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Long-Term Chloroquine Therapy in Rheumatoid Arthritis
Long"Term Chloroquine Therapy in Rheumatoid Arthritis* From the Department of Medicine, Harvard Medical School and the Medical Services of the Massachusetts general Hospital, Boston
EVAN CALKINS, M.D. Professor of Medicine, llarvard Medical School; Director, Robert W. Lovelt Memorial Unit, Massachusetts General II ospital
Assi.~tant
ALAN S. COHEN, M.D. Assistant Professor of Medicine, Boston University School of Director, Arthritis and Connective Tissue Disease Section, M assachusetls M emorialllospita/s
j}{edic'ine;
CHARLES L. SHORT, M.D. Assistant Clinical Professor of Medicine, llarvard Medical School; Consulting Visiting Physician, M assachusetls Generalll o.~pital
of antirheumatic agents of greater potency than salicylates, yet devoid of the undesirable metabolic effeets of corticosteroids, presents one of the greatest challenges to physicians and investigators interested in the alleviation of rheumatic diseases. Among the eompounds which may be of importance in this area are the 4-aminoquinolines, notably chloroquine and hydroxychloroquine. Initially investigated during the Second World War as part of an intensive program for the development of improved antimalarial compounds, l, 3 their use as antirheumatic agents was introduced, in part, as an extension of attempts to use antimalarial compounds in the treatment of discoid lupus and lupus erythematosus disseminatus,ll, 12, 13, 15 and in part as a result of the apparent incidental benefit of these agents when given, as antimalarials, to individuals who happened to have rheumatoid arthritis. Interest in the possible efficacy of ehloroquine in rheumatoid arthritis THE DEVELOPMENT
* This is publieation No. 2!l2 from the Robert W. Lovett Memorial Laboratories for the Study of Crippling Disease. Grants in support of these investigations have been received from the Commonwealth Fund, National Institute of Arthritis and Metabolic Diseases (Grant No. A-I064) and the Eli Lilly Company.
1219
1220
EVAN CALKINS, ALAN S. COHEN, CHARLES
L.
SHORT
was stimulated by the extensive, though uncontrolled, clinical observations of BagnalP and others, and short-term controlled studies confirmed the fact that chloroquine is seemingly capable of exerting an antiinflammatory action in patients with rheumatoid arthritis.5, 6 It must be emphasized, however, that neither uncontrolled clinical observations on the one hand, nor short-term controlled studies on the other provide a satisfactory answer to the question: "Do these compounds constitute effective drugs in the management of patients with rheumatoid arthritis?" The capricious nature of rheumatoid arthritis, prone as it is to unheralded and apparently spontaneous remissions and exacerbations, renders it a difficult disease to study from the therapeutic point of view. 4 This is especially true when the agent is one, like chloroquine, which gradually accumulates in the tissues and may not exert its therapeutic effect until after six or eight weeks of treatment. For these reasons, it is apparent that evaluation of the potential therapeutic role of the 4-aminoquinolines requires long-term controlled observation. Such investigations, lasting for a period of at least one year, are exceedingly difficult to carry out. Nevertheless, two large-scale studies of this sort have been reported and merit review. A very smallscale pilot study was also undertaken in this clinic and will be reported briefly. The first report of a controlled double blind study of the effects of chloroquine treatment of rheumatoid arthritis, over the course of one year, was that of Freedman and Steinberg.7 These investigators selected for study 107 patients with active rheumatoid arthritis from three cooperating clinics. Fifty-three patients were given chloroquine sulfate (400 mg. per day), and 42 of these completed the one year's trial. Fifty-four were given placebo; of these 40 finished the trial. All patients were maintained on 40 grains of aspirin per day. The patients were evaluated periodically by means of objective examinations and tests and laboratory studies. Published data, however, compare the findings at the onset of the study with those at the conclusion. The results showed that one-half of the control group thought they had improved, but objective evaluation indicated that only 30 per cent had improved, whereas 25 per cent were worse. Of the 42 patients who received and tolerated chloroquine, 90 per cent felt they had improved; 80 per cent showed objective improvement; and only 5 per cent were worse. Significant differences between the two groups were noted in studies of joint tenderness, grip strength, walking time, erythrocyte sedimentation rate, and estimates of functional capacity and disease activity. No difference was noted between the treated and control groups as regards hemoglobin levels. It should be pointed out that the chloroquine group contained nine patients with disease of less than two years' duration, whereas the placebo group contained only four individuals in thi::-; eategory. The authors state that analysis of the data pertaining only to
Long-Term Chloroquine Therapy in Rheumatoid Arthritis
1221
those patients with diseases of over one year's duration yielded results comparable to those outlined above. The second one year study of the effects of chloroquine in rheumatoid arthritis was reported by Popert et al. 14 These investigators included in their study, in addition to outpatients not responding to conservative treatment, all patients with rheumatoid arthritis who entered the two participating hospitals, excepting a few who experienced rapid spontaneous improvement within two or three weeks of hospitalization. The patients were divided into six strata in accordance with sex, duration of disease, and results of the sheep cell agglutination test. Patients in each stratum were assigned to treatment or chloroquine groups, in order of admission to the study. Some of the patients were simultaneously treated with corticosteroids, and occasionally phenylbutazone was used. The study was not conducted on a strictly "double-blind" basis since the senior author, who was responsible for the arrangements and who carried out 25 per cent of the follow-up assessments, knew which patient was receiving the active agent (chloroquine diphosphate, 250 mg.) and which the "placebo" (chloroquine diphosphate, 2.5 mg. per day). A total of 134 patients were studied for periods of between one and two years. When the data at the end of the study were compared with those at the onset, it was apparent that significant differences between the treatment and placebo groups were noted as regards estimates of disease activity, functional capacity, grip strength, erythrocyte sedimentation rate, and sheep cell agglutination test. The differences between treated and untreated groups were greater in patients with disease of less than two years' duration than in those with longer duration, especially those with positive sheep cell tests. No differences were noted by x-ray-both treated and untreated groups exhibited the same progression. The pilot study which was conducted in our own clinic involved 15 patients with active peripheral rheumatoid arthritis. They ranged in age from 29 to 69 years and had experienced sustained disease activity for periods ranging between 27:2 and 20 years. All but two were females. Sera from all patients but two (numbers 7 and 10) yielded positive results in the latex fixation testP Prior to the study, all patients had been maintained on a conservative regimen, including salicylates. None of them had received gold or corticosteroid therapy. PROCEDURE
The study drugs were bottled, labeled, and dispensed in the following manner. Each of the three observers was assigned two series of bottles A and B. This was accomplished by use of the table of random numbers 18 and by separate coding of capsules at a separate institution. Each patient was maintained on one capsule ("A" drug) daily (250 mg. of chloroquine
1222
EVAN CALKINS, ALAN S. COHEN, CHARLES
L.
