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Vitamin A therapy in patients with Crohn's disease
GASTKOENTEKOLOGY
1985:88:51&I
Vitamin A Therapy in Patients With Crohn’s Disease J. P. WRIGHT,
A. S. MEE, A. PARFITT, I. N. MARKS, D. G. BURNS, M. SHERMAN, N. TIGLER-WYBRANDI, and S. ISAACS The Gastrointestinal Informatics, Groote
Clinic, Schuur
Department of Medicine, University of Cape Town Hospital, Cape Town, Republic of South Africa
Vitamin A therapy has been claimed in isolated reports to be of benefit to patients with Crohn’s disease. To investigate this further, 86 patients were entered into a long-term double-blind study of vitamin A, 50,000 U twice daily, as compared with placebo. After a mean of 14.1 mo of treatment there was no significant difference between the groups as measured by a variety of activity indices (including the National Cooperative Crohn’s Disease Activity Index), the number of acute attacks, and the surgical rate. No toxic effects of vitamin A were observed A has not during the study. In this study vitamin been shown to be of benefit to patients with Crohn’s disease who are in remission.
Patients with Crohn’s disease may have low serum vitamin A levels (1) and indeed vitamin A therapy has been reported to be of benefit in this chronic disease (2). It has been suggested that changes in the ultrastructure of the intestinal epithelium that are induced by vitamin A may be the cause (3). The exact relationship between vitamin A and Crohn’s disease is, however, not clear. In view of the limited therapeutic options open to patients with Crolm’s disease, a double-blind prospective trial of vitamin A versus placebo has been performed to establish whether it is useful in preventing relapse in patients with Crohn’s disease.
Received January 10, 1984. Accepted August 21, 1984. Address requests for reprints to: Dr. J. P. Wright, Gastrointestinal Clinic, Groote Schuur Hospital, Cape Town 7925. Republic of South Africa. This work was supported by the South African Medical Research Council and the Harry Crossley Foundation. The vitamin A and placebo tablets were donated by Lennon Limited. e 1985 by the American Gastroenterological Association 0016.5085/85/$3,30
and Department
Methods Patients Eighty-six patients with established Crohn’s disease in whom clinical activity had remained stable for at least 3 mo were entered into the study. The diagnosis had been made by standard clinical, radiologic, aud histologic criteria. Written informed consent was obtained from all patients and the study was approved by the University of Cape Town Ethical Review Committee.
Medication Patients were randomized to receive either a tablet of vitamin A acetate, 50,000 U twice daily, or an identical placebo tablet. Treatment was to be continued for a minimum of 9 or a maximum of 15 mo or until the patient was withdrawn from the study. The serum vitamin A levels were assayed in all patients each month using the trifluoracetic acid method (4). The vitamin A levels and all possible side effects were referred to an independent observer for assessment and management. Patients were instructed to discontinue all vitamin supplements but to continue with medication prescribed for their Crohn’s disease.
Patient
Assessment
Patients were seen and clinically assessed at entry and monthly thereafter for the duration of the study. The clinical data required to calculate the activity indices as well as the hemoglobin, erythrocyte sedimentation rate, serum albumin, aspartate transaminase, alkaline phosphatase, and C-reactive protein results were entered into a specifically written computer datafile which calculated the National Cooperative Crohn’s Disease Study (NCCDS) and the “van Hees” activity indices (5,6). For the purposes of this study clinical relapses were defined as either
Abbreviations Crohn’s Disease
used in this paper: Study.
NCCDS. National
(hoprrative
February
Table
1985
1. Patient
VITAMIN A THERAPY IN CRfJHN’S DISEASE
Characteristics
Patients
at Entry Into Study
Vitamin A 43
Number Male/female Age (~4 Weight (kg] Months since diagnosed Previously resected Extent of disease Colonic IleocoloniL Ileal Ethnic group White Coloured’ Black ’ Mean f SEM. ” p groups not included
Placebo 43
18125
17126
36.8
2 2.1”
38.7
t
65.4
2 2.2”
60.0
? 1.6U,”
60.5
? 8.7a
58.2
+ 8.9”
12
15
11
11
10
13
22
19
20
23
21
19
2.1”
2 <
0.05. “Indian, Asian, and other ethnic in the other two groups.
abdominal pain with or without diarrhea accompanied by systemic symptoms such as pyrexia, or increased diarrhea with or without malabsorption. When relapse occurred patients were treated as clinically indicated, including surgery or steroids, or both. The randomization code was not broken and the patients continued participation in the study.
