of long-term functional capacity is also supported by some reports. Increased DMARD use was associated with better long-term HAQ values in patients in the ARAMIS database [31]. Improved function was also seen in RA patients who tolerated i.m. gold, sulphasalazine or penicillamine for longer periods in a British study [37]. Furthermore, less progression of functional disability of the patients who had continuing care from rheumatologists in comparison to those who had only intermittent care [44] may, though not discussed, also have been influenced by the more extensive use of DMARDs in these patients.

In early RA, disease activity appears to be the most important explanatory factor for decreased functional capacity [1]. On the other hand, as RA advances, the contributive role of tissue damage reportedly grows [5]. In the present study, despite a longer disease duration, the current disease activity separated most strikingly the groups with poor or well-preserved functional capacity.

The increasing proportion of our patients treated with DMARD combinations over time demonstrates that in some RA patients even the `sawtooth' treatment strategy is insufficient. We must emphasize that despite aggressive DMARD therapy, high clinical disease activity was present in some of our cases even 8–13 yr after the onset of RA. On the other hand, the number of patients without any DMARDs increased over time; 21 (19%) of the patients were in remission without DMARDs at the time of evaluation.

In conclusion, the observation of the improved functional outcome (compared to historical controls) in our 111 patients treated according to the `sawtooth' strategy from diagnosis up to an average of 13 yr is promising. Aggressive therapy with traditional DMARDs appears to have a considerable impact on the result.


    Acknowledgments
 
We thank the Journal of Rheumatology and Professor Fries for permission to use Fig. 3Go. This study was supported by grants from Central Finland Health Care District and Kuopio University Hospital (EVO-funding), Finland.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 15 September 1998; revised version accepted 6 July 1999.