SHORT
or placebo). If undesirable side effects occurred, tlw patient was given the accompanying "13" drug of that number-i.e., if 1 A was chloroquine, then 1 B was hydroxychloroquine; if 1 A was placebo, then 1 13 was placebo. Neither physician, patifmt, nurse or dinie secretary knew whether a given patient was on drug or placebo. When the code was broken, it was found that eight patients had been maintained on placebo, while seven had received chloroquine. Toxic symptoms had developed in three of the latter patients. Two of the patients (Nos. 8 and 9) had been successfully shifted to hydroxychloroquine and maintained on this agent throughout the remainder of the study (nine and eleven months respectively). The third patient (No. 5), who had received chloroquine for six months at the time she developed toxic symptoms, did not tolerate hydroxychloroquine, and her trial had to be discontinued at this time. The study drug was also discontinued in three placebo-treated patients-in one (No. 2-after five months) because of flare-up of psoriasis; in a second (No. G-after six months) because of severe vasomotor symptoms; and in the third (No. l:-n after an eight months' trial because continued disease activity dem:llIded other treatment. One placebo-treated patient (No. 12) was lost to follow-up after onc month. The patients were evaluated at intervals of approximately two months. They maintained daily diaries recording the duration of morning stiffness, the time before onset of fatigue, the number of aspirin tablets consumed, and possible side effects. At each evaluation visit, a detailed history was taken and a thorough physical examination was performed, including an assessment of all peripheral joints, with grading of each with regard to swelling, tenderness and range of motion. Grip strength was recorded for each hand. ID The physician coneluded his evaluation with an overall estimate of disease activity. Laboratory data included erythrocyte sedimentation rate (Rourke Ernstene 16 ), white blood cell count and differential, urinalysis, and the latex fixation testY Data were assessed by means of calculating the Systemic Index,)O using the modified scheme which does not inelude the hemoglobin. Data for sedimentation rates (1 minute-Rourke Ernstene) were assessed in accordance with a modified scaIe,9 since the Lansbury Scale requires the Westergren or Cutler method. The "percentage of absolute improvement"5 was calculated for each time of evaluation. "Absolute improvement or worsening" of over 15 per cent was considered significant." The overall change in articular findings, by physical examination, were evaluated in the following manner. It was considered that improvement had occurred if effusions had disappeared, soft tissue thickening markedly lessened, tenderness had disappeared, and range of motion had detectably increased in the majority of the joints, if no new joints had become involved, and no new nodules had appeared. If these criteria were not met, the patient's physical status was regarded as unchanged or worse.
1223
Long-Term Chloroquine Therapy in Rheumatoid Arthritis RESULTS
The courses exhibited by the placebo-treated cases, as judged from systemic indices, are recorded in Figure 1, and the overall assm;sment of the case~ is summarized in Table 1. Clear-cut improvement, as mea~mred by the iwstemie index and by articular examination, was observed in only one patient (No. 10). Another, Case 3, manifested improvement by all criteria over the first ten months of study, but then experienced a clinical relapse, such that, at the end of a year, there was only slight improvement (22 per cent). Patient 6, an individual noted for pronounced psychm;omatic components to her disease, showed a markedly erratic course, and the agent (placebo) had to be discontinued after six months because of the development of severe vasomotor phenomena. At this time there was some improvement in articular manifestations but none in the systemic index. None of the other patients manifested improvement either by systemic index or by objective findings. The courses exhibited by the seven patients who received chloroquine or hydroxychloroquine are shown in Figure 2. All five of the patients who received preparation "A" (chloroquine) throughout exhibited, at least initially, some degree of improvement as judged by the systemic indices. In four of the patients this was accompanied by a lessening in the swelling, heat and tenderness of the involved joints. On the other hand, this initial favorable response was sustained throughout the study in only two of the patients (Nos. 11 and 14, designated in Figure 2 by the solid lines). In two of the other eases, Nos. 1 and 7, marked increases in disease activity occurred after six and eight months respectively. By Table 1. Results of a )ne-Year Double-Blind Controlled Study of Effects of Chloroquine or Hydroxychloroquine Therapy in 15 Patients with Rheumatoid Arthritis
Placebo
4-Aminoquinoline
CLINICAL RESPONSE
Chiefly Hydroxychloroquine Chloroquine (200 mg./day) (250 mg./day) ConsiHtent improvement (12 months) .. Transitory improvement (6 months) Followed by relapse ......... . Followed by toxic symptoms ...... . No change .......... . Worse .... . Lost to follow-up ..... .
2
2
1
4 ] ]
8
5
1224
EVAN CALKINS, ALAN 160
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~--- ~~-
COHEN, CHAHLES
L.
SHOW!'
~-
PLACEBO TREATED PATIENTS
[2
140
~/3
,,3
/.
