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Increased frequency of diabetes mellitus in patients with bullous pemphigoid: A case-control study
Volume 11 Nt,mber 6 December, 1984 REFERENCES I. Harber LC, Holloway RM, Wheatley VR, Baer RL: Immunologic and biophysical studies in solar urticaria. J Invest Dermatol 41:439-443, 1963. 2. Epstein JH, Vandenberg J J, Wright WL: Solar urticaria. Arch Dermatol 88:135-141, 1963. 3. Epstein JH: Solar urticaria. Int J Dermatol 16:388-390, 1977. 4. Horio T, Minami K: Solar urticaria: Photoallergen in a patient's serum. Arch Dermatol 113:157-160, 1977.
Solar urticaria
5. Horio T: Photoallergic urticaria induced by visible light. Arch Dermatol 114:1761-1764, 1978. 6. Hasei K, lchihashi M: Solar urticaria: Determination of action and inhibition spectra. Arch Dermatol 118:346350, 1982. 7. Torinuki W, Kumai N, Miura T: Solar urticaria inhibited by visible light. Dermatologica 166:151-155, 1983.
Increased frequency of diabetes mellitus in patients with bullous pemphigoid: A case-control study Tsu-Yi Chuang, M.D., M.P.H.,* Wiwat Korkij, M . D . , Keyoumars Soltani, M.D., Joseph Clayman, M . D . , and Jan Cook, M.D. Madison, WI, and Chicago, IL A case-control study was designed to assess the occurrence rate of primary diabetes mellitus (DM) in patients with bullous pemphigoid (BP) by retrospectively reviewing the records of our thirty histopathologically and immunopathologically proved cases of BP from the past 10 years. One hundred twenty patients were selected as controls, which included two names immediately before and two names immediately after each case of BP in our histopathology record book. The occurrence rate of primary DM prior to the administration of systemic corticosteroids was significantly higher in patients with BP than in the controls (20% and 2.5%, respectively; p = 0.004). Among patients over 50 years of age, this occurrence rate was again higher in patients with BP than in the controls (23% and 3.6% respectively; p = 0.02). This study suggests a higher than chance association of BP and primary DM. (J AM ACAD DERMA'rOL 11:1099-1102, 1984.)
Bullous pemphigoid (BP) is a chronic blistering dermatosis characterized by the subepidermal Fromthe Departmentof Medicine,Sectionof Dermatology,University of Chicago PritzkcrSchoolof Medicine. Accepted for publicationJuly 12, 1984. Reprint requests to: Dr. Tsu-Yi Chuang, Section of Dermatology. Department of Medicine, Universityof Wisconsin, 600 Highland Ave., Madison, WI 53792. *Section of Dermatology, Departmentof Medicine, Universityof Wisconsin, Madison.
separation within the lamina lucida of the epidermal basement membrane zone (BMZ). BP is induced by circulating anti-BMZ antibodies that can activate the complement system. Other immune-mediated diseases, including systemic lupus erythematosus, polymyosit!s, ulcerative colitis, rheumatoid arthritis, polymyalgia rheumatica, thyroid disorders, pernicious anemia, thymic hypoplasia with hemolytic anemia, alopecia areata, myasthenia gravis with thymoma, factor V in1099
1100
Journal of the American Academy of Derrnatology
Chuang et al
T a b l e I. Clinical data o f six bullous pemphigoid patients with diabetes mellitus*
Race
Peak fasting sugar level (mg/dl)
BP
DM
manifestation
Complication
F
B
636
7/82
56
F
B
315
9/80
3
80
M
W
336
8/80
Ketonuria + glycosuria + Glycosuria+ + + + using insulin Glycosuria+ + + +
Cataract; arteriosclerotic Cataract; diabetic toot --
4
67
F
B
416
11/78
58
F
B
164
12/77
6
64
F
W
124
12/74
Ketonuria + glycosuria+ + + Obesity ANA 1:20 (+) (on chlorpropamide [Diabinese])
Arteriosclerotic retinopathy
5
6 yr before BP 19 yr before BP 5 yr before BP 5 yr before BP 19 yr before BP 3 yr before BP
Case No.
