Department of Rheumatology, Evangelisches Fachkrankenhaus, Ratingen,
1 Clinic for Internal Medicine I, Centre for Rheumatic Diseases, Bad Abbach and
2 Ludwig-Maximilians University, School of Medicine, Munich, Germany
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Abstract |
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Methods. In a randomized, double-blind fashion, 174 patients from two centres were assigned to receive weekly intramuscular injections of either 15 mg MTX or 50 mg GSTM. After 12 months, the study was continued as an open prospective study for an additional 2 yr, administering the same amount of MTX and half of the GSTM dose. Radiographic outcomes were assessed by standardized methods in all patients at baseline and after 6, 12, 24 and 36 months.
Results. Intention-to-treat analysis showed that patients treated with MTX had higher radiographic scores and more erosive joints at all follow-up points. However, there was no statistically significant difference between the two treatment groups. The progression rate was significantly slower during the second and third years of follow-up in both groups. Baseline and time-integrated (area under the curve over 6 months) disease activity parameters were good predictors of radiographic outcome after 3 yr. Seropositivity was not an independent predictor of progression. However, patients who were positive for rheumatoid factor had higher time-integrated disease activity (with less response to treatment) and thus their disease was significantly more progressive.
Conclusion. Both of the disease-modifying compounds used in this study, MTX and GSTM, were able to reduce the slope of radiographic progression during 3 yr of follow-up. There was some advantage for parenteral gold but no significant intergroup difference.
KEY WORDS: Rheumatoid arthritis, Radiology, Methotrexate, Gold, Clinical trials.
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Introduction |
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Methotrexate (MTX), one of the disease-modifying anti-rheumatic drugs (DMARDs) used most frequently in RA patients, has demonstrated clinical efficacy in the therapy of RA, both in controlled short-term [35] and in long-term studies [613]; moreover, there is an indication that MTX slows radiographic progression [6, 8, 10, 12, 1422].
Parenteral gold salts have a long history in the treatment of RA. Several studies have shown the ability of gold to slow radiographic progression significantly [2328]. However, compared with MTX, gold salts induce more side-effects [10, 2932].
Although the discontinuation rate in gold-treated patients is higher than in MTX-treated patients only during the first 6 months of treatment [33] and the number of patients staying on the drug long-term does not differ between the two compounds [34], the use of gold salts has declined substantially. Research has revealed no significant difference in efficacy between MTX and GSTM [30, 31, 35]. However, most of these studies used small samples, did not include radiographic outcomes and had a short follow-up period.
The aim of this study was the long-term comparison of MTX and GSTM in patients with early and active RA, focusing on the radiographic outcome. Additionally, we were interested in the identification of potential predictors of radiographic outcome after 3 yr. Radiographic outcome after 12 months [36] and the clinical outcome results from this study have been reported previously [37, 38].
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Patients and methods |
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Patients were excluded if they had one or more of the following criteria: presence of deformities (e.g. ulnar deviation, subluxation); advanced radiographic changes (Larsen stage IIIV); prior treatment with MTX or GSTM; treatment with any other DMARD during the previous 3 months; intra-articular steroid injection within the previous 4 weeks.
Therapy
After randomization, patients received either 15 mg MTX or 50 mg GSTM by intramuscular injection weekly for 12 months in a double-blind fashion. Thereafter, the study was continued as an open prospective trial in which the GSTM dose was reduced by half (50 mg at 2-week intervals); patients receiving MTX remained on their original dose. None of the subjects was supplemented with folate. The parenteral MTX dose of 15 mg translates to an oral dose of 21.4 mg assuming a mean bioavailability of 70%.
Patients were allowed to receive concomitant treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids (<10 mg prednisolone equivalent/day). If side-effects appeared, the study medication was discontinued for up to 2 weeks and was reinstituted thereafter. If the toxicity remained or reappeared, the corresponding study medication was discontinued permanently, and patients were switched to another DMARD, preferably with the counter-study medication, e.g. MTX in the case of GSTM toxicity.