SYSTEMIC INDEX
"
40
20
~
10
"--_---'-_---'_ _-"---_---'-___ J _ _ -1. _ _ 10
TIME
12
(MONTHS)
Fig. 1. This figure depicts the course of 8 patients with active rheumatoid arthriti~ who underwent treatment with placebo. The ordinate depicts the disease activity as (~stimated by the systemic index. lo The data for those patients whose course was variable is depicted by lines. Data for patients with no ehange in index is shown by the unconnected dots. A double bar 11 beside a dot or line indicates that the drug was discontinued because of an apparent toxic effect. A single bar 1 indicates that it was discontinued for other reasons (see text).
the end of the study, one of these patients exhibited some net improvement in objective manifestations of arthritis. The other was no better than at the onset of treatment. The fifth patient who showed initial improvement, No. 5, developed symptoms of toxicity requiring discontinuation of treatment after six months. At this time, she exhibited definite improvement, as judged by the systemic index, and the articular examination. The t,,,"o patients who received preparation "B" (hydroxychloroquine) throughout the major part of the study did not fare so well. One of these (Case 9), shown in Figure 2 by the unconnected dots, showed no change throughout the first eight months, but subsequently exhibited slight improvement. Patient 8, who was initially only moderately active, exhibited increased evidences of disease activity, as shown by the dotted line. Of the three patients in the entire group who exhibited consistent improvement, onc (placebo-treated) maintained a negative latex fixation test throughout; the other two, in whom the response was associated with 4-aminoquinoline treatment, exhibited consistently positive reactions in a titer of 1/5120 or higher. In general, it can be stated that 4-aminoquinoline treatment waH not associated with any change ill the
Lo ng-T el'm Chlo1'Oqu,i ne T hempy in Rheumato'id A l'thl'it'is
1225
"-""-I CHLOROQUINE OR HYDROXY-CHLOROQUINE -~-"-"----------------
TREATED PATIENTS
120
•
•
~8
. . . . I.
~
J \ :
SYSTEMIC INDEX
"/",: "
I
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60
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,
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: 40: .... _____ ...... : 20
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,
Y
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TIME (MONTHS)
Fig. 2. This figure depicts the course of 7 patients during 4-aminoquinoline treatment, The solid lines depict the course of 3 patients who were judged to improve. The broken lines refer to 2 patients who exhibited transitory improvement only. The dotted line depicts the course of a patient who became worse. The other designations are as recorded for Figure 1.
latex fixation test, and that, in this pilot study, there was no association hetween the reaction in this test and the clinical course or response to treatment. No changes in radiologic findings were observed in this onc year period. COMMENT
The pilot study, reported above, is based upon sueh a small group of patients that no definite conchUlions are justified. On the other hand, it illustrates one point of eonsiderable interest. Had the investigation been discontinued after six months, it would have appeared that significant benefit had been achieved in five of the seven 4-aminoquinoline treated patients, and in all of the patients who had received ehloroquine. (The dose of hydroxychloroquine which was employed [200 mg. per day] is less than that now regarded as optimal [600 to 800 mg. per day]). Subsequent months, however, saw the occurrence of major relapses in two of these patients and toxicity in a third, resulting in sustained improvement in only two of the 4-aminoquinoline treated eases. These results, based on an f'xtremely small group of eases, cannot he n~garded in the same light as the two large seale studies reported ahove, bot.h of which showed that, in large groups of patients followed over the
1226
EVAN CALKINS, ALAN S. COHEN, CHARLES
L.
SHORT
course of a year, the group receiving chloroquine exhibited significant improvement, in certain regards, as compared with those receiving placebo. On the other hand, this small scale study raises this question: Is it possible that the beneficial effects of chloroquine which are manifested in a study of clinical experience of relatively short duration (three to twelve months) will not be borne out, to as great a degree, over the course of longer periods? Furthermore, it is our impression that chloroquine and its analogues may hold much greater therapeutic potentialities for certain patients with rheumatoid arthritis than for others. In this regard, our overall clinical experience may be of interest. In the three years that we have been studying antimalarial compounds in our clinic, the agents have been employed in a total of 54 cases. All but one have been followed in the clinic since starting the drug. Thirty-four of these patients were given the drugs incident to double-blind controlled studies. Upon completion of the study, however, the patients have been followed by different members of the clinic staff and treated with whatever agent, if any, that seemed appropriate. Twenty additional patients were started on one of the 4-aminoquinolines for therapeutic purposes. The drug has been discontinued in 25 of the 53 patients who have been followed-in five of them because of toxic effects, in 18 because it was clearly ineffective, and in two because of clinical remission. In the remaining 28 patients the drug has been continuously administered to the present time. In 11 of these eases, the agent has been given continuously for a period of four or more years. Further study will be necessary to determine whether this continuous administration reflects a truly beneficial action or habit on the part of the physician and/or patient. SUGGESTIONS FOR USAGE OF 4-AMINOQUlNOLINES
In conclusion, a few comments should be made concerning the pharmacology of these agents and their manner of usage. Excellent pharmacological studies carried out on experimental animals during the Second World Warl, 3 have indicated that they are well absorbed by mouth. They are stored in the cells of the reticuloendothelial system, especially the liver, kidney and lung. They accumulate in these tissues gradually over the course of time and reach concentrations approximately 400 to 700 times those in plasma. Following saturation of the tissues, satisfactory blood levels can be maintained by small doses of the drug by mouth. A reminder of the fact that the drug is widely stored in the body is provided by the white depoRitR which have been observed in the corneas of a number of patients who have received prolonged therapy with this agent. 8, 19 The occurrence of this complication appears to be to some extent the result of individual propensity, since it is not necessarily related to the dose employed. The deposits may cause the patient to experience blurred vision and halos around lights, suggestive of those
