Original Article
A Randomized Study of the Effect of Withdrawing Hydroxychloroquine Sulfate in Systemic Lupus Erythematosus
N Engl J Med 1991; 324:150-154January 17, 1991
- Abstract
- Abstract
Background.
The antimalarial drug hydroxychloroquine is thought to be effective in controlling some of the manifestations of systemic lupus erythematosus, but its effectiveness has not been demonstrated conclusively. Methods. We conducted a six-month, randomized,
double-blind,
placebo-controlled study of the effect of discontinuing hydroxychloroquine sulfate treatment in 47 patients with clinically stable systemic lupus erythematosus. The patients were randomly assigned to continue their same dose of hydroxychloroquine (n = 25) or to receive placebo (n = 22) for 24 weeks. Ten patients in each group were also taking prednisone.
Results.
The relative risk of a clinical flare-up, defined as the development of specific clinical manifestations of systemic lupus erythematosus or an increase in their severity, was 2.5 times higher (95 percent confidence interval, 1.08 to 5.58) in the patients taking placebo than in those continuing to take hydroxychloroquine (16 of 22 patients vs. 9 of 25 had flare-ups), and the time to a flare-up was shorter (P = 0.02). The relative risk of a severe exacerbation of disease that required withdrawal from the study was 6.1 times higher (95 percent confidence interval, 0.72 to 52.44) for the patients taking placebo (5 of 22 patients vs. 1 of 25 had severe exacerbations of disease). Changes in the dose of prednisone were not different in the two groups.
Conclusions.
Patients with quiescent systemic lupus erythematosus who are taking hydroxychloroquine are less likely to have a clinical flare-up if they are maintained on the drug. (N Engl J Med 1991; 324:150–4.)
Media in This Article
Figure 1
Life Table of Time to a Clinical Flare-up for Patients Randomly Assigned to Continue Taking Hydroxychloroquine (Circles) or to Receive Placebo (Squares).Figure 2
Life Table of Time to a Severe Exacerbation of Disease Activity for Patients Randomly Assigned to Continue Taking Hydroxychloroquine (Circles) or to Receive Placebo (Squares).Article Activity
- Article
THE antimalarial drugs hydroxychloroquine, chloroquine, and quinacrine are believed to be effective in controlling lesions of the skin and mucous membranes, as well as the malaise, easy fatigability, arthritis, and pleuritic pain of systemic lupus erythematosus.1 2 3 4 5 6 7 Also, they may permit the use of lower doses of systemic corticosteroids.8 9 10 However, there has been a need for data from randomized clinical trials to support the use of antimalarial agents in systemic lupus erythematosus.1 2 3 4 5
Although antimalarial agents,11 12 13 particularly hydroxychloroquine,14 have been shown to be safe, many patients and physicians are reluctant to use them indefinitely.5 , 15 , 16 Because of the absence of definite experimental evidence to support the use of such agents in systemic lupus erythematosus and uncertainty about the justification for long-term therapy, we performed a 24-week multicenter, randomized, placebo-controlled, double-blind study of the effect of hydroxychloroquine in stable systemic lupus erythematosus.
Methods
Selection of Patients
The criteria for inclusion in the study were the presence of four.or more conditions in the past indicating the diagnosis of systemic lupus erythematosus as defined by the American Rheumatism Association17; treatment with hydroxychloroquine at a dose of 100 to 400 mg per day for at least six months; stable disease, defined as clinical remission or minimal disease activity for at least three months; permission from the patient's personal physician to enroll the patient; and provision of informed consent. The reasons for exclusion were any of the following: age less than 16 years, a daily dose of hydroxychloroquine of more than 6.5 mg per kilogram of body weight, ophthalmologic evidence of retinopathy, or any coexisting illness of such a nature that an increase in the activity of systemic lupus erythematosus might seriously compromise the patient's health.
