Low-dose prednisolone in addition to the initial disease-modifying antirheumatic drug in patients with early active rheumatoid arthritis reduces joint destruction and increases the remission rateA two-year randomized trial.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 52, No. 11, November 2005, pp 3360–3370 DOI 10.1002/art.21298 © 2005, American College of Rheumatology Low-Dose Prednisolone in Addition to the Initial Disease-Modifying Antirheumatic Drug in Patients With Early Active Rheumatoid Arthritis Reduces Joint Destruction and Increases the Remission Rate A Two-Year Randomized Trial Björn Svensson,1 Annelies Boonen,2 Kristina Albertsson,3 Désirée van der Heijde,2 Catharina Keller,4 and Ingiäld Hafström,3 for the BARFOT Study Group Objective. To assess the efficacy of low-dose prednisolone on joint damage and disease activity in patients with early rheumatoid arthritis (RA). Methods. At the start of their initial treatment with a disease-modifying antirheumatic drug (DMARD), patients with early (duration <1 year) active RA were randomly assigned to receive either 7.5 mg/day prednisolone or no prednisolone for 2 years. Radiographs of the hands and feet were obtained at baseline and after 1 and 2 years and scored according to the Sharp score as modified by van der Heijde. Remission was defined as a Disease Activity Score in 28 joints of <2.6. Bone mineral density was measured by dual x-ray absorptiometry at baseline and after 2 years. Results. Of the 250 patients included, 242 completed the study and 225 had radiographs available both at baseline and at 2 years. At 2 years, the median and interquartile range (IQR) change in total Sharp score was lower in the prednisolone group than in the noprednisolone group (1.8 [IQR 0.5–6.0] versus 3.5 [IQR 0.5–10]; P ⴝ 0.019). In the prednisolone group, there were fewer newly eroded joints per patient after 2 years (median 0.5 [IQR 0–2] versus 1.25 [IQR 0–3.25]; P ⴝ 0.007). In the prednisolone group, 25.9% of patients had radiographic progression beyond the smallest detectable difference compared with 39.3% of patients in the no-prednisolone group (P ⴝ 0.033). At 2 years, 55.5% of patients in the prednisolone group had achieved disease remission, compared with 32.8% of patients in the no-prednisolone group (P ⴝ 0.0005). There were few adverse events that led to withdrawal. Bone loss during the 2-year study was similar in the 2 treatment groups. Conclusion. Prednisolone at 7.5 mg/day added to the initial DMARD retarded the progression of radiographic damage after 2 years in patients with early RA, provided a high remission rate, and was well tolerated. Therefore, the data support the use of low-dose prednisolone as an adjunct to DMARDs in early active RA. Supported by grants from the Swedish Rheumatism Association, the 80-Year Foundation of King Gustaf V, the Ugglas Foundation, the Börje Dahlins Foundation, the Gorthon Foundation in Helsingborg, and Stiftelsen för Rörelsehindrade i Skåne. 1 Björn Svensson, MD, PhD: University of Lund, Lund, Swe2 den; Annelies Boonen, MD, PhD, Désirée van der Heijde, MD, PhD: University Hospital Maastricht and Caphri Research Institute, Maastricht, The Netherlands; 3Kristina Albertsson, MD, Ingiäld Hafström, MD, PhD: Karolinska University Hospital, Stockholm, Sweden; 4 Catharina Keller, MD: Helsingborg’s Lasarett, Helsingborg, Sweden. Members of the BARFOT Study Group include Monica Ahlmén, MD, PhD, Johan Bratt, MD, PhD, Kristina Forslind, MD, PhD, Ingiäld Hafström, MD, PhD, Catharina Keller, MD, Ido Leden, MD, Bengt Lindell, MD, Ingemar Petersson, MD, PhD, Björn Svensson, MD, PhD, Annika Teleman, MD, and Jan Theander, MD. Address correspondence to Björn Svensson, MD, PhD, Blistorpsvägen 546, 290 38 Villands Vånga, Sweden. E-mail: firstname.lastname@example.org. Address reprint requests to Ingiäld Hafström, MD, PhD, Department of Rheumatology, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden. E-mail: email@example.com. Submitted for publication February 17, 2005; accepted in revised form June 23, 2005. Today it is generally accepted that early diagnosis and early suppression of inflammation are important requisites for a favorable outcome in rheumatoid arthritis (RA). Glucocorticoids are powerful antiinflammatory agents, and ever since Hench et al (1) showed a dramatic 3360 LOW-DOSE PREDNISOLONE IN EARLY RHEUMATOID ARTHRITIS effect of cortisone treatment in a patient with serious established RA, glucocorticoids have been used in the treatment of patients with active RA. However, high daily doses of glucocorticoids over the long term have considerable toxicity, hampering their use. Therefore, alternative treatment approaches have been explored, such as short-term high-dose therapy and low-dose treatment as monotherapy or in combination with conventional disease-modifying antirheumatic drugs (DMARDs). The pivotal question is whether these regimens are able to reduce the progression of joint destruction and provide sustained reduction of disease activity with an acceptable level of toxicity (2–5). A beneficial effect of low-dose prednisolone on radiographic damage was not found in the first studies evaluating radiographic outcome (6–8). However, those studies were performed in patients with late RA, and an effect in early disease remained possible. Therefore, the 