Long-Term Chloroquine Therapy in Rheumatoid Arthritis
1227
seen in glaucoma. They rarely cause loss in visual activity, however. The deposits are best seen in the slit-lamp, and patients who are receiving therapy with this agent should receive examination by this technique at intervals of six months or at the most a year. The deposits usually disappear when the drug is discontinued. It is our practice to employ the 4-aminoquinolines in patients with rheumatoid arthritis in the following manner. Patients are considered for treatment if they have sustained activity which does not respond to full doses of salicylates over four to six months and to a regimen which is restricted as is deemed indicated from overall assessment of the case. In these "unresponsive cases," in which other forms of therapy are deemed advisable, we usually favor a trial of therapy with chloroquine or hydroxychloroquine before giving any serious consideration to corticosteroid therapy. Chloroquine is generally employed in a starting dose of 250 mg. per day, although in some cases in which a more vigorous start is deemed advisable an initial dose of 500 mg. per day is employed. If the larger dose is employed, however, it is always reduced, after a period of not more than three months, to 250 mg. per day, and after a period of six months, to 250 mg. three or four times per week. It must be anticipated that many patients will exhibit toxic reactiomi. These require discontinuation of the drug in approximately 10 to 20 per cent of cases. The most common toxic effcct is a metallic taste and epigastric burning semiation. The latter has not thus far presaged the development of peptic ulcers. A sense of inner tremulousness, and of telescoping vision may also be noted. Leukopenia is occasionally seen, but agranulocytosis is very rare, if seen at all. Comeal deposits have been mentioned above and constitute one of the most serious toxic effects. In general, all of these adverse reactions, inelnding in most instances the corneal deposits, disappear following discontinuation of the drug, but because of the accumulation of the drug in the tissues its manifestations may persist for up to a month after stopping it. Dramatic rebounds of disease aetivity, often noted following cessation of corticoid therapy, are not seen immediately following discontinuation of treatment with chloroquine or hydroxychloroquine. If a given patient has a minor side effect, a trial of therapy with hydroxychloroquine (400 mg. per day) is usually undertaken. Leukopenia, rash and corneal opacities, however, are usually considered grounds for discontinuing 4-aminoquinolille therapy. In summary, it is our opiuion, upon presently available evidence, that whereas chloroquine and its analogues are capable of exerting, in shortterm study, significant antirheumatic action, prolonged administration of the drug results in elear-cut sustained benefit, unassociated with unpleasant side reactions, in only a minority of patients. Nevertheless, this admittedly rather slim advantage provides encouragement that
1228
EVAN CALKINS, ALAN S. COHEN, CHARLES
L.
SHORT
ultimately more effective agents will be devised and, in the meantime, may provide welcome benefit for the occasional patient. Acknowledgments The authors are indebted to Dr. WaIter Bauer for encouragement and assistance throughout this study, and to the Winthrop Laboratories for pharmaceutical preparations.
REFERENCES I. Alving, A. S. and others: Studies on Chronic Toxicity of Chloroquine (SN-7618) .J. Clin. Invest. 27: 60 (Suppl. 3. Part Il) 1948. 2. Bagnall, A. W.: Value of Chloroquine in Rheumatoid Disease. Canad. M. A.•J. 77: 182, 1957. 3. Berliner, R. W. and others: Studies on Chemotherapy of Human Malarias: VI. Physiological Disposition, Antimalarial Activity and Toxicity of Several Derivatives of 4-Aminoquinoline. J. Clin. Invest. 27: 98 (Suppl. 3, Part Il) 1948. 4. Calkins, E. and others: Therapeutic Evaluation in Rheumatoid ArthritiR. Arthritis & Rheum. 3: 101, 1960. 5. Cohen, A. S. and Calkins, E.: Controlled Study of Chloroquine as Antirheumatic Agent. Arthritis & Rheum. 1: 297, 1958. G. Freedman, A.: Chloroquine and Rheumatoid Arthritis. Ann. Rheumat. Dis. 15: 251,1956. 7. Freedman, A. and Steinberg, V. L.: Chloroquine in Rheumatoid Arthritis. A Double Blindfold Trial of Treatment for One Year. Ann. Rheumat. Dis. 19: 243,1960. 8. Hobbs, H. E. and Calnan, C. D.: Visual Disturbances with Antimalarial Drugs, with Particular Reference to Chloroquine Keratopathy. Arch. Dermal,. 80: 557,1959. 9. Lansbury, J.: Personal communication. 10. Lansbury, J.: Numerical Method of Evaluating Status of Rheumatoid Arthritis. Ann. Rheumat. Dis. 17: 101, 1958. 11. Martenstein, H.: Lupus Erythematosus and Tubercular Cervical Adenopathy; Treatment with Plasmochin. Zentralbl. Haut-Geschlkrkh. 27: 248, 1928. 12. Page, F.: Treatment of Lupus Erythematosus with Mepacrine. Lancet 2: 755, 1951. 1:3. Payne, J. F.: Postgraduate Lecture on Lupus Erythematosus. The Clin ..J. 4: 223,1894. 14. Popert, A. J., Meijers, K. A. E., Sharp, J. and Bier, F.: Chloroquine Diphosphate in Rheumatoid Arthritis. Ann. Rheumat. Dis. 20: 18, 1961. 15. Prokoptchouk, A. J.: Treatment of Lupus Erythematosus with Acriquin('. Vestnik vener. i derm. 2/3: 23, 1940. ](1. Rourke, M. D. and Ernstene, A. C.: Method for Correcting Erythrocyte Sedimentation Rate for Variations in Cell Volume Percentage of Blood ..r. Clin. Invest. 8: 545, 1930. 17. Singer, J. M. and Plotz, C. M.: Latex Fixation Test. 1. Application to Serologie Diagnosis of Rheumatoid Arthritis. Am. J. Med. 21: 888, 1956. 18. Snedecor, G. W.: Statistical Methods. Ames, Iowa, Iowa State College Prpss, 1946. IH. lIeller, R. W. and Deering, D.: Corneal Complication of Chloroquine (Amlen) Phosphate Therapy. J.A.M.A. 168: 2263,19.58. Massachusetts General Hospital Hoston 14, Massachusetts
EVAN CALKINS, M.D. Professor of Medicine, llarvard Medical School; Director, Robert W. Lovelt Memorial Unit, Massachusetts General II ospital
Assi.~tant
ALAN S. COHEN, M.D. Assistant Professor of Medicine, Boston University School of Director, Arthritis and Connective Tissue Disease Section, M assachusetls M emorialllospita/s
j}{edic'ine;
CHARLES L. SHORT, M.D. Assistant Clinical Professor of Medicine, llarvard Medical School; Consulting Visiting Physician, M assachusetls Generalll o.~pital
