973
LONG-TERM COLCHICINE TREATMENT IN CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER DEBORAH ZEMER, AVI LIVNEH, YEHUDA L. DANON., MORDECHAI PRAS, and EZRA SOHAR Three hundred fifty children (younger than age 16) who had familial Mediterranean fever (FMF) were given continuous prophylactic treatment with colchicine (1-2 mg/day) for 6-13 years. Complete remission of febrile attacks was achieved in 64% of the patients, and partial remission in 31 %. Protracted attacks of arthritis virtually disappeared. None of the children developed amyloidosis while on the colchicine regimen. Side effects of colchicine were insignificant, and did not prompt permanent discontinuation of treatment in any of the children. Their growth, development, and subsequent fertility were normal. The efficacy of long-term colchicine treatment of children with FMF makes early diagnosis life saving.
Familial Mediterranean fever (FMF) is an autosoma1 recessive disorder occurring in people of Mediterranean and Armenian descent. The disease usually becomes manifest through brief attacks of fever accompanied by peritonitis, arthritis, or pleuritis, and usually followed, but sometimes preceded, by sysFrom the Department of Medicine, Heller Institute of Medical Research, Sheba Medical Center, Tel Aviv University Medical School, and the Division of Pediatric Immunology, Beilinson Hospital, Petah-Tikva, Israel. Supported in part by a grant from the Doron Foundation, 1990.
Deborah Zemer, MD: Senior Physician, Department of Medicine, Sheba Medical Center; Avi Livneh, MD: Senior Physician, Department of Medicine, Sheba Medical Center; Yehuda L. Danon, MD: Professor of Pediatrics, Tel Aviv University; Mordechai Pras, MD: Professor of Medicine, Tel Aviv University; Ezra Sohar, MD: Professor of Medicine, Tel Aviv University. Address reprint requests to Deborah Zemer, MD, Heller Institute of Medical Research, Sheba Medical Center, TelHashomer 52621, Israel. Submitted for publication August 1, 1990; accepted in revised form February 28, 1991. Arthritis and Rheumatism, Vol. 34, No. 8 (August 1991)
temic amyloidosis, which causes renal failure. The metabolic deviation underlying the disorder has not yet been elucidated (1). A deficiency of C5a inhibitor in the joint fluids and peritoneal fluids of FMF patients may play a role in the evolution of the characteristic febrile attacks (2). Abnormalities in the metabolism of catecholamine have been implicated as a pathogenetic mechanism, and the use of 2 diagnostic tests has been proposed: the metaraminol provocation test and a blood test for high plasma levels of dopamine phydroxylase in untreated patients (3,4). The former carries the risk of serious side effects and is not pathognomonic (5-7), whereas the latter has not been verifiable, either by us or by other investigators (8). The location of the gene for FMF has not yet been identified. Attacks of FMF are characterized by spiking fever and acute inflammation, which is manifested clinically as peritonitis, arthritis, or pleuritis (1). The episodes usually remit spontaneously within 1 2 4 8 hours, and between attacks, the patients appear to be well. During the illness, a patient will experience several forms of FMF attacks, but the monotonous recurrence of one type over many years is not uncommon. Any form of the attack may be the presenting symptom. The amyloidosis is systemic, of the AA type, and manifests as nephropathy . It becomes clinically overt upon the appearance of proteinuria, which is mild and intermittent at first but, later, is sustained and increasing toward nephrotic proportions, and after 6-12 years, progresses to uremia and renal death. The course of overt amyloidosis, however, varies widely. In children in particular, it is often fulminating; most of them experience renal failure within 5 years of the
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ZEMER ET AL
Table 1. Age distribution of colchicine-treated children with familial Mediterranean fever
Age at disease onset, no. (%)*
Age at initiation of colchicine, no. (%)
55 6-10 11-15 16-20 221
269 (82) 51 (16) 9 (3) -
67 (19) 1 1 1 (32) 172 (49) -
-
2 (1) 30 (9) 74 (21) 110 (31) 134 (38)
Total
329 (101)
350 (100)
350 (100)
Age group (years)
-
Table 2. Presenting symptoms of colchicine-treated children with familial Mediterranean fever
Type of attack Present age, no. (%)
* Age at disease onset could not be determined in 21 patients. The percentage is more than 100 due to rounding of each percentage within the category. onset of proteinuria. During the era prior to colchicine therapy for FMF, 90% of our patients who died were younger than age 40, and 12.5% of them were younger than age 15. The youngest patient to die of amyloidosis was 5 years old. The incidence of amyloidosis varies among the different ethnic groups. It is rare among Armenians (9) and Ashkenazi Jews, and is prevalent among Anatolian Turks (10) and Sephardic Jews. An analysis of 470 of our patients prior to the use of colchicine for FMF, 75% of whom were North African Jews, showed that the genetically determined fate of these patients is to die of amyloidosis at a young age (1 1). Prolonged colchicine treatment for FMF was introduced in 1973. In daily doses of 1-2 mg, irrespective of the patient’s age or weight, this has proved to be the only effective treatment. This regimen prevents the febrile attacks in most patients and arrests the development of amyloidosis (12-16). We report here our experience with long-term prophylactic therapy with colchicine in children with FMF.
