Background Oral glucocorticoids are widely used to treat patientswith rheumatoid arthritis, but their effect on joint destruction,as assessed radiologically, is uncertain.
Methods We conducted a randomized, double-blind trial comparingoral prednisolone (7.5 mg daily for two years) with placeboin 128 adults with active rheumatoid arthritis of less thantwo years' duration. Except for systemic corticosteroids, othertreatments could be prescribed. The primary outcome variableswere the progression of damage as seen on radiographs of thehand after one and two years, as measured by the Larsen index,and the appearance of erosions in hands that had no erosionsat base line. The radiographs were viewed jointly by a radiologistand a rheumatologist who were unaware of the treatment assignmentand the time point at which the films were obtained.
Results The statistical analysis of radiologically detectedchanges was based on 106 patients for whom there were filmsobtained at base line and two years later. After two years,the Larsen scores increased by a mean of 0.72 unit in the prednisolonegroup, indicating very little change, and by 5.37 units in theplacebo group, indicating substantial joint destruction (P =0.004). Of the 212 hands of these patients, 147 (69.3 percent)had no erosions at the start of the study. At two years, 15of the 68 such hands in the prednisolone group (22.1 percent)and 36 of the 79 such hands in the placebo group (45.6 percent)had acquired erosions (difference, 23.5 percentage points; 95percent confidence interval, 5.9 to 40.7; P = 0.007). The patientsin the prednisolone group had greater reductions than the patientsin the placebo group in scores on an articular index and forpain and disability at 3 months; for pain at 6 months; and fordisability at 6, 12, and 15 months (all P<0.05). There wasno difference between groups in standardized scores for theacute-phase response. The adverse events were typical of thoseencountered with antirheumatoid drugs.
Conclusions In patients with early, active rheumatoid arthritis,prednisolone (7.5 mg daily) given for two years in additionto other treatments substantially reduced the rate of radiologicallydetected progression of disease.
Rheumatoid arthritis causes the inflammation and progressivedestruction of joints. Nonsteroidal antiinflammatory drugs helpto control symptoms. Specific antirheumatoid drugs (such asgold salts, penicillamine, and methotrexate) suppress inflammationbut increase the number of adverse reactions. Oral glucocorticoidshave been used for over four decades to treat patients withrheumatoid arthritis, but their role and value have been debated.1Nevertheless, glucocorticoids are widely used; 24 percent ofpatients with rheumatoid arthritis at one British hospital weretaking prednisolone daily,1 and 15 percent of patients at aDutch clinic were receiving corticosteroids.2 Glucocorticoidsprovide symptomatic benefit3 and may prevent joint destruction.3,4,5Studies of their effect on the radiographically detected progressionof disease are difficult to interpret, because they have beenpoorly controlled6,7 or too short8 or have used unacceptablyhigh doses of medication.7 We conducted a randomized, double-blind,placebo-controlled trial of a fixed daily dose of prednisolone(7.5 mg), in addition to other treatments, in patients withactive rheumatoid arthritis.
Methods
Study Design
The study protocol was approved by the hospital ethics committeeat each participating center. From May 1989 through May 1991,consecutive patients 18 to 69 years of age who had had rheumatoidarthritis9 for less than two years that was currently active(defined by the presence of >6 painful joints, >3 jointswith active synovitis, and early-morning stiffness for >20minutes and an erythrocyte sedimentation rate of >28 mm perhour, a plasma viscosity >1.72, or a level of C-reactiveprotein >10 mg per liter) were invited to participate. Atarget size of 160 patients was calculated for the trial byextrapolation from the figures given by West,5 assuming a lineardose–response curve for the effect of prednisolone anda 90 percent power to detect a 50 percent reduction in the progressionof joint erosion over two years.10 A record of those who declinedto participate was kept, with their stated reasons.