of antirheumatic agents of greater potency than salicylates, yet devoid of the undesirable metabolic effeets of corticosteroids, presents one of the greatest challenges to physicians and investigators interested in the alleviation of rheumatic diseases. Among the eompounds which may be of importance in this area are the 4-aminoquinolines, notably chloroquine and hydroxychloroquine. Initially investigated during the Second World War as part of an intensive program for the development of improved antimalarial compounds, l, 3 their use as antirheumatic agents was introduced, in part, as an extension of attempts to use antimalarial compounds in the treatment of discoid lupus and lupus erythematosus disseminatus,ll, 12, 13, 15 and in part as a result of the apparent incidental benefit of these agents when given, as antimalarials, to individuals who happened to have rheumatoid arthritis. Interest in the possible efficacy of ehloroquine in rheumatoid arthritis THE DEVELOPMENT
* This is publieation No. 2!l2 from the Robert W. Lovett Memorial Laboratories for the Study of Crippling Disease. Grants in support of these investigations have been received from the Commonwealth Fund, National Institute of Arthritis and Metabolic Diseases (Grant No. A-I064) and the Eli Lilly Company.
1219
1220
EVAN CALKINS, ALAN S. COHEN, CHARLES
L.
SHORT
was stimulated by the extensive, though uncontrolled, clinical observations of BagnalP and others, and short-term controlled studies confirmed the fact that chloroquine is seemingly capable of exerting an antiinflammatory action in patients with rheumatoid arthritis.5, 6 It must be emphasized, however, that neither uncontrolled clinical observations on the one hand, nor short-term controlled studies on the other provide a satisfactory answer to the question: "Do these compounds constitute effective drugs in the management of patients with rheumatoid arthritis?" The capricious nature of rheumatoid arthritis, prone as it is to unheralded and apparently spontaneous remissions and exacerbations, renders it a difficult disease to study from the therapeutic point of view. 4 This is especially true when the agent is one, like chloroquine, which gradually accumulates in the tissues and may not exert its therapeutic effect until after six or eight weeks of treatment. For these reasons, it is apparent that evaluation of the potential therapeutic role of the 4-aminoquinolines requires long-term controlled observation. Such investigations, lasting for a period of at least one year, are exceedingly difficult to carry out. Nevertheless, two large-scale studies of this sort have been reported and merit review. A very smallscale pilot study was also undertaken in this clinic and will be reported briefly. The first report of a controlled double blind study of the effects of chloroquine treatment of rheumatoid arthritis, over the course of one year, was that of Freedman and Steinberg.7 These investigators selected for study 107 patients with active rheumatoid arthritis from three cooperating clinics. Fifty-three patients were given chloroquine sulfate (400 mg. per day), and 42 of these completed the one year's trial. Fifty-four were given placebo; of these 40 finished the trial. All patients were maintained on 40 grains of aspirin per day. The patients were evaluated periodically by means of objective examinations and tests and laboratory studies. Published data, however, compare the findings at the onset of the study with those at the conclusion. The results showed that one-half of the control group thought they had improved, but objective evaluation indicated that only 30 per cent had improved, whereas 25 per cent were worse. Of the 42 patients who received and tolerated chloroquine, 90 per cent felt they had improved; 80 per cent showed objective improvement; and only 5 per cent were worse. Significant differences between the two groups were noted in studies of joint tenderness, grip strength, walking time, erythrocyte sedimentation rate, and estimates of functional capacity and disease activity. No difference was noted between the treated and control groups as regards hemoglobin levels. It should be pointed out that the chloroquine group contained nine patients with disease of less than two years' duration, whereas the placebo group contained only four individuals in thi::-; eategory. The authors state that analysis of the data pertaining only to
Long-Term Chloroquine Therapy in Rheumatoid Arthritis
1221
those patients with diseases of over one year's duration yielded results comparable to those outlined above. The second one year study of the effects of chloroquine in rheumatoid arthritis was reported by Popert et al. 14 These investigators included in their study, in addition to outpatients not responding to conservative treatment, all patients with rheumatoid arthritis who entered the two participating hospitals, excepting a few who experienced rapid spontaneous improvement within two or three weeks of hospitalization. The patients were divided into six strata in accordance with sex, duration of disease, and results of the sheep cell agglutination test. Patients in each stratum were assigned to treatment or chloroquine groups, in order of admission to the study. Some of the patients were simultaneously treated with corticosteroids, and occasionally phenylbutazone was used. The study was not conducted on a strictly "double-blind" basis since the senior author, who was responsible for the arrangements and who carried out 25 per cent of the follow-up assessments, knew which patient was receiving the active agent (chloroquine diphosphate, 250 mg.) and which the "placebo" (chloroquine diphosphate, 2.5 mg. per day). A total of 134 patients were studied for periods of between one and two years. When the data at the end of the study were compared with those at the onset, it was apparent that significant differences between the treatment and placebo groups were noted as regards estimates of disease activity, functional capacity, grip strength, erythrocyte sedimentation rate, and sheep cell agglutination test. The differences between treated and untreated groups were greater in patients with disease of less than two years' duration than in those with longer duration, especially those with positive sheep cell tests. No differences were noted by x-ray-both treated and untreated groups exhibited the same progression. The pilot study which was conducted in our own clinic involved 15 patients with active peripheral rheumatoid arthritis. They ranged in age from 29 to 69 years and had experienced sustained disease activity for periods ranging between 27:2 and 20 years. All but two were females. Sera from all patients but two (numbers 7 and 10) yielded positive results in the latex fixation testP Prior to the study, all patients had been maintained on a conservative regimen, including salicylates. None of them had received gold or corticosteroid therapy. PROCEDURE
The study drugs were bottled, labeled, and dispensed in the following manner. Each of the three observers was assigned two series of bottles A and B. This was accomplished by use of the table of random numbers 18 and by separate coding of capsules at a separate institution. Each patient was maintained on one capsule ("A" drug) daily (250 mg. of chloroquine
1222
EVAN CALKINS, ALAN S. COHEN, CHARLES
L.