Study Centers
The study was coordinated at the Montreal General Hospital. The patients were enrolled at Notre Dame Hospital in Montreal (10 patients), the Montreal General Hospital (16 patients), the Ottawa General Hospital (8 patients), the Royal Victoria Hospital in Montreal (6 patients), and Hamilton Civic Hospital in Hamilton, Ontario (7 patients). The study was approved by the appropriate ethics committee at each site.
Randomization and Blinding
The schedule of randomization was based on a table of random numbers with blocking in blocks of four.18 Distinct randomization schedules were used for each center and according to whether the patients were or were not receiving treatment with prednisone. The randomization code was provided to the center investigator in sealed, uniquely numbered, opaque envelopes to be opened in the event of an emergency.
Because hydroxychloroquine has an unpleasant taste, the placebo tablets were each dusted during manufacturing with less than 1 mg of hydroxychloroquine. The active and placebo medications were identical in appearance but differed in shape from the tablets available commercially. The patients were advised at the time of enrollment that the study drug had been specially prepared and that the tablets would not only have a different appearance from the usual ones but might also have a different taste.
Treatment Regimen
Because of the prolonged half-life of hydroxychloroquine,19 it was not considered necessary to reduce the dosage of the drug gradually. Thus, the patients were randomly assigned either to continue taking their customary dose of hydroxychloroquine or to receive placebo (both supplied by Winthrop Laboratories, Sterling Drug, Canada, Aurora, Ont.).
Zero-Time Assessment
At zero time all patients provided a detailed history and had a physical examination and an ophthalmologic assessment to exclude retinopathy. Laboratory tests included a complete blood count, a Venereal Disease Research Laboratory test, liver-function tests, an anti—double-stranded DNA test, urinalysis, a 24-hour urine collection for measurement of creatinine clearance and protein excretion, and measurement of the erythrocyte sedimentation rate, partial-thromboplastin time, blood urea nitrogen, serum creatinine, serum immunoglobulins (IgG, IgA, and IgM), C3, and C4. Data were collected to calculate the Lupus Activity Criteria Count20 and the systemic lupus erythematosus Disease Activity Index.21 All subjects completed an Arthritis Impact Measurement Scales questionnaire to assess their general health.22 , 23
Follow-up Assessments
The duration of the study was 24 weeks. Every four weeks the patients were assessed by the center investigator for manifestations of systemic lupus erythematosus and underwent laboratory tests for the erythrocyte sedimentation rate, blood urea nitrogen level, and serum creatinine level, in addition to a complete blood count and urinalysis. A new bottle containing 70 tablets was provided, and the patients were questioned about whether they might have omitted to take any medication. In addition, pills were counted. At each visit the patients were questioned about the development of adverse effects. The patients were evaluated with an Amsler grid24 at every second visit, and a complete ophthalmologic examination was performed after 24 weeks.
Primary Outcome
The primary outcome measure was defined as the time to the development of a clinical flare-up of systemic lupus erythematosus on the basis of the development of specific clinical manifestations defined according to the American Rheumatism Association Glossary,25 or an increase in their severity. Details of the scoring of severity are available from the authors. The specific manifestations were alopecia; malar rash; discoid rash; photosensitive rash; another skin rash attributable to systemic lupus erythematosus, including lupus erythematosus profundus, cutaneous vasculitis, or bullous lesions; nasopharyngeal ulcers; lymphadenopathy; pleuritis; pericarditis; arthritis; and an increase in constitutional symptoms. In addition, any patient with a severe exacerbation of disease as defined below was considered to have had a clinical flare-up.
Secondary Outcomes
Two secondary outcomes were defined: a change in the required dose of prednisone and a severe exacerbation of disease. A severe exacerbation of disease was one that resulted in the withdrawal of the patient from the study and consisted of any of the following: nervous system involvement, vasculitis, active glomerulonephritis, myositis, an increase in symptoms or signs that in the investigator's opinion constituted a severe exacerbation of disease, or any other manifestation for which the investigator thought it necessary to initiate prednisone or to increase the dose. Patients who had a severe exacerbation of disease were withdrawn from the study.