1995 study by Kirwan and the Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group was met with great interest. In this placebo-controlled study in patients with early RA, Kirwan et al (9) found that 7.5 mg/day prednisolone, given for 2 years in addition to optional other treatments, reduced joint destruction. However, when prednisolone was stopped, joint destruction returned to the same level as that in the control group (10). In a more recent randomized trial (11), it was shown that prednisolone at a dosage of 10 mg/day retarded the progression of joint damage over a period of 2 years. In that study, prednisolone was compared with placebo and was not added to DMARDs. The short-term clinical effectiveness of low-dose glucocorticoid treatment in patients with early RA is widely established and supported by 2 meta-analyses (12,13). When given for periods of ⬃6 months, glucocorticoids are effective in reducing signs and symptoms of RA when used as comedication with DMARDs (14). However, the clinical response has not consistently been shown to persist beyond that time (9,11). Since it is increasingly accepted that early and sustained control of the inflammatory process is crucial to the prevention of radiographic damage and long-term disability (15–17), we conducted a randomized study in clinical practice on the medium-term (2 years) effects on radiographic damage (primary outcome) and disease activity (secondary outcome) of low-dose prednisolone added to the initial DMARD in patients with early RA. PATIENTS AND METHODS Study design. The study was a 2-year, multicenter, open randomized trial comparing the addition of 7.5 mg/day 3361 prednisolone to DMARD therapy with DMARD therapy alone. The patients had not previously been treated with DMARDs. The primary end point was the difference in changes in radiographic damage scores after 2 years; the secondary end points were remission rates and differences in disease activity and function. The patients were recruited from the 6 centers involved in the BARFOT (Better Anti-rheumatic Farmacotherapy) Study Group. The BARFOT study is a long-term multicenter observational study of an inception cohort of patients with early RA in southern Sweden (18). No formal sample size calculation was performed. However, according to the calculation described in the study by Kirwan et al (9), 160 patients would be sufficient to detect a 50% reduction in the progression of joint erosion over 2 years. Since the study by Kirwan et al and the present study have a similar design (although the present study adds radiographs of the feet and a more sensitive method for scoring radiographic progression), 250 patients seemed to be sufficient to detect a statistically significant difference in radiographic progression. The randomization was done as block randomization for each center according to a central randomization program with stratification for sex. The choice of DMARD was left to the treating physicians, who followed the recommended treatment strategy in Sweden at the time of the study. Concomitant treatment with nonsteroidal antiinflammatory drugs (NSAIDs) was permitted, and intraarticular steroid injections were allowed except during the 2 weeks preceding a clinical evaluation. All patients were given 1,000 mg/day calcium carbonate or calcium gluconate. The study was approved by the Ethics Committee. Patients. Patients were eligible for study if they were diagnosed as having RA according to the 1987 revised criteria of the American College of Rheumatology (formerly, the American Rheumatism Association) (19), were ages 18–80 years, had a disease duration of ⱕ1 year, had active disease (defined as a Disease Activity Score in 28 joints [DAS28]  of ⬎3.0), and were started by the treating rheumatologist on the first DMARD. Exclusion criteria were earlier treatment with glucocorticoids for RA or other diseases, previous treatment with DMARDs, or contraindication for glucocorticoid therapy. Furthermore, patients with previous fragility fractures were excluded, as well as patients ages ⬍65 years with a T score lower than ⫺2.5 on bone mineral densitometry and patients ages ⱖ65 years with a Z score of less than ⫺1. Overall, 250 consecutive outpatients were included in the study between September 1995 and December 1999. They were recruited from 840 RA patients entering the BARFOT program during the same period. Of these 840 patients, 80 did not meet the inclusion criteria (disease activity and age), while 334 met one of the exclusion criteria (most frequently, earlier glucocorticoid treatment [131 patients] or osteoporosis [96 patients]). Furthermore, 43 patients were considered to need glucocorticoid therapy because of highly active disease and were thus not included, 30 patients were missed, and 94 patients did not consent to participate. Overall, 259 patients were randomized. Of these, 9 patients were randomized (5 to the prednisolone group and 4 to the no-prednisolone group) but were withdrawn since they did not have RA (3 patients) or were not given a single dose of the stipulated drug(s) within 3 months (6 patients). All patients gave their informed consent. 