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Long-term colchicine prophylaxis in children with familial Mediterranean fever (recurrent hereditary polyserositis)
Clinical and laboratory observations Long-term colchicine prophylaxis in children with familial Mediterranean fever (recurrent hereditary polyserositis) Hassan A. M a j e e d , FRCPI, DCH, J a m e s E, Carroll, MD, Faisal A. Khuffash, MRCP, DCH, a n d Z e i n a t Hijazi, MRCP, DCH From the Department of Pediatrics, Faculty of Medicine, University of Kuwait, and the Pediatrics Department, Mubarak Hospital (Teaching) Kuwait
Familial Mediterranean fever, also known as recurrent hereditary polyserositis, is an inherited multisystem disease of unknown etiology characterized by recurrent, painful, selflimited episodes of peritonitis, pleuritis, arthritis, and erysipelas-like erythema, occurring singly or in combination, usually associated with fever. It characteristically affects children of certain ethnic groups, primarily Arabs, Sephardic Jews, and Armenians5-3 The main complication of the disease is the development of amyloidosis. In large series of mainly adult patients, onset before the age of 10 years ranged between 49% and 62% and the mean age at onset ranged between 12.6 and 13.8 years14; in a recent report of 88 children, the mean age at onset was 4.9 years. 3 Colchicine was first introduced for the management of FMF by Goldfinger4 in 1972. Several studies addressing the therapeutic effect of colchicine in adults with FMF have been reported, 5, 6 and colchicine has been shown to prevent or ameliorate the complication of amyloidosis.7 However, colchicine therapy has side effects, including nausea, vomiting, mild diarrhea, azoospermia, bone marrow suppression, transient alopecia, malabsorption, myopathy, neuropathy, and chromosomal abnormalities.8 Information on the therapeutic response and safety of long-term colchicine prophylaxis in children with FMF is not available. Lehman et al. 9 and Branski et al. 1~described eight and six children, respectively, who were followed up Submitted for publication Oct. 31, 1989; accepted Dec. 18, 1989. Reprint requests: H. A. Majeed, FRCPI, DCH, Professor, Department of Pediatrics, Kuwait University Faculty of Medicine, P. O. Box 24923, 13110, Safat, Kuwait.
9/26/18993
for only 3 months. The purpose of this study was to explore the dosage, therapeutic response, and safety of long-term colchicine prophylaxis in children with FMF. METHODS The children were referred by their family physicians. All children were hospitalized and had had extensive laboratory investigations, as described in a previous report2; the diagnosis was based on the criteria of Heller et al. 11 Once the diagnosis was confidently made, another interview with the mother was conducted, with special emphasis on the frequency, duration, and severity of the episodes, after which colchicine therapy was started. Follow-up. Patients were seen in the FMF clinic of one of us (H.A.M.) once every 2 months, or more frequently when needed. At each outpatient visit a history was taken with FMF
Familial Mediterranean fever
emphasis on compliance with treatment and the occurrence of FMF, including the frequency, severity, and duration of episodes, and the occurrence of new signs or symptoms. Full physical examination and dipstick urine tests for protein and blood were conducted; other laboratory tests were performed when necessary. At the end of the study (September 1989) all children had liver and kidney function tests (SMAC 20, Technieon Instruments Corp., Tarrytown, N.Y.), complete hemogram, and urine analysis for protein and blood. Twenty-eight children had full neurologic examination by one of us (J.C.) and analysis of blood for creatine kinase activity. Dose of eolchieine. A daily dose of 0.5 mg was given to
997
998
Clinical and laboratory observations
The Journal of Pediatrics June 1990
Table. Effect of continuous colchicine prophylaxis in 32 children with F M F Continuous colchicine prophylaxis
No. of children Mean observation period (patient-yr) Total observation period (patient-yr) Total No. of episodes/patient-yr Mean frequency/patient-yr Mean duration of attack (hr)
Before
After
32 3.4 108.8 628 l 9.6* 52*
32 2.4 78 104 3.2* 3.6*
*p = 0.0005