Statistical Analysis
On the basis of previous reports1 , 2 , 26 , 27 and the clinical opinion of the principal investigator, it was estimated that 70 percent of the patients taking placebo would have an increase in objective manifestations of disease. A 50 percent reduction in the rate of clinical flareups was considered a clinically important difference. For an alpha error of 0.05 (two-sided) and a beta error of 0.30, the estimated sample needed was 24 subjects per group.28
For the univariate comparisons of base-line characteristics of the two groups of patients, chi-square analysis, Fisher's exact test, or Student's t-test was performed for descriptive purposes. For the primary and secondary outcomes, life-table analysis and the Mantel–Cox test were used to test differences between the hydroxychloroquine and placebo groups. A Cox proportional-hazards model29 was used to assess the differences between groups, with control for the stratification variables (study center and concomitant use of prednisone), and to estimate the relative risks and 95 percent confidence intervals for these outcomes.30
The change in the dose of prednisone over the course of the study was assessed with use of a repeated-measures analysis of variance.31 All tests were two-sided, and an alpha error less than 0.05 was considered significant. The data were analyzed with use of SAS 1987 (SAS Institute, Cary, N.C.) and BMDP 1988 (University of California, Los Angeles).
Both the patients and the center investigators were asked to state at the time of termination of the study or a patient's early withdrawal whether they believed the assigned medication had been hydroxychloroquine or placebo. To assess unblinding, the kappa statistic was used as a measure of agreement beyond that caused by chance.32 The guesses by the physicians and patients about whether hydroxychloroquine or placebo had been given were compared with the actual identities of the agents received.
Results
Fifty-three patients fulfilled the study criteria and were enrolled in the trial between September 1986 and November 1987. Six patients who would be out of the area for more than one month during the study period were excluded. Twenty-five patients were randomly assigned to continue taking hydroxychloroquine, and 22 to take placebo. At zero time, the group assigned to take hydroxychloroquine was comparable to that assigned to take placebo with respect to all the base-line variables, including all laboratory tests (Table 1Table 1
Demographic and Clinical Characteristics of the 47 Patients at Entry into the Study, According to Treatment Group.*). None of the differences between the groups were clinically important, and only the difference in the level of IgG was statistically significant. Since more than 30 statistical tests were performed, this difference may have arisen by chance.No patient had to decrease or discontinue the dose of the study medication because of an adverse event. Five patients had minor events that were possibly related to the study medication (one each with light-headedness and increased appetite in the placebo group, and one each with bruising, nausea, and diaphoresis in the hydroxychloroquine group).
The dose of prednisone was decreased in two patients. One patient taking hydroxychloroquine had the prednisone dose decreased from 10 mg to 5 mg daily without a subsequent flare-up. Another patient assigned to placebo had a clinical flare-up eight weeks after the prednisone dose was decreased from 7.5 mg to 5 mg daily. No patient taking nonsteroidal antiinflammatory drugs had the dose altered during the study.
One patient randomly assigned to hydroxychloroquine withdrew from the study after six weeks because she did not desire to continue; neither the center investigator nor the patient had noted any change in the activity of her disease. Data for this patient are included up to the time of her withdrawal from the study.
Compliance with the study medications was greater than 90 percent in all but one patient. This patient discontinued the study medication one third of the way through the final month, because she attributed the occurrence of a severe exacerbation of disease to the study medication.