Statistical
Analysis
A clinically important difference between the two treatment groups was judged to be 25% as measured by the NCCDS and 5% by the “van Hees” indices. These levels were chosen on the basis of clinical experience and the observed distribution around the mean of each index. The differences between the two therapeutic groups were tested by the Student’s t-test and xZ analysis. Changes in disease activity were tested by the repeated-measure t-test and relapse rate was analyzed by the life-table method.
There was no relationship between the initial serum vitamin A levels and the patients’ age and sex or the duration, extent, and activity of the Crohn’s disease. Serum levels of vitamin A became significantly different between the two groups after 5 mo of therapy (Figure 1). The activity indices were similar in the two groups throughout the study [Figure 2). The p risk for detecting a difference of 25% in the NCCDS and 5% in the “van Hees” indices within the 95% confidence limit varied between 0.50 and 0.76. There was no correlation between vitamin A levels, activity indices, the separate components of the indices, or the laboratory parameters measured. The clinical relapse rate was similar in the two groups A group and 6 (Figure 3). Five patients in the vitamin patients in the placebo group underwent surgical resection during the study. On discontinuing therapy the serum vitamin A levels in the active therapy groups fell to the pretreatment levels, but there was no concomitant change in the measured disease activity during this period (Figure 2). Nine patients in the vitamin A group and 8 patients in the placebo group were on steroid therapy at entry into the study. Steroid therapy was withdrawn during the study from 2 patients in the vitamin A group and 6 patients in the placebo group; the steroid dose was reduced in 3 patients in the vitamin A group and 1 patient in the placebo group. Four patients in the vitamin A group and 1 patient in the placebo group continued on low-dose steroid treatment throughout the study.
Discussion Crohn’s disease symptoms and, in this
Results
is characterized study. a clinical
by chronic relapse rate
-
PLACEBO ??
The 86 patients were entered into study followed for a mean of 14.1 mo (range 9-23 mo). two groups were identical in all aspects except weight [Table 1). There was no difference in withdrawal rate between the two groups (Table Table
2. Withdrawals
From
duration
patient
5(3,4.7.11.11)
2(7.10) 2(2,2)
l(71
2(1.8)
death
l(6)
of follow-up
is indicated
P < o-01 p c 0.02
Placebo
I(31
Social reason Pregnant The
and The for the 2).
group
Vitamin A
Reason
Postoperative
*
??
Studv Treatment
Poor compliance Default Admission
513
2(1-l]
2(12,6]
2(4,9)
2(2.3)
in months
in parentheses.
before
withdrawal
of each
Figure
1.
Serum vitamin A in the two groups. The vitamin A group was treated with 50.000 II daily. Therapy was discontinued after 15 mo.
514
WRIGHT
GASTROENTEROLOGY
ET AL.
VAN
88. No. 2
HEES
MONTHS
Figure
Vol.
2. The calculated National Cooperative Crohn’s Disease Study (NCCDS) and the “van Hees” indices in the two treatment groups during the study. Patients who suffered an acute relapse were not withdrawn from the
Figure
.