No. (%) of patients*
Abdominal Articular Fever alone Pleuritic
234 (70) 54 (16) 30 (9) 16 ( 5 )
Total
334 (100)
* Presenting symptoms
could not be determined in 16 patients; percentages were therefore based on the 334 children whose presenting symptoms were known.
tis attack, pleuritis and orchitis are also features of FMF, in 5% and in 3% of patients, respectively. Seventy-five percent of our patients experienced articular attacks; in 16% of them, this was the presenting symptom and may even have been the only symptom for some time. As a rule, this attack is a short-lived monarthritis, mostly of the lower extremities, usually disappearing after 12-72 hours, and without sequelae, despite the pain, immobility, and possible effusion. In approximately 5% of the patients who had articular attacks, the episodes were protracted, lasting more than 4 weeks and as long as 1 year, with the potential of causing irreversible damage to the affected joint (17). Most frequently affected are the knee, hip, and ankle joints. An often neglected symptom of FMF is short bouts of fever that last a few hours, and are not accompanied by serositis (1). In children, this may be the presenting symptom, followed later on by typical attacks of FMF, which confirm the diagnosis. Eighty-two percent of the children were age 5 or younger at the onset of symptoms (Table 1). When colchicine therapy was started, only 19% of the children were age 5 or younger; 32% were between ages 6 and 10, and 49% were between ages 1 1 and 15. These age differences indicate the considerable delay between the onset of the disease and the initiation of treatment. At present, 110 patients are between ages 16 and 20, and 134 are in their third decade of life; more than two-thirds of the children have been taking colchicine for 6 or more years, 62 of them for 11-13 years.
RESULTS PATIENTS AND METHODS Three hundred fifty children (177 boys and 173 girls) were prescribed a regimen of prophylactic colchicine before reaching age 16 (Table 1). All were of Jewish Mediterranean extraction; 75% of them were descended from North African Jews. The most frequent symptom was the abdominal attack, which was experienced by 95% of the total FMF patient population; and it was the presenting sign in 70% (Table 2). The episode presents as an acute peritonitis accompanied by high fever, and it regresses spontaneously after 48-72 hours. Being of dramatic character and drawing much attention and diagnostic efforts, this feature became the hallmark of FMF. Occurring together or independently of the peritoni-
Having had no experience with long-term colchicine treatment in children, and finding no such reports in the literature, the initial dosage was set at 0.5 mg/day, which soon proved insufficient for most of them. The dosage was increased to 1 mg/day. If remission from attacks of FMF was not achieved, the dosage was increased to 1.5 mg/day and, subsequently, to a maximum dosage of 2 mg/day, in 2 divided doses. The 17 patients whose attacks did not remit with 2 mg of colchicine did not respond to higher dosages. They have been maintained on a regimen of 2 mg daily for a mean duration of 13 years, and none of
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COLCHICINE FOR CHILDREN WITH FMF
them has thus far developed amyloidosis. At present, 40% of the children in this series are receiving 1 mg of colchicine daily, 25% are taking 1.5 mg, and 35% take 2 mg/day. As has been the case in other chronic conditions, there is a certain lack of compliance with having to take medications daily. Among the factors associated with noncompliance is the reluctance of some physicians to prescribe long-term colchicine therapy for children and young adults. Omission of the colchicine treatment, for even a few days, usually provoked an acute attack of FMF in our patients. Side effects of the colchicine were mostly mild. Diarrhea and nausea were most common, and often proved transient and controllable with symptomatic treatment. Desensitization by progressively increasing the dosages of colchicine (18) made it possible to continue the treatment in 4 patients whose severe diarrhea was not alleviated by symptomatic treatment, and in 3 other patients with angioneurotic edema, epistaxis, and leukopenia, respectively. The latter patient, a 7-year-old girl, had been taking colchicine for 1 year (daily dose 1 mg). Two weeks after undergoing drainage of a dental abscess, her white blood cell count was found to be 1,800/mm3, with a differential cell count of 31% polymorphonuclear cells, 8% band forms, 47% lymphocytes, 10% monocytes, 3% eosinophils, and 1% basophils; the colchicine therapy was discontinued. Shortly after discontinuation of the colchicine, the leukocyte count recovered, but the febrile attacks resumed. Two attempts to reinstitute colchicine therapy, at 1 mg/day, caused a decrease in the white blood cell count to 2,200/mm3 and to 3,220/mm3, respectively. We administered colchicine orally, at 0.001 mg diluted in physiologic saline, and the dose was doubled daily until day 10, when 0.5 mg was given. This dosage was continued for 3 months, and her blood cell count was checked each week. The dosage was then increased to 0.75 mg/day and, after 3 months, to 1.0 mg/day. She has been maintained at this dosage for the last year. The blood cell count has remained normal, and she has had a remission of most of the attacks. There was complete remission of attacks in 64% of our treated pediatric patients. Partial remission, which was defined as either a significant decrease in the frequency and severity of all forms of attacks or a remission of one form (usually, abdominal) but not of another (usually, arthritic), was experienced by an additional 31% of the patients. Noteworthy is the observation that of the 15 youngsters who experienced protracted arthritis, it occurred in only 1 patient, in the
Table 3. Mean height of colchicine-treated and untreated children with familial Mediterranean fever compared with control subjects, at age 17* Untreated cohorts born 1955-1960 Males Patients Controls Females Patients Controls
*
Treated cohorts born 1966-1970
168.34 0.16 172.52 2 0.68
171.86 2 0.90 173.40 2 0.20
158.41 2 0.99 161.57 2 0.18
160.67 2 0.87 162.65 2 0.22
* Data were obtained at the compulsory medical examination prior to military service. Values are the mean 2 SEM centimeters.