There was no evidence of unblinding by either patients or physicians. Sixty-four percent of the time, the physicians guessed correctly the group to which patients had been assigned. The patients were correct 53 percent of the time. The kappa statistics were 0.26 and 0.08, respectively. A kappa statistic of less than 0.40 suggests poor agreement.32
Clinical flare-ups occurred in 16 patients assigned to placebo (73 percent) and in 9 of those assigned to continue taking hydroxychloroquine (36 percent). Life-table analysis showed that the two groups of patients differed significantly with respect to the distributions of times to a clinical flare-up (P = 0.02) (Fig. 1Figure 1
Life Table of Time to a Clinical Flare-up for Patients Randomly Assigned to Continue Taking Hydroxychloroquine (Circles) or to Receive Placebo (Squares).). On the basis of analysis with the Cox proportional-hazards model, the relative risk of a clinical flare-up among the patients taking placebo was 2.5 times higher than among the patients taking hydroxychloroquine (95 percent confidence interval, 1.08 to 5.58). Inclusion of the stratification variables did not alter these results.Overall, 25 patients had new objective clinical manifestations that met the definition of a clinical flare-up. Of the 25, 16 (64 percent) had manifestations that had been cited as indications for the initial prescription of hydroxychloroquine. In 6 of the 25 patients (24 percent), the clinical flare-up involved manifestations that had been detected previously, in addition to one or more new ones. In only three patients (12 percent) did the flare-up consist entirely of manifestations that had not been noted previously. These results were similar in both the hydroxychloroquine and the placebo groups. The 25 patients had a total of 61 manifestations (median, 2.0; range, 1 to 4). Of the 61, 24 were cutaneous, including 2 involving alopecia; 13 patients had nasopharyngeal ulcers, 13 had arthritis, and 11 had constitutional signs and symptoms.
Five of the patients taking placebo (23 percent) and one of the patients continuing to take hydroxychloroquine (4 percent) had severe exacerbations of disease activity that prompted their withdrawal from the study. Life-table analysis demonstrated that the comparison between groups of the distribution of times to a severe exacerbation approached statistical significance (P = 0.06) (Fig. 2Figure 2
Life Table of Time to a Severe Exacerbation of Disease Activity for Patients Randomly Assigned to Continue Taking Hydroxychloroquine (Circles) or to Receive Placebo (Squares).). On the basis of analysis with the Cox proportional-hazards model, the relative risk of a severe exacerbation of disease in patients taking placebo as compared with those taking hydroxychloroquine was 6.1 (95 percent confidence interval, 0.72 to 52.44). This result was unchanged when we controlled for the stratification variables.Of the six patients withdrawn from the study because of a severe exacerbation of disease activity, a single patient in the hydroxychloroquine group and two in the placebo group were withdrawn because of severe exacerbations of polyarthritis, constitutional conditions, or mucocutaneous manifestations. Three additional subjects taking placebo were withdrawn because of major organ flare-ups that required hospitalization. In one patient vasculitic ulcers developed over the upper extremities that required treatment with azathioprine and subsequently with pulses of intravenous cyclophosphamide; one had transverse myelitis requiring treatment with high-dose corticosteroids; and in the third membranous glomerulonephritis with nephrotic syndrome developed that was confirmed on renal biopsy and that responded to treatment with high-dose corticosteroids.
The repeated-measures analysis of variance revealed no significant differences between treatment groups in the change in prednisone dose (P = 0.27). At the 24-week assessment, the 22 patients randomly assigned to placebo had increased their dose of prednisone by an average of 2.7 mg per day, as compared with an average increase of 0.4 mg per day in the 25 who continued to take hydroxychloroquine (difference between groups, 2.3 mg per day; 95 percent confidence interval, —2.4 to 6.9 mg per day). It would have been difficult to detect a difference in the amount of prednisone received because of the small number of patients and the low doses used.
Discussion
The results of this randomized clinical trial of hydroxychloroquine in systemic lupus erythematosus demonstrate that the discontinuation of treatment with this drug in patients with quiescent disease is associated with a 2.5-fold increase in the risk of new clinical manifestations or, in the case of previous manifestations, a recurrence or an increase in severity.
