Rheumatology

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Rheumatology 2002; 41: 1346-1356
© 2002 British Society for Rheumatology

Review

Evidence from clinical trials and long-term observational studies that disease-modifying anti-rheumatic drugs slow radiographic progression in rheumatoid arthritis: updating a 1983 review

T. Pincus^1,, G. Ferraccioli², T. Sokka^1,,3, A. Larsen⁴, R. Rau⁵, I. Kushner⁶ and F. Wolfe⁷

¹ Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University School of Medicine, 203 Oxford House, Nashville, TN 37232-4500, USA,
² Division of Rheumatology, Department of Internal Medicine, DPMSC, School of Medicine of Udine, 33100 Udine, Italy,
³ Jyvaskyla Central Hospital, 40620 Jyvaskyla, Finland,
⁴ Rheumatology Department, Kongsvinger Sjukehus, N-2226 Kongsvinger, Norway,
⁵ Evangelisches Fachkrankenhaus, Rheumaklinik, Rosenstrasse 2, D-40882 Ratingen, Germany,
⁶ Division of Rheumatology, Case Western Reserve University, MetroHealth Medical Center Campus, 2500 MetroHealth Drive, Cleveland, OH 44109-1998 and
⁷ Wichita Arthritis Center, 1035 North Emporia, #230, Wichita, KS 67214, USA

	Abstract

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Earlier reports, including a comprehensive 1983 review, had indicated that slowing of radiographic progression was relatively unusual in treatment of rheumatoid arthritis (RA) using traditional disease modifying anti-rheumatic drugs. However, in recent years, slowing of radiographic progression has been documented in a number of clinical trials, as well as long-term observational studies, with use of (in alphabetical order) adalimumab, anakinra, corticosteroids, cyclophosphamide, cyclosporin, etanercept, gold salts, infliximab, leflunomide, methotrexate and sulphasalazine. At this time, disease modification is a realistic goal in the clinical care of patients with RA. Documentation of improved long-term outcomes requires long-term observational data over 5–20 yr to supplement data from randomized controlled clinical trials over 6–24 months.

	Introduction

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Medical management of rheumatoid arthritis (RA) is directed to the control or reduction of inflammatory activity in order to prevent or slow joint damage and maintain or improve functional status [1–3]. Many drugs have efficacy to reduce RA inflammatory activity over a period of a year or less [4, 5]. However, it is well established that inflammatory indicators may be stable or improved considerably over 1–10 yr, whereas radiographic joint damage progresses [6–12]. Therefore, it remains open in the minds of many physicians whether drugs that are efficacious in clinical trials over 3 yr or less are effective over many years to slow and possibly prevent joint damage [13, 14]. A 1983 review concluded that most studies of drugs which have been termed ‘disease-modifying anti-rheumatic drugs' [15] or even ‘remission-inducing drugs' [16, 17] have indicated little evidence for significant effects on radiographic progression [18].

Since publication of that review, new agents, including methotrexate [19–22], cyclosporin A [23, 24], leflunomide [25, 26], etanercept [27, 28], infliximab [29] and anakinra [30], have been approved for use in RA. Furthermore, effective quantitative scoring methods to assess radiographic damage have been refined by Sharp [31, 32] and Larsen [33–36], and others who have modified these methods [37–39]. Many studies using these quantitative radiographic scores suggest that the newer agents may be truly disease-modifying anti-rheumatic drugs (DMARDs), which appear to have greater efficacy than earlier drugs used for RA and may slow radiographic progression.

In theory, it would appear optimal to document the long-term effectiveness of DMARDs in RA with randomized controlled clinical trials. Indeed, considerable evidence has been accumulated in clinical trials since 1983 that modification of radiographic progression is possible at this time in most patients with RA. However, short-term clinical trials may give favourable impressions which are not seen in long-term observational studies [40–42]. For example, a meta-analysis of clinical trials suggested similar efficacy of methotrexate, sulphasalazine, injectable gold and penicillamine in clinical trials [43], while long-term continuation of methotrexate over periods of 2 yr or longer was considerably greater than those of the other drugs [44, 45] suggesting better efficacy of and/or less adverse effects of methotrexate compared with the other drugs. The discrepancy of these results appeared to be explained by selection criteria and a short time frame, as well as other limitations of clinical trials [41, 42].