hip joint, during colchicine treatment. In 2 of these patients, joint destruction reached a degree which required joint replacement surgery. Amyloidosis has not become manifest in any of the children who did not have proteinuria when the colchicine was started, even those whose attacks failed to respond to therapy. In 17 patients, colchicine was started when proteinuria was already present. During treatment, end-stage renal disease occurred within 1-5 years in 4 of them, 4 have remained stable for 7-16 years, and the proteinuria has disappeared completely in 9. In another 3 patients, proteinuria appeared after an 18-24-month lapse in treatment. In 1 of them, a 14-year-old boy, proteinuria decreased after colchicine was reinstituted, and his condition has remained stable over 4 years. In the other 2 patients, ages 5 and 7, end-stage renal disease occurred within a year, despite reinstitution of treatment, and both have received renal transplants. No deviation from normal growth or development was observed in the treated patients. Analysis of data obtained at the compulsory medical examination prior to military service, at age 17, revealed that the mean height of the colchicine-treated cohort with FMF had increased compared with the mean height of the cohort of FMF patients who had not received prolonged therapy with colchicine (years 1955-1960), and now approaches normal standards (Table 3). None of the male patients and only 6 of the female patients have had serious reproductive problems. ‘Twenty-four men of this group have married, and 19 of them have fathered children, all of whom are normal. Of the 95 women who have married, 31 have experienced 48 pregnancies, all of which were conceived while the woman was following the colchicine regimen; 21 of these women had been receiving colchicine treatment for more than 10 years prior to their
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ZEMER ET AL
first pregnancy. All continued the colchicine treatment during the pregnancy. Forty-four of the 48 pregnancies produced full-term normal infants. Four pregnancies terminated in spontaneous abortion during the first trimester, all of which were in women who had had at least one other uneventful pregnancy during colchicine treatment. No fetal abnormalities occurred in this series; the mean length of pregnancy and the mean birth weight of the infants were within normal ranges. Amniocentesis is recommended in all instances where one of the parents follows a regimen of longterm colchicine treatment, to exclude chromosomal aberrations possibly related to the colchicine. This recommendation is based on 2 cases of trisomy 21 found in our first series of 91 pregnancies in colchicinetreated FMF patients (unrelated to this series). One infant with trisomy 21 was born before amniocentesis was recommended as a routine procedure in these patients. The other case of trisomy 21 was identified at amniocentesis, and the fetus was aborted. Among a total of 420 amniocenteses performed country-wide in colchicine-treated women with FMF, no additional cases have thus far been detected.
DISCUSSION The diagnosis of familial Mediterranean fever must be made according to clinical evidence, since there is no specific diagnostic test available. The combination of irregularly recurrent, short, febrile episodes with abdominal, arthritic, or pleuritic symptoms in an otherwise healthy child, together with a Mediterranean or Armenian ethnic origin or parental consanguinity, and the presence of other cases in the family, suggest the diagnosis. When arthritis is the presenting symptom, or when it occurs in the child who has not been diagnosed as having FMF, the rheumatologist will be the physician who confronts the problem, makes an early diagnosis, and starts treatment. The mode of action of colchicine in preventing the attacks and amyloidosis of FMF is unclear. Its investigation is hampered by difficulties in following its metabolism in the body. It can be assumed that its action in preventing attacks is divorced from its action in the formation of amyloid, since in some patients, a high rate of attacks is not changed by colchicine therapy, but amyloidosis does not develop. This dichotomy seems to be an additional indication that amyloid in FMF is not secondary to the attacks, but rather, is an independent phenotypical character of FMF, which cames an ethnic variation in its expression.