Clinical, laboratory and radiographic evaluation
Standardized clinical and laboratory assessments were scheduled at baseline and after 6, 12, 24 and 36 months.
Standard anteroposterior X-rays of the hands and feet were taken at the same time-points. All films were scored according to a validated scoring method [40]. The method evaluates erosive changes in 38 joints or regions (interphalangeal joints of both thumbs, proximal interphalangeal joints 25, metacarpophalangeal joints 15, os naviculare, os lunatum, radius, ulna, interphalangeal joints of both big toes, and metatarsophalangeal joints 25). Grading of the joints involved semiquantitative evaluation of the joint surface involved in the destructive process: grade 1, definite erosion, <20% destruction of joint surface; grade 2, 2040% destruction of the joint surface; grade 3, 4160% destruction of the joint surface; grade 4, 6180% destruction of the joint surface; grade 5, >80% destruction of the joint surface. Summary scores could range from 0 to 190.
All films were evaluated by a single reader (GH), who was blinded to the study medication but knew the chronological sequence of the films. The intrarater reliability of this reader was excellent and has been reported elsewhere [40]. The intraclass correlation coefficient was 0.89. The smallest detectable difference was 5.3 score units, corresponding to 2.8% of the maximum possible score.
Statistical analysis
Sample size estimates were based on a 20% difference in radiographic scores, 80% power at a 5% level, resulting in 80 patients per treatment group.
All patients were considered for intention-to-treat analysis. Descriptive statistics were used to describe sociodemographic, clinical, laboratory and radiographic variables at the different study points. The two treatment groups were compared using the t-test for continuous variables and the 2 test for categorical variables. Fisher's exact test was used whenever expected cell counts exceeded 5.
The primary outcome measure of this analysis was radiographic progression under the originally randomized treatment regimen. We used paired t-statistics to compare radiographic outcome variables (summary score, number of erosions) from baseline to 12 months, 12 months to 24 months, 24 months to 36 months and baseline to 36 months.
We calculated the proportions of patients who progressed by 5, 10, 20 and >20% of the maximal possible score (190) after 12, 24 and 36 months of follow-up.
We explored whether seropositivity might predict radiographic outcome and calculated radiographic scores and the number of erosive joints, depending on the presence or absence of rheumatoid factor (RF).
Furthermore, we calculated the correlations of different disease activity parameters at baseline and time-integrated over the first 6 months of treatment with radiographic progression. A multivariate linear regression analysis was performed to calculate the relationships of the different predictors with damage progression.
We performed all analyses on subjects who completed the first 12 months on their originally assigned treatment (completer analysis).
Statistical procedures were performed on a personal computer using the SAS statistical software, version 6.12 (SAS Institute Inc., Cary, NC). For all analyses, the level of statistical significance was set at P<0.05.
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Results |
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The demographic, clinical and laboratory variables of these patients have been published previously [36]. In brief, the patients in the MTX and GSTM groups were 54 and 57 yr old respectively and had a median disease duration of 11.5 and 11.2 months; 38 and 33% were on low-dose steroids (<10 mg prednisone/day). They had clinically active disease. The C-reactive protein (CRP) concentration was 4.1 mg/dl in the MTX group and 4.6 in the GSTM group. Disease was erosive in all patients; in the MTX and GSTM groups the mean number of eroded joints was 4.2 and 4.6 respectively and the mean radiographic score was 5.8 and 4.6, representing 3.0 and 2.4% of the maximum possible score of 190.
Thirty patients (17.2%) could not be assessed after 36 months because of death (n=8) or because they were otherwise lost to follow-up (n=22). A detailed description of dropouts and information about toxicity has been provided elsewhere [38].
Intention-to-treat analysis
Radiographic score
The distribution of radiographic scores for patients treated with MTX and GSTM is displayed in Fig. 1 and Table 1A
. There was no statistical difference in radiographic scores between the two treatment groups at baseline or after 6, 12, 24 and 36 months.
