Efficacy of Intermittent Colchicine Therapy in Familial Mediterranean Fever DANIEL G. WRIGHT, M.D.; SHELDON M. WOLFF, M.D., F.A.C.P.; ANTHONY S. FAUCI, M.D.; and DAVID W. ALLING, M.D., Ph.D.; Bethesda, Maryland

Nine patients with familial Mediterranean fever (FMF) were admitted to a controlled, double-blind trial to determine if there are patients with this disease who are able to abort their acute episodes of pain and fever with short courses of colchicine taken at the onset of attacks. Five patients completed their treatment assignments, and colchicine was significantly effective in aborting the attacks of three but was ineffective in two. The remaining four patients could not be assessed because of insufficient numbers of courses. During the 10 months of the trial, 28 courses of colchicine and 3 1 of placebo were taken during the early stages of FMF attacks. Twenty-one ( 7 5 % ) colchicine courses were followed by attacks considered to have been aborted, compared to only three ( 1 0 % ) placebo courses. This trial shows that patients can recognize the prodrome of their FMF attacks and that some patients can consistently abort their attacks with short courses of colchicine taken at the very onset of symptoms.

SEVERAL CONTROLLED TRIALS have shown that chronic colchicine therapy markedly reduces the episodic attacks of painful serositis with fever that characterize familial Mediterranean fever (FMF) (1-3). Several investigators have stressed that although colchicine is quite effective in preventing FMF attacks when taken prophylactically, this drug is ineffective in altering an attack once it has begun (4, 5). However, the first clinical report of colchicine therapy in FMF indicated that this drug effectively shortened an FMF attack with arthritis (6). In addition, we have been able to follow a patient with FMF who reported that he could regularly abort his attacks by a short course of three to five colchicine tablets (0.6 mg) taken over as many hours if he began medication soon after recognizing the prodrome of an attack. Others have alluded to similar patients who appeared able to treat their disease successfully with short courses of colchicine taken only at times of FMF attacks (5). Clinical experience with chronic colchicine therapy in gouty arthritis has not revealed any significant long-term hazards of the drug regimens shown to be effective in FMF. However, the use of chronic colchicine in gout has been • From the Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health; Bethesda, Maryland.

almost exclusively limited to older persons, while most patients with FMF are diagnosed before the age of 20 years (7). Because instances of aneuploidy (8) and azoospermia (9) have been reported in persons taking colchicine daily, we have been hesitant to commit young patients, particularly women of childbearing age, to possible life-long treatment with daily colchicine. Therefore, we have considered it essential to establish whether or not intermittent courses of colchicine may be an effective treatment for some patients with FMF. In this report we present results of a double-blind, controlled trial designed to evaluate the efficacy of intermittent colchicine therapy in aborting attacks of FMF. Materials and Methods PATIENTS

Nine adults (four women, five men) with a history of frequent FMF attacks were selected for study. Some of these patients participated in our previous studies on colchicine prophylaxis (1). Attacks in these patients were characterized by acute, short-lived episodes of peritonitis or pleuritis, usually with fever. All patients were free of hepatic, renal, and hematologic abnormalities as measured by ordinary laboratory criteria. Most patients were taking chronic colchicine at time of entry to the study. Women did not receive anovulatory drugs during the study, although they were cautioned to avoid pregnancy. Other medications such as aspirin or propoxyphene were taken ad libitum. Informed consent was obtained from all patients. RANDOMIZATION, DRUG REGIMENS, AND EVALUATION OF ATTACKS

Separate courses of colchicine*, 0.6-mg tablets, and placebo*, numbered in sequence, were supplied to each patient. The order of colchicine and placebo courses was determined by a randomization scheme (10), which, for any given number of assignments, tends to yield approximately equal numbers of the two types of treatments. Each course consisted of 10 tablets. On entry into the study, patients were instructed to carry the tablets marked course number 1 with them and begin this course at the onset of an FMF attack. Each course was to be taken: six tablets on the first day (one tablet every hour for 4 h; then every 2 h for 4 h) and two tablets on each of the 2 following days (one tablet approximately every 12 h for 2 days). Each patient was specifically warned not to wait until an attack was well underway before beginning a course of medicine. Rather, each was told to begin medication at the earliest suspicion that an attack was about to occur and not to be concerned about * Colchicine and placebo were supplied by E. Lilly and Co. Indianapolis, Indiana. The tablets were bottled, coded, and dispensed by the Pharmaceutical Development Service at the National Institutes of Health. The placebo consisted of 76 mg of lactose, 24.2 mg of starch powder, and 0.58 mg of magnesium stearate.

