Multiple sclerosis and other immunologic diseases 4 *
Seyfert S, Klapps P, Meisel C, Fischer T, Junghan U. Multiple sclerosis and other immunologic diseases. Acta Neurol Scand 1990: 81: 37-42. A characteristic feature of immunologic diseases is their association with each other. For multiple sclerosis (MS), several retrospective studies reported increased as well as expected coincidence rates with other immunologic diseases. We conducted a prospective case-control study of MS patients and healthy volunteers and found 13/101 MS patients and 2/97 controls with such diseases (P= 0.009, chi-square test), as well as 47/88 MS patients versus 31/95 controls with a variety of circulating autoantibodies (P= 0.004, chi-square test). These results speak for an increased coincidence of MS with other immunologic diseases and support I the idea that MS is also an immunologic disease.
S. Seyfert, P. Klapps, C. Meisel, T. Fischer, U. Junghan Neurologische Klinik und Poliklinik, Klinikum Steglitz, Freie Universitat Berlin, West Berlin
Key words: multiple sclerosis; other immunologic diseases: autoantibody PD Dr. med. Sepp Seyfert, Neurologische Klinik und Poliklinik, Klinikum Steglitz, Freie Universitat Berlin, Hindenburgdamm 30, D-1000 Berlin 45
I
Accepted for publication June 13, 1989
In the pathogenesis of multiple sclerosis (MS), an exogenous factor (37), a genetically determined disposition (58) and immunologic disturbances (63,66) seem to be relevant. Because of the latter 2 conditions, MS is mostly thought of as an immunologic disease. A typical feature of such diseases, increased coincidence with each other (20), has not yet been clearly established in MS. A few retrospective studies revealed expected coincidence rates (9, 17, 27, 5 l), whereas others, also retrospective, found an increased coincidence of MS with myasthenia gravis (32, 46, 53, 54), ankylosing spondylitis (34, 57), ulcerative colitis (49), iridocyclitis (25, 59) and other immunologic disturbances (2). We therefore conducted a prospective case-control study, in which MS patients and a sex- and age-matched control group of healthy volunteers were evaluated for other immunologic diseases and for circulating autoantibodies.
clinically probable MS (48). These 101 patients will be referred to as MS patients (age 17-72 years, mean 38; disease duration 0.5-33 years, mean 8; course: relapsing-remitting in 6 1, chronic progressive in 12, both features in 28; disability scores according to Kurtzke (36): 0-2 in 48, 3-5 in 30 and 6-8 in 23; immunosuppressive medication - steroids and/or azathioprin - during the past 3 months in 23/101). A further 29 patients (22 women, 7 men) were diagnosed as having possible multiple sclerosis (40) or isolated optic neuritis; they are not included in this report. Unselected clinic personnel (60 women, 37 men) participated as controls (age 16-60 years, mean 37). All patients and controls were informed about the aim and the details of the study and were included only after formal consent; no patient or control withdrew.
Material and methods
Besides the appropriate workup, all patients and controls were specifically questioned by one of us (S S) for previous or actual immunologic diseases of other organs. If such diseases had been present, the necessary exclusive or confirmatory tests were done. Previous medical records were checked. The sera of all patients and controls were tested for antinuclear antibodies (Ab) = ANA (rat kidney), antimitochondrial Ab = AMA (rat kidney), smooth-muscle Ab = SMA (rat kidney), parietal cell Ab = PCA (monkey stomach), islet cell Ab (human pancreas), anti-adrenal Ab (human adrenal), antistriated muscle Ab = HMA (monkey heart muscle), antipituitary Ab (human fetal pituitary, PD Dr. W. Scherbaum, Ulm) - by indirect immunofluore-
Over 18 months all patients admitted to hospital with MS were evaluated, altogether 141 patients (97 women, 44 men). Eleven patients (10 women, 1man) with differing final diagnoses were excluded. The problem of an MS mimicking CNS disease in systemic lupus erythematosus or Sjogren syndrome (3, 4, 22) was carefully considered (1, 50). Eighty-five patients (55 women, 30 men) were classified as clinically definite MS, 16 patients (10 women, 6 men) as
Presented in part to the 103. Wandervers. sudwestd. Neurol. Psychiat.: Baden-Baden, June 13-14, 1987.