To be enrolled in this study, patients had to have stable systemic lupus erythematosus. They had tolerated antimalarial agents for an average of three years. Thus, patients who had taken hydroxychloroquine and had the drug discontinued because of adverse effects or lack of response to treatment could not have been enrolled. Their exclusion by the discontinuation design of our study would tend to overestimate the efficacy of hydroxychloroquine and to underestimate its toxicity.33 Although the results are applicable to patients such as those who entered the study, less dramatic results with regard to both efficacy and toxicity might have been obtained had the more traditional randomized design been used. Nonetheless, studies of the use of antimalarial agents in rheumatoid arthritis have suggested that hydroxychloroquine is tolerated well and that withdrawal from treatment on account of adverse events is uncommon.34 , 35 Also, antimalarial agents are generally used as an adjunct to other treatments for systemic lupus erythematosus, such as nonsteroidal antiinflammatory agents and topical or systemic corticosteroids,1 , 2 , 4 so that one might well expect clinicians to continue treating patients with the disease with antimalarial agents for prolonged periods.
The results are compatible with the accepted clinical belief that antimalarial agents are effective in managing systemic lupus erythematosus and with findings in previous uncontrolled case series.2 , 26 , 27 The results of the retrospective controlled study of Rudnicki et al.1 are remarkably similar to those reported here. They noted that antimalarial agents significantly suppressed the development of new objective clinical manifestations of disease activity. We did not expect to see a major difference in the incidence of severe exacerbations of disease between the two groups because the sample was small, the elimination half-life of the drug long, and the study only six months in duration. There was a six-fold increase in the number of severe exacerbations of disease in the patients randomly assigned to placebo, and three of the five severe exacerbations in this group were of major clinical consequence. Although antimalarial agents have been considered effective for mild inflammation in systemic lupus erythematosus, it is conceivable that their general effect may be sufficient to control at least partially the inflammatory processes that are considered to be the most severe. Further studies are required to address this question specifically.
The results of this randomized discontinuation trial suggest that patients whose systemic lupus erythematosus is inactive or mildly active but stable after prolonged treatment with hydroxychloroquine are less likely to have new manifestations of disease or a recurrence or increase in activity of existing manifestations if they continue to take this drug. These results confirm the clinical belief that hydroxychloroquine can maintain the clinical quiescence of systemic lupus erythematosus.
We are indebted to Ms. Barbara Cont for expert assistance in the preparation of the manuscript; to Dr. William Gerstein and Dr. Ralph Kern for their collaboration in defining dermatologie and neurologic outcomes, respectively; and to Iain Blair, M.D., of Winthrop Laboratories, Sterling Drug, Canada, for supplying the active and placebo tablets of hydroxychloroquine.
Address reprint requests to Dr. John Esdaile, Montreal General Hospital, 1650 Cedar Ave., Montreal, PQ H3G 1A4, Canada.
Supported by a grant (5–265–87) from the Arthritis Society of Canada and a grant from the Lupus Society of Quebec. Winthrop Laboratories, Sterling Drug, Canada, supplied the study medication. Dr. Esdaile is a Senior Research Scholar of the Fonds de la recherche en santé du Québec. Dr. Senécal is a Clinical Research Scholar of the Arthritis Society of Canada.
Source Information
* Members of the Canadian Hydroxychloroquine Study Group were as follows: Methods Center: Vivian Bykerk, M.D., John Sampalis, Ph.D., and John M. Esdaile, M.D., M.P.H., Montreal General Hospital, McGill University. Clinical investigators; Denis Choquette, M.D., and Jean-Luc Senécal, M.D., Notre Dame Hospital, University of Montreal; Vivian Bykerk, M.D., and Deborah Danoff, M.D., Montreal General Hospital, McGill University; C. Douglas Smith, M.D., Ottawa General Hospital, University of Ottawa; Alfred Cividino, M.D., Hamilton Civic Hospital, McMaster University; and C. Kirk Osterland, M.D., and Carol Yeadon, M.D., Royal Victoria Hospital, McGill University.
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