The decrease in C5a inhibitor that has been found in peritoneal and serosal fluids of FMF patients has suggested that there is inadequate suppression of the inflammatory response to CSa, which can be released accidentally in minute quantities as a response to trivial stimuli. Neutrophils, chemotactically attracted to the site of C5a release, generate the release of additional chemotactic factors, which attract more neutrophils, all of which is unopposed by the regulatory mechanism of C5a inhibitor. This deficiency of chemotactic inhibitory activity may therefore be responsible for the explosive nature of the inflammatory attack. This also provides for a possible mode of action of colchicine as prophylaxis for the attacks of FMF: By suppressing the motility of neutrophils to the site of C5a release, colchicine arrests the evolution of the inflammatory process before it becomes rampant. But, once the inflammatory process has gained momentum, colchicine administration is not effective (2). Colchicine interferes with sol-gel transformation, which is known to inhibit the formation of intracellular fibrillar structures that are vital to mitosis and motility. It is tempting to speculate that the drug likewise prevents the extracellular assembly of amyloid subunits into mature amyloid fibrils (19). In order to prevent amyloidosis, once the diagnosis of FMF is made, all our patients are given life-long prophylactic therapy with colchicine, regardless of age, response of the attacks, or stage of nephropathic amyloidosis. Even FMF patients who have undergone renal transplantation are continued on the colchicine regimen in order to prevent amyloid deposition in the transplanted kidney (20). This recommendation includes patients whose attacks did not subside while they were taking the maximum daily dose of colchicine. Indeed, of our 17 patients whose FMF attacks were not modified by colchicine treatment, none developed amyloidosis over a mean period of 13 years. This is in contrast to the 30% incidence of amyloidosis over the course of 2-9 years in untreated patients (1,16). The ominous aspect of noncompliance with the prescribed regimen is highlighted by the 3 cases cited above; amyloidosis developed after a relatively short lapse in treatment in all 3 children. The study group is still quite young, and most of those who have married have not yet started a family. We have had no indication of fertility problems in the men of this study group or among the entire patient population. This is consistent with the previous report of normal spermatogram findings and normal levels of
COLCHICINE FOR CHILDREN WITH FMF male hormones among colchicine-treated males (2 1). Among the females in our cohort, the occurrence of serious fertility problems was considerably lower than the level reached before colchicine was used to treat FMF. Previously, mechanical problems due to fibrous adhesions and ovulatory disturbances were the main causes of sterility in women with FMF (22). Awareness that, in vitro, colchicine arrests cell division in the metaphase, made us reluctant to prescribe the drug for prolonged use in young children. However, since it became clear that colchicine treatment significantly improved the prognosis and quality of life of patients with FMF, it could not be legitimately withheld from children with FMF. Our data show that long-term prophylactic treatment with colchicine does not have adverse effects on growth or development, nor does it produce any other major side effects in children. We therefore recommend its institution, in adequate dosages, as soon as the diagnosis of FMF is made.
REFERENCES 1. Sohar E, Gafni J, Pras M, Heller H: Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med 43:227-253, 1967 2. Matzner Y, Brzezinski A: C5a-inhibitor deficiency in peritoneal fluids from patients with familial Mediterranean fever. N Engl J Med 31 1:287-290, 1984 3. Barakat MH, El-Khawad AO, Gumaa KA, El-Sobki N, Fenech FF: Metaraminol provocative test: a specific diagnostic test for familial Mediterranean fever. Lancet L656-657, 1984 4. Barakat MH, Gumaa KA, Malhas LN, Nabil IE, Moussa MA, Fenech FF: Plasma dopamine betahydroxylase: rapid diagnostic test for recurrent hereditary polyserositis. Lancet 11: 1280-1283, 1988 5 . Buades J, Bassa A, Altes J , Vicens JM, Cabrer B: The metaraminol test and adverse cardiac effects. Ann Intern Med 1113259-260, 1989 6. Huppertz HI, Michels H: The metaraminol provocation test in the diagnosis of familial Mediterranean fever. Monatsschr Kinderheilkd 136:243-245, 1988 7. Cattan D, Dervichian M, Courillon A, Nurit Y : Metaraminol provocation test for familial Mediterranean fever. Lancet 1:1130-1131, 1984