Age (yr)
Sex
1
74
2
Date of diagnosis
Clinical
Cataract
*A DM case is definedas a patient with at least two separateassaysof fasting serum glucoselevelsof >120 mg/dl. The patient must not have been on systemicglucocorticosteroidtherapyprior to eitherassay. hibitor deficiency, and primary biliary cirrhosis, have been infrequently associated with BP. 1-4 Similarly, various autoimmune diseases and auto: immune polyendocrinopathies have concurred with primarily the insulin-dependent D M (type I), which often presents with islet cell autoantibodies. ~ The association of primary D M and BP in a number of our patients prompted us to evaluate the coincidence of DM in our patients diagnosed as having BP in the past 10 years. MATERIALS AND METHODS Between January 1973 and December 1982, we saw thirty confirmed cases of BP (including 3 cicatricial pemphigoid patients) at the university clinic. The diagnosis was confirmed histopathologically in twenty-nine patients and immunopathologically in all patients (28 having positive direct immunofluorescence test and the other 2 having positive indirect immunofluorescence test only). DM was defined by elevated fasting venous whole blood sugar levels (>120 mg/dl) on at least two separate occasions with or without positive oral glucose tolerance tests, according to the criteria set by the National Diabetes Data Group) Clinical manifestations of DM were used only to substantiate the diagnosis of DM. The clinical data regarding six BP patients who also had primary DM are summarized in Table I. For the purpose of comparison, four controls were selected for each BP case from the skin biopsy record books. Controls were the ones whose names appeared immediately before (2 names) and after (2 names) the name
of each of the thirty BP patients. One hundred twenty controls were thus selected, three of which h a d primary DM. Because the number of primary DM patients was small (less than 5), two-sided Fisher's exact test was chosen for the purpose of statistical analysis. N o t e that patients who had steroid-induced DM (3 patients in the BP group and 1 patient in the control group) were not included in this comparison. There was one additional BP patient in our series who had DM 20 years before the onset of BP and a positive family history o f DM but lacked current objective data to substantiate the diagnosis. This case was also excluded from the BPDM group and from the statistical comparison. The general features of cases and controls are summarized in Table II. RESULTS There w e r e more w o m e n (20) and w h i t e s (16) than men (10) and nonwhites (14) in our p a t i e n t s with BP. T h e i r average age was 64 with a range from 5 to 85 years. Only four patients were younger than 50 years o f age. Their ages w e r e 5, 13, 28, and 42 years. The control group o f 120 patients also had higher numbers o f w o m e n (71 vs 49 men) and whites (67 vs 53 n o n w h i t e s ) . T h e i r average age was 53 years with a range f r o m 8 days to 88 years. Over half o f the control group h a d an age less than 50 years (Table II). Primary D M was found in six (20%) o f the case group a n d three (2.5%) o f the control group. The d i f f e r e n c e
Volume 11 Number 6 December, 1984
of occurrence rate of DM in these two groups was statistically significant (p = 0.004, two-sided Fisher's exact test). Overall, there were twenty-six BP cases and fifty-six controls aged 50 years or over. Their average ages were 71 years and 64 years, respectively. When only these two subgroups were compared, the prevalence of DM was six (23.1%) and two (3.6%) for the cases and controls, respectively (p = 0.02, two-sided Fisher's exact test). The age-specific prevalence rates of DM in the general population have been studied for residents of Rochester, MN. r When these age-specific rates were applied to our case and control groups, the expected number o f DM patients in our BP case group was 1.7. The observed number of DM patients in the case group, however, was six. This was significantly higher than the expected number (observed/expected ratio = 3.5, p < 0.05). The latter two comparisons indicated that even after the age was controlled, the difference in the occurrence rate of DM between case and control groups persisted. On the other hand, the observed and expected numbers of DM patients