These considerations suggest that the ‘best evidence’ concerning the slowing of radiographic progression in RA would require data from long-term clinical observational studies, in addition to short-term randomized clinical trials and meta-analyses. Each type of study has strengths and weaknesses. Randomized controlled clinical trials provide the best method of comparing the efficacy of a drug vs placebo or another drug without the inevitable biases of patients and their physicians in choices of therapies. However, long-term clinical trials to compare a drug vs placebo are not possible in RA because of logistical and ethical considerations [46], and clinical trials over short periods in RA and other chronic diseases are not invariably generalizable to long-term outcomes [42]. Long-term observational studies, in contrast to clinical trials, were initially required to establish radiographic progression in RA [47–54], and are needed to document definitively the amelioration or prevention of radiographic damage over time. However, long-term observational studies are intrinsically difficult to interpret because of the absence of a control group to determine whether an apparently favourable effect of a drug results from the therapy or some other aspect, such as patient selection, change in disease severity, and other limitations.

It may require decades for definitive evidence that DMARDs effect long-term slowing of radiographic progression in RA. However, patients and their physicians cannot await such evidence over the next 5–20 yr, during which time joint damage is likely to progress without effective treatment. Therefore, recognizing methodological concerns regarding both clinical trials over 2 yr or less and long-term observational studies, a summary of evidence concerning specific agents is presented in this review. This review presents neither a meta-analysis nor a comprehensive review, but a summary of data which support the concept that radiographic progression may be slowed in RA with many contemporary therapies.

	Injectable gold salts

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
In an early randomized controlled clinical trial in 1974, Sigler et al. [55] reported that radiographic progression over 2 yr was significantly less in patients who were treated with injectable gold compared with those treated with placebo (Table 1). However, other early studies indicated that treatment with gold did not slow radiographic progression [56]. In a later clinical trial, Van Riel et al. [57] found that radiographic progression over 48 weeks was significantly less in patients who were treated with injectable gold thioglucose than in those treated with oral gold (auranofin). Furthermore, a statistically significant increase in the number of new erosions was seen in auranofin-treated patients but not in patients treated with injectable gold. A similar result was found in a study by Rau et al. over 3 yr [58].

View this table: [in this window] [in a new window]   TABLE 1. Randomized controlled clinical trials indicating slowing of radiographic progression in patients with RA

 
Rau et al. [59] (Table 1) also treated 102 patients who had erosive RA over a median of 14 months with either weekly parenteral methotrexate or gold sodium thiomalate. No significant difference was seen between the two groups according to Ratingen-modified Larsen scores. However, radiographic progression was less between 6 and 12 months of treatment compared with 0–6 months, suggesting a slowing of radiographic progression. These results suggested that slowing of radiographic progression was achieved with either full-dose gold salts or methotrexate (see below).

A clinical trial of patients with RA of less than 2 yr duration indicated that patients who were treated early with auranofin had better outcomes at 2 yr than patients in whom DMARD treatment was delayed by 8 months [60]. In a follow-up study at 5 yr, differences between the two groups in Larsen radiographic scores were seen at each year, which widened in later years, suggesting ‘the existence of a therapeutic window in RA within the first 2 years of disease’ [61] (Table 2).

View this table: [in this window] [in a new window]   TABLE 2. Clinical observational studies which demonstrate slowing of radiographic progression in patients with RA

 
In a long-term observational study (Table 2), Luukkainen [62] reported in 1977 that patients treated with injectable gold early in the course of illness had less radiographic progression than those treated with gold at later stages of disease, and concluded that ‘the earlier the treatment was initiated, the better was the result’.