SHORT
or placebo). If undesirable side effects occurred, tlw patient was given the accompanying "13" drug of that number-i.e., if 1 A was chloroquine, then 1 B was hydroxychloroquine; if 1 A was placebo, then 1 13 was placebo. Neither physician, patifmt, nurse or dinie secretary knew whether a given patient was on drug or placebo. When the code was broken, it was found that eight patients had been maintained on placebo, while seven had received chloroquine. Toxic symptoms had developed in three of the latter patients. Two of the patients (Nos. 8 and 9) had been successfully shifted to hydroxychloroquine and maintained on this agent throughout the remainder of the study (nine and eleven months respectively). The third patient (No. 5), who had received chloroquine for six months at the time she developed toxic symptoms, did not tolerate hydroxychloroquine, and her trial had to be discontinued at this time. The study drug was also discontinued in three placebo-treated patients-in one (No. 2-after five months) because of flare-up of psoriasis; in a second (No. G-after six months) because of severe vasomotor symptoms; and in the third (No. l:-n after an eight months' trial because continued disease activity dem:llIded other treatment. One placebo-treated patient (No. 12) was lost to follow-up after onc month. The patients were evaluated at intervals of approximately two months. They maintained daily diaries recording the duration of morning stiffness, the time before onset of fatigue, the number of aspirin tablets consumed, and possible side effects. At each evaluation visit, a detailed history was taken and a thorough physical examination was performed, including an assessment of all peripheral joints, with grading of each with regard to swelling, tenderness and range of motion. Grip strength was recorded for each hand. ID The physician coneluded his evaluation with an overall estimate of disease activity. Laboratory data included erythrocyte sedimentation rate (Rourke Ernstene 16 ), white blood cell count and differential, urinalysis, and the latex fixation testY Data were assessed by means of calculating the Systemic Index,)O using the modified scheme which does not inelude the hemoglobin. Data for sedimentation rates (1 minute-Rourke Ernstene) were assessed in accordance with a modified scaIe,9 since the Lansbury Scale requires the Westergren or Cutler method. The "percentage of absolute improvement"5 was calculated for each time of evaluation. "Absolute improvement or worsening" of over 15 per cent was considered significant." The overall change in articular findings, by physical examination, were evaluated in the following manner. It was considered that improvement had occurred if effusions had disappeared, soft tissue thickening markedly lessened, tenderness had disappeared, and range of motion had detectably increased in the majority of the joints, if no new joints had become involved, and no new nodules had appeared. If these criteria were not met, the patient's physical status was regarded as unchanged or worse.
1223
Long-Term Chloroquine Therapy in Rheumatoid Arthritis RESULTS
The courses exhibited by the placebo-treated cases, as judged from systemic indices, are recorded in Figure 1, and the overall assm;sment of the case~ is summarized in Table 1. Clear-cut improvement, as mea~mred by the iwstemie index and by articular examination, was observed in only one patient (No. 10). Another, Case 3, manifested improvement by all criteria over the first ten months of study, but then experienced a clinical relapse, such that, at the end of a year, there was only slight improvement (22 per cent). Patient 6, an individual noted for pronounced psychm;omatic components to her disease, showed a markedly erratic course, and the agent (placebo) had to be discontinued after six months because of the development of severe vasomotor phenomena. At this time there was some improvement in articular manifestations but none in the systemic index. None of the other patients manifested improvement either by systemic index or by objective findings. The courses exhibited by the seven patients who received chloroquine or hydroxychloroquine are shown in Figure 2. All five of the patients who received preparation "A" (chloroquine) throughout exhibited, at least initially, some degree of improvement as judged by the systemic indices. In four of the patients this was accompanied by a lessening in the swelling, heat and tenderness of the involved joints. On the other hand, this initial favorable response was sustained throughout the study in only two of the patients (Nos. 11 and 14, designated in Figure 2 by the solid lines). In two of the other eases, Nos. 1 and 7, marked increases in disease activity occurred after six and eight months respectively. By Table 1. Results of a )ne-Year Double-Blind Controlled Study of Effects of Chloroquine or Hydroxychloroquine Therapy in 15 Patients with Rheumatoid Arthritis
Placebo
4-Aminoquinoline
CLINICAL RESPONSE
Chiefly Hydroxychloroquine Chloroquine (200 mg./day) (250 mg./day) ConsiHtent improvement (12 months) .. Transitory improvement (6 months) Followed by relapse ......... . Followed by toxic symptoms ...... . No change .......... . Worse .... . Lost to follow-up ..... .
2
2
1
4 ] ]
8
5
1224
EVAN CALKINS, ALAN 160
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~--- ~~-
COHEN, CHAHLES
L.
SHOW!'
~-
PLACEBO TREATED PATIENTS
[2
140
~/3
,,3
/.