in the control group were very close (observed/expected number = 3/3.3). The negligible difference between these two numbers demonstrates that well-documented prevalence rates of diabetics from a general population are indeed suitable for the estimation of the expected number of diabetics for a clinic population like ours. The subtypes of DM were hard to classify due to the retrospective nature of the present study and the lack of adequate data. DISCUSSION The present case-control study provides the statistical evidence to substantiate the association of BP and DM. To the best of our knowledge, this is the first case-control evaluation of the relationship between these two disease entities. Several points should be addressed to avoid misinterpretation of the results. The case group, selected from a university clinic population, cannot be without selection bias. Severely ill and complicated cases are usually referred to these clinics for highly specialized management. These patients presumably could
Diabetes mellitus with bullous pemphigoid
1101
Table II. General features of eases and controls -
,
No. of patients Age (average), yr Sex, M:F Race, white:nonwhite No. of diabetics
i
Cases(BP)]Controls 30 64.4 1:2 1: 1 6
120 52.5 1:1.4 1:0.8 3
have multiple problems, including DM. Because the case and control groups were selected from the same population source, however, selection bias resulting from the heavy reliance of our practice on referral patients was minimized. There was neither a sampling bias nor a response bias active in this study (we collected all cases of BP diagnosed in the past 10 years, and the diagnosis of DM was based on objective data, not on subjective response by patients). The objective nature of the data (blood sugar levels) also minimized the potential bias resulting from overenthusiastic investigators who might have eagerly looked for clues of D M in certain cases. One example of avoiding such a bias is the exclusion of the only BP case in the final analysis, whose DM occurred 20 years previously by history but lacked sugar level data to substantiate the diagnosis of DM. We assume that our control group was an appropriate one because: (1) These controls visited the same clinic and received the same procedure (biopsy) and similar help, about the same time as our BP cases. The selection bias active in the case group is thus balanced by this approach. (2) The number of controls versus cases is four to one, which is generally considered to be the most adequate ratio to minimize the sampling bias. (3) The nature of diseases in the control group was not predetermined to avoid prejudicial factors, and, in fact, their histopathologic diagnoses varied from normal skin to dermatitis, mycosis fungoides, and metastatic lung cancer. The difference in average ages in the case and control groups, as revealed in Table II, raised the concern over the influence of age in the occurrence rate of DM. The higher frequency of DM in our case group over the control group could be pardally due to its higher average age. It is known that both BP and DM often develop in elderly
1102
Journal of the American Academyof Dermatology
Chuang et al
patients. Two different methods w e r e used to eliminate the effect of age factor. O n e was the comparison between subgroups aging 5 0 years or over, and the other was the application of published age-specific prevalence rates o f DM. The prevalence of DM in BP cases remained higher even after age was controlled by the preceding two methods. The higher prevalence of D M in our BP cases is therefore valid. The 20% occurrence rate of DM in t h e present BP patient group could have been underestimated because of our rigorous criteria for defining DM, i.e., the exclusion of secondary diabetics and also diabetic patients without adequate objective data. In their open study, Downham and Chapel a reported that 41% of their thirty-four B P patients had DM. The mechanism underlying the association of BP and DM is unknown. Diabetics h a v e a lower threshold than normal individuals f o r suctioninduced blister. ~ This fragility may contribute to the induction of BP by various mechanisms. Since autoimmune mechanisms may be active in both BP and type I DM, we speculate t h a t similar pathogenetic mechanisms may also be responsible for this association. Bassiouny