children 5 years of age or younger; 0.5 mg was given twice daily to older children. The dosage was then modified according to the response. Effect of colchicine, The frequency, severity, and duration of episodes before colchicine therapy were obtained from the mother during the special interview and at each outpatient visit. Statistical analysis for differences in frequency was performed with the chi-square test, and the significance of differences was assessed with the Student t test. RESULTS Of 58 children with FMF under our care, 32 were selected for this study; the main requirements were reliability of the parents and compliance with treatment. All the children were of Arab origin; 22 (69%) were Palestinian (22% of the population in Kuwait are Palestinian), 7 (22%) Lebanese, 2 (6%) Syrian, and 1 (3%) Egyptian. The ratio of boys to girls was 1:1.7 (12:20). The family history of 17 children (53%) was positive for FMF. Peritonitis developed in 31 children (97%), pleuritis developed in 20 (63%), arthritis developed in 16 (50%), and cutaneous manifestations developed in 10 (31%). Fever was present in all children. The age at onset varied between 4 months and 9 years, with a mean of 3.7 years. The total observation periods before and after colchicine therapy were 108.8 patient-years and 78 patient-years, respectively. The frequency of attacks before colchicine therapy ranged between 6 and 40/ patient-year with a mean of 19.6/patient-year, whereas it ranged up to 8/patient-year with a mean of 3.2/patientyear after colchicine therapy (p = 0.0005, Table). The majority of FMF episodes that developed in children receiving colchieine therapy were mild and brief. Twelve children, 5 years of age or less, were given a daily dose of colchieine, 0.5 mg. The mean age at the start of treatment was 3.2 years. Follow-up ranged between 1 and
5 years with a mean of 2.6 years. In five children the dose had to be raised to 0.5 mg twice daily at the mean age of 7 years. Twenty children older than 5 years were given 0.5 mg twice daily. The mean age at start of treatment was 8.6 years. Follow-up ranged between 1 and 5.5 years with a mean of 2.3 years. In seven children the dosage had to be raised to 0.5 mg three times daily at a mean age of 12.6 years. Children frequently stopped therapy when the disease was suppressed. This was followed by recurrence of severe episodes, usually within 1 week of stopping therapy; however, the disease was successfully suppressed by resumption of colchicine therapy. Similarly, reduction of the dosage that successfully suppressed the disease resulted in the same effect. In three patients, transient mild diarrhea responded to reduction of dosage; resumption of the initial dosage was easily achieved. Neurologic examination revealed no signs or symptoms of myopathy or neuropathy, and creatine kinase activity was also normal. In none of the patients did other signs or symptoms of colchicine toxicity, proteinuria, or amyloidosis develop during a total mean follow-up period of 5.8 years (before and after colehicine). DISCUSSION We did not conduct a double-blind, crossover protocol, because the children would have been denied continuous access to a treatment that was likely to be effective; furthermore, colchicine appears to allay the development of amyloidosis.7 Because of the variability in the frequency of attacks, which are known to occur over long periods of time, 13 we chose to compare the number of attacks before starting colehicine prophylaxis (obtained from the mothers' history) with the number of attacks occurring during colchicine therapy, as reported in the follow-up clinic during an extended period. This study showed a definite prophylactic effect of colehicine in children with FMF. Moreover, the ameliorating effect of colchicine in those children in whom episodes developed while they were receiving therapy was obvious; the pain was mild and of short duration. This study also showed that a daily dose of 0.5 rag, 1 nag, and 1.5 mg of colchicine were effective in children aged less than 7 years, 7 to 12.6 years, and more than 12.6 years, respectively. Of the eight children with a mean age of 1l years reported by Lehman et al., 9 the attacks were suppressed by a daily dose of 1.2 mg in five children and 1.8 mg in three children. The side effects of eolchicine in our patients were minor and benign. In three children transient diarrhea developed, which responded to reduction of the dosage; resumption of the original dosage was easily achieved. In none of the patients did clinicalsigns and symptoms suggestive of colch-