43
37
28
18
13
13
13
13
x
43
40
26
16
13
1,
11
II
of patients 3. The percentage during the study. Calculated The number of patients in the each 3-ma interval is shown
remaining in remission by the life-table method. study at the beginning of beneath the x-axis.
study.
per year. Objective measurements of disof -50% ease activity and the documentation of clinical relapse were therefore important in evaluating response to therapy. A number of published “activity indices” as well as laboratory parameters were used in this study but were unable to detect any difference between the two groups. ~5~&500/, probability that this The disappointing study may have missed a significant difference between the groups is largely dependent on the predetermined “clinically important difference” of 25% for the NCCDS and 5% for the “van Hees” indices. The two groups of patients were closely matched at entry with the age, sex, and racial distribution and the extent of the disease previously reported from the Cape Town area (7). Although the two groups appeared very similar throughout the study, the delay in the appearance of a significant difference in vitamin A levels may have masked a therapeutic benefit. This delay could be due to some patients taking intermittent vitamin supplements before the study, although all patients discontinued this therapy on entry. This delay in achieving high levels of vitamin A in the active group is countered by the subsequent 12 mo of significantly different blood
levels which might have been expected to show any therapeutic advantages of vitamin A. Furthermore, the fall in vitamin A levels on discontinuing therapy (Figure 1) without any demonstrable change in activity suggests that vitamin A therapy does not influence disease activity in patients with Crohn’s disease.
References 1. Camilo ME, Pinto G, Melo MJ, Pinto Correira J. Vitamin A and zinc in inflammatory bowel disease. Stand J Gastroenterol 1982:17(Suppl 78):357. 2. Skogh M, Sundquist T, Tagesson C. Vitamin A in Crohn’s disease. Lancet 198O;i:766. 3. Dvorak AM. Vitamin A in Crohn’s disease. Lancet 1980;i: 1303-4. 4. Neeld JB, Pearson WN. Macro-micromethods for the determination of serum vitamin A using trifluoroacetic acid. J Nutr 1963;79:454-62. 5. Best WR, Becktal JM, Singleton JW. Kern F. Development of a Crohn’s disease activity index. Gastroenterology 1976;70:439% 44. 6. Van Hees P, van Elteren PH, van Lier HJJ. van Tongern JHM. An index of inflammatory activity in patients with Crohn’s disease. Gut 1980;21:279-86. 7. Wright JP, Marks IN, Jameson C. Garisch JAM, Burns DG. Kottler RE. Inflammatory bowel disease in Cape Town, 19751980. Part II. Crohn’s disease. S Afr Med J 1983;63:226-9.
1985:88:51&I
Vitamin A Therapy in Patients With Crohn’s Disease J. P. WRIGHT,
A. S. MEE, A. PARFITT, I. N. MARKS, D. G. BURNS, M. SHERMAN, N. TIGLER-WYBRANDI, and S. ISAACS The Gastrointestinal Informatics, Groote
Clinic, Schuur
Department of Medicine, University of Cape Town Hospital, Cape Town, Republic of South Africa
Vitamin A therapy has been claimed in isolated reports to be of benefit to patients with Crohn’s disease. To investigate this further, 86 patients were entered into a long-term double-blind study of vitamin A, 50,000 U twice daily, as compared with placebo. After a mean of 14.1 mo of treatment there was no significant difference between the groups as measured by a variety of activity indices (including the National Cooperative Crohn’s Disease Activity Index), the number of acute attacks, and the surgical rate. No toxic effects of vitamin A were observed A has not during the study. In this study vitamin been shown to be of benefit to patients with Crohn’s disease who are in remission.
Patients with Crohn’s disease may have low serum vitamin A levels (1) and indeed vitamin A therapy has been reported to be of benefit in this chronic disease (2). It has been suggested that changes in the ultrastructure of the intestinal epithelium that are induced by vitamin A may be the cause (3). The exact relationship between vitamin A and Crohn’s disease is, however, not clear. In view of the limited therapeutic options open to patients with Crolm’s disease, a double-blind prospective trial of vitamin A versus placebo has been performed to establish whether it is useful in preventing relapse in patients with Crohn’s disease.
Received January 10, 1984. Accepted August 21, 1984. Address requests for reprints to: Dr. J. P. Wright, Gastrointestinal Clinic, Groote Schuur Hospital, Cape Town 7925. Republic of South Africa. This work was supported by the South African Medical Research Council and the Harry Crossley Foundation. The vitamin A and placebo tablets were donated by Lennon Limited. e 1985 by the American Gastroenterological Association 0016.5085/85/$3,30
and Department
Methods Patients Eighty-six patients with established Crohn’s disease in whom clinical activity had remained stable for at least 3 mo were entered into the study. The diagnosis had been made by standard clinical, radiologic, aud histologic criteria. Written informed consent was obtained from all patients and the study was approved by the University of Cape Town Ethical Review Committee.