Prednisolone (7.5 mg) and identical tablets of placebo wereprepared and labeled specifically for the study by the pharmacyat the Bristol Royal Infirmary. The tablets were distributedto pharmacies at 13 participating centers. Randomization wasperformed in blocks of six subjects at each center, and exceptin an emergency, the randomization codes were not broken untilafter the main analysis. After providing written informed consent,eligible patients were assigned the next available study numberat the center where they were recruited. They were instructedto take the assigned study medication each day. After two years,the dose was tapered, with treatment for two weeks on alternatedays followed by treatment for two weeks every third day, andthen discontinued. Throughout the study, their physicians werefree to prescribe any other treatment for the patients exceptsystemic corticosteroids.
Outcome Variables
The two primary outcome variables were the progression of damageas detected on radiographs of the hands at entry and one andtwo years later and the development of erosions on hands thathad no erosions at base line. All available radiographs weresent to the coordinating center and viewed jointly by the sameexperienced radiologist and rheumatologist. The same light wasused to view all the films. To ensure similar conditions forthe assessment of each patient's radiographs and to avoid thepossible development of bias over the several sittings requiredto read and score the radiographs, the films were viewed inrandomly ordered groups of 30. Each group included the threefilms for each of 10 randomly selected patients. All markingsthat might identify the patients were covered. The conditionof each hand was classified as erosive or nonerosive, and eachfinger or wrist joint was then scored by the method of Larsenet al.,11 which grades joint damage on a scale from 0 (for aradiologically normal joint) to 5 (for a joint with maximaldestruction) with reference to a standard atlas of radiographs.11The assessments were made jointly by the two observers. TheLarsen index (with scores ranging from 0 to 140) was subsequentlycalculated for each radiograph by adding the scores obtainedfor each finger and wrist joint.
Secondary outcomes were assessed every three months. They includedchanges in the degree of disability (as measured by the HealthAssessment Questionnaire12), joint inflammation (as measuredby an articular index of tender and swollen peripheral joints,weighted for joint size13), pain over the previous 24 hours(as assessed on a visual-analogue scale14), and acute-phaseresponses (as measured by the erythrocyte sedimentation rate,the level of C-reactive protein, or plasma viscosity, dependingon the center). Records of other treatments, adverse reactions,weight, and blood pressure were also kept.
Statistical Analysis
The statistical analysis used the chi-square test to compareproportions and Student's t-test to compare means.10 Becauseof their skewed distributions, Larsen scores were log-transformedbefore the group comparisons were made. The difference in logvalues between the base-line and follow-up examinations wascalculated for each patient. The means of these differenceswere compared between groups, and their 95 percent confidenceintervals were determined by Student's t-test.10 Because differentcenters used different methods to measure acute-phase responses,the values were standardized so that the data could be combined.Z scores10 (standard normal variables) were calculated by takingall available values for each patient and expressing them againas the number of standard deviations from the mean of thosevalues. For each time point, the mean and standard deviationof these standardized scores were calculated to derive groupvalues. All statistical tests were two-tailed, and a P valueof 0.05 or less was taken to indicate statistical significance.
Results
Of the 162 patients invited to participate in the study, 34declined to do so, for the following reasons: concern aboutthe adverse effects of corticosteroids (14 patients) or of medicationsgenerally (3), inconvenient location of the study center (4),unwillingness to receive placebo due to an anticipated needfor corticosteroid therapy (4), too short an interval sincediagnosis (1), and unspecified reasons (8). The remaining 128patients were treated at 13 centers; the patients' characteristicsare shown in Table 1. In general, the study patients had moderatelysevere joint inflammation. All had had their disease for lessthan two years (mean, slightly over one year). Eleven patientsdid not subsequently undergo radiography of the hands becausethey were lost to follow-up (one each was withdrawn with carcinomaof the lung, cerebral tumor, and a changed rheumatologic diagnosis,and eight moved away or declined to take the study medication).These patients and three others whose initial radiographs werelost were excluded from the analysis. Treatment was discontinuedin six patients (two in the placebo group and one in the prednisolonegroup because of hypertension and weight gain, and one eachin the placebo group because of diabetes, the initiation ofcorticosteroid therapy, and a refusal of further medication);these six patients were subsequently followed and analyzed aspart of their initial treatment groups. Of the remaining 114patients, 11 did not appear for radiography at year 1, and 8did not appear for radiography at year 2. In the prednisolonegroup, 49 patients had films for all three time points, whereas54 patients had films only at entry and year 1 and 57 patientshad films only at entry and year 2. The statistical analysesof changes on the films for years 1 and 2 were based on these103 and 106 patients, respectively. Patients who declined toparticipate or were lost to follow-up were distributed evenlyacross the 13 participating centers.