Test protocol
37
Seyfert et a1 scence; for anti-DNA Ab (E. coli-dsDNA, Amersham, UK), intrinsic factor blocking Ab (DPC, USA), thyrotropin binding inhibiting Ab = TBIAb (human thyroid, Prof. Dr. H. Schleusener, Berlin) by radioassay; for thyreoglobulin Ab, thyroidal microsomal Ab (Wellcome, UK) and rheumatoid factor (Behringwerke, Frankfurt) - by agglutination tests. All patients had a glucose tolerance test, a TRH stimulation test and a Schilling test. Thirty of 101 MS patients without recent clinical MS activity or steroid treatment and without contraindications underwent a hypothalamus-pituitary test with application of insulin-induced hypoglycemia, protirelin and gonadorelin and determination of cortisol, thyroid-stimulating hormone, somatotropin, prolactin, luteotropin and follitropin. Thirty-six of 101 patients from the last third of the patient collecting period were HLA-typed for A, B, C, and DR with a standard microlymphocyto-toxicity test (Prof. Dr. Ewald, Mannheim). The results were evaluated statistically with the chi-square test, if appropriate with Yates’ correction, with Fisher’s exact test and a binomial test. Results Other immunologic diseases in MS patients and controls
Thirteen of 101 MS patients and 2/97 controls had one or more immunologic diseases of non-nervous organs. The difference was significant for the total number of affected patients and controls (P= 0.009, chi-square test), but not for the single additional diseases. The following were found: 0 Graves’ disease and endocrine orbitopathy: 4 female MS patients, 2 female controls (1 MS patient also suffered from urticaria); 0 latent Graves’ disease (diffuse goiter, repeatedly suppressed basal and poststimulatory TSH that was otherwise unexplained, pathologic TBIAb titer): 2 female MS patients; 0 primary hypothyroidism (with antithyroid antibodies): 2 female MS patients (1 probably had had an acute inflammatory neuropathy in childhood); 0 alopecia areata or totalis: 1 female MS patient each; 0 chronic sacroiliitis and arthritis: 1 female MS patient (HLA B 27 negative); 0 ankylosing spondylitis: 1 male MS patient (HLA B 27 positive); and 0 ulcerative colitis: 1 male MS patient. One further male MS patient with acute uveitis of possible immunologic cause was not included. By clinical and/or laboratory evidence, no patient and no control suffered from other immunologic diseases.
Serum autoantibodies in MS patients and controls
Forty-seven of 88 MS patients versus 31/95 controls had serum autoantibodies against antigens of one or more non-nervous organs (13 MS patients and 2 controls with other immunologic diseases and possibly hereto associated autoantibodies were excluded). The difference was significant for the total number of patients/controls with autoantibodies (P = 0.004, chi-square test), for those with parietal cell Ab (lOj88 MS patients versus 0/95 controls, P < 0.05, Fisher’s exact test) and for those with antinuclear Ab (9/88 MS patients versus 1/95 controls, P < 0.05, Fisher’s exact test). The other autoantibodies were also found more often in the MS group (NS) (Table 2). Most titers were at low or medium levels: MAK at 1 :400-1 : 6400, TBIAb 0.03-0.76, steroid cell Ab I : 2, pituitary Ab 1 : 80, PCA 1 : 50-1 : 800, SMA 1 : 10-1 : 100, ANA 1 : 10-1 : 50, DNA binding capacity 36-44%, RF 20-40 IU/ml, HMA 1 : 80. The titers tended to be higher in the MS patients. No autoantibodies against pancreatic islet cells, intrinsic factor or mitochondria were found in any MS patient or control. HLA phenotypes
Among the 36 HLA-typed MS patients, only DR2 was found significantly more often (22/36 MS patients = 61.1%) than in 2 population samples (West Berlin blood donors: DR2 in 36.3% (39); Europeans: DR2 in 25.1 % (12); P < 0.005 for each, binomial test). The other MS-associated HLA phenotypes A3 and B7 were found in 13/36 (36.1 %) and in 15/36 patients (41.7%), respectively. Interestingly, our MS patients with additional immunologic diseases and/or serum autoantibodies (27 patients) significantlyless often showed the MS typical phenotypic combinations A3/B7, A3/DR2, B7/DR2 and A3/B7/DR2 than the MS patients without such immunologic disturbances (9 patients, P < 0.05, Fisher’s exact test). Discussion
This prospective case-control study of the coincidence of MS with other immunologic diseases identilied 13/101 MS patients and 2/97 controls with such diseases. The difference was significant for the total number of affected patients and controls, but not for the single immunologic diseases. Considering the total number of patients and controls with coincident diseases is reasonable, however, because the immunologic pathogenesis is in focus here. The result, therefore, speaks for an increased coincidence of MS with other immunologic diseases, which in turn supports the idea that MS is an immunologic disease.