Medication Patients were randomized to receive either a tablet of vitamin A acetate, 50,000 U twice daily, or an identical placebo tablet. Treatment was to be continued for a minimum of 9 or a maximum of 15 mo or until the patient was withdrawn from the study. The serum vitamin A levels were assayed in all patients each month using the trifluoracetic acid method (4). The vitamin A levels and all possible side effects were referred to an independent observer for assessment and management. Patients were instructed to discontinue all vitamin supplements but to continue with medication prescribed for their Crohn’s disease.
Patient
Assessment
Patients were seen and clinically assessed at entry and monthly thereafter for the duration of the study. The clinical data required to calculate the activity indices as well as the hemoglobin, erythrocyte sedimentation rate, serum albumin, aspartate transaminase, alkaline phosphatase, and C-reactive protein results were entered into a specifically written computer datafile which calculated the National Cooperative Crohn’s Disease Study (NCCDS) and the “van Hees” activity indices (5,6). For the purposes of this study clinical relapses were defined as either
Abbreviations Crohn’s Disease
used in this paper: Study.
NCCDS. National
(hoprrative
February
Table
1985
1. Patient
VITAMIN A THERAPY IN CRfJHN’S DISEASE
Characteristics
Patients
at Entry Into Study
Vitamin A 43
Number Male/female Age (~4 Weight (kg] Months since diagnosed Previously resected Extent of disease Colonic IleocoloniL Ileal Ethnic group White Coloured’ Black ’ Mean f SEM. ” p groups not included
Placebo 43
18125
17126
36.8
2 2.1”
38.7
t
65.4
2 2.2”
60.0
? 1.6U,”
60.5
? 8.7a
58.2
+ 8.9”
12
15
11
11
10
13
22
19
20
23
21
19
2.1”
2 <
0.05. “Indian, Asian, and other ethnic in the other two groups.
abdominal pain with or without diarrhea accompanied by systemic symptoms such as pyrexia, or increased diarrhea with or without malabsorption. When relapse occurred patients were treated as clinically indicated, including surgery or steroids, or both. The randomization code was not broken and the patients continued participation in the study.
Statistical
Analysis
A clinically important difference between the two treatment groups was judged to be 25% as measured by the NCCDS and 5% by the “van Hees” indices. These levels were chosen on the basis of clinical experience and the observed distribution around the mean of each index. The differences between the two therapeutic groups were tested by the Student’s t-test and xZ analysis. Changes in disease activity were tested by the repeated-measure t-test and relapse rate was analyzed by the life-table method.
There was no relationship between the initial serum vitamin A levels and the patients’ age and sex or the duration, extent, and activity of the Crohn’s disease. Serum levels of vitamin A became significantly different between the two groups after 5 mo of therapy (Figure 1). The activity indices were similar in the two groups throughout the study [Figure 2). The p risk for detecting a difference of 25% in the NCCDS and 5% in the “van Hees” indices within the 95% confidence limit varied between 0.50 and 0.76. There was no correlation between vitamin A levels, activity indices, the separate components of the indices, or the laboratory parameters measured. The clinical relapse rate was similar in the two groups A group and 6 (Figure 3). Five patients in the vitamin patients in the placebo group underwent surgical resection during the study. On discontinuing therapy the serum vitamin A levels in the active therapy groups fell to the pretreatment levels, but there was no concomitant change in the measured disease activity during this period (Figure 2). Nine patients in the vitamin A group and 8 patients in the placebo group were on steroid therapy at entry into the study. Steroid therapy was withdrawn during the study from 2 patients in the vitamin A group and 6 patients in the placebo group; the steroid dose was reduced in 3 patients in the vitamin A group and 1 patient in the placebo group. Four patients in the vitamin A group and 1 patient in the placebo group continued on low-dose steroid treatment throughout the study.