Table 1. Base-Line Characteristics of the 128 Study Patients According to Treatment Assignment.
The radiographically detected progression of rheumatoid arthritisduring the study is shown in Figure 1. The base-line valuesshow that a few patients with more severe damage were includedin the placebo group, including one patient with an extremelyhigh Larsen score. There was no significant base-line differencebetween groups, however, when the mean values were comparedafter log transformation (P = 0.48) (Table 1) or by the Mann–Whitneytest (median for placebo, 0 [interquartile range, 0 to 5]; medianfor prednisolone, 0 [0 to 4]; median difference, 0 [0 to 0];P = 0.83).
Figure 1. Scores on the Larsen Index during Treatment, According to Study Group.
The mean values at entry into the study and one and two years thereafter, expressed in Larsen units, were as follows: prednisolone group, 2.65, 3.38, and 3.37, respectively; placebo group, 6.23, 9.86, and 11.60; difference between groups, 3.58, 6.48, and 8.23. P = 0.479, P = 0.033, and P = 0.002 for the respective group differences as calculated from log-transformed scores. The mean changes after one and two years were as follows: prednisolone group, 0.73 and 0.72, respectively; placebo group, 3.63 and 5.37; difference between groups, 2.90 and 4.65. P = 0.052 and P = 0.004 for the respective group differences as calculated from log-transformed scores.
Disease progressed to a mean of 0.73 Larsen unit in the prednisolonegroup after one year and to a mean of 0.72 Larsen unit aftertwo years, indicating very little change in radiographicallydetected joint damage. In the placebo group, the mean progressionof disease after one year was to 3.63 Larsen units and aftertwo years to 5.37 Larsen units, indicating substantial jointdestruction that was similar to the progression usually expectedin early erosive disease. The statistical differences betweengroups in the changes in Larsen scores at one and two yearswere calculated from the changes in the log-transformed scores.The mean (±SD) changes in log-transformed scores afterone year were as follows: prednisolone group, 0.02±0.39;placebo group, 0.19±0.48; difference, 0.17 (95 percentconfidence interval, 0 to 0.34; P = 0.052). The changes aftertwo years were as follows: prednisolone group, 0.02±0.43;placebo group, 0.30±0.52; difference, 0.28 (95 percentconfidence interval, 0.09 to 0.47; P = 0.004).
In the group of 106 patients with radiographs obtained at bothbase line and two years, 147 of their 212 hands (69 percent)did not have erosions at the start of the study. In the groupof 49 patients with radiographs for all three time points, erosionshad developed after one year on 18 of 68 such hands in the prednisolonegroup (26 percent) and 30 of 79 such hands in the placebo group(38 percent), a difference of 18.9 percent (95 percent confidenceinterval, 1.7 to 35.7 percent; P = 0.018). After two years,the comparable figures were 15 of 68 hands (22.1 percent) and36 of 79 hands (45.6 percent), a difference of 23.5 percentagepoints (95 percent confidence interval, 5.9 to 40.7; P = 0.007).