MS & immunologic diseases The study furthermore showed a higher rate of all tested serum autoantibodies in the MS group compared with the controls. This was significant for the total number of patients and controls with autoantibodies and for patients and controls with PCA and with ANA. Autoantibodies are markers of immunologic diseases: at medium or lower titers they are usually a concomitant feature of immunologic diseases of other organs. Some are also found in
apparently healthy people, especially at older age. Since the rate of the autoantibodies in the MS group was higher than in the age-matched control group, they probably are a concomitant immunologic disturbance here. This fits with the increased rate of immunologic diseases in the MS patients and supports the above conclusions. Comparing the rates of coincident immunologic diseases and of autoantibodies of a sample with their prevalences allows
Table 1 a Coincidenceof MS with other immunologic diseasesin samples of MS (la)and insamplesof other immunologicdiseases (1b). Resultsfrom this series and from the literature. The coincidence of 51 15 immunologic diseases with MS is higher than expected from prevalence (binomial test, bold figures). (tcalculated from the median or upper median value of all available studies); (49) ... see references). ~
~~
Rate of coincident immunologic disease in MS present series
literature series Graves' disease Prim. hypo thyroid. TYPO I diab. mell. Addison's disease Pernicious anemia Prim. bil. cirrhosis Crohn's disease Ulc. colitis
61101
21326-151828
95% confidence limits of controls present series (no data in lit.)
in MS (t1
2/97
1.0-3.0
rate of imm. disease from prevalence
0.5-0.65
19.171
123.611
11326-1 I69
21101
0197
0.04-7.8
OllOl
0197
0.1-1.2
OllOl
0197
0.01-1.8
0/101
0197
0.01-1.8
0.17-0.23
OllOl
0197
0-0.6
0.0008-0.0018
OllOl
0197
0-0.6
0.002-0.0035
11101
0197
0.03-5.4
0.01-0.04
11101
0197
0.2-1.4
19. 17, 221
123)
11326-41828
0.18-0.23
19, 17)
164)
01828-11326 19. 171
11828-1 142 19,17,241
1141
01326-1 1828 19. 171
121)
01326-11828 19. 171
155)
01326-21828 19. 17)
Rheum. arthrit. Ank. spondylit. Uveitis
0.7-1.5
1551
11255-51828
N
19, 17. 331
1.8-2.2
1431
01326-1 1828
21101
0197
0.2-7.0
0/101
0197
0.7-4.3
21101
1/97
0.2-7.0
OllOl
0197
0.03-0.9
OllOl
0197
0-36
01101
0197
0.03-0.9
0.11-0.15
19. 171
1161
01 127-14152 16.7,8,10. 11, 15,25,44,47,59)
Alopecia areata Vitiligo
01326-11828 19, 171
01326-21828 19. 17)
Myasthenia gravis Chron. inflamm. neuropathy
01828-911146
0.005-0.008
19, 17.32,531
146)
01326-21828 19, 171
Table 1 b Rate of coincident MS in samples of immunol. disease (literature series) Ulc. colitis
9
1012216
95% confidence limits of MS in samples prevalence of MS of imm. disease (t) 0.16-1.17
1491
Ank. spondylit.