	Sulphasalazine

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Van der Heijde et al. [63] observed in a clinical trial over 48 weeks (Table 1) that 22 patients treated with sulphasalazine had 2.1 new erosions and a total score of 7.3 (van der Heijde modified Sharp scale), while patients treated with hydroxychloroquine had 8.3 new erosions and a total score of 17.3 (P<0.01). Further observations confirmed that sulphasalazine slowed radiographic progression more than hydroxychloroquine over 3 yr [64]. An observational study also suggested that sulphasalazine was superior to no therapy [65] (Table 2).

	D-Penicillamine

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Carroll et al. [66] found greater radiographic progression in patients who received sulphasalazine compared with D-penicillamine over 1 yr, but this difference was not statistically significant (Table 1). On the basis of this one study, it may be suggested that D-penicillamine may have a modest effect in slowing radiographic progression in RA.

	Methotrexate

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
In a clinical trial (Table 1), Jeurissen et al. [67] found that patients treated weekly with low-dose methotrexate 7.5 mg orally had significantly fewer new erosions and higher levels of radiographic stabilization than patients treated daily with azathioprine 100 mg orally. Weinblatt et al. [68] demonstrated in another randomized controlled clinical trial that patients treated over 9 months with methotrexate had significantly lower increases in erosion and joint space narrowing scores than patients treated with auranofin. Drosos et al. [69] reported statistically significant differences in radiographic progression of 30 patients treated with methotrexate compared with 30 patients treated with D-penicillamine over 5 yr; among patients treated with methotrexate, 15 were stable, nine were worse and six were healed, compared with 22 stable, eight worse and none healed among the D-penicillamine-treated patients.

Some early observational studies suggested that methotrexate did not slow radiographic progression in patients with advanced RA [70, 71]. However, the authors recognized that continued progression might occur when patients are treated late in their disease, after considerable irreversible joint damage has arisen. Hanrahan et al. [70] suggested that ‘if methotrexate is to be used, a more aggressive approach be adopted to reduce not only symptoms but signs of active disease’.

Later long-term observational studies indicated slowing of radiographic progression with methotrexate (Table 2). Weinblatt et al. [72] noted that erosions were improved or unchanged in eight of 14 patients who took methotrexate over 3 yr. When 10 of these patients were re-examined in 1992 at 84 months, six had progressed, three were unchanged and one showed healing [73]. Kremer and Lee [74] observed that after 24 months of methotrexate treatment 14 of 22 patients were unchanged, eight had improved and none had worsened, and after 26–60 months 16 were unchanged, six worsened and none improved.

Reykdal et al. [75] found that the mean rate of progression was reduced sharply after institution of methotrexate compared with before methotrexate. Rau et al. [76] found that mean radiographic scores progressed significantly more in patients treated with earlier DMARDs, including injectable gold, D-penicillamine and antimalarial drugs, over a mean of 8.1 yr of disease than over a subsequent 48-month period with methotrexate therapy. The authors suggested that methotrexate may slow radiographic progression after poor responses to other DMARDs.

Maravic et al. [77] found evidence of radiographic stabilization over 1 yr in 23 of 29 patients treated with methotrexate who had a mean of 6.6 months of disease (Table 2). These findings were in contrast to earlier observations by this group in 1990 [71] showing that there was little evidence for slowing of radiographic progression in patients with a mean duration of disease of 12.9 yr. These authors also concluded that stabilization of radiographs is more likely if patients are treated early in disease [77].

An uncontrolled study with intriguing results was reported by Rich et al. [78], who analysed radiographic progression in 24 patients who were treated with methotrexate (Table 2). Over 10 months after baseline, 72% of patients with baseline erosions showed radiographic progression compared with only 31% with no baseline erosions. Furthermore, an almost four-fold higher rate of progression of erosions was seen in patients who already had baseline erosions compared with those who did not have baseline erosions.

Without a control group, results of the long-term observational studies could be interpreted to suggest simply that patients with more severe disease are likely to progress more rapidly than patients with milder disease. However, the results are also consistent with the interpretation that methotrexate slows radiographic progression and possibly prevents the development of erosions in at least certain patients. Although control data are not available in the observational studies cited above, the data cumulatively suggest that the expected rate of progression of radiographic damage in RA is slowed by methotrexate.