The clinical responses of the patients are summarized in Figure 2A,Figure 2B, Figure 2C, and Figure 2D. The mean score forpain in the prednisolone group decreased from 1.35 units atbase line to 0.88 unit after three months (a reduction of 0.47unit), whereas the mean score for pain in the placebo groupdecreased from 1.52 units at base line to 1.18 units after threemonths (a reduction of 0.34 unit). The reduction in the placebogroup was 25 percent less than that in the prednisolone group(95 percent confidence interval, 8 to 41 percent; P<0.001).Similarly, after three months the patients in the placebo grouphad 63 percent less reduction (95 percent confidence interval,54 to 72 percent) in their disability scores than the patientsin the prednisolone group (from 1.34 to 1.19, as compared witha reduction from 1.21 to 0.80; P<0.001) and 41 percent lessreduction (95 percent confidence interval, 4 to 84 percent)in the articular index (from 209 to 142 in the placebo group,as compared with 208 to 97 in the prednisolone group; P<0.05).The prednisolone group also had a greater reduction in painat 6 months and in disability at 6, 12, and 15 months. Therewas no difference between groups in standardized scores forthe acute-phase response.
Figure 2. Changes in Clinical Variables during Treatment, According to Study Group.
Group means and 95 percent confidence intervals are shown for the prednisolone () and placebo () groups. Pain scores (Panel A) were derived from a visual-analogue scale14 that recorded the severity of pain over the previous 24 hours on a scale ranging from 0 (no pain) to 3.0 (worst possible pain). Disability scores (Panel B) were derived from the disability scale of the Health Assessment Questionnaire12,14 and were expressed on a scale ranging from 0 (no disability) to 3.0 (inability to perform most activities of daily living). Scores for joint inflammation (Panel C) were assessed by an articular index of inflamed joints13 and were expressed on a scale ranging from 0 (no joint inflammation) to 534 (all joints of the hands and wrists inflamed). The acute-phase response (Panel D) was reported as a standardized score (the number of standard deviations from the mean) for each patient to allow a variety of methods to be used to measure the overall acute-phase response for the group (see the Methods section).
There were no significant differences between groups at eachreview in the proportion of patients treated with nonsteroidalantiinflammatory drugs (mean percentage, diclofenac, 23 percent;naproxen, 18 percent; aspirin, 15 percent; indomethacin, 12percent; ibuprofen, 8 percent; piroxicam, 4 percent; and otheragents, 15 percent) or with specific antirheumatoid drugs (intramusculargold, 8 percent; penicillamine, 30 percent; sulfasalazine, 26percent; methotrexate, 4 percent; and other agents, 3 percent).Nor did the proportion of patients who reported adverse reactionsdiffer between groups at each review according to type of treatment(mean percentage, gold, 22 percent; penicillamine, 19 percent;sulfasalazine, 8 percent; methotrexate, 32 percent; and otheragents, 10 percent). The adverse reactions reported includedthrombocytopenia, rash, proteinuria, elevated serum aminotransferaselevels, transient malaise, and altered bowel habits. These werein keeping with well-recognized patterns of adverse reactionsto specific antirheumatoid drugs.15
Discussion
Fixed daily doses of 7.5 mg of prednisolone, given in additionto other treatments for a two-year period, substantially reducedthe rate of radiologically detected progression of disease inpatients with early, active rheumatoid arthritis. The majorityof the patients in this study also received specific antirheumatoidtherapy, and this treatment was distributed equally betweenthe prednisolone and the placebo groups. The evidence that treatmentcan interrupt the progression of joint damage in rheumatoidarthritis is sparse.16,17 Sigler et al.18 compared intramusculargold with placebo in 32 patients and concluded that it reducedthe rate of radiologically detected progression. This finding,which was in contrast with those of other studies of gold treatment,19may have been due to the unconventional method of analysis andan imbalance in the severity of disease in the two study groupsrather than to any pharmacologic action.16 The radiologic studyof Luukkainen et al.20 is often cited in support of the efficacyof gold, but it was an uncontrolled comparison of patients treatedwith several agents, including chloroquine and glucocorticoids,and it lacked defined criteria for the start of treatment.16
A more recent double-blind study of antirheumatoid drugs, withentry criteria similar to those we used, compared hydroxychloroquinewith sulfasalazine21 in 50 patients. That study did not havea placebo group. Among the patients who originally had no erosions,72 percent acquired them during treatment with hydroxychloroquine,and 36 percent did so during treatment with sulfasalazine. Thisdifference was significant (P<0.02), but the result in thesulfasalazine group was similar to that in our placebo group.The patients in our prednisolone group had little overall diseaseprogression as measured by the Larsen index, and only 17 percentof patients who originally had no erosions acquired them duringthe first year. Our two-year results are consistent with thoseof earlier studies of glucocorticoids in patients with rheumatoidarthritis, such as the retrospective follow-up by West5 of thepatients in the original Medical Research Council and NuffieldFoundation trial.3,4
Most of the patients we studied had clinical improvement, aswould be expected when patients with active rheumatoid arthritisbegin a specific therapy. The addition of prednisolone acceleratedthis response, but as observed in earlier reports,3,4 this additionalsymptomatic benefit did not persist into the second year oftreatment.