3362 SVENSSON ET AL Table 1. Baseline characteristics of 250 patients treated or not treated with prednisolone* Prednisolone No-prednisolone group group (n ⫽ 119) (n ⫽ 131) Age at inclusion, mean ⫾ SD years 51 ⫾ 14 Disease duration, mean ⫾ SD months 6.5 ⫾ 3.5 Women, % 65 RF positive, % 66 Current or previous smoker, % 65 DAS28, mean ⫾ SD (range 0–10) 5.28 ⫾ 1.11 HAQ score, mean ⫾ SD (range 0–3) 1.01 ⫾ 0.59 SOFI index, mean ⫾ SD (range 0–44) 8⫾5 CRP level, median (IQR) mg/liter 22 (10–51) 59 ⫾ 13 5.8 ⫾ 2.9 63 66 61 5.42 ⫾ 1.04 0.98 ⫾ 0.65 9⫾7 22 (10–54) * RF ⫽ rheumatoid factor; DAS28 ⫽ Disease Activity Score in 28 joints; HAQ ⫽ Health Assessment Questionnaire; SOFI ⫽ Signals of Functional Impairment; CRP ⫽ C-reactive protein; IQR ⫽ interquartile range. Radiographic evaluation. Anteroposterior radiographs of the hands and feet were obtained at each center at study entry and after 1 and 2 years. Radiographic damage was scored according to the Sharp method as modified by van der Heijde (SHS) (21), which includes the hands and feet and allows for the separate presentation of a total score (range 0–448), an erosion score (range 0–280), and a joint space narrowing (JSN) score (range 0–168). Two trained readers (AB and KA) who were blinded to the patient’s treatment assignment read the radiographs independently in chronological order. Readers were allowed to score improvement in scores. Chronological scoring was preferred, since this method has been shown to have a better signal-to-noise ratio compared with paired readings (22). The interobserver intraclass correlation coefficients (ICCs) between the 2 readers were 0.91 and 0.93 for the erosion score, 0.90 and 0.93 for the JSN score, and 0.93 and 0.94 for the total score at baseline and after 2 years, respectively. The interobserver ICC for change in the total score from baseline to 2 years was 0.94. Clinical evaluations. Clinical assessment took place at the start of the study (baseline) and at 3, 6, 12, 18, and 24 months (end point). Disease activity was measured by the DAS28. A patient’s disease was considered to be in remission if the DAS28 was ⬍2.6 (23). Other laboratory assessments included the C-reactive protein (CRP) level and rheumatoid factor (RF) positivity according to the standard method used at each center. Functional disability was assessed using the Swedish version of the Stanford Health Assessment Questionnaire (HAQ) (24). The HAQ score ranges from 0 to 3, and a higher score indicates a higher degree of disability. Functional impairment was measured by the Signals of Functional Impairment (SOFI) index, a performance test consisting of 4 items for hand function, 3 for upper limb function, and 4 for lower limb function. Each item is scored according to 3 alternatives (0, 1, and 2), allowing a maximum SOFI index of 44, and a higher score indicates a higher degree of functional impairment (25). Adverse events were registered at the followup visits and were either spontaneously reported or revealed by laboratory values. Bone mineral density (BMD) measurement. BMD was measured by dual x-ray absorptiometry (DXA) with a densitometer (Lunar, Madison, WI). Assessment of BMD was made at the lumbar spine (L2–L4; anteroposterior view) and at the left hip (femoral neck). BMD was expressed in gm/cm2 and as a Z score (the number of SDs from the mean in healthy ageand sex-matched people, values for which were obtained from Lunar’s combined European/US reference population ). Statistical analysis. Efficacy analyses were performed on the 250 patients treated or not treated with prednisolone at baseline according to the intent-to-treat analysis. For the patients who dropped out of the study, the clinical data from the last observation were carried forward. Since the number of missing radiographs was rather small (7.6% at baseline and 6% at study end point), and since only 8 patients dropped out, a completer analysis was performed for the radiographic data. For radiographic outcome, the medians and interquartile ranges (IQRs) are presented for baseline and change scores after 1 and 2 years. The Mann-Whitney U test was used as the primary test for the total, erosion, and JSN scores analyzed separately. The corresponding means and SDs are also presented in a table. In addition, cumulative probability plots of the change scores (from end point to baseline) were Figure 1. Distribution of the study patients, by treatment group. LOW-DOSE PREDNISOLONE IN EARLY RHEUMATOID ARTHRITIS 3363 Table 2. Comparison of baseline radiographic damage scores and changes in the total, erosion, and JSN scores at 1 and 2 years, as assessed by the modified Sharp/van der Heijde scoring method, by treatment group* Mean ⫾ SD Median (IQR) Variable (no. of patients) Total score at baseline (231)† Erosion score at baseline (231)† JSN score at baseline (231)† Change in total score at 1 year (214)‡ Change in total score at 2 years (225)§ Change in erosion score at 1 year (214)‡ Change in erosion score at 2 years (225)§ Change in JSN score at 1 year (214)‡ Change in JSN score at 2 years (225)§ Prednisolone group No-prednisolone group P Prednisolone group No-prednisolone group 1.5 (0–4.0) 0.5 (0–1.5) 1.0 (0–2.5) 1.0 (0–3.0) 1.8 (0.5–6.0) 0.0 (0–1.5) 0.5 (0–2.0) 0.0 (0–2.0) 1.0 (0–4.0) 1.5 (0–4.0) 0.5 (0–1.5) 0.5 (0–2.5) 2.0 (0–5.0) 3.5 (0.5–10) 0.5 (0–3.0) 1.5 (0–4.5) 0.5 (0–2.5) 2.0 (0–5.0) 0.88 0.49 0.94 0.035 0.019 0.005 0.019 0.14 0.08 4.1 ⫾ 9.2 1.9 ⫾ 5.0 2.2 ⫾ 4.6 2.4 ⫾ 4.6 5.2 ⫾ 9.0 0.8 ⫾ 1.6 1.9 ⫾ 3.6 1.5 ⫾ 