SYSTEMIC INDEX
"
40
20
~
10
"--_---'-_---'_ _-"---_---'-___ J _ _ -1. _ _ 10
TIME
12
(MONTHS)
Fig. 1. This figure depicts the course of 8 patients with active rheumatoid arthriti~ who underwent treatment with placebo. The ordinate depicts the disease activity as (~stimated by the systemic index. lo The data for those patients whose course was variable is depicted by lines. Data for patients with no ehange in index is shown by the unconnected dots. A double bar 11 beside a dot or line indicates that the drug was discontinued because of an apparent toxic effect. A single bar 1 indicates that it was discontinued for other reasons (see text).
the end of the study, one of these patients exhibited some net improvement in objective manifestations of arthritis. The other was no better than at the onset of treatment. The fifth patient who showed initial improvement, No. 5, developed symptoms of toxicity requiring discontinuation of treatment after six months. At this time, she exhibited definite improvement, as judged by the systemic index, and the articular examination. The t,,,"o patients who received preparation "B" (hydroxychloroquine) throughout the major part of the study did not fare so well. One of these (Case 9), shown in Figure 2 by the unconnected dots, showed no change throughout the first eight months, but subsequently exhibited slight improvement. Patient 8, who was initially only moderately active, exhibited increased evidences of disease activity, as shown by the dotted line. Of the three patients in the entire group who exhibited consistent improvement, onc (placebo-treated) maintained a negative latex fixation test throughout; the other two, in whom the response was associated with 4-aminoquinoline treatment, exhibited consistently positive reactions in a titer of 1/5120 or higher. In general, it can be stated that 4-aminoquinoline treatment waH not associated with any change ill the
Lo ng-T el'm Chlo1'Oqu,i ne T hempy in Rheumato'id A l'thl'it'is
1225
"-""-I CHLOROQUINE OR HYDROXY-CHLOROQUINE -~-"-"----------------
TREATED PATIENTS
120
•
•
~8
. . . . I.
~
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SYSTEMIC INDEX
"/",: "
I
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,
,\ 'v'
: 40: .... _____ ...... : 20
..
,
Y
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TIME (MONTHS)
Fig. 2. This figure depicts the course of 7 patients during 4-aminoquinoline treatment, The solid lines depict the course of 3 patients who were judged to improve. The broken lines refer to 2 patients who exhibited transitory improvement only. The dotted line depicts the course of a patient who became worse. The other designations are as recorded for Figure 1.
latex fixation test, and that, in this pilot study, there was no association hetween the reaction in this test and the clinical course or response to treatment. No changes in radiologic findings were observed in this onc year period. COMMENT
The pilot study, reported above, is based upon sueh a small group of patients that no definite conchUlions are justified. On the other hand, it illustrates one point of eonsiderable interest. Had the investigation been discontinued after six months, it would have appeared that significant benefit had been achieved in five of the seven 4-aminoquinoline treated patients, and in all of the patients who had received ehloroquine. (The dose of hydroxychloroquine which was employed [200 mg. per day] is less than that now regarded as optimal [600 to 800 mg. per day]). Subsequent months, however, saw the occurrence of major relapses in two of these patients and toxicity in a third, resulting in sustained improvement in only two of the 4-aminoquinoline treated eases. These results, based on an f'xtremely small group of eases, cannot he n~garded in the same light as the two large seale studies reported ahove, bot.h of which showed that, in large groups of patients followed over the
1226
EVAN CALKINS, ALAN S. COHEN, CHARLES
L.
SHORT
course of a year, the group receiving chloroquine exhibited significant improvement, in certain regards, as compared with those receiving placebo. On the other hand, this small scale study raises this question: Is it possible that the beneficial effects of chloroquine which are manifested in a study of clinical experience of relatively short duration (three to twelve months) will not be borne out, to as great a degree, over the course of longer periods? Furthermore, it is our impression that chloroquine and its analogues may hold much greater therapeutic potentialities for certain patients with rheumatoid arthritis than for others. In this regard, our overall clinical experience may be of interest. In the three years that we have been studying antimalarial compounds in our clinic, the agents have been employed in a total of 54 cases. All but one have been followed in the clinic since starting the drug. Thirty-four of these patients were given the drugs incident to double-blind controlled studies. Upon completion of the study, however, the patients have been followed by different members of the clinic staff and treated with whatever agent, if any, that seemed appropriate. Twenty additional patients were started on one of the 4-aminoquinolines for therapeutic purposes. The drug has been discontinued in 25 of the 53 patients who have been followed-in five of them because of toxic effects, in 18 because it was clearly ineffective, and in two because of clinical remission. In the remaining 28 patients the drug has been continuously administered to the present time. In 11 of these eases, the agent has been given continuously for a period of four or more years. Further study will be necessary to determine whether this continuous administration reflects a truly beneficial action or habit on the part of the physician and/or patient. SUGGESTIONS FOR USAGE OF 4-AMINOQUlNOLINES