162

Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 09/14/2018

Annals of Internal Medicine 86:162-165, 1977

Table 1. Treatment of Familial Mediterranean Fever Attacks with Colchicine and Placebo

Patient

Age

Sex

Outcome

Aborted A B C D E F G H I Total

yrs 30 18 51 54 38 26 19 51 48

Mild

Severe

0 0 1 2 0 0 0 0 0 3

0 0 0 0 2 1 1 0 0 4




9 11 16 6 4 5 4 2 2 59

* Patient was actively participating when study was terminated.

the possibility of a "false alarm." At the end of each course patients recorded signs and symptoms on forms provided them. Specifically, patients recorded the date and time that medication was begun; whether abdominal or pleuritic chest pain occurred, and if so for how long; whether there was a fever of 37.8 °C [100 °F] or higher; and whether they themselves considered the attack to have been aborted, milder than usual, or of typical severity. Patients also made note of any symptoms of diarrhea or nausea that occurred while taking the medicine. In addition, they were asked to guess whether they were taking colchicine or placebo. Patients then related this information to one of the investigators (D.W.), usually by telephone. An attack was evaluated as having been aborted if three conditions were met: symptoms of serositis did not persist more than 8 h after the course of medicine had been begun; fever ( > 37.8 °C) did not occur; and the patient asserted that the attack had been aborted. Each patient then began to carry his next course of medicine to be used at the onset of the next attack. If a patient reported symptoms of nausea or diarrhea, the number of tablets taken in all subsequent courses was reduced. TERMINATION OF THE STUDY

As the study progressed, the outcome of each course in aborting FMF attacks was reported to the statistician (D.A.), who was the only investigator to have access to the list of treatment assignments. The patient was classified as a colchicine success if [1] five unaborted attacks occurred on placebo but all colchicine courses were followed by aborted attacks; or [2] seven unaborted attacks occurred on placebo and all but one colchicine course were followed by aborted attacks. The patient was classified as a colchicine failure if two unaborted attacks occurred on colchicine therapy. As soon as a patient was classified as a success or failure, his series of treatment assignments was ended. This experimental design has been used previously (1, 11). The null hypothesis was that colchicine is no more effective than placebo in aborting attacks of FMF; from this hypothesis and the fact that randomization was used in assigning treatment, it follows that if an attack is not aborted, there is an equal chance that the patient took placebo or colchicine at the onset of symptoms. It can then be calculated that the probabilities of the patterns of results described above are 1/32 and 5/256, respectively; the combined probability is 0.051, which is the level of significance. After five patients had completed the trial according to these criteria, an analysis of the data was made for all patients, and it was decided to terminate the study. By this time three patients (F, G, and H) had dropped out of the study on their own. Two of these patients had been attack-free on chronic colchicine therapy before entering the trial, and they found that having attacks again was too disruptive to their lives to complete the trial. The other patient became discouraged and dropped out after four consecutive courses failed to alter his FMF attacks (three of the courses were placebo).

Results

The individual experience of each patient during the 10-month trial is described in Table 1. Three patients completed the trial as colchicine successes, each with results that indicated colchicine to be effective in aborting attacks at the 5 % level of significance. With two of these patients (A and B), all colchicine courses resulted in aborted attacks, while none of the placebo courses did so. With the other patient (C), all but one colchicine course (six of seven) resulted in aborted attacks, and the attack not aborted by colchicine was considered milder than usual. Two patients completed the trial as colchicine failures. One of these (E) appeared to derive no benefit from colchicine, with two typical attacks on colchicine. The other ( D ) , however, appeared to benefit from the drug somewhat. Of four attacks treated with colchicine, two were aborted and two were considered mild; both attacks treated with placebo were considered severe. Although the two aborted attacks that were recorded among the remaining four patients occurred on colchicine therapy, these patients did not complete a sufficient number of courses such that an evaluation of the effect of colchicine could be made individually. Among the three patients classified as successes on colchicine treatment, 94% of the colchicine courses and 11% of the placebo courses were followed by aborted attacks. Among the remaining six patients 45% of the colchicine and 8% of the placebo courses were followed by aborted attacks. Overall, there was a 75% success rate for colchicine and 10% for placebo courses. The percent for colchicine may be an overestimate of the corresponding percent for patients with FMF in general, because the three patients considered successes in this trial received appreciably more treatment courses than did the remaining six patients. Two patients (B and C) experienced diarrhea early in the trial, and the number of tablets taken in subsequent courses was reduced to four on the first day and one on the next 2 days. Further symptoms attributable to colchicine did not occur. Often the patients accurately guessed whether they were taking colchicine or placebo courses. However, the patients almost always appeared to base their guesses on the efficacy of the medicine in altering their Wright et al. • Colchicine and Familial Mediterranean Fever

Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 09/14/2018

163

attacks; all colchicine courses that did not result in aborted attacks were thought to be placebo. Moreover, it should be emphasized that an attack was considered to have been aborted only if two objective criteria were met: symptoms lasted less than 8 h, and fever did not occur. For the patients who were therapeutic successes (A, B, and C ) , there were clear distinctions in the objective determinants of aborted and unaborted attacks. The duration of symptoms in aborted attacks was less than 8 h, while all but one of the 18 unaborted attacks in these patients were characterized by symptoms lasting more than 24 h, and symptoms persisted more than 48 h in 15 of these 18 attacks. The one "mild" attack that lasted less than 24 h was also the one unaborted attack that occurred on colchicine in Patient C. Previous experience with colchicine did not appear to affect the results of these patient studies. Among the five patients who completed their treatment assignments, three had taken chronic colchicine before this study (A, C, and E ) , and two had not previously experienced colchicine (B and D ) ; both types of patients were colchicine successes and colchicine failures. When the intervals of time between attacks after colchicine courses were compared with those after placebo courses, no significant differences were seen. The mean interval between attacks after colchicine was 15.1 ± 1.8 days and after placebo, 20.1 ± 5 days. The latter group of intervals included a single large value (129 days) from Patient I, who experienced only two attacks during the trial and hence did not contribute any intervals after a course of colchicine to the combined data. If this long interval is eliminated, the mean interval length becomes 15.4 ± 1.9 days. One of the patients (B) experienced significantly longer intervals between attacks after colchicine courses (19.0 ± 3.3 days) than after placebo courses (7.8 ± 0 . 5 days). Discussion

This trial shows that in some patients with F M F , short courses of colchicine taken at the onset of attacks are effective in aborting the acute pain and fever characteristic of the attacks. The patients who were considered colchicine successes in this trial have all continued to take intermittent colchicine with benefit. They have reported that four to five tablets (0.6 mg) taken hourly at the onset of the attacks are sufficient by themselves to abort the attacks and that tablets taken subsequently are unnecessary to maintain this effect. One patient (C) has noted, however, that although typical F M F symptoms and fever are eliminated by colchicine, there is often a vague malaise that persists 2 to 3 days, the usual duration of untreated attacks. In none of these patients did F M F symptoms recur after completion of the colchicine courses that successfully aborted F M F attacks. Indeed, in one patient colchicine courses were followed by significantly prolonged intervals between F M F attacks. The results of this trial emphasize the variability with which patients with F M F respond to colchicine. Previous controlled trials of chronic colchicine in F M F have also indicated a variable response by patients to this drug (1-3). 164

Because of this variability among patients, we believe that colchicine response should not be used as a diagnostic indicator in F M F , a disease that can mimic diverse medical and surgical conditions. Although most patients with F M F appear to respond quite satisfactorily to prophylactic colchicine and some patients should benefit from intermittent therapeutic colchicine as used in this trial, a poor or partial response to colchicine cannot be used to rule out F M F as a diagnostic possibility when other clinical indicators favor this diagnosis. Conversely, the natural history of F M F and of conditions that it mimics is sufficiently unpredictable that it may be misleading to make a diagnosis of F M F on the basis of an apparent response to colchicine without ruling out other possibilities. Patients in this trial were specifically warned not to be concerned with "false alarms" but to take their courses of medicine at the earliest suspicion that an F M F attack was about to occur. Nonetheless, there was little indication that courses of medicine were taken inappropriately, for only three of 31 placebo courses were not accompanied by definite F M F attacks. Instead, the patients proved accurate in recognizing the prodromata of their attacks. It is likely that the initiation of colchicine therapy early during the prodrome of F M F attacks is important if the drug is to be effective. Our results contrast with the reports of others who have found colchicine ineffective in altering F M F symptoms when taken only at times of attacks (4, 5 ) , and these different results may be explained by differences in timing the start of therapy. This trial shows that some patients with F M F can clearly abort their acute inflammatory symptoms with short courses of colchicine taken at the onset of an attack. Colchicine's action in F M F is not limited to chronic suppression of the disease. As in gout, colchicine can also interrupt inflammatory processes of this disease when administered early in an attack. The small number of patients that completed this study does not permit an accurate estimate of the proportion of patients with F M F in general who will respond to colchicine at the onset of attacks. However, intermittent colchicine treatment should be attempted in all patients with F M F , particularly young patients before they are committed to chronic therapy with this drug. ACKNOWLEDGMENTS: Portions of this paper have appeared in abstract form: WRIGHT DG, FAUCI AS, WOLFF SM: The efficacy of

intermittent colchicine therapy in familial Mediterranean fever. Clin Res 23:41SA, 1975. Received 3 August 1976; revision accepted 30 October 1976. • Requests for reprints should be addressed to Daniel G. Wright, M.D.; Building 10, Room 11N-218, National Institutes of Health; Bethesda, MD 20014. References 1. DINARELLO CA, WOLFF SM, GOLDFINGER, SE, et al: Colchicine

therapy for familial Mediterranean fever. A double-blind trial. N Engl J Med 291:934-937, 1974 2. ZEMER D, REVACH M, PRAS M, et al: A controlled trial of

colchicine in preventing attacks of familial Mediterranean fever. N Engl J Med 291:932-934, 1974 3. GOLDSTEIN RC, SCHWABE AD: Prophylactic colchicine therapy

in familial Mediterranean fever. A controlled, double-blind study. Ann Intern Med 81:792-794, 1974 4. SOHAR E, GAFNI J, PRAS M, et al: Familial Mediterranean fever.