3.8 3.3 ⫾ 6.4 4.8 ⫾ 9.6 1.9 ⫾ 4.0 2.9 ⫾ 6.4 5.3 ⫾ 9.3 9.1 ⫾ 14.3 2.4 ⫾ 4.0 4.0 ⫾ 6.8 2.9 ⫾ 6.0 5.0 ⫾ 8.6 * P values represent the significance of the difference between medians, as determined by Mann-Whitney U test. JSN ⫽ joint space narrowing; IQR ⫽ interquartile range; JSN score ⫽ joint space narrowing score. † There were 109 and 122 patients, respectively, in the prednisolone and no-prednisolone groups. ‡ There were 99 and 115 patients, respectively, in the prednisolone and no-prednisolone groups. § There were 108 and 117 patients, respectively, in the prednisolone and no-prednisolone groups. constructed. These are visual presentations of all individual data made by plotting the observed cumulative proportion against the corresponding change score (27). Next, we determined the number of newly eroded joints (number of joints per patient that changed from an erosion score of 0 at baseline to any higher score at 1 and 2 years) and the proportion of patients with progression greater than the smallest detectable difference (SDD) (28). For clinical variables, group changes were presented as the mean ⫾ SD (or, in the case of the CRP level, as the median [IQR] as well) at baseline and after 3, 6, 12, 18, and 24 months. We also calculated the percentages of patients with disease in remission (DAS28 ⬍2.6) in the 2 groups after 1 and 2 years. To test for differences in change between groups, the Mann-Whitney U test or the t-test for independent samples was used for continuous variables, and the chi-square test was used for proportions. Analysis of covariance was used with age as a covariate to correct for the possible effect on outcome variables of a statistically significant difference in mean age between the treatment groups. All significance tests were 2-tailed and were conducted at the 5% significance level. The statistical analyses were performed using SPSS 13.0 statistical software (SPSS, Chicago, IL). RESULTS Demographics and patient characteristics. Table 1 presents the baseline demographics and clinical characteristics of the patients. Of 250 patients who were treated, 119 had been randomized to treatment with 7.5 mg/day prednisolone and 131 to no prednisolone therapy. Sixty-four percent of patients were women, 66% were RF-positive, and 62% were current or previous smokers. The 2 groups of patients were very comparable at baseline, except for age. One hundred sixteen patients in the prednisolone group and 126 in the noprednisolone group completed the 2-year followup pe- riod (Figure 1). One patient in the prednisolone group died, 1 moved from the district, and 1 was lost to followup; 2 patients in the no-prednisolone group moved and 3 were lost to followup. Of the 116 completers in the prednisolone group, 8 patients stopped prednisolone treatment because of diabetes (n ⫽ 1), weight gain (n ⫽ 2), proteinuria (n ⫽ 1), or unwillingness to continue prednisolone therapy (n ⫽ 4), and 16 patients received a prednisolone dosage lower (n ⫽ 14) or higher (n ⫽ 2) than the prescribed 7.5 mg/day at various times during the study. Of the 126 completers in the no-prednisolone group, 7 patients started prednisolone because of extraarticular manifestations, allergic symptoms, or increased disease activity (Figure 1). Concomitant treatment. In accordance with the study protocol, DMARDs were given to all patients. In the prednisolone group, 50% started with methotrexate (MTX) and 35% with sulfasalazine (SSZ), and the corresponding values for the no-prednisolone group were 53% and 37%. The mean ⫾ SD MTX dosage was 10.1 ⫾ 2.64 mg/week in the prednisolone group and 11 ⫾ 3.08 mg/week in the no-prednisolone group (P ⫽ 0.11). The SSZ dosage was, in general, 2 gm/day. At the 2-year visit, several patients in each group had switched from treatment with SSZ, and at that time, 15.4% in the prednisolone group and 16.9% in the no-prednisolone group were no longer receiving DMARDs. There were no statistically significant differences between the groups for types of DMARDs, either at baseline (P ⫽ 0.43) or after 2 years (P ⫽ 0.76). The mean ⫾ SD duration of DMARD treatment was 21.5 ⫾ 5 months in the prednisolone group and 20.6 ⫾ 5.1 months in the no-prednisolone group (P ⫽ 0.15). 3364 NSAIDs were taken by 85% and 87% of patients in the prednisolone and no-prednisolone groups, respectively, at baseline (P ⫽ 0.62). At 2 years, however, only 44% of patients in the prednisolone group were taking NSAIDs, compared with 65% in the no-prednisolone group (P ⫽ 0.001). Patients in the prednisolone group were injected intraarticularly with a mean ⫾ SD of 41 ⫾ 60 mg of triamcinolone hexacetonide equivalents during the first year compared with 90 ⫾ 87 mg in the no-prednisolone group (P ⫽ 0.0005). During the second year, these doses were 23 ⫾ 40 mg and 38 ⫾ 55 mg, respectively (P ⫽ 0.017). Radiographic progression. Radiographs were available for 231 patients at baseline, 224 patients at the 1-year followup visit, and 235 patients at the 2-year followup visit. Two hundred fourteen patients had radiographs both at baseline and after 1 year, and 225 patients had radiographs both at baseline and after 2 years. Baseline characteristics of the 25 patients without available radiographs at baseline and after 2 years (see Table 1) did not differ from those of the 225 patients with available radiographs (data not shown). The baseline radiographic scores were similar in the 2 groups of patients (Table 2). As can be seen in Table 2, the change in total score was less pronounced after 1 and 2 years in the prednisolone group than in the no-prednisolone group, and the difference between the groups was already statistically significant at 1 year. The median (IQR) change in the total score was 1.0 (0–3.0) after 1 year and 1.8 (0.5–6.0) after 2 years for the prednisolone group and 2.0 (0–5.0) after 1 year and 3.5 (0.5–10) after 2 years for the no-prednisolone group. In addition, the erosion score changed significantly less in the prednisolone group at both time points, and there was a similar, nonsignificant trend for the JSN score (Table 2). The differences in change scores (from end point to baseline) between the treatment groups are further illustrated as probability plots in Figure 2. The rate of joint damage before entering the study was similar in the 2 treatment groups. Thus, the median total score at baseline divided by the disease duration expressed in years was 3 (IQR 0–8) for the prednisolone group and 3.3 (IQR 0–10) for the noprednisolone group (P ⫽ 0.49). The mean ⫾ SD change in total score in the first year was 2.4 ⫾ 4.6 in the prednisolone group and 5.3 ⫾ 9.3 in the no-prednisolone group; in the second year, these values were 2.9 ⫾ 5.6 and 4.0 ⫾ 6.7, respectively. In the prednisolone group, 53.2% of the patients had erosions at baseline, and 77.2% had erosions after 2 SVENSSON ET AL Figure 2. Probability plots demonstrating differences between the 2 treatment groups in change in the total score (A), erosion score (B), and joint space narrowing (JSN) score (C) over 2 years. LOW-DOSE PREDNISOLONE IN EARLY RHEUMATOID ARTHRITIS 3365 Figure 3. Differences between treatment groups in improvement in the Disease Activity Score in 28 joints (DAS28) (A), C-reactive protein (CRP) level (B), Health Assessment Questionnaire (HAQ) score (C), and Signals of Functional Impairment (SOFI) index (D) over 2 years. Values are the mean. CI ⫽ confidence interval; ANCOVA ⫽ analysis of covariance. years. In the no-prednisolone group, these values were 59.0% and 80.2%, respectively. The development of erosions in a previously unaffected joint differed significantly between the treatment groups. Thus, in the prednisolone group, there was a median of 0 (IQR 0–1) and 0.5 (IQR 0–2) newly eroded joints after 1 and 2 years, respectively. The corresponding values were 0.5 (IQR 0–2) and 1.25 (IQR 0–3.25) in the no-prednisolone group (between-group P values were 0.004 and 0.007 at 1 and 2 years, respectively). The SDD was calculated to be 5.8. After the 2 study years, 25.9% of patients receiving prednisolone had radiographic progression greater than the SDD compared with 39.3% of patients not receiving prednisolone (P ⫽ 0.033). In the prednisolone group, but not in the noprednisolone group, patients with disease in remission had significantly less worsening of the total score and the erosion score than patients with disease not in remission at 2 years: median change in total score 1 (IQR 0–3.5) versus 4 (IQR 1–10.5) (P ⫽ 0.002) and median change in erosion score 0.5 (IQR 0–1) versus 1.5 (IQR 0.5–4) (P ⫽ 0.0005). In the no-prednisolone group, the corresponding values were as follows: median change in total score 2.5 (IQR 0.5–8) versus 3.5 (IQR 0.5–11) (P ⫽ 0.45) and median change in erosion score 1 (IQR 0–2.5) versus 1.5 (IQR 0.5–6) (P ⫽ 0.09). When we considered the entire group independently of treatment assignment, patients with disease remission had a smaller increase in the total score than did patients without disease remission (median 1.5 [IQR 0.5–5] versus 3.5 [IQR 0.5–10.5]; P ⫽ 0.002) and a smaller increase in the erosion score (median 0.5 [IQR 0–2] versus 1.5 [IQR 0.5–5.5]; P ⫽ 0.0005). Clinical efficacy. Disease activity, measured as the DAS28, decreased in both groups but significantly more in the prednisolone group. Differences between the 2 groups were already seen at 3 months and were present at all time points thereafter (Figure 3A). Thus, 3366 in the prednisolone group, the mean ⫾ SD DAS28 decreased from 5.3 ⫾ 1.1 at baseline to 2.7 ⫾ 1.5 after 1 year and 2.7 ⫾ 1.3 after 2 years. The corresponding values in the no-prednisolone group were 5.4 ⫾ 1.0, 3.3 ⫾ 1.5, and 3.2 ⫾ 1.4. After 1 year, 51.3% of patients in the prednisolone group had achieved disease remission (DAS28 ⬍2.6) compared with 39.2% of patients in the noprednisolone group (P ⫽ 0.06). After 2 years, this difference had increased to 55.5% in the prednisolone group compared with 32.8% in the no-prednisolone group (P ⫽ 0.0005). The CRP level, not included in the DAS28, fell rapidly in both treatment groups (Figure 3B), from a median of 22 mg/liter (IQR 10–51) at baseline to 9 mg/liter (IQR 4–10) after 1 year and 9 mg/liter (IQR 4–11) after 2 years in the prednisolone group and from 22 mg/liter (IQR 10–54) at baseline to 10 mg/liter (IQR 4–14) after 1 year and 9 mg/liter (IQR 4–12) after 2 years in the no-prednisolone group. These differences between the groups were not significant. The HAQ score showed a significantly greater reduction in the prednisolone group than in the noprednisolone group at all time points measured during followup (Figure 3C). The mean ⫾ SD HAQ score in the prednisolone group