1 1 121-1 145
0.08-0.1 140, 651
0.12-3.5
113. 34, 57)
Chron. uveitis
51255
0.6-4.6
0.05-0.06
1251
Myasthenia gravis
01440-2 194 127.28,29.32,46,51,53,54)
0.09-1.2 140, 651
39
Seyfert et a1 Table 2. Frequency of serum auto-antibodies against non-nervous structures in MS patients. Results from this series (88 MS pts and 95 controls without additional immunologic disease) and from the literature. 11/14auto-antibody species were found in MS with a relative risk > 1 compared to controls, and 3/7 auto-antibody species were identified in MS more often than expected from prevalence (binomial test, bold figures). (tcalculatedfrom the median or upper median value of all available studies; (22.35.671: see references) ~
Rate of serum auto-antibodies in MS
ThyreoglobAb Thyroid microsornal Ab TSH recept.-Ab Islet cell Ab Steroid cell Ab Pituitary Ab
literature series
present series
2/110-8/69
0/88
31175-4/50
present series
0/95
Relative risk (t) MS versus controls
1
95% confidence limits of auto-antibody rate in MS (t) from prevalence (age-adj.)
0.2-6.4
(22, 35, 671
4/50-151110
8/175-6 / 50
2/95
2.1
3.5-15.2
2/88 4/51
1 .a 1 2.1
9/97
3/95 0/95 1 /95 0/41
>1
1.9-12.8 0-3.6 0.6-8.5 3.2-21.0
io/aa
4/105-3/50
0/95
2.75
4.9-17.6
0/95
1
0-3.6
2/95
2.4
7.7-38.5
5/88 5/88
o/aa 11/33 0/50-7/69 0/69 1221
4/69-10126
4/88
1/36-10/30
0/69-4/105 0/51-22/27
0/88
1/105
0/95
4.0
0-3.6
9/88
0/30-4/20
1/95
2.5
4.1-19.7
Oil 1-23/45
0.2-0.5 (301
1.4-2.2 1301
(2, 17, 19.22.31,38,45,52.60,671
DNA-Ab
1.1-1.7 1301
(17, 22, 451
ANA
3.4-4.5 130)
0/88
117,22.31,41,42,45.60l
AMA
4.1-5.4 1301
147. 22, 67)
Intrinsic fact. Ab SMA
1.2-1.9 1301
135. 671
I261
PCA
controls literature series
6/88
0/200-9/30
2/95
3.2
2.2-12.6
5/88
0/36-3/30
2/95
2.7
0.1-19.6
15, 18. 31, 561
RF
0/69-6/30
HMA
1 /55
another statistical estimate of the coincidence rates. An overview over all available studies (Tables 1,2) also points to an increased rate of immunologic diseases and autoantibodies in MS. Because of the relatively small sample size of most series, including ours, the patient selection, and the use of prevalences from different populations, the above conclusions may be regarded with caution. On the other hand, the comparison of our MS group with an independent control group and the independence of our patient selection from the occurrence of other immunologic diseases support the validity of this series. An increased coincidence of MS with immunologic diseases, just as that among these diseases, leads to the question of common pathogenetic factors. They are not known, but should lie in genetic disposition (62). A search for genetic subgroups, as indicated by the HLA phenotypic differences in our sample, and identification of HLA subtypes more closely correlated to the diseases, should give further insight. Acknowledgement The financial support of the HLA typing by the Sanitatsrat Dr. med. Arthur Arnstein-Stiftung, Berlin, is gratefully recognized.
40
1.9-2.6 30
(22, 42, 45, 67, 681
0/60
>1
0.05-9.7
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Seyfert S, Klapps P, Meisel C, Fischer T, Junghan U. Multiple sclerosis and other immunologic diseases. Acta Neurol Scand 1990: 81: 37-42. A characteristic feature of immunologic diseases is their association with each other. For multiple sclerosis (MS), several retrospective studies reported increased as well as expected coincidence rates with other immunologic diseases. We conducted a prospective case-control study of MS patients and healthy volunteers and found 13/101 MS patients and 2/97 controls with such diseases (P= 0.009, chi-square test), as well as 47/88 MS patients versus 31/95 controls with a variety of circulating autoantibodies (P= 0.004, chi-square test). These results speak for an increased coincidence of MS with other immunologic diseases and support I the idea that MS is also an immunologic disease.