Volume 116 Number 6 icine toxicity, including neuropathy or myopathy, develop. Because of the striking effect of colchicine in arresting mitosis in the metaphase, s the possible role of colchicine in chromosomal abnormalities has been raised. Two children with Down syndrome were born to gout patients receiving continuous colchicine treatment. 12, 13 Ehrenfeld et al. 14 reported that the rates for miscarriage and infertility were high in 36 women with F M F who were receiving continuous colchicine therapy but were similar to those reported for women with F M F before colchicine therapy was introduced; all 16 infants born to mothers receiving colchicine therapy during pregnancy were normal. Furthermore, Cohen et al. 15 showed no increase in the mitotic rate, percent tetraploidy, and chromosomal breakage in lymphocytic cultures in patients with F M F who were receiving colchicine therapy. Fertility problems associated with azoospermia or impairment of sperm penetration may develop in as many as 20% of male F M F patients receiving long-term colchicine therapy~ 16 The possible mechanisms of colchicine action are complex and beyond the scope of this report. In the majority of our patients who discontinued colchicine treatment within the first 2.4 years of prophylaxis, severe episodes developed within a short time. The question of when to stop colchicine prophylaxis in children with F M F remains an important issue. The recurrent attacks are usually irregular and unpredictable, and long-term, spontaneous remissions are not unusual. 14 These remissions may tempt clinicians to discontinue colchicine prophylaxis when the disease seems to be under control. Recently, long-term continuous colchicine prophylaxis was shown to prevent the development of amyloidosis and further deterioration of renal function in early amyloidosis. 7 At the present stage of our knowledge, the question cannot be confidently answered. Meanwhile, we believe that because of the effect of colchicine in reducing the frequency of attacks, thus allowing children to resume their educational and social activities, and because of the drug's effect in the prevention of amyloidosis, as was shown in adults, 7 children with F M F should not be denied long-term colchicine prophylaxis.
Clinical and laboratory observations
999
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 1967;43:227-52. 2. Barakat M, Karnik AM, Majeed HA. Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs: a study of 175 patients and review of the literature. Q J Med 1986;60:83747. 3. Majeed HA, Barakat M. Familial Mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases. Eur J Pediatr 1989;148:636-41. 4. Goldfinger SE. Colchicine for familial Mediterranean fever [Letter]. N Engl J Med 1972;287:1302. 5. Zemer D, Revach M, Pras M, et al. A controlled trial of colchicine in preventing attacks of familial Mediterranean fever. N Engl J Med 1974;291:932-4. 6. Dinarello CA, Wolff SM, Goldfinger SE, et al. Colchicine therapy for familial Mediterranean fever: a double-blind trial. N Engl J Med 1974;291:934-7. 7. Zemer D, Pras M, Sohar E, et al. Colchicine in the treatment and prevention of amyloidosis of familial Mediterranean fever. N Engl J Med 1986;314:1001-5. 8. MalkinsonFD. Colchicine:newusesofanolddrug [Editorial]. Arch Dermatol 1982;118:453-7. 9. Lehman TJA, Peters RS, Hanson V, Schwabe A. Long-term colchicine therapy of familial Mediterranean fever. J PEDIATR 1978;93:876-8. 10. Bransky D, Gross-Kieselstein E, Abraham A. Colchicine therapy in familial Mediterranean fever: prophylactic benefit in 6 childhood patients. Clin Pediatr 1978;17:14-5. 11. Heller H, Sohar E, Sherf L. Familial Mediterranean fever. Arch Intern Med 1958;102:50-6. 12. Ferreria NR, Buoniconti A. Trisomy after colchicine therapy [Letter]. Lancet 1968;2: 1304. 13. Ferreria NR, Frota-Pessoao D. Trisomy after colchicine therapy [Letter]. Lancet 1969;1:1160. 14. Ehrenfeld M, Brezinski A, Levy M, Eliakim M. Family and obstetric history in patients with familial Mediterranean fever on long-term colchicine therapy. Br J Obstet Gynaecol 1987; 94:1186-91. 15. Cohen M, Levy M, Eliakim M. A cytogenic evaluation of long-term colehicine therapy in the treatment of familial Mediterranean fever. Am J Med Sci 1977;247:147-52. 16. Ehrenfeld M, Levy M, Margalioth E J, Eliakim M. The effects of long-term colchicine therapy on male fertility in patients with familial Mediterranean fever. Andrology 1986; 18:420-6.