February 1977 • Annals of Internal Medicine • Volume 86 • Number 2

Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 09/14/2018

A survey of 470 cases and review of the literature. Am J Med 43:227-253, 1967

5. SCHWABE AD, PETERS RS:

Familial

Mediterranean fever in

Armenians. Analysis of 100 cases. Medicine (Baltimore) 53:453462, 1974 6. MAMOU H: Maladie periodique amylogene. Sem Hop Paris 31: 388-391, 1955 7. WOLFF SM: Familial Mediterranean fever (familial paroxysmal polyserositis), in Harrison's Principles of Internal Medicine, 7th

therapy and aneuploid cells. Rev Bras Pesqui Med Biol 6:141148, 1973 9. MERLIN HE: Azoospermia caused by colchicine—a case report. Fertil Steril 23:180-181, 1972 10. EFRON B: Forcing a sequential experiment to be balanced. Biometrika 58:403-417, 1971 11. FRANK MM, SERGENT JS, KANE MA, et al: Epsilon aminocaproic

acid therapy of hereditary angioneurotic edema. A double-blind study. N Engl J Med 286:808-812, 1972

ed., edited by WINTROBE MM, THORN GW, ADAMS RD, et al.

New York, McGraw-Hill Book Co., 1974, pp. 1068-1071 8. FERREIRA NR,

BUONICONTI A,

FROTA-PESSOA O:

Colchicine

Henry Miller, M.D., F.R.C-P. 13 December 1913—25 August 1976 The British Health Service—1966 In brief . . . the failures of Flexner's concepts as they have been applied in Britain spring mainly from a national parsimony, evident in affluent as well as difficult times, and from a complacent acceptance of the amateurish and second-best. It is tempting but not entirely fair to attribute all our present difficulties to the succession of politicians nominally responsible for Health and Education during the past two critical decades. It is easy to forget that we owe the initiation of the Health Service to a politician of genius—and that the medical profession's contribution of that stage presented a classical combination of the obstructive and the ineffective: it is ironical that today the profession champions the Service against the politicians' neglect. It is unthinkable, however, that Aneurin Bevan's political heirs will bring themselves to supervise the dismemberment of their party's greatest achievement. Nor is it possible to believe that the melancholy procession of mostly unmemorable incumbents who passed through the Ministry of Health during thirteen years of Conservative Government were all as ineffectual as the present state of the service might suggest. It is now clear that the advisers on whom they had to rely were inaccurate in their estimates of the inevitably rising cost of an increasingly technological service and of the number of doctors required to man it—as well as in the ingenuous misconception that it would reduce the incidence of illness. The pattern of sickness in a community depends on complex factors, and it is of course materially altered by the quantity and quality of medical care available. But neither the gradual improvement in the public health that is clearly discernible nor the more dramatic conquest of specific diseases can be expected to reduce the load on medical services. A dead patient presents no economic problem, but one rescued by modern treatment remains susceptible to other illnesses that bring with them fresh demands on our resources. Despite the seriousness of the present situation I am sustained by a conviction that the financial problems of medicine in our society will be overcome. Except for an eccentric fringe, the profession and the public are committed to the splendid conception of a comprehensive public medical service and are more inclined to meet its cost than in the case of many more dubious Governmental activities. The misconception that private practice can make any serious contribution to the provision of modern medical care is too pathetic to merit serious discussion: it may furnish consolation to the sufferer from a minor ailment but has little to offer in renal failure or ventricular fibrillation. When the public becomes fully aware of the disparity between the medical service that is available and that which is possible, some Government will find the money, even if by some form of personal taxation specifically earmarked for the purpose. When we say we cannot afford properly equipped universities or a truly comprehensive Health Service, all we are really saying is that we prefer to spend our money in other ways. Henry Miller Fifty Years After Flexner The Lancet 2:647-654, 24 September 1966

Wright et a\. • Colchicine and Familial Mediterranean Fever

Downloaded From: https://annals.org/ by a Glasgow Univ Library User on 09/14/2018

165

Efficacy of intermittent colchicine therapy in familial Mediterranean fever.

Efficacy of Intermittent Colchicine Therapy in Familial Mediterranean Fever DANIEL G. WRIGHT, M.D.; SHELDON M. WOLFF, M.D., F.A.C.P.; ANTHONY S. FAUCI...
782KB Sizes 0 Downloads 0 Views