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8. Ben-Chetrit E, Gutman A, Levy M: Dopamine-betahydroxylase activity in familial Mediterranean fever. Lancet I:176, 1990 9. Schwabe AD, Peters RS: Familial Mediterranean fever in Armenians: analysis of 100 cases. Medicine (Baltimore) 53:453462, 1974 10. Ozedemir AL, Sokmen C: Familial Mediterranean fever among the Turkish people. Am J Gastroenterol 51:311316, 1969 11. Gafni J, Ravid M, Sohar E: The role of amyloidosis in familial Mediterranean fever: a population study. Isr J Med Sci 4:995-999, 1986 12. Goldfinger SE: Colchicine for familial Mediterranean fever. N Engl J Med 287:1302, 1972 13. Zemer D, Revach M, Pras M, Modan B, Schor S, Sohar E, Gafni J: A controlled trial of colchicine in preventing attacks of familial Mediterranean fever. N Engl J Med 291 1932-934, 1974 14. Dinarello CA, Wolff SM, Goldfinger SE, Dale DC, Alling DW: Colchicine therapy for familial Mediterranean fever: a double-blind trial. N Engl J Med 291:934 937, 1974 15. Goldstein RC, Schwabe AD: Prophylactic colchicine therapy in familial Mediterranean fever: a controlled double-blind study. Ann Intern Med 81:792-794, 1974 16. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J: Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med 314:lOOl-1005, 1986 17. Sneh E, Pras M, Michaeli D, Shahin N , Gafni J: Protracted arthritis in familial Mediterranean fever. Rheumatol Rehabil 16: 102-106, 1977 18. Cabili S, Shemer Y , Revach M, Pras M: Allergic reactions and desensitization to colchicine in familial Mediterranean fever. Rheumatologie 12:207-208, 1982 19. Kedar I, Ravid M, Sohar E, Gafni J: Colchicine inhibition of casein-induced amyloidosis in mice. Isr J Med Sci 10:787-789, 1974 20. Livne A, Zemer D, Siegal B, Laor A, Sohar E, Pras M: Colchicine prevents kidney-transplant amyloidosis in familial Mediterranean fever (FMF). Nephron (in press) 21. Levy M, Yaffe C: Testicular function in patients with familial Mediterranean fever on long-term colchicine treatment. Fertil Steril 29:667-668, 1978 22. Ismajovich B, Zemer D, Revach M, Serr DM, Sohar E: The causes of sterility in females with familial Mediterranean fever. Fertil Steril 24:844-847, 1973
LONG-TERM COLCHICINE TREATMENT IN CHILDREN WITH FAMILIAL MEDITERRANEAN FEVER DEBORAH ZEMER, AVI LIVNEH, YEHUDA L. DANON., MORDECHAI PRAS, and EZRA SOHAR Three hundred fifty children (younger than age 16) who had familial Mediterranean fever (FMF) were given continuous prophylactic treatment with colchicine (1-2 mg/day) for 6-13 years. Complete remission of febrile attacks was achieved in 64% of the patients, and partial remission in 31 %. Protracted attacks of arthritis virtually disappeared. None of the children developed amyloidosis while on the colchicine regimen. Side effects of colchicine were insignificant, and did not prompt permanent discontinuation of treatment in any of the children. Their growth, development, and subsequent fertility were normal. The efficacy of long-term colchicine treatment of children with FMF makes early diagnosis life saving.
Familial Mediterranean fever (FMF) is an autosoma1 recessive disorder occurring in people of Mediterranean and Armenian descent. The disease usually becomes manifest through brief attacks of fever accompanied by peritonitis, arthritis, or pleuritis, and usually followed, but sometimes preceded, by sysFrom the Department of Medicine, Heller Institute of Medical Research, Sheba Medical Center, Tel Aviv University Medical School, and the Division of Pediatric Immunology, Beilinson Hospital, Petah-Tikva, Israel. Supported in part by a grant from the Doron Foundation, 1990.
Deborah Zemer, MD: Senior Physician, Department of Medicine, Sheba Medical Center; Avi Livneh, MD: Senior Physician, Department of Medicine, Sheba Medical Center; Yehuda L. Danon, MD: Professor of Pediatrics, Tel Aviv University; Mordechai Pras, MD: Professor of Medicine, Tel Aviv University; Ezra Sohar, MD: Professor of Medicine, Tel Aviv University. Address reprint requests to Deborah Zemer, MD, Heller Institute of Medical Research, Sheba Medical Center, TelHashomer 52621, Israel. Submitted for publication August 1, 1990; accepted in revised form February 28, 1991. Arthritis and Rheumatism, Vol. 34, No. 8 (August 1991)