Familial Mediterranean fever, also known as recurrent hereditary polyserositis, is an inherited multisystem disease of unknown etiology characterized by recurrent, painful, selflimited episodes of peritonitis, pleuritis, arthritis, and erysipelas-like erythema, occurring singly or in combination, usually associated with fever. It characteristically affects children of certain ethnic groups, primarily Arabs, Sephardic Jews, and Armenians5-3 The main complication of the disease is the development of amyloidosis. In large series of mainly adult patients, onset before the age of 10 years ranged between 49% and 62% and the mean age at onset ranged between 12.6 and 13.8 years14; in a recent report of 88 children, the mean age at onset was 4.9 years. 3 Colchicine was first introduced for the management of FMF by Goldfinger4 in 1972. Several studies addressing the therapeutic effect of colchicine in adults with FMF have been reported, 5, 6 and colchicine has been shown to prevent or ameliorate the complication of amyloidosis.7 However, colchicine therapy has side effects, including nausea, vomiting, mild diarrhea, azoospermia, bone marrow suppression, transient alopecia, malabsorption, myopathy, neuropathy, and chromosomal abnormalities.8 Information on the therapeutic response and safety of long-term colchicine prophylaxis in children with FMF is not available. Lehman et al. 9 and Branski et al. 1~described eight and six children, respectively, who were followed up Submitted for publication Oct. 31, 1989; accepted Dec. 18, 1989. Reprint requests: H. A. Majeed, FRCPI, DCH, Professor, Department of Pediatrics, Kuwait University Faculty of Medicine, P. O. Box 24923, 13110, Safat, Kuwait.
9/26/18993
for only 3 months. The purpose of this study was to explore the dosage, therapeutic response, and safety of long-term colchicine prophylaxis in children with FMF. METHODS The children were referred by their family physicians. All children were hospitalized and had had extensive laboratory investigations, as described in a previous report2; the diagnosis was based on the criteria of Heller et al. 11 Once the diagnosis was confidently made, another interview with the mother was conducted, with special emphasis on the frequency, duration, and severity of the episodes, after which colchicine therapy was started. Follow-up. Patients were seen in the FMF clinic of one of us (H.A.M.) once every 2 months, or more frequently when needed. At each outpatient visit a history was taken with FMF
Familial Mediterranean fever
emphasis on compliance with treatment and the occurrence of FMF, including the frequency, severity, and duration of episodes, and the occurrence of new signs or symptoms. Full physical examination and dipstick urine tests for protein and blood were conducted; other laboratory tests were performed when necessary. At the end of the study (September 1989) all children had liver and kidney function tests (SMAC 20, Technieon Instruments Corp., Tarrytown, N.Y.), complete hemogram, and urine analysis for protein and blood. Twenty-eight children had full neurologic examination by one of us (J.C.) and analysis of blood for creatine kinase activity. Dose of eolchieine. A daily dose of 0.5 mg was given to
997
998
Clinical and laboratory observations
The Journal of Pediatrics June 1990
Table. Effect of continuous colchicine prophylaxis in 32 children with F M F Continuous colchicine prophylaxis
No. of children Mean observation period (patient-yr) Total observation period (patient-yr) Total No. of episodes/patient-yr Mean frequency/patient-yr Mean duration of attack (hr)
Before
After
32 3.4 108.8 628 l 9.6* 52*
32 2.4 78 104 3.2* 3.6*
*p = 0.0005