et al 1~reported that glucosylated skin collagen, which increases during nonenzymatic glucosylation of collagen in diabetics, is capable of inducing the production of autoantibodies with specificity directed against the modified collagen. They also proved that serum of streptozotocininduced diabetic rats contains antibodies capable of binding to glucosylated rat skin collagen. Nonenzymatic glucosylation in the diabetic state may involve various noncollagen proteins that may also become targets for autoantibodies in diabetic patients. H In BP, IgG anti-BMZ autoantibodies bind to the glycoprotein antigen in the lamina lucida. This activates the complement system, which, in turn, produces factors that induce
mast cells and eosinophils to release proteinases. These could degrade the BMZ and form blisters. 1~ One may speculate that the glycoprotein in the lamina lucida may be nonenzymatically glucosylated in diabetic patients. This could serve as the antigen that initiates the autoimmune process, leading to blister formation. The significant association of BP and DM as demonstrated by the present case-control study suggests that this possibility is worthy of further investigation. REFERENCES
1. Ahmed AR, Hardy D: Bullous pemphigoid: Family of autoimmune disease. Int J Dermatol 20:541-543, 1981. 2. Lynfield YL, Green K, Gopal R: Bullous pemphlgoid and multiple autoimmune diseases. J AM ACAD DERtaha'Or. 9:257-26l, 1983. 3. BloomfieldS, Stockdill G, Barnetson RStC: Thymic hypoplasia, autoimmune hemolytic anemia and juvenile pemphigoid in an infant. Br J Demmtol 106:353-355, 1982. 4. James WD: Bullous pemphigoid, myasflaeniagravis and thymoma. Arch Dermatol 120:397, 1984. 5. Naji A, Silvers WK, Barker CF: Autoimmunity and type 1 (insulin-dependent) diabetes mellitus. Transplantation 36:355-361, 1983. 6. National Diabetes Data Group: Classification and diagnosis of diabetes mellitusand other categories of glucose intolerance. Diabetes 28:1039-1057, 1979. 7. Palumbo PJ, Elveback LR, Chu C-P, et al: Diabetes mellitus: Incidence, prevalence, survivorship and causes of death in Rochester, Minnesota, 1945-1970. Diabetes 25:566-573, 1976. 8. DownhamFF, ChapelTA: Bullous pemphigoid: Therapy in patients with and without diabetes mellitus. Arch Dermatol 114:1629-1642, 1978. 9. BernsteinJE, Levine LE, Medenica MM, et al: Reduced threshold to suction-induced blister formation in insulin-dependent diabetics. J AM Ac.*~ DERMATOL 8:790-791, 1983. 10. Bassiouny AR, Rosenberg H, McDonald TL: Glucosylated collagen is antigenic. Diabetes 32:1182-1184, 1983. 11. Brownlee M, CeramiA: The biochemistryof the complications of diabetes mellitus. Annu Rev Biochem 50:385-432, 1981. 12. Sams WM Jr, Gammon WR: Mechanism of lesion production in pemphigus and pemphigoid. J AM ACAO D~RMA'rOL6:431-449, 1982.
Solar urticaria
5. Horio T: Photoallergic urticaria induced by visible light. Arch Dermatol 114:1761-1764, 1978. 6. Hasei K, lchihashi M: Solar urticaria: Determination of action and inhibition spectra. Arch Dermatol 118:346350, 1982. 7. Torinuki W, Kumai N, Miura T: Solar urticaria inhibited by visible light. Dermatologica 166:151-155, 1983.
Increased frequency of diabetes mellitus in patients with bullous pemphigoid: A case-control study Tsu-Yi Chuang, M.D., M.P.H.,* Wiwat Korkij, M . D . , Keyoumars Soltani, M.D., Joseph Clayman, M . D . , and Jan Cook, M.D. Madison, WI, and Chicago, IL A case-control study was designed to assess the occurrence rate of primary diabetes mellitus (DM) in patients with bullous pemphigoid (BP) by retrospectively reviewing the records of our thirty histopathologically and immunopathologically proved cases of BP from the past 10 years. One hundred twenty patients were selected as controls, which included two names immediately before and two names immediately after each case of BP in our histopathology record book. The occurrence rate of primary DM prior to the administration of systemic corticosteroids was significantly higher in patients with BP than in the controls (20% and 2.5%, respectively; p = 0.004). Among patients over 50 years of age, this occurrence rate was again higher in patients with BP than in the controls (23% and 3.6% respectively; p = 0.02). This study suggests a higher than chance association of BP and primary DM. (J AM ACAD DERMA'rOL 11:1099-1102, 1984.)