S. Seyfert, P. Klapps, C. Meisel, T. Fischer, U. Junghan Neurologische Klinik und Poliklinik, Klinikum Steglitz, Freie Universitat Berlin, West Berlin
Key words: multiple sclerosis; other immunologic diseases: autoantibody PD Dr. med. Sepp Seyfert, Neurologische Klinik und Poliklinik, Klinikum Steglitz, Freie Universitat Berlin, Hindenburgdamm 30, D-1000 Berlin 45
I
Accepted for publication June 13, 1989
In the pathogenesis of multiple sclerosis (MS), an exogenous factor (37), a genetically determined disposition (58) and immunologic disturbances (63,66) seem to be relevant. Because of the latter 2 conditions, MS is mostly thought of as an immunologic disease. A typical feature of such diseases, increased coincidence with each other (20), has not yet been clearly established in MS. A few retrospective studies revealed expected coincidence rates (9, 17, 27, 5 l), whereas others, also retrospective, found an increased coincidence of MS with myasthenia gravis (32, 46, 53, 54), ankylosing spondylitis (34, 57), ulcerative colitis (49), iridocyclitis (25, 59) and other immunologic disturbances (2). We therefore conducted a prospective case-control study, in which MS patients and a sex- and age-matched control group of healthy volunteers were evaluated for other immunologic diseases and for circulating autoantibodies.
clinically probable MS (48). These 101 patients will be referred to as MS patients (age 17-72 years, mean 38; disease duration 0.5-33 years, mean 8; course: relapsing-remitting in 6 1, chronic progressive in 12, both features in 28; disability scores according to Kurtzke (36): 0-2 in 48, 3-5 in 30 and 6-8 in 23; immunosuppressive medication - steroids and/or azathioprin - during the past 3 months in 23/101). A further 29 patients (22 women, 7 men) were diagnosed as having possible multiple sclerosis (40) or isolated optic neuritis; they are not included in this report. Unselected clinic personnel (60 women, 37 men) participated as controls (age 16-60 years, mean 37). All patients and controls were informed about the aim and the details of the study and were included only after formal consent; no patient or control withdrew.
Material and methods
Besides the appropriate workup, all patients and controls were specifically questioned by one of us (S S) for previous or actual immunologic diseases of other organs. If such diseases had been present, the necessary exclusive or confirmatory tests were done. Previous medical records were checked. The sera of all patients and controls were tested for antinuclear antibodies (Ab) = ANA (rat kidney), antimitochondrial Ab = AMA (rat kidney), smooth-muscle Ab = SMA (rat kidney), parietal cell Ab = PCA (monkey stomach), islet cell Ab (human pancreas), anti-adrenal Ab (human adrenal), antistriated muscle Ab = HMA (monkey heart muscle), antipituitary Ab (human fetal pituitary, PD Dr. W. Scherbaum, Ulm) - by indirect immunofluore-
Over 18 months all patients admitted to hospital with MS were evaluated, altogether 141 patients (97 women, 44 men). Eleven patients (10 women, 1man) with differing final diagnoses were excluded. The problem of an MS mimicking CNS disease in systemic lupus erythematosus or Sjogren syndrome (3, 4, 22) was carefully considered (1, 50). Eighty-five patients (55 women, 30 men) were classified as clinically definite MS, 16 patients (10 women, 6 men) as
Presented in part to the 103. Wandervers. sudwestd. Neurol. Psychiat.: Baden-Baden, June 13-14, 1987.
Test protocol
37
Seyfert et a1 scence; for anti-DNA Ab (E. coli-dsDNA, Amersham, UK), intrinsic factor blocking Ab (DPC, USA), thyrotropin binding inhibiting Ab = TBIAb (human thyroid, Prof. Dr. H. Schleusener, Berlin) by radioassay; for thyreoglobulin Ab, thyroidal microsomal Ab (Wellcome, UK) and rheumatoid factor (Behringwerke, Frankfurt) - by agglutination tests. All patients had a glucose tolerance test, a TRH stimulation test and a Schilling test. Thirty of 101 MS patients without recent clinical MS activity or steroid treatment and without contraindications underwent a hypothalamus-pituitary test with application of insulin-induced hypoglycemia, protirelin and gonadorelin and determination of cortisol, thyroid-stimulating hormone, somatotropin, prolactin, luteotropin and follitropin. Thirty-six of 101 patients from the last third of the patient collecting period were HLA-typed for A, B, C, and DR with a standard microlymphocyto-toxicity test (Prof. Dr. Ewald, Mannheim). The results were evaluated statistically with the chi-square test, if appropriate with Yates’ correction, with Fisher’s exact test and a binomial test. Results Other immunologic diseases in MS patients and controls
Thirteen of 101 MS patients and 2/97 controls had one or more immunologic diseases of non-nervous organs. The difference was significant for the total number of affected patients and controls (P= 0.009, chi-square test), but not for the single additional diseases. The following were found: 0 Graves’ disease and endocrine orbitopathy: 4 female MS patients, 2 female controls (1 MS patient also suffered from urticaria); 0 latent Graves’ disease (diffuse goiter, repeatedly suppressed basal and poststimulatory TSH that was otherwise unexplained, pathologic TBIAb titer): 2 female MS patients; 0 primary hypothyroidism (with antithyroid antibodies): 2 female MS patients (1 probably had had an acute inflammatory neuropathy in childhood); 0 alopecia areata or totalis: 1 female MS patient each; 0 chronic sacroiliitis and arthritis: 1 female MS patient (HLA B 27 negative); 0 ankylosing spondylitis: 1 male MS patient (HLA B 27 positive); and 0 ulcerative colitis: 1 male MS patient. One further male MS patient with acute uveitis of possible immunologic cause was not included. By clinical and/or laboratory evidence, no patient and no control suffered from other immunologic diseases.