temic amyloidosis, which causes renal failure. The metabolic deviation underlying the disorder has not yet been elucidated (1). A deficiency of C5a inhibitor in the joint fluids and peritoneal fluids of FMF patients may play a role in the evolution of the characteristic febrile attacks (2). Abnormalities in the metabolism of catecholamine have been implicated as a pathogenetic mechanism, and the use of 2 diagnostic tests has been proposed: the metaraminol provocation test and a blood test for high plasma levels of dopamine phydroxylase in untreated patients (3,4). The former carries the risk of serious side effects and is not pathognomonic (5-7), whereas the latter has not been verifiable, either by us or by other investigators (8). The location of the gene for FMF has not yet been identified. Attacks of FMF are characterized by spiking fever and acute inflammation, which is manifested clinically as peritonitis, arthritis, or pleuritis (1). The episodes usually remit spontaneously within 1 2 4 8 hours, and between attacks, the patients appear to be well. During the illness, a patient will experience several forms of FMF attacks, but the monotonous recurrence of one type over many years is not uncommon. Any form of the attack may be the presenting symptom. The amyloidosis is systemic, of the AA type, and manifests as nephropathy . It becomes clinically overt upon the appearance of proteinuria, which is mild and intermittent at first but, later, is sustained and increasing toward nephrotic proportions, and after 6-12 years, progresses to uremia and renal death. The course of overt amyloidosis, however, varies widely. In children in particular, it is often fulminating; most of them experience renal failure within 5 years of the
974
ZEMER ET AL
Table 1. Age distribution of colchicine-treated children with familial Mediterranean fever
Age at disease onset, no. (%)*
Age at initiation of colchicine, no. (%)
55 6-10 11-15 16-20 221
269 (82) 51 (16) 9 (3) -
67 (19) 1 1 1 (32) 172 (49) -
-
2 (1) 30 (9) 74 (21) 110 (31) 134 (38)
Total
329 (101)
350 (100)
350 (100)
Age group (years)
-
Table 2. Presenting symptoms of colchicine-treated children with familial Mediterranean fever
Type of attack Present age, no. (%)
* Age at disease onset could not be determined in 21 patients. The percentage is more than 100 due to rounding of each percentage within the category. onset of proteinuria. During the era prior to colchicine therapy for FMF, 90% of our patients who died were younger than age 40, and 12.5% of them were younger than age 15. The youngest patient to die of amyloidosis was 5 years old. The incidence of amyloidosis varies among the different ethnic groups. It is rare among Armenians (9) and Ashkenazi Jews, and is prevalent among Anatolian Turks (10) and Sephardic Jews. An analysis of 470 of our patients prior to the use of colchicine for FMF, 75% of whom were North African Jews, showed that the genetically determined fate of these patients is to die of amyloidosis at a young age (1 1). Prolonged colchicine treatment for FMF was introduced in 1973. In daily doses of 1-2 mg, irrespective of the patient’s age or weight, this has proved to be the only effective treatment. This regimen prevents the febrile attacks in most patients and arrests the development of amyloidosis (12-16). We report here our experience with long-term prophylactic therapy with colchicine in children with FMF.
No. (%) of patients*
Abdominal Articular Fever alone Pleuritic
234 (70) 54 (16) 30 (9) 16 ( 5 )
Total
334 (100)
* Presenting symptoms
could not be determined in 16 patients; percentages were therefore based on the 334 children whose presenting symptoms were known.
tis attack, pleuritis and orchitis are also features of FMF, in 5% and in 3% of patients, respectively. Seventy-five percent of our patients experienced articular attacks; in 16% of them, this was the presenting symptom and may even have been the only symptom for some time. As a rule, this attack is a short-lived monarthritis, mostly of the lower extremities, usually disappearing after 12-72 hours, and without sequelae, despite the pain, immobility, and possible effusion. In approximately 5% of the patients who had articular attacks, the episodes were protracted, lasting more than 4 weeks and as long as 1 year, with the potential of causing irreversible damage to the affected joint (17). Most frequently affected are the knee, hip, and ankle joints. An often neglected symptom of FMF is short bouts of fever that last a few hours, and are not accompanied by serositis (1). In children, this may be the presenting symptom, followed later on by typical attacks of FMF, which confirm the diagnosis. Eighty-two percent of the children were age 5 or younger at the onset of symptoms (Table 1). When colchicine therapy was started, only 19% of the children were age 5 or younger; 32% were between ages 6 and 10, and 49% were between ages 1 1 and 15. These age differences indicate the considerable delay between the onset of the disease and the initiation of treatment. At present, 110 patients are between ages 16 and 20, and 134 are in their third decade of life; more than two-thirds of the children have been taking colchicine for 6 or more years, 62 of them for 11-13 years.