Bullous pemphigoid (BP) is a chronic blistering dermatosis characterized by the subepidermal Fromthe Departmentof Medicine,Sectionof Dermatology,University of Chicago PritzkcrSchoolof Medicine. Accepted for publicationJuly 12, 1984. Reprint requests to: Dr. Tsu-Yi Chuang, Section of Dermatology. Department of Medicine, Universityof Wisconsin, 600 Highland Ave., Madison, WI 53792. *Section of Dermatology, Departmentof Medicine, Universityof Wisconsin, Madison.
separation within the lamina lucida of the epidermal basement membrane zone (BMZ). BP is induced by circulating anti-BMZ antibodies that can activate the complement system. Other immune-mediated diseases, including systemic lupus erythematosus, polymyosit!s, ulcerative colitis, rheumatoid arthritis, polymyalgia rheumatica, thyroid disorders, pernicious anemia, thymic hypoplasia with hemolytic anemia, alopecia areata, myasthenia gravis with thymoma, factor V in1099
1100
Journal of the American Academy of Derrnatology
Chuang et al
T a b l e I. Clinical data o f six bullous pemphigoid patients with diabetes mellitus*
Race
Peak fasting sugar level (mg/dl)
BP
DM
manifestation
Complication
F
B
636
7/82
56
F
B
315
9/80
3
80
M
W
336
8/80
Ketonuria + glycosuria + Glycosuria+ + + + using insulin Glycosuria+ + + +
Cataract; arteriosclerotic Cataract; diabetic toot --
4
67
F
B
416
11/78
58
F
B
164
12/77
6
64
F
W
124
12/74
Ketonuria + glycosuria+ + + Obesity ANA 1:20 (+) (on chlorpropamide [Diabinese])
Arteriosclerotic retinopathy
5
6 yr before BP 19 yr before BP 5 yr before BP 5 yr before BP 19 yr before BP 3 yr before BP
Case No.
Age (yr)
Sex
1
74
2
Date of diagnosis
Clinical
Cataract
*A DM case is definedas a patient with at least two separateassaysof fasting serum glucoselevelsof >120 mg/dl. The patient must not have been on systemicglucocorticosteroidtherapyprior to eitherassay. hibitor deficiency, and primary biliary cirrhosis, have been infrequently associated with BP. 1-4 Similarly, various autoimmune diseases and auto: immune polyendocrinopathies have concurred with primarily the insulin-dependent D M (type I), which often presents with islet cell autoantibodies. ~ The association of primary D M and BP in a number of our patients prompted us to evaluate the coincidence of DM in our patients diagnosed as having BP in the past 10 years. MATERIALS AND METHODS Between January 1973 and December 1982, we saw thirty confirmed cases of BP (including 3 cicatricial pemphigoid patients) at the university clinic. The diagnosis was confirmed histopathologically in twenty-nine patients and immunopathologically in all patients (28 having positive direct immunofluorescence test and the other 2 having positive indirect immunofluorescence test only). DM was defined by elevated fasting venous whole blood sugar levels (>120 mg/dl) on at least two separate occasions with or without positive oral glucose tolerance tests, according to the criteria set by the National Diabetes Data Group) Clinical manifestations of DM were used only to substantiate the diagnosis of DM. The clinical data regarding six BP patients who also had primary DM are summarized in Table I. For the purpose of comparison, four controls were selected for each BP case from the skin biopsy record books. Controls were the ones whose names appeared immediately before (2 names) and after (2 names) the name
of each of the thirty BP patients. One hundred twenty controls were thus selected, three of which h a d primary DM. Because the number of primary DM patients was small (less than 5), two-sided Fisher's exact test was chosen for the purpose of statistical analysis. N o t e that patients who had steroid-induced DM (3 patients in the BP group and 1 patient in the control group) were not included in this comparison. There was one additional BP patient in our series who had DM 20 years before the onset of BP and a positive family history o f DM but lacked current objective data to substantiate the diagnosis. This case was also excluded from the BPDM group and from the statistical comparison. The general features of cases and controls are summarized in Table II. RESULTS There w e r e more w o m e n (20) and w h i t e s (16) than men (10) and nonwhites (14) in our p a t i e n t s with BP. T h e i r average age was 64 with a range from 5 to 85 years. Only four patients were younger than 50 years o f age. Their ages w e r e 5, 13, 28, and 42 years. The control group o f 120 patients also had higher numbers o f w o m e n (71 vs 49 men) and whites (67 vs 53 n o n w h i t e s ) . T h e i r average age was 53 years with a range f r o m 8 days to 88 years. Over half o f the control group h a d an age less than 50 years (Table II). Primary D M was found in six (20%) o f the case group a n d three (2.5%) o f the control group. The d i f f e r e n c e