Discussion Crohn’s disease symptoms and, in this
Results
is characterized study. a clinical
by chronic relapse rate
-
PLACEBO ??
The 86 patients were entered into study followed for a mean of 14.1 mo (range 9-23 mo). two groups were identical in all aspects except weight [Table 1). There was no difference in withdrawal rate between the two groups (Table Table
2. Withdrawals
From
duration
patient
5(3,4.7.11.11)
2(7.10) 2(2,2)
l(71
2(1.8)
death
l(6)
of follow-up
is indicated
P < o-01 p c 0.02
Placebo
I(31
Social reason Pregnant The
and The for the 2).
group
Vitamin A
Reason
Postoperative
*
??
Studv Treatment
Poor compliance Default Admission
513
2(1-l]
2(12,6]
2(4,9)
2(2.3)
in months
in parentheses.
before
withdrawal
of each
Figure
1.
Serum vitamin A in the two groups. The vitamin A group was treated with 50.000 II daily. Therapy was discontinued after 15 mo.
514
WRIGHT
GASTROENTEROLOGY
ET AL.
VAN
88. No. 2
HEES
MONTHS
Figure
Vol.
2. The calculated National Cooperative Crohn’s Disease Study (NCCDS) and the “van Hees” indices in the two treatment groups during the study. Patients who suffered an acute relapse were not withdrawn from the
Figure
.
43
37
28
18
13
13
13
13
x
43
40
26
16
13
1,
11
II
of patients 3. The percentage during the study. Calculated The number of patients in the each 3-ma interval is shown
remaining in remission by the life-table method. study at the beginning of beneath the x-axis.
study.
per year. Objective measurements of disof -50% ease activity and the documentation of clinical relapse were therefore important in evaluating response to therapy. A number of published “activity indices” as well as laboratory parameters were used in this study but were unable to detect any difference between the two groups. ~5~&500/, probability that this The disappointing study may have missed a significant difference between the groups is largely dependent on the predetermined “clinically important difference” of 25% for the NCCDS and 5% for the “van Hees” indices. The two groups of patients were closely matched at entry with the age, sex, and racial distribution and the extent of the disease previously reported from the Cape Town area (7). Although the two groups appeared very similar throughout the study, the delay in the appearance of a significant difference in vitamin A levels may have masked a therapeutic benefit. This delay could be due to some patients taking intermittent vitamin supplements before the study, although all patients discontinued this therapy on entry. This delay in achieving high levels of vitamin A in the active group is countered by the subsequent 12 mo of significantly different blood
levels which might have been expected to show any therapeutic advantages of vitamin A. Furthermore, the fall in vitamin A levels on discontinuing therapy (Figure 1) without any demonstrable change in activity suggests that vitamin A therapy does not influence disease activity in patients with Crohn’s disease.
References 1. Camilo ME, Pinto G, Melo MJ, Pinto Correira J. Vitamin A and zinc in inflammatory bowel disease. Stand J Gastroenterol 1982:17(Suppl 78):357. 2. Skogh M, Sundquist T, Tagesson C. Vitamin A in Crohn’s disease. Lancet 198O;i:766. 3. Dvorak AM. Vitamin A in Crohn’s disease. Lancet 1980;i: 1303-4. 4. Neeld JB, Pearson WN. Macro-micromethods for the determination of serum vitamin A using trifluoroacetic acid. J Nutr 1963;79:454-62. 5. Best WR, Becktal JM, Singleton JW. Kern F. Development of a Crohn’s disease activity index. Gastroenterology 1976;70:439% 44. 6. Van Hees P, van Elteren PH, van Lier HJJ. van Tongern JHM. An index of inflammatory activity in patients with Crohn’s disease. Gut 1980;21:279-86. 7. Wright JP, Marks IN, Jameson C. Garisch JAM, Burns DG. Kottler RE. Inflammatory bowel disease in Cape Town, 19751980. Part II. Crohn’s disease. S Afr Med J 1983;63:226-9.