RESULTS PATIENTS AND METHODS Three hundred fifty children (177 boys and 173 girls) were prescribed a regimen of prophylactic colchicine before reaching age 16 (Table 1). All were of Jewish Mediterranean extraction; 75% of them were descended from North African Jews. The most frequent symptom was the abdominal attack, which was experienced by 95% of the total FMF patient population; and it was the presenting sign in 70% (Table 2). The episode presents as an acute peritonitis accompanied by high fever, and it regresses spontaneously after 48-72 hours. Being of dramatic character and drawing much attention and diagnostic efforts, this feature became the hallmark of FMF. Occurring together or independently of the peritoni-
Having had no experience with long-term colchicine treatment in children, and finding no such reports in the literature, the initial dosage was set at 0.5 mg/day, which soon proved insufficient for most of them. The dosage was increased to 1 mg/day. If remission from attacks of FMF was not achieved, the dosage was increased to 1.5 mg/day and, subsequently, to a maximum dosage of 2 mg/day, in 2 divided doses. The 17 patients whose attacks did not remit with 2 mg of colchicine did not respond to higher dosages. They have been maintained on a regimen of 2 mg daily for a mean duration of 13 years, and none of
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COLCHICINE FOR CHILDREN WITH FMF
them has thus far developed amyloidosis. At present, 40% of the children in this series are receiving 1 mg of colchicine daily, 25% are taking 1.5 mg, and 35% take 2 mg/day. As has been the case in other chronic conditions, there is a certain lack of compliance with having to take medications daily. Among the factors associated with noncompliance is the reluctance of some physicians to prescribe long-term colchicine therapy for children and young adults. Omission of the colchicine treatment, for even a few days, usually provoked an acute attack of FMF in our patients. Side effects of the colchicine were mostly mild. Diarrhea and nausea were most common, and often proved transient and controllable with symptomatic treatment. Desensitization by progressively increasing the dosages of colchicine (18) made it possible to continue the treatment in 4 patients whose severe diarrhea was not alleviated by symptomatic treatment, and in 3 other patients with angioneurotic edema, epistaxis, and leukopenia, respectively. The latter patient, a 7-year-old girl, had been taking colchicine for 1 year (daily dose 1 mg). Two weeks after undergoing drainage of a dental abscess, her white blood cell count was found to be 1,800/mm3, with a differential cell count of 31% polymorphonuclear cells, 8% band forms, 47% lymphocytes, 10% monocytes, 3% eosinophils, and 1% basophils; the colchicine therapy was discontinued. Shortly after discontinuation of the colchicine, the leukocyte count recovered, but the febrile attacks resumed. Two attempts to reinstitute colchicine therapy, at 1 mg/day, caused a decrease in the white blood cell count to 2,200/mm3 and to 3,220/mm3, respectively. We administered colchicine orally, at 0.001 mg diluted in physiologic saline, and the dose was doubled daily until day 10, when 0.5 mg was given. This dosage was continued for 3 months, and her blood cell count was checked each week. The dosage was then increased to 0.75 mg/day and, after 3 months, to 1.0 mg/day. She has been maintained at this dosage for the last year. The blood cell count has remained normal, and she has had a remission of most of the attacks. There was complete remission of attacks in 64% of our treated pediatric patients. Partial remission, which was defined as either a significant decrease in the frequency and severity of all forms of attacks or a remission of one form (usually, abdominal) but not of another (usually, arthritic), was experienced by an additional 31% of the patients. Noteworthy is the observation that of the 15 youngsters who experienced protracted arthritis, it occurred in only 1 patient, in the
Table 3. Mean height of colchicine-treated and untreated children with familial Mediterranean fever compared with control subjects, at age 17* Untreated cohorts born 1955-1960 Males Patients Controls Females Patients Controls
*
Treated cohorts born 1966-1970
168.34 0.16 172.52 2 0.68
171.86 2 0.90 173.40 2 0.20
158.41 2 0.99 161.57 2 0.18
160.67 2 0.87 162.65 2 0.22
* Data were obtained at the compulsory medical examination prior to military service. Values are the mean 2 SEM centimeters.
hip joint, during colchicine treatment. In 2 of these patients, joint destruction reached a degree which required joint replacement surgery. Amyloidosis has not become manifest in any of the children who did not have proteinuria when the colchicine was started, even those whose attacks failed to respond to therapy. In 17 patients, colchicine was started when proteinuria was already present. During treatment, end-stage renal disease occurred within 1-5 years in 4 of them, 4 have remained stable for 7-16 years, and the proteinuria has disappeared completely in 9. In another 3 patients, proteinuria appeared after an 18-24-month lapse in treatment. In 1 of them, a 14-year-old boy, proteinuria decreased after colchicine was reinstituted, and his condition has remained stable over 4 years. In the other 2 patients, ages 5 and 7, end-stage renal disease occurred within a year, despite reinstitution of treatment, and both have received renal transplants. No deviation from normal growth or development was observed in the treated patients. Analysis of data obtained at the compulsory medical examination prior to military service, at age 17, revealed that the mean height of the colchicine-treated cohort with FMF had increased compared with the mean height of the cohort of FMF patients who had not received prolonged therapy with colchicine (years 1955-1960), and now approaches normal standards (Table 3). None of the male patients and only 6 of the female patients have had serious reproductive problems. ‘Twenty-four men of this group have married, and 19 of them have fathered children, all of whom are normal. Of the 95 women who have married, 31 have experienced 48 pregnancies, all of which were conceived while the woman was following the colchicine regimen; 21 of these women had been receiving colchicine treatment for more than 10 years prior to their
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first pregnancy. All continued the colchicine treatment during the pregnancy. Forty-four of the 48 pregnancies produced full-term normal infants. Four pregnancies terminated in spontaneous abortion during the first trimester, all of which were in women who had had at least one other uneventful pregnancy during colchicine treatment. No fetal abnormalities occurred in this series; the mean length of pregnancy and the mean birth weight of the infants were within normal ranges. Amniocentesis is recommended in all instances where one of the parents follows a regimen of longterm colchicine treatment, to exclude chromosomal aberrations possibly related to the colchicine. This recommendation is based on 2 cases of trisomy 21 found in our first series of 91 pregnancies in colchicinetreated FMF patients (unrelated to this series). One infant with trisomy 21 was born before amniocentesis was recommended as a routine procedure in these patients. The other case of trisomy 21 was identified at amniocentesis, and the fetus was aborted. Among a total of 420 amniocenteses performed country-wide in colchicine-treated women with FMF, no additional cases have thus far been detected.