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Number of erosive joints
Patients treated with MTX showed a greater increase in the number of erosive joints than patients treated with gold. The differences between the two study groups were, however, not statistically significant at any follow-up point. Within each treatment group, the number of erosive joints changed significantly from baseline to 12 months and during the second and third years of treatment (Table 1C). The increase was significantly greater during the first than during the second year in both groups, while the difference between the second and third years was significant only in the MTX group.
Predictors of radiographically detectable damage
We correlated clinical and laboratory variables as well as functional status at baseline with radiographic progression during 36 months to examine their predictive validity for radiological outcome. Because the course of several values during the first 6 months of follow-up would be a better predictor of radiographic outcome than a single value at baseline and would include treatment effects, we calculated an approximation to the area under the curve (AUC) for each variable during the first 6 months. The corresponding correlation coefficients are shown in Table 3.
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Effect of seropositivity
While there were no significant differences in the radiographic score and in the number of erosive joints at baseline between seropositive and seronegative patients, there were significant differences between the two groups after 1, 2 and 3 yr. Also, seropositive subjects progressed significantly faster during the first, second and third years (Table 4). The decrease in radiographic progression between the first and subsequent years was greater in seronegative than in seropositive patients, but the progression rate during the third year was significantly less than in the first year in seropositive patients also.
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In all models, seropositivity remained a significant predictor of radiographic outcome, independently of the corresponding radiographic score or the number of erosive joints at baseline.
Effect of disease activity
As shown in Table 3, there was a significant correlation between disease activity parameters [erythrocyte sedimentation rate (ESR), CRP, thrombocyte count, leucocyte count, disease activity score (DAS) and swollen joint count (baseline and AUC over 6 months)] and radiographic scores after 36 months as well as after 12 and 24 months. ESR at baseline and time-integrated over the first 6 months correlated slightly better than CRP with radiographic scores after 36 months and also after 12 and 24 months. The pattern of correlation was similar when the number of erosive joints was regarded as the outcome.
We then fitted multivariable linear regression models with radiographic score and number of erosive joints after 36 months and corresponding difference scores between baseline and 36 months as dependent variables and assigned CRP, ESR, thrombocyte count and swollen joint count as independent variables. Controlling for age, gender and therapy, the disease activity variables remained independent predictors of radiographic outcome. We then added RF status to the model, which did not modify the effect of disease activity on radiographic outcome. Furthermore, the AUC swollen joint count and the AUC thrombocyte count remained clearly significant in multivariate linear regression (P<0.01) with ESR and RF as other covariables. RF was not further significantly associated with radiographic progression in this multivariate model. This is explained by the fact that RF-positive patients had a higher acute phase response, and the two factors did not act independently.
Analysis of completers
Seventy-three patients receiving MTX and 53 patients receiving GSTM completed 12 months of follow-up on their original study medication. The magnitude of radiographic scores and the number of erosive joints at baseline and after 12, 24 and 36 months were similar to values for the entire patient population, with higher scores in the MTX group but no statistically significant differences between the two treatment groups. As with the intention-to-treat population, there was also a flattening of the progression curve in the radiographic score and the number of erosive joints after the first year of treatment (Table 1B and D
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Bivariate associations between clinical and laboratory variables and radiographic scores remained similar to those found in the intention-to-treat analysis.
Seropositive patients had a higher radiographic score after 36 months than seronegative patients, but the difference was not statistically significant (17.2 vs 11.3, P=0.08). In contrast, the number of erosive joints after 36 months was significantly higher in seropositive patients (12.2 vs 6.9, P=0.01).
Changes in radiographic score and the number of erosive joints between the different observation points were significantly different between seropositive and seronegative patients, except the changes in radiographic scores between months 12 and 24 (1.8 vs 3.2, P=0.14).