	Cyclosporin A

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Several randomized controlled clinical trials have indicated that cyclosporin A slows radiographic progression (Table 1). Forre [79] found that radiographic Larsen scores were unchanged over 48 weeks in 61 patients treated with cyclosporin A compared with an increase of 0.17 units in 61 patients treated with placebo (P<0.004). An open-label clinical trial at 32 sites in Italy indicated that 167 patients who were treated with cyclosporin A had significantly lower increases over 12 months in joint erosion and damage scores than 173 patients treated with other DMARDs, including chloroquine, hydroxychloroquine, auranofin, injectable gold, D-penicillamine and sulphasalazine [80]. Drosos et al. [81] treated 103 patients with RA of less than 3 yr duration with cyclosporin A or methotrexate over 2 yr, and reported no significant progression of radiographic scores in either group (Table 1).

Radiographic progression in 54 patients with early RA who took cyclosporin A was less than in patients who took chloroquine over 2 yr, although differences were not statistically significant [82] (Table 2). In 375 patients treated in Germany and Scandinavia (Table 2), gold injections and cyclosporin A resulted in similar slowing of radiographic progression [83], with further significant slowing in patients in both groups who also took concurrent corticosteroids (less than 7.5 mg prednisolone/day) (see below). These results are consistent with the interpretation that treatment with cyclosporin A, gold injections and methotrexate each has the capacity to slow radiographic progression.

	Leflunomide

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Several clinical trials indicate slowing of radiographic progression with leflunomide (Table 1). Smolen et al. [25] found that radiographic progression was significantly less in patients treated over 24 weeks with either leflunomide or sulphasalazine than in those treated with placebo; no differences were seen between patients who took either DMARD. Strand et al. [26] reported that radiographic progression was significantly lower in patients treated with leflunomide or methotrexate than in those treated with placebo over 12 months; differences between methotrexate and leflunomide were not significant. In another analysis, Sharp et al. [84] reported that patients treated for 12 months with leflunomide or sulphasalazine showed similar, significant reductions in expected radiographic progression. No long-term observational data concerning leflunomide are available.

	Etanercept

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Etanercept is a tumour necrosis factor (TNF) receptor:Fc fusion protein inhibitor with clinical efficacy in patients with RA when used as a single agent [27, 85] and in combination with methotrexate [28]. In a randomized trial over 1 yr, Sharp scores increased by 0.47 in patients who received etanercept vs 1.03 in patients who received methotrexate, suggesting that etanercept slowed radiographic progression slightly more than methotrexate, but that both drugs showed favourable effects compared with expected results [85] (Table 1).

	Infliximab

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Infliximab, a mouse-human chimeric monoclonal antibody to TNF-, has also been found to have clinical efficacy in patients with RA as a single agent [86, 87] and in combination with methotrexate [29, 88]. In a clinical trial (ATTRACT) with a randomized design, addition of infliximab to methotrexate in patients who had persistently active disease while taking methotrexate indicated essentially no radiographic progression over 54 weeks compared with patients taking methotrexate only (Table 1) therefore infliximab can slow radiographic progression in RA [88]. It should be recognized, however, that the patients in this study had to have ‘failed’ or have had only partial responses to methotrexate in order to be included in this study.

	Anakinra

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Anakinra is an interleukin 1 receptor antagonist (IL1-Ra) and has been documented in clinical trials to have efficacy compared with placebo in patients with RA [30]. Analyses of radiographic progression at 24 and 48 weeks according to Genant-modified Sharp and Larsen scores indicated slowing of radiographic progression relative to placebo [89] (Table 1). The rate of progression between 24 and 48 weeks was reduced compared with 0–24 weeks, perhaps reflecting a lag phase after initiation of treatment in the detection of slowing of radiographic progression.

	Adalimumab

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
A fully human anti-TNF antibody, adalimumab (D2E7), was used to treat patients with RA over 1 yr. No evidence of any radiographic progression was seen over the 1-yr period, in contrast to substantial progression in the preceding year in available radiographs of participating patients (Table 1) [90]. In another study, 15/36 (42%) patients who were treated with adalimumab presented no radiographic progression over 2 yr [91] (Table 2). This biological agent is not yet approved by the Food and Drug Administration in the USA.