DISCUSSION The diagnosis of familial Mediterranean fever must be made according to clinical evidence, since there is no specific diagnostic test available. The combination of irregularly recurrent, short, febrile episodes with abdominal, arthritic, or pleuritic symptoms in an otherwise healthy child, together with a Mediterranean or Armenian ethnic origin or parental consanguinity, and the presence of other cases in the family, suggest the diagnosis. When arthritis is the presenting symptom, or when it occurs in the child who has not been diagnosed as having FMF, the rheumatologist will be the physician who confronts the problem, makes an early diagnosis, and starts treatment. The mode of action of colchicine in preventing the attacks and amyloidosis of FMF is unclear. Its investigation is hampered by difficulties in following its metabolism in the body. It can be assumed that its action in preventing attacks is divorced from its action in the formation of amyloid, since in some patients, a high rate of attacks is not changed by colchicine therapy, but amyloidosis does not develop. This dichotomy seems to be an additional indication that amyloid in FMF is not secondary to the attacks, but rather, is an independent phenotypical character of FMF, which cames an ethnic variation in its expression.
The decrease in C5a inhibitor that has been found in peritoneal and serosal fluids of FMF patients has suggested that there is inadequate suppression of the inflammatory response to CSa, which can be released accidentally in minute quantities as a response to trivial stimuli. Neutrophils, chemotactically attracted to the site of C5a release, generate the release of additional chemotactic factors, which attract more neutrophils, all of which is unopposed by the regulatory mechanism of C5a inhibitor. This deficiency of chemotactic inhibitory activity may therefore be responsible for the explosive nature of the inflammatory attack. This also provides for a possible mode of action of colchicine as prophylaxis for the attacks of FMF: By suppressing the motility of neutrophils to the site of C5a release, colchicine arrests the evolution of the inflammatory process before it becomes rampant. But, once the inflammatory process has gained momentum, colchicine administration is not effective (2). Colchicine interferes with sol-gel transformation, which is known to inhibit the formation of intracellular fibrillar structures that are vital to mitosis and motility. It is tempting to speculate that the drug likewise prevents the extracellular assembly of amyloid subunits into mature amyloid fibrils (19). In order to prevent amyloidosis, once the diagnosis of FMF is made, all our patients are given life-long prophylactic therapy with colchicine, regardless of age, response of the attacks, or stage of nephropathic amyloidosis. Even FMF patients who have undergone renal transplantation are continued on the colchicine regimen in order to prevent amyloid deposition in the transplanted kidney (20). This recommendation includes patients whose attacks did not subside while they were taking the maximum daily dose of colchicine. Indeed, of our 17 patients whose FMF attacks were not modified by colchicine treatment, none developed amyloidosis over a mean period of 13 years. This is in contrast to the 30% incidence of amyloidosis over the course of 2-9 years in untreated patients (1,16). The ominous aspect of noncompliance with the prescribed regimen is highlighted by the 3 cases cited above; amyloidosis developed after a relatively short lapse in treatment in all 3 children. The study group is still quite young, and most of those who have married have not yet started a family. We have had no indication of fertility problems in the men of this study group or among the entire patient population. This is consistent with the previous report of normal spermatogram findings and normal levels of
COLCHICINE FOR CHILDREN WITH FMF male hormones among colchicine-treated males (2 1). Among the females in our cohort, the occurrence of serious fertility problems was considerably lower than the level reached before colchicine was used to treat FMF. Previously, mechanical problems due to fibrous adhesions and ovulatory disturbances were the main causes of sterility in women with FMF (22). Awareness that, in vitro, colchicine arrests cell division in the metaphase, made us reluctant to prescribe the drug for prolonged use in young children. However, since it became clear that colchicine treatment significantly improved the prognosis and quality of life of patients with FMF, it could not be legitimately withheld from children with FMF. Our data show that long-term prophylactic treatment with colchicine does not have adverse effects on growth or development, nor does it produce any other major side effects in children. We therefore recommend its institution, in adequate dosages, as soon as the diagnosis of FMF is made.
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