children 5 years of age or younger; 0.5 mg was given twice daily to older children. The dosage was then modified according to the response. Effect of colchicine, The frequency, severity, and duration of episodes before colchicine therapy were obtained from the mother during the special interview and at each outpatient visit. Statistical analysis for differences in frequency was performed with the chi-square test, and the significance of differences was assessed with the Student t test. RESULTS Of 58 children with FMF under our care, 32 were selected for this study; the main requirements were reliability of the parents and compliance with treatment. All the children were of Arab origin; 22 (69%) were Palestinian (22% of the population in Kuwait are Palestinian), 7 (22%) Lebanese, 2 (6%) Syrian, and 1 (3%) Egyptian. The ratio of boys to girls was 1:1.7 (12:20). The family history of 17 children (53%) was positive for FMF. Peritonitis developed in 31 children (97%), pleuritis developed in 20 (63%), arthritis developed in 16 (50%), and cutaneous manifestations developed in 10 (31%). Fever was present in all children. The age at onset varied between 4 months and 9 years, with a mean of 3.7 years. The total observation periods before and after colchicine therapy were 108.8 patient-years and 78 patient-years, respectively. The frequency of attacks before colchicine therapy ranged between 6 and 40/ patient-year with a mean of 19.6/patient-year, whereas it ranged up to 8/patient-year with a mean of 3.2/patientyear after colchicine therapy (p = 0.0005, Table). The majority of FMF episodes that developed in children receiving colchieine therapy were mild and brief. Twelve children, 5 years of age or less, were given a daily dose of colchieine, 0.5 mg. The mean age at the start of treatment was 3.2 years. Follow-up ranged between 1 and
5 years with a mean of 2.6 years. In five children the dose had to be raised to 0.5 mg twice daily at the mean age of 7 years. Twenty children older than 5 years were given 0.5 mg twice daily. The mean age at start of treatment was 8.6 years. Follow-up ranged between 1 and 5.5 years with a mean of 2.3 years. In seven children the dosage had to be raised to 0.5 mg three times daily at a mean age of 12.6 years. Children frequently stopped therapy when the disease was suppressed. This was followed by recurrence of severe episodes, usually within 1 week of stopping therapy; however, the disease was successfully suppressed by resumption of colchicine therapy. Similarly, reduction of the dosage that successfully suppressed the disease resulted in the same effect. In three patients, transient mild diarrhea responded to reduction of dosage; resumption of the initial dosage was easily achieved. Neurologic examination revealed no signs or symptoms of myopathy or neuropathy, and creatine kinase activity was also normal. In none of the patients did other signs or symptoms of colchicine toxicity, proteinuria, or amyloidosis develop during a total mean follow-up period of 5.8 years (before and after colehicine). DISCUSSION We did not conduct a double-blind, crossover protocol, because the children would have been denied continuous access to a treatment that was likely to be effective; furthermore, colchicine appears to allay the development of amyloidosis.7 Because of the variability in the frequency of attacks, which are known to occur over long periods of time, 13 we chose to compare the number of attacks before starting colehicine prophylaxis (obtained from the mothers' history) with the number of attacks occurring during colchicine therapy, as reported in the follow-up clinic during an extended period. This study showed a definite prophylactic effect of colehicine in children with FMF. Moreover, the ameliorating effect of colchicine in those children in whom episodes developed while they were receiving therapy was obvious; the pain was mild and of short duration. This study also showed that a daily dose of 0.5 rag, 1 nag, and 1.5 mg of colchicine were effective in children aged less than 7 years, 7 to 12.6 years, and more than 12.6 years, respectively. Of the eight children with a mean age of 1l years reported by Lehman et al., 9 the attacks were suppressed by a daily dose of 1.2 mg in five children and 1.8 mg in three children. The side effects of eolchicine in our patients were minor and benign. In three children transient diarrhea developed, which responded to reduction of the dosage; resumption of the original dosage was easily achieved. In none of the patients did clinicalsigns and symptoms suggestive of colch-