decreased from 1.0 ⫾ 0.6 at baseline to 0.4 ⫾ 0.5 at 1 year and 0.5 ⫾ 0.5 at 2 years. The corresponding values in the no-prednisolone group were 1.0 ⫾ 0.7, 0.6 ⫾ 0.6, and 0.7 ⫾ 0.6. The SOFI index decreased significantly more in the prednisolone group than in the no-prednisolone group (Figure 3D). The mean ⫾ SD SOFI index in the prednisolone group decreased from 8 ⫾ 5 at baseline to 4 ⫾ 5 after 1 year and 4 ⫾ 5 after 2 years. The corresponding values in the no-prednisolone group were 9 ⫾ 7, 6 ⫾ 6, and 7 ⫾ 6. BMD findings. DXA data were available for 189 patients both at baseline and after 2 years. At baseline and after 2 years, BMD at the lumbar spine did not differ significantly between the prednisolone and noprednisolone groups (mean ⫾ SD 1.14 ⫾ 0.16 gm/cm2 and 1.11 ⫾ 0.16 gm/cm2 versus 1.17 ⫾ 0.21 gm/cm2 and 1.16 ⫾ 0.21 gm/cm2, respectively). Since patients in the prednisolone group were somewhat younger, Z scores were also calculated. A difference was found between the prednisolone and no-prednisolone groups both at baseline (0.19 ⫾ 1.19 versus 0.74 ⫾ 1.67, respectively; P ⫽ 0.010) and after 2 years (⫺0.1 ⫾ 1.19 versus 0.58 ⫾ 1.66, respectively; P ⫽ 0.001). However, the decrease in Z score during the 2 study years did not differ significantly between the prednisolone and no-prednisolone SVENSSON ET AL Table 3. Adverse reactions leading to temporary or permanent withdrawal in the 2 treatment groups* System, adverse reaction Endocrine Diabetes Bleeding Gastrointestinal Nausea Dyspepsia Hematologic Leukopenia Thrombocytopenia Hepatic Elevated liver enzymes Pulmonary Pneumonitis Renal Proteinuria Dermatologic Alopecia Cushingoid appearance Hypertrichosis Rash Striae Various, including infections Abscess Stomatitis Fever Headache Tinnitus Weight gain Weight loss Vertigo Not specified Prednisolone group No-prednisolone group 1† 1 0 0 0 0 1 2 1 1 3 0 4 2 1 0 2† 0 1 1† 0 6 1† 0 0 1 9 0 0 1 2 0 0 1† 1 1 0 1 0 0 2 1 1† 0 0 1 * Disease-modifying antirheumatic drugs were the predominant cause of adverse reactions. † Caused by prednisolone in 1 patient. groups (⫺0.29 ⫾ 0.51 versus ⫺0.16 ⫾ 0.68, respectively; P ⫽ 0.13). BMD at the femoral neck did not differ significantly at baseline and after 2 years between the prednisolone and no-prednisolone groups (0.91 ⫾ 0.15 gm/ cm2 and 0.90 ⫾ 0.16 gm/cm2 versus 0.90 ⫾ 0.15 gm/cm2 and 0.87 ⫾ 0.15 gm/cm2, respectively), and there was no significant difference in Z scores (0.01 ⫾ 1.1 and ⫺0.06 ⫾ 1.13 versus 0.22 ⫾ 1.02 and 0.06 ⫾ 1.04, respectively). Further, there was no difference between the prednisolone and no-prednisolone groups in change in Z score at the femoral neck from baseline to 2 years (⫺0.07 ⫾ 0.49 and ⫺0.16 ⫾ 0.45, respectively; P ⫽ 0.16). Adverse events. Prednisolone was generally well tolerated, since the frequency of adverse reactions was small in both groups. Drug treatment was withdrawn temporarily or permanently in 26 patients in the prednisolone group and in 24 patients in the no-prednisolone LOW-DOSE PREDNISOLONE IN EARLY RHEUMATOID ARTHRITIS group (Table 3). Most withdrawals were caused by the DMARD given, while prednisolone was judged to be the cause in 5 patients in the prednisolone group; these 5 patients withdrew due to diabetes, proteinuria, striae and ecchymoses, weight gain and cushingoid appearance, and weight gain. DISCUSSION The present study shows that low-dose prednisolone added to the initial DMARD treatment in patients with early RA in a clinical setting reduces the progression of joint damage, controls inflammation, improves physical functioning, and is well tolerated. The progression of erosions and, to a lesser extent, JSN, which represent different aspects of structural damage, were retarded by prednisolone. Prednisolone not only retarded progression in already affected joints, but also prevented the development of erosions in previously unaffected joints. Moreover, the number of patients with progression of joint damage was lower in the prednisolone group than in the no-prednisolone group when radiographic progression (the total score) greater than the SDD was calculated. Only a few studies of patients with early RA have evaluated the effects of glucocorticoid treatment on radiographic damage. These studies have used different designs, evaluation methods, and glucocorticoid doses. The first study to suggest the ability of prednisolone to slow the progression of radiographic damage in early RA was a 2-year study by the Medical Research Council (29). Investigators in that study reported that at a mean dosage of 15 mg/day, prednisolone given for 2 years to patients with early RA resulted in less radiographic damage than did aspirin alone. Results of a placebo-controlled study of 10 mg/ day prednisolone as monotherapy in early RA were recently reported by Van Everdingen et al (11). SSZ was allowed as a rescue drug after the first 6 months. Similar to the results in the present study, the change from baseline in the SHS after 1 and 2 years was less pronounced in the group of patients receiving prednisolone. However, in the study by Van Everdingen et al, the radiographic progression, calculated as the mean increase in the total score per year, was higher than that in the present study (8 versus 2.6 per year in the prednisolone groups and 14.5 versus 4.4 per year in the no-prednisolone