In conclusion, a few comments should be made concerning the pharmacology of these agents and their manner of usage. Excellent pharmacological studies carried out on experimental animals during the Second World Warl, 3 have indicated that they are well absorbed by mouth. They are stored in the cells of the reticuloendothelial system, especially the liver, kidney and lung. They accumulate in these tissues gradually over the course of time and reach concentrations approximately 400 to 700 times those in plasma. Following saturation of the tissues, satisfactory blood levels can be maintained by small doses of the drug by mouth. A reminder of the fact that the drug is widely stored in the body is provided by the white depoRitR which have been observed in the corneas of a number of patients who have received prolonged therapy with this agent. 8, 19 The occurrence of this complication appears to be to some extent the result of individual propensity, since it is not necessarily related to the dose employed. The deposits may cause the patient to experience blurred vision and halos around lights, suggestive of those
Long-Term Chloroquine Therapy in Rheumatoid Arthritis
1227
seen in glaucoma. They rarely cause loss in visual activity, however. The deposits are best seen in the slit-lamp, and patients who are receiving therapy with this agent should receive examination by this technique at intervals of six months or at the most a year. The deposits usually disappear when the drug is discontinued. It is our practice to employ the 4-aminoquinolines in patients with rheumatoid arthritis in the following manner. Patients are considered for treatment if they have sustained activity which does not respond to full doses of salicylates over four to six months and to a regimen which is restricted as is deemed indicated from overall assessment of the case. In these "unresponsive cases," in which other forms of therapy are deemed advisable, we usually favor a trial of therapy with chloroquine or hydroxychloroquine before giving any serious consideration to corticosteroid therapy. Chloroquine is generally employed in a starting dose of 250 mg. per day, although in some cases in which a more vigorous start is deemed advisable an initial dose of 500 mg. per day is employed. If the larger dose is employed, however, it is always reduced, after a period of not more than three months, to 250 mg. per day, and after a period of six months, to 250 mg. three or four times per week. It must be anticipated that many patients will exhibit toxic reactiomi. These require discontinuation of the drug in approximately 10 to 20 per cent of cases. The most common toxic effcct is a metallic taste and epigastric burning semiation. The latter has not thus far presaged the development of peptic ulcers. A sense of inner tremulousness, and of telescoping vision may also be noted. Leukopenia is occasionally seen, but agranulocytosis is very rare, if seen at all. Comeal deposits have been mentioned above and constitute one of the most serious toxic effects. In general, all of these adverse reactions, inelnding in most instances the corneal deposits, disappear following discontinuation of the drug, but because of the accumulation of the drug in the tissues its manifestations may persist for up to a month after stopping it. Dramatic rebounds of disease aetivity, often noted following cessation of corticoid therapy, are not seen immediately following discontinuation of treatment with chloroquine or hydroxychloroquine. If a given patient has a minor side effect, a trial of therapy with hydroxychloroquine (400 mg. per day) is usually undertaken. Leukopenia, rash and corneal opacities, however, are usually considered grounds for discontinuing 4-aminoquinolille therapy. In summary, it is our opiuion, upon presently available evidence, that whereas chloroquine and its analogues are capable of exerting, in shortterm study, significant antirheumatic action, prolonged administration of the drug results in elear-cut sustained benefit, unassociated with unpleasant side reactions, in only a minority of patients. Nevertheless, this admittedly rather slim advantage provides encouragement that
1228
EVAN CALKINS, ALAN S. COHEN, CHARLES
L.
SHORT
ultimately more effective agents will be devised and, in the meantime, may provide welcome benefit for the occasional patient. Acknowledgments The authors are indebted to Dr. WaIter Bauer for encouragement and assistance throughout this study, and to the Winthrop Laboratories for pharmaceutical preparations.
REFERENCES I. Alving, A. S. and others: Studies on Chronic Toxicity of Chloroquine (SN-7618) .J. Clin. Invest. 27: 60 (Suppl. 3. Part Il) 1948. 2. Bagnall, A. W.: Value of Chloroquine in Rheumatoid Disease. Canad. M. A.•J. 77: 182, 1957. 3. Berliner, R. W. and others: Studies on Chemotherapy of Human Malarias: VI. Physiological Disposition, Antimalarial Activity and Toxicity of Several Derivatives of 4-Aminoquinoline. J. Clin. Invest. 27: 98 (Suppl. 3, Part Il) 1948. 4. Calkins, E. and others: Therapeutic Evaluation in Rheumatoid ArthritiR. Arthritis & Rheum. 3: 101, 1960. 5. Cohen, A. S. and Calkins, E.: Controlled Study of Chloroquine as Antirheumatic Agent. Arthritis & Rheum. 1: 297, 1958. G. Freedman, A.: Chloroquine and Rheumatoid Arthritis. Ann. Rheumat. Dis. 15: 251,1956. 7. Freedman, A. and Steinberg, V. L.: Chloroquine in Rheumatoid Arthritis. A Double Blindfold Trial of Treatment for One Year. Ann. Rheumat. Dis. 19: 243,1960. 8. Hobbs, H. E. and Calnan, C. D.: Visual Disturbances with Antimalarial Drugs, with Particular Reference to Chloroquine Keratopathy. Arch. Dermal,. 80: 557,1959. 9. Lansbury, J.: Personal communication. 10. Lansbury, J.: Numerical Method of Evaluating Status of Rheumatoid Arthritis. Ann. Rheumat. Dis. 17: 101, 1958. 11. Martenstein, H.: Lupus Erythematosus and Tubercular Cervical Adenopathy; Treatment with Plasmochin. Zentralbl. Haut-Geschlkrkh. 27: 248, 1928. 12. Page, F.: Treatment of Lupus Erythematosus with Mepacrine. Lancet 2: 755, 1951. 1:3. Payne, J. F.: Postgraduate Lecture on Lupus Erythematosus. The Clin ..J. 4: 223,1894. 14. Popert, A. J., Meijers, K. A. E., Sharp, J. and Bier, F.: Chloroquine Diphosphate in Rheumatoid Arthritis. Ann. Rheumat. Dis. 20: 18, 1961. 15. Prokoptchouk, A. J.: Treatment of Lupus Erythematosus with Acriquin('. Vestnik vener. i derm. 2/3: 23, 1940. ](1. Rourke, M. D. and Ernstene, A. C.: Method for Correcting Erythrocyte Sedimentation Rate for Variations in Cell Volume Percentage of Blood ..r. Clin. Invest. 8: 545, 1930. 17. Singer, J. M. and Plotz, C. M.: Latex Fixation Test. 1. Application to Serologie Diagnosis of Rheumatoid Arthritis. Am. J. Med. 21: 888, 1956. 18. Snedecor, G. W.: Statistical Methods. Ames, Iowa, Iowa State College Prpss, 1946. IH. lIeller, R. W. and Deering, D.: Corneal Complication of Chloroquine (Amlen) Phosphate Therapy. J.A.M.A. 168: 2263,19.58. Massachusetts General Hospital Hoston 14, Massachusetts