Four patients had adverse events that may have been attributableto corticosteroid therapy. Two events (hypertension in one patientand hypertension and weight gain in another) occurred in theprednisolone group, and two (diabetes and hypertension) occurredin the placebo group. There were no significant increases inweight or blood pressure in either group. The 7.5-mg dose ofprednisolone was chosen22 in the light of clinical experienceand reported adverse effects23 to provide the best chance ofreducing radiologically detected progression while minimizingcomplications. A recent case–control study24 has suggested,however, that even in low doses, corticosteroids may predisposepatients with rheumatoid arthritis to fractures, infections,and gastrointestinal ulcers and bleeding. In that study thepatients treated with corticosteroids had more severe diseasethan those in the control group. The possible induction of osteoporosismay be counterbalanced by increased physical activity or reducedjoint inflammation in the treated patients.
Our findings have implications for the understanding of rheumatoidarthritis. We found that the development of erosions, clinicalsymptoms, and to some extent the acute-phase response can occurindependently of each other after glucocorticoid treatment.The dissociation of these three aspects of the disease arguesagainst combining them in a single measure25 and challengesresearchers to identify their differing control mechanisms.
Supported by a grant (K27) from the Arthritis and RheumatismCouncil.
We are indebted to Mrs. Sara Selley and Mrs. Shelagh Snow fortheir invaluable contributions to the administration of thisstudy.
* The investigators and study centers participating in the Arthritisand Rheumatism Council Low-Dose Glucocorticoid Study Group arelisted in the Appendix.
Source Information
Address reprint requests to Dr. Kirwan at the University Department of Medicine, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom.
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Appendix
The following investigators and study centers, all in the UnitedKingdom, participated in the Arthritis and Rheumatism CouncilLow-Dose Glucocorticoid Study: M. Byron, Stoke Mandeville Hospital,Aylesbury; P. Dieppe, Bristol Royal Infirmary, Bristol; C. Eastmond,City Hospital, Aberdeen; J. Halsey, Lancaster Moor Hospital,Lancaster; P. Hickling, Mount Gould Hospital, Plymouth; P. Hollingworth,Southmead Hospital, Bristol; R. Jacoby, Princess Elizabeth Hospital,Exeter; A. Kirk, Amersham Hospital, Amersham; J. Kirwan, BristolRoyal Infirmary; C. Moran, Christchurch Hospital, Christchurch;D. Reid, City Hospital, Aberdeen; T. Swannell, City Hospital,Nottingham; and D. Yates, Taunton and Somerset Hospital, Taunton.Additional investigators: C. Cooper and E. George, both in Bristol.Nonrecruiting study participants: D. Forbes, Bristol Royal Infirmary;J. Jessop, University Hospital of Wales, Cardiff; and I. Watt,Bristol Royal Infirmary.
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Previous
) and placebo (
) groups. Pain scores (Panel A) were derived from a visual-analogue scale