	Corticosteroids

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
The use of corticosteroids in RA remains controversial, primarily because of possible undesirable side-effects [92–95]. Evidence for slowing of radiographic progression has been available for >45 yr. The Empire Rheumatism Council study published in 1955 [96] indicated that patients who received an average of 69 mg/day of cortisone (14 mg prednisone equivalent) for 1 yr had less radiographic progression than patients who received 4 g/day of aspirin, although these differences were not statistically significant. Another study, however, indicated significantly less progression in 41 patients who received prednisolone 20 mg/day for 2 yr and 10 mg/day for a third year compared with 36 patients who received high-dose aspirin for 2 yr [97]. Radiographic progression was seen in 17% of patients who were treated with prednisolone after 1 yr and 41% at 2 yr, compared with 47% who were treated with aspirin after 1 yr and 72% after 2 yr, with advantage to corticosteroids in both hands and feet. Three-year differences between the groups were not significant, perhaps because patients who were treated initially with aspirin were given prednisolone during the third year or because of a lower steroid dose. In a long-term analysis, 51% of patients who had received prednisolone had new erosions, in contrast to 94% of patients treated with aspirin alone who had new erosions [98].

Kirwan et al. [99] conducted a randomized controlled clinical trial over 2 yr, observing that, among 147 patients who had no erosions at baseline, only 15 of 68 patients (22%) who took 7.5 mg prednisolone daily developed erosions compared with 36 of 79 who took placebo (46%), a statistically significant and clinically meaningful difference. Evidence for corticosteroid effects on radiographic progression is also seen in another three clinical trials. Zeidler et al. [83] treated patients with gold injections or cyclosporin A, as noted above. They found significant slowing of radiographic progression in patients in both groups who took corticosteroids (less than 7.5 mg prednisolone/day) compared with those who took no corticosteroids. Rau et al. treated 190 patients with early RA with either injectable gold (60%) or methotrexate (40%), as well as either prednisolone 5 mg/day or placebo in a 2-yr randomized controlled clinical trial [100]. Radiographic progression was significantly less in patients who took prednisolone compared with placebo with either DMARD during the first year of the study, and was minimal in all patients during the second year. A recent report from Utrecht in The Netherlands indicated significantly lower radiographic progression in 40 patients who were randomized to treatment with prednisone 10 mg daily than in 41 patients randomized to placebo over 2 yr [101].

	Combination drug regimens

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Two reports involving combination DMARD therapy plus prednisolone demonstrate unequivocal evidence that treatment slows radiographic progression (Table 1). Boers et al. [102] conducted a clinical trial in The Netherlands in which patients with RA of less than 2 yr duration (mean 4 months) were randomized to receive either sulphasalazine or a combination of sulphasalazine, methotrexate and high-dose short-term prednisolone. Patients who took the triple combination regimen had lower degrees of radiographic progression than patients who took sulphasalazine monotherapy, with lower radiographic scores after 5 yr of disease also [103].

The Finnish RA Combination Therapy Trial (Fin-RACo) study of patients with early RA who had not received DMARDs randomized patients to a combination of sulphasalazine, methotrexate, hydroxychloroquine and prednisolone vs a single DMARD. The initial single DMARD was sulphasalazine; after 3 months, sulphasalazine could be replaced by methotrexate (or another DMARD if appropriate) as the single DMARD, so that patients randomized to the single DMARD group always took one DMARD during the first 2 yr of the study [104] (Table 1). Radiographic progression after 5 yr was significantly less in the patients who received the combination, although some progression was seen even with the combination regimen [105].

	General analyses of DMARD effects on radiographic progression

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
Alarcon et al. [106] performed a meta-analysis in 1992 which indicated that methotrexate slowed radiographic progression more than azathioprine, but similarly to injectable gold salts. Van Riel et al. compared the results of three different clinical trials and concluded that patients treated with injectable gold, sulphasalazine or methotrexate showed significantly less radiographic progression than patients treated with oral gold, hydroxychloroquine or azathioprine. Rau and Herborn [112] described healing phenomena with gold injections and methotrexate, and others have also described healing phenomena [72, 108–111, 113], although healing has been described only in a few patients.