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Discussion |
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We restricted inclusion to patients with early but erosive disease. Because erosions developing early in the course of disease indicate progressive RA with relatively poor prognosis [41], we decreased the likelihood of diagnostic uncertainty, spontaneous remission or the response to NSAIDs alone. The severity of disease in our patients was further underlined by an average number of swollen joints greater than 15 (out of 38 that were evaluated), morning stiffness lasting longer than 90 min, significantly decreased grip strength and substantial limitation of functional capacity. On the other hand, we excluded patients who had already demonstrated joint deformities or whose disease was too advanced (joints with Larsen grade III or higher) to avoid floor effects in the radiographic evaluation.
Both treatment groups achieved significant clinical improvement [37, 38]. Only 11% of the patients in both treatment groups demonstrated substantial radiographic progression and reached greater than 20% of the maximum possible score after 3 yr, while approximately 50% had nearly no progression and reached less than 5% of the maximum possible score.
During the first year of treatment, 23% of patients had no progression at all and 56% showed less progression than the minimal detectable change. These data compare favourably with the most recent results with tumour necrosis factor inhibitors.
Intention-to-treat analysis showed that patients treated with MTX had higher radiographic scores and more erosive joints at all follow-up points. However, there was no statistically significant difference between the two treatment groups. Although the difference was not significant, GSTM seemed to halt progression more than MTX throughout follow-up.
Disease progression was significantly reduced during the second year of follow-up when compared with the first year, and was further reduced during the third year. This finding cannot be explained by a ceiling effect, as the mean radiographic scores after 36 months accounted for less than 10% of the maximal achievable score in both treatment groups. It is also unlikely that the effect is explained by the natural course of the disease; we could not prove this as it is not possible to withhold active treatment from RA patients in long-term clinical trials. The decrease in the rate of progression with time is compatible with the view that disease-modifying drugs reduce the rate of damage progression when the activity of the disease is controlled. The correlation between radiographic progression and parameters of disease activity, with a time lag of 6 (12) months, is well established [42, 43]. The reduction in radiographic progression during the second 6 (12) months when compared with the first 6 (12) months has been observed in several studies with conventional DMARDs as well as with interleukin 1 receptor antagonist (IL1-RA) in patients with RA: the inhibition of radiographic progression with IL-1RA was more pronounced in the second than in the first half-year [44]. A delay in the onset of effect on clinical and radiographic parameters becomes obvious when comparing slow-acting with fast-acting drugs. The combination of 5 mg prednisone with a DMARD (MTX or parenteral gold) in early active RA inhibited radiographic progression significantly more during the first 6 (12) months than DMARD plus placebo, while there was nearly no difference in progression during the second year [45, 46]. Etanercept reduced progression significantly more than MTX during the first 6 months, but the progression rate was the same with both treatments during the second 6 months [47].
We were also interested in identifying predictors of radiographic progression that were independent of treatment effects. Higher values of laboratory and clinical disease activity parameters (ESR, CRP, leucocyte and thrombocyte counts, swollen joint count, DAS) at baseline were predictive of radiographic progression after 3 yr of follow-up. This effect was more pronounced when we used an approximation to the AUC for these variables during the first 6 months. This observation supports the treatment effect of both DMARDs in our study. Our findings are in line with other reports that confirm an association between elevated laboratory parameters of disease activity and radiographic progression [10, 4850].
The impact of RF positivity on radiographic outcome was also explored. Patients who were positive for RF at baseline demonstrated faster radiographic progression during the observation period. Previous studies have reported conflicting resultssome confirmed our results [5153] but others did not demonstrate an association between positive rheumatoid serology and the progression of bone erosions [5456]. In our study, RF did not remain an independent predictor of progression when disease activity parameters were added to a multivariate linear regression analysis; the more pronounced progression in RF-positive patients can be explained by a higher level of time-integrated disease activity, indicating less response to treatment.
The importance of radiographs as the principal outcome measure has been acknowledged by recommendations from the OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) initiative and the ACR, both of which recommend the inclusion of radiographs as an outcome measure in RA trials of 1 yr or longer [2, 57].
While our study and previous research have demonstrated that parenteral gold and methotrexate have very similar effects on clinical and laboratory variables, the present trial demonstrates similar effects on radiographic outcomes after 3 yr.
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Notes |
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References |
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