Serum autoantibodies in MS patients and controls
Forty-seven of 88 MS patients versus 31/95 controls had serum autoantibodies against antigens of one or more non-nervous organs (13 MS patients and 2 controls with other immunologic diseases and possibly hereto associated autoantibodies were excluded). The difference was significant for the total number of patients/controls with autoantibodies (P = 0.004, chi-square test), for those with parietal cell Ab (lOj88 MS patients versus 0/95 controls, P < 0.05, Fisher’s exact test) and for those with antinuclear Ab (9/88 MS patients versus 1/95 controls, P < 0.05, Fisher’s exact test). The other autoantibodies were also found more often in the MS group (NS) (Table 2). Most titers were at low or medium levels: MAK at 1 :400-1 : 6400, TBIAb 0.03-0.76, steroid cell Ab I : 2, pituitary Ab 1 : 80, PCA 1 : 50-1 : 800, SMA 1 : 10-1 : 100, ANA 1 : 10-1 : 50, DNA binding capacity 36-44%, RF 20-40 IU/ml, HMA 1 : 80. The titers tended to be higher in the MS patients. No autoantibodies against pancreatic islet cells, intrinsic factor or mitochondria were found in any MS patient or control. HLA phenotypes
Among the 36 HLA-typed MS patients, only DR2 was found significantly more often (22/36 MS patients = 61.1%) than in 2 population samples (West Berlin blood donors: DR2 in 36.3% (39); Europeans: DR2 in 25.1 % (12); P < 0.005 for each, binomial test). The other MS-associated HLA phenotypes A3 and B7 were found in 13/36 (36.1 %) and in 15/36 patients (41.7%), respectively. Interestingly, our MS patients with additional immunologic diseases and/or serum autoantibodies (27 patients) significantlyless often showed the MS typical phenotypic combinations A3/B7, A3/DR2, B7/DR2 and A3/B7/DR2 than the MS patients without such immunologic disturbances (9 patients, P < 0.05, Fisher’s exact test). Discussion
This prospective case-control study of the coincidence of MS with other immunologic diseases identilied 13/101 MS patients and 2/97 controls with such diseases. The difference was significant for the total number of affected patients and controls, but not for the single immunologic diseases. Considering the total number of patients and controls with coincident diseases is reasonable, however, because the immunologic pathogenesis is in focus here. The result, therefore, speaks for an increased coincidence of MS with other immunologic diseases, which in turn supports the idea that MS is an immunologic disease.