Volume 11 Number 6 December, 1984
of occurrence rate of DM in these two groups was statistically significant (p = 0.004, two-sided Fisher's exact test). Overall, there were twenty-six BP cases and fifty-six controls aged 50 years or over. Their average ages were 71 years and 64 years, respectively. When only these two subgroups were compared, the prevalence of DM was six (23.1%) and two (3.6%) for the cases and controls, respectively (p = 0.02, two-sided Fisher's exact test). The age-specific prevalence rates of DM in the general population have been studied for residents of Rochester, MN. r When these age-specific rates were applied to our case and control groups, the expected number o f DM patients in our BP case group was 1.7. The observed number of DM patients in the case group, however, was six. This was significantly higher than the expected number (observed/expected ratio = 3.5, p < 0.05). The latter two comparisons indicated that even after the age was controlled, the difference in the occurrence rate of DM between case and control groups persisted. On the other hand, the observed and expected numbers of DM patients in the control group were very close (observed/expected number = 3/3.3). The negligible difference between these two numbers demonstrates that well-documented prevalence rates of diabetics from a general population are indeed suitable for the estimation of the expected number of diabetics for a clinic population like ours. The subtypes of DM were hard to classify due to the retrospective nature of the present study and the lack of adequate data. DISCUSSION The present case-control study provides the statistical evidence to substantiate the association of BP and DM. To the best of our knowledge, this is the first case-control evaluation of the relationship between these two disease entities. Several points should be addressed to avoid misinterpretation of the results. The case group, selected from a university clinic population, cannot be without selection bias. Severely ill and complicated cases are usually referred to these clinics for highly specialized management. These patients presumably could
Diabetes mellitus with bullous pemphigoid
1101
Table II. General features of eases and controls -
,
No. of patients Age (average), yr Sex, M:F Race, white:nonwhite No. of diabetics
i
Cases(BP)]Controls 30 64.4 1:2 1: 1 6
120 52.5 1:1.4 1:0.8 3
have multiple problems, including DM. Because the case and control groups were selected from the same population source, however, selection bias resulting from the heavy reliance of our practice on referral patients was minimized. There was neither a sampling bias nor a response bias active in this study (we collected all cases of BP diagnosed in the past 10 years, and the diagnosis of DM was based on objective data, not on subjective response by patients). The objective nature of the data (blood sugar levels) also minimized the potential bias resulting from overenthusiastic investigators who might have eagerly looked for clues of D M in certain cases. One example of avoiding such a bias is the exclusion of the only BP case in the final analysis, whose DM occurred 20 years previously by history but lacked sugar level data to substantiate the diagnosis of DM. We assume that our control group was an appropriate one because: (1) These controls visited the same clinic and received the same procedure (biopsy) and similar help, about the same time as our BP cases. The selection bias active in the case group is thus balanced by this approach. (2) The number of controls versus cases is four to one, which is generally considered to be the most adequate ratio to minimize the sampling bias. (3) The nature of diseases in the control group was not predetermined to avoid prejudicial factors, and, in fact, their histopathologic diagnoses varied from normal skin to dermatitis, mycosis fungoides, and metastatic lung cancer. The difference in average ages in the case and control groups, as revealed in Table II, raised the concern over the influence of age in the occurrence rate of DM. The higher frequency of DM in our case group over the control group could be pardally due to its higher average age. It is known that both BP and DM often develop in elderly