groups). The lower progression rate in the present study may likely be due to the fact that all patients started concomitant DMARD treatment with the goal of achieving disease remission. The addition of 3367 prednisolone further slowed the radiographic progression in a way that may justify the use of glucocorticoids early in the disease. The design of the COBRA (Combinatietherapie Bij Reumatoı̈de Artritis) study, comparing a combination of prednisolone, MTX, and SSZ with SSZ alone (30), differs from the present study in that a high initial prednisolone dosage was used and 2 DMARDs were started concomitantly. However, concordant with the results of the present study, prednisolone had a superior effect on radiographic progression. Because of the study design, it cannot be concluded that the beneficial effects were due to prednisolone, since MTX was also included in the combination treatment arm. However, support for a role of prednisolone in the COBRA study is provided by the results of another study of patients with early RA, in which the combination of MTX and SSZ, without prednisolone, was not superior to SSZ alone with regard to disease activity and structural changes over the 5 years of followup (31). The study by Kirwan et al in 1995 (9) had a design similar to that of the present study. Prednisolone at 7.5 mg/day for 2 years was compared with no prednisolone in patients with early RA (disease duration ⬍2 years). In that study, only 71% of the patients received concomitant treatment with DMARDs, and only ⬃80% of the randomized patients were available for evaluation. Furthermore, the patients in the placebo group had more severe disease at baseline. Nevertheless, the results showing that prednisolone retarded joint destruction in the hands, as measured by the Larsen score, were consistent with the findings in the present study, in which all patients were started on DMARD therapy, the 2 treatment groups were equal in terms of the baseline radiographic score, and 90% of the randomized patients were eligible for radiographic evaluation including both the hands and feet. Thus, it is of interest to note that all these different studies support the notion that glucocorticoids may retard radiographic damage in early RA. Two further studies on the effect of low-dose prednisolone on radiographic damage have been performed in patients with early RA. Unfortunately, both of these studies are difficult to evaluate because of methodologic difficulties. In the study by Rau et al (32), 5 mg/day prednisolone was compared with no prednisolone in DMARD-treated patients with early RA. The authors concluded that prednisolone in this setting decreases radiographic progression. However, only 76 of the 196 included patients completed the 2 years of the study, making the authors’ conclusion somewhat difficult to interpret. 3368 A recent study by Capell et al (33) compared the addition of 7 mg/day prednisolone to SSZ with the addition of placebo to SSZ, but the investigators failed to find a superior effect of the combination on radiographic progression. However, as pointed out by Kirwan and Boers (34), the results presented in the study by Capell et al on radiographic damage cannot be adequately interpreted. As reviewed above, a limited number of studies support the notion that glucocorticoids may retard radiographic damage in early RA. More studies have shown short-term beneficial clinical effects of low-dose prednisolone treatment of RA (14). To our knowledge, the present study is the first to demonstrate that lowdose prednisolone taken in addition to DMARDs improves inflammatory symptoms and signs for as long as 2 years. This finding contrasts with the results of some other studies, which fail to demonstrate effects on clinical symptoms for more than a few months (9,11). This discrepancy is not likely to be due to a difference in DMARD treatment between the groups in the present study, since the various DMARDs used were similar in the 2 groups and the mean number of months that each group took DMARDs was also comparable. Furthermore, the mean dosage of MTX was similar in the 2 treatment groups. Finally, NSAID use was significantly more frequent in the no-prednisolone group. Other possible reasons for the divergent results could be differences in study design, populations, and DMARD treatment strategies. The previous studies used a smaller number of patients (9,11), disease duration at baseline was longer, disease activity was defined differently, and baseline disability score was higher (9). In one study (9), only 71% of the patients were given DMARDs at inclusion into the study and 40% of the patients had had previous DMARD treatment. In another study (11), only 53% of the patients received DMARDs in combination with prednisolone, and then only as a rescue drug and not before 6 months. In the present study, all patients were started on DMARDs, which resulted in a higher disease remission rate in the prednisolone group, an outcome not described in reports of earlier studies (9,11). The relevance of maintained suppression of inflammation for retarding joint damage has been documented in several reports (35,36). The notion that early suppression of inflammation may further influence the rate of radiographic progression for several years is supported by the present data