Further evidence that radiographic progression is slowed by DMARD therapy was reported by Abu-Shakra et al. [114], who compared two groups of 22 patients with RA for 16 yr; one group had been treated with DMARDs in Israel and the other group had not received DMARDs in the former Soviet Union before emigrating to Israel (Table 2). Scores for erosions, joint-space narrowing and joint damage were significantly higher in former Soviet Union patients than in Israeli patients. While there were undoubtedly differences between the two groups of non-randomized patients in addition to the DMARD treatment, such as genetic or nutritional factors which may influence disease severity, the data are consistent with a DMARD effect. Furthermore, the findings are of considerable interest, as 16-yr controlled studies in patients with non-DMARD-treated RA almost certainly will never be performed [46].

Sokka et al. [115] compared the Larsen scores of 85 patients who were treated continuously with DMARDs according to the ‘sawtooth’ strategy [116] during the 1980s and 1990s with the scores of 103 patients in an earlier cohort in whom intramuscular gold or hydroxychloroquine had been discontinued due to toxicity or lack or loss of efficacy in most of the patients during the 1970s (Table 2). Larsen scores were significantly lower in the more extensively treated cohort over 8 yr of observation. Again, there were undoubted differences between the two groups of patients in addition to more vs less aggressive DMARD treatment, but the data are again consistent with a DMARD effect. These results are of interest as 8-yr controlled studies in patients with RA are not likely to be performed.

	Summary of DMARD effects on radiographic progression

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 
A summary of the studies discussed above is presented in Table 3. Methotrexate, cyclosporin A, injectable gold, leflunomide, etanercept, infliximab, anakinra, D2E7, corticosteroids and sulphasalazine have been reported in at least two studies to provide statistically significant advantages over placebo or other DMARDs in the slowing of radiographic progression. The effectiveness of these agents has not been seen consistently in all studies, which may perhaps be explained in part by features of the studies that may render it difficult to demonstrate slowing of radiographic progression, such as a relatively short time of observation or the inclusion primarily of patients with long-standing disease. While oral gold, penicillamine, hydroxychloroquine and azathioprine may have some effects in slowing radiographic progression, these effects appear minimal at best. The drugs which clearly slow structural damage in patients with RA may be termed truly ‘disease-modifying drugs' [117, 118].

View this table: [in this window] [in a new window]   TABLE 3. Drugs with documented capacity to slow radiographic progression in RA, listed in alphabetical order

 
Because there is firm evidence of disease modification, the possibility that DMARDs prevent, rather than merely retard, radiographic progression might be realistic at this time. This must be studied in patients with minimal or no radiographic damage, although disease activity at baseline might be demonstrated with ultrasound or magnetic resonance imaging [119–122]. The availability of powerful new drugs renders possible the goal of prevention of organ damage through control of dysregulation in a chronic disease, as in the modern approach to hypertension, diabetes and other diseases. Because many patients with early arthritis may not develop erosive disease [123, 124], large numbers of patients would be required for clinical trials as well as long-term observational studies in order to provide sufficient statistical power to assess the prevention of radiographic abnormalities. Nonetheless, the goal of prevention of joint damage would appear a realistic opportunity at this time for the rheumatology community.

	Acknowledgments

 
The authors were supported in part by the Jack C. Massey Foundation, Aventis, Novartis and Amgen.

	Notes

 
Correspondence to: T. Pincus, Vanderbilt University School of Medicine, Division of Rheumatology and Immunology, 203 Oxford House, Nashville, TN 37232, USA.

	References

Top Abstract Introduction Injectable gold salts Sulphasalazine d-Penicillamine Methotrexate Cyclosporin A Leflunomide Etanercept Infliximab Anakinra Adalimumab Corticosteroids Combination drug regimens General analyses of DMARD... Summary of DMARD effects... References

 

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Submitted 19 February 2002; Accepted 28 June 2002

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