1102
Journal of the American Academyof Dermatology
Chuang et al
patients. Two different methods w e r e used to eliminate the effect of age factor. O n e was the comparison between subgroups aging 5 0 years or over, and the other was the application of published age-specific prevalence rates o f DM. The prevalence of DM in BP cases remained higher even after age was controlled by the preceding two methods. The higher prevalence of D M in our BP cases is therefore valid. The 20% occurrence rate of DM in t h e present BP patient group could have been underestimated because of our rigorous criteria for defining DM, i.e., the exclusion of secondary diabetics and also diabetic patients without adequate objective data. In their open study, Downham and Chapel a reported that 41% of their thirty-four B P patients had DM. The mechanism underlying the association of BP and DM is unknown. Diabetics h a v e a lower threshold than normal individuals f o r suctioninduced blister. ~ This fragility may contribute to the induction of BP by various mechanisms. Since autoimmune mechanisms may be active in both BP and type I DM, we speculate t h a t similar pathogenetic mechanisms may also be responsible for this association. Bassiouny et al 1~reported that glucosylated skin collagen, which increases during nonenzymatic glucosylation of collagen in diabetics, is capable of inducing the production of autoantibodies with specificity directed against the modified collagen. They also proved that serum of streptozotocininduced diabetic rats contains antibodies capable of binding to glucosylated rat skin collagen. Nonenzymatic glucosylation in the diabetic state may involve various noncollagen proteins that may also become targets for autoantibodies in diabetic patients. H In BP, IgG anti-BMZ autoantibodies bind to the glycoprotein antigen in the lamina lucida. This activates the complement system, which, in turn, produces factors that induce
mast cells and eosinophils to release proteinases. These could degrade the BMZ and form blisters. 1~ One may speculate that the glycoprotein in the lamina lucida may be nonenzymatically glucosylated in diabetic patients. This could serve as the antigen that initiates the autoimmune process, leading to blister formation. The significant association of BP and DM as demonstrated by the present case-control study suggests that this possibility is worthy of further investigation. REFERENCES
1. Ahmed AR, Hardy D: Bullous pemphigoid: Family of autoimmune disease. Int J Dermatol 20:541-543, 1981. 2. Lynfield YL, Green K, Gopal R: Bullous pemphlgoid and multiple autoimmune diseases. J AM ACAD DERtaha'Or. 9:257-26l, 1983. 3. BloomfieldS, Stockdill G, Barnetson RStC: Thymic hypoplasia, autoimmune hemolytic anemia and juvenile pemphigoid in an infant. Br J Demmtol 106:353-355, 1982. 4. James WD: Bullous pemphigoid, myasflaeniagravis and thymoma. Arch Dermatol 120:397, 1984. 5. Naji A, Silvers WK, Barker CF: Autoimmunity and type 1 (insulin-dependent) diabetes mellitus. Transplantation 36:355-361, 1983. 6. National Diabetes Data Group: Classification and diagnosis of diabetes mellitusand other categories of glucose intolerance. Diabetes 28:1039-1057, 1979. 7. Palumbo PJ, Elveback LR, Chu C-P, et al: Diabetes mellitus: Incidence, prevalence, survivorship and causes of death in Rochester, Minnesota, 1945-1970. Diabetes 25:566-573, 1976. 8. DownhamFF, ChapelTA: Bullous pemphigoid: Therapy in patients with and without diabetes mellitus. Arch Dermatol 114:1629-1642, 1978. 9. BernsteinJE, Levine LE, Medenica MM, et al: Reduced threshold to suction-induced blister formation in insulin-dependent diabetics. J AM Ac.*~ DERMATOL 8:790-791, 1983. 10. Bassiouny AR, Rosenberg H, McDonald TL: Glucosylated collagen is antigenic. Diabetes 32:1182-1184, 1983. 11. Brownlee M, CeramiA: The biochemistryof the complications of diabetes mellitus. Annu Rev Biochem 50:385-432, 1981. 12. Sams WM Jr, Gammon WR: Mechanism of lesion production in pemphigus and pemphigoid. J AM ACAO D~RMA'rOL6:431-449, 1982.