Volume 116 Number 6 icine toxicity, including neuropathy or myopathy, develop. Because of the striking effect of colchicine in arresting mitosis in the metaphase, s the possible role of colchicine in chromosomal abnormalities has been raised. Two children with Down syndrome were born to gout patients receiving continuous colchicine treatment. 12, 13 Ehrenfeld et al. 14 reported that the rates for miscarriage and infertility were high in 36 women with F M F who were receiving continuous colchicine therapy but were similar to those reported for women with F M F before colchicine therapy was introduced; all 16 infants born to mothers receiving colchicine therapy during pregnancy were normal. Furthermore, Cohen et al. 15 showed no increase in the mitotic rate, percent tetraploidy, and chromosomal breakage in lymphocytic cultures in patients with F M F who were receiving colchicine therapy. Fertility problems associated with azoospermia or impairment of sperm penetration may develop in as many as 20% of male F M F patients receiving long-term colchicine therapy~ 16 The possible mechanisms of colchicine action are complex and beyond the scope of this report. In the majority of our patients who discontinued colchicine treatment within the first 2.4 years of prophylaxis, severe episodes developed within a short time. The question of when to stop colchicine prophylaxis in children with F M F remains an important issue. The recurrent attacks are usually irregular and unpredictable, and long-term, spontaneous remissions are not unusual. 14 These remissions may tempt clinicians to discontinue colchicine prophylaxis when the disease seems to be under control. Recently, long-term continuous colchicine prophylaxis was shown to prevent the development of amyloidosis and further deterioration of renal function in early amyloidosis. 7 At the present stage of our knowledge, the question cannot be confidently answered. Meanwhile, we believe that because of the effect of colchicine in reducing the frequency of attacks, thus allowing children to resume their educational and social activities, and because of the drug's effect in the prevention of amyloidosis, as was shown in adults, 7 children with F M F should not be denied long-term colchicine prophylaxis.
Clinical and laboratory observations
999
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 1967;43:227-52. 2. Barakat M, Karnik AM, Majeed HA. Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs: a study of 175 patients and review of the literature. Q J Med 1986;60:83747. 3. Majeed HA, Barakat M. Familial Mediterranean fever (recurrent hereditary polyserositis) in children: analysis of 88 cases. Eur J Pediatr 1989;148:636-41. 4. Goldfinger SE. Colchicine for familial Mediterranean fever [Letter]. N Engl J Med 1972;287:1302. 5. Zemer D, Revach M, Pras M, et al. A controlled trial of colchicine in preventing attacks of familial Mediterranean fever. N Engl J Med 1974;291:932-4. 6. Dinarello CA, Wolff SM, Goldfinger SE, et al. Colchicine therapy for familial Mediterranean fever: a double-blind trial. N Engl J Med 1974;291:934-7. 7. Zemer D, Pras M, Sohar E, et al. Colchicine in the treatment and prevention of amyloidosis of familial Mediterranean fever. N Engl J Med 1986;314:1001-5. 8. MalkinsonFD. Colchicine:newusesofanolddrug [Editorial]. Arch Dermatol 1982;118:453-7. 9. Lehman TJA, Peters RS, Hanson V, Schwabe A. Long-term colchicine therapy of familial Mediterranean fever. J PEDIATR 1978;93:876-8. 10. Bransky D, Gross-Kieselstein E, Abraham A. Colchicine therapy in familial Mediterranean fever: prophylactic benefit in 6 childhood patients. Clin Pediatr 1978;17:14-5. 11. Heller H, Sohar E, Sherf L. Familial Mediterranean fever. Arch Intern Med 1958;102:50-6. 12. Ferreria NR, Buoniconti A. Trisomy after colchicine therapy [Letter]. Lancet 1968;2: 1304. 13. Ferreria NR, Frota-Pessoao D. Trisomy after colchicine therapy [Letter]. Lancet 1969;1:1160. 14. Ehrenfeld M, Brezinski A, Levy M, Eliakim M. Family and obstetric history in patients with familial Mediterranean fever on long-term colchicine therapy. Br J Obstet Gynaecol 1987; 94:1186-91. 15. Cohen M, Levy M, Eliakim M. A cytogenic evaluation of long-term colehicine therapy in the treatment of familial Mediterranean fever. Am J Med Sci 1977;247:147-52. 16. Ehrenfeld M, Levy M, Margalioth E J, Eliakim M. The effects of long-term colchicine therapy on male fertility in patients with familial Mediterranean fever. Andrology 1986; 18:420-6.