showing that the DAS28 was already strongly reduced after 3 months of treatment with prednisolone, which, together with a sus- SVENSSON ET AL tained effect on disease activity, resulted both in a reduced erosion score and in a strong trend toward reduced progression of JSN. Such an impact of early suppression of disease activity has been further suggested by the results of a followup of the COBRA study, in which the patients in the combination group continued to have a slower rate of progression after 4 years (37). Results of the present study and of the COBRA followup study imply that early suppression of inflammation decreases the progression of both erosions and JSN, thus emphasizing further the necessity of reducing inflammation at an early stage of the disease (16). Investigators in some studies (38,39) have discussed the possibility of a different pathogenesis of synovial inflammation and joint destruction, suggesting that the ability of drugs to retard radiographic damage can only partly be explained by suppression of disease activity. Of the patients with remission of disease in the present study, only those in the prednisolone group showed significantly reduced radiographic progression (in spite of an almost identical DAS28 in the 2 groups). This raises the possibility that prednisolone may reduce joint damage by a mechanism different from that by which it reduces inflammation, e.g., by a direct effect on bone turnover (40). In addition to the beneficial effects on radiographic damage and disease activity, prednisolone treatment resulted in better physical functioning, as proven by larger improvement in scores on the HAQ and SOFI index. It is recognized that, especially early in the disease, the HAQ score is primarily influenced by disease activity and to a lesser extent by radiographic damage (41). On the other hand, the SOFI index (25) reflects structural damage already present in early RA, and it may therefore be a valuable outcome variable in the evaluation of treatment in early RA. A concern with prednisolone treatment has been its inhibitory effect on bone formation, at least in high doses. However, in low doses, it has been suggested that this inhibitory effect may be compensated by the ability of prednisolone to suppress disease activity and the consequent inflammation-mediated bone resorption. This idea was strengthened by the present finding that bone loss was not significantly more pronounced in the group of patients receiving prednisolone. It is of note that the measurement of BMD does not reflect all of the aspects of bone that contribute to its resistance against fractures. The patients participating in the present study were recruited to the BARFOT program, whose patient population is believed to be representative of patients LOW-DOSE PREDNISOLONE IN EARLY RHEUMATOID ARTHRITIS with early RA, since most RA patients with disease of recent onset are referred to the rheumatology departments in these regions. However, the inclusion and exclusion criteria for the present study limited participation to 30% of eligible patients. The issue of external validity of study populations is important, but it is only infrequently addressed in clinical trials. It is important to emphasize that in the present study, the mean ⫾ SD DAS28 of 5.4 ⫾ 1.1 was similar to that in the total group of 840 patients included in the BARFOT program during the inclusion period (5.3 ⫾ 1.3). Therefore, it cannot be argued that external validity was limited by a selection of patients with very high disease activity, as was recently suggested by Sokka and Pincus (42) when discussing the external validity in trials of biologics. In the present study, ineligibility was most often caused by some exclusion criterion, of which previous low bone mass (96 patients) was one of the most common and required by the Ethics Committee. This high frequency of osteoporosis in early, untreated RA was an unexpected finding that we have studied further and reported elsewhere (43). Also of interest, 94 patients did not consent to participate, which may reflect a common negative attitude in the society toward prednisolone treatment. Although this was a randomized controlled study, it was performed in, and intended to reproduce, the clinical practice setting. Therefore, blinding was not performed and a placebo was not used. A weakness (or strength, since it reflects clinical practice?) of this study might be that a predefined DMARD algorithm was not used. Instead, the choice of DMARD was left to the treating physicians, who followed the recommended treatment strategy in Sweden at the time of the study. For that reason, DMARDs became similarly prescribed in the 2 study groups. Further, the lack of blinding and of placebo control did not seem to have a major effect on the results, since the DMARD prescriptions were similar in the 2 treatment groups and the radiograph readers were blinded to treatment strategies and clinical data. Instead, the no-prednisolone group received more NSAIDs and more intraarticular steroids, which might underscore the differences between the 2 groups. Indeed, such increased treatment in the control group may mask a superior symptomatic effect of prednisolone, as has been suggested by Van Everdingen et al (44). 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