MS & immunologic diseases The study furthermore showed a higher rate of all tested serum autoantibodies in the MS group compared with the controls. This was significant for the total number of patients and controls with autoantibodies and for patients and controls with PCA and with ANA. Autoantibodies are markers of immunologic diseases: at medium or lower titers they are usually a concomitant feature of immunologic diseases of other organs. Some are also found in
apparently healthy people, especially at older age. Since the rate of the autoantibodies in the MS group was higher than in the age-matched control group, they probably are a concomitant immunologic disturbance here. This fits with the increased rate of immunologic diseases in the MS patients and supports the above conclusions. Comparing the rates of coincident immunologic diseases and of autoantibodies of a sample with their prevalences allows
Table 1 a Coincidenceof MS with other immunologic diseasesin samples of MS (la)and insamplesof other immunologicdiseases (1b). Resultsfrom this series and from the literature. The coincidence of 51 15 immunologic diseases with MS is higher than expected from prevalence (binomial test, bold figures). (tcalculated from the median or upper median value of all available studies); (49) ... see references). ~
~~
Rate of coincident immunologic disease in MS present series
literature series Graves' disease Prim. hypo thyroid. TYPO I diab. mell. Addison's disease Pernicious anemia Prim. bil. cirrhosis Crohn's disease Ulc. colitis
61101
21326-151828
95% confidence limits of controls present series (no data in lit.)
in MS (t1
2/97
1.0-3.0
rate of imm. disease from prevalence
0.5-0.65
19.171
123.611
11326-1 I69
21101
0197
0.04-7.8
OllOl
0197
0.1-1.2
OllOl
0197
0.01-1.8
0/101
0197
0.01-1.8
0.17-0.23
OllOl
0197
0-0.6
0.0008-0.0018
OllOl
0197
0-0.6
0.002-0.0035
11101
0197
0.03-5.4
0.01-0.04
11101
0197
0.2-1.4
19. 17, 221
123)
11326-41828
0.18-0.23
19, 17)
164)
01828-11326 19. 171
11828-1 142 19,17,241
1141
01326-1 1828 19. 171
121)
01326-11828 19. 171
155)
01326-21828 19. 17)
Rheum. arthrit. Ank. spondylit. Uveitis
0.7-1.5
1551
11255-51828
N
19, 17. 331
1.8-2.2
1431
01326-1 1828
21101
0197
0.2-7.0
0/101
0197
0.7-4.3
21101
1/97
0.2-7.0
OllOl
0197
0.03-0.9
OllOl
0197
0-36
01101
0197
0.03-0.9
0.11-0.15
19. 171
1161
01 127-14152 16.7,8,10. 11, 15,25,44,47,59)
Alopecia areata Vitiligo
01326-11828 19, 171
01326-21828 19. 17)
Myasthenia gravis Chron. inflamm. neuropathy
01828-911146
0.005-0.008
19, 17.32,531
146)
01326-21828 19, 171
Table 1 b Rate of coincident MS in samples of immunol. disease (literature series) Ulc. colitis
9
1012216
95% confidence limits of MS in samples prevalence of MS of imm. disease (t) 0.16-1.17
1491
Ank. spondylit.
1 1 121-1 145
0.08-0.1 140, 651
0.12-3.5
113. 34, 57)
Chron. uveitis
51255
0.6-4.6
0.05-0.06
1251
Myasthenia gravis
01440-2 194 127.28,29.32,46,51,53,54)
0.09-1.2 140, 651
39
Seyfert et a1 Table 2. Frequency of serum auto-antibodies against non-nervous structures in MS patients. Results from this series (88 MS pts and 95 controls without additional immunologic disease) and from the literature. 11/14auto-antibody species were found in MS with a relative risk > 1 compared to controls, and 3/7 auto-antibody species were identified in MS more often than expected from prevalence (binomial test, bold figures). (tcalculatedfrom the median or upper median value of all available studies; (22.35.671: see references) ~
Rate of serum auto-antibodies in MS
ThyreoglobAb Thyroid microsornal Ab TSH recept.-Ab Islet cell Ab Steroid cell Ab Pituitary Ab
literature series
present series
2/110-8/69
0/88
31175-4/50
present series
0/95
Relative risk (t) MS versus controls
1
95% confidence limits of auto-antibody rate in MS (t) from prevalence (age-adj.)
0.2-6.4
(22, 35, 671
4/50-151110
8/175-6 / 50
2/95
2.1
3.5-15.2
2/88 4/51
1 .a 1 2.1
9/97
3/95 0/95 1 /95 0/41
>1
1.9-12.8 0-3.6 0.6-8.5 3.2-21.0
io/aa
4/105-3/50
0/95
2.75
4.9-17.6
0/95
1
0-3.6
2/95
2.4
7.7-38.5
5/88 5/88
o/aa 11/33 0/50-7/69 0/69 1221
4/69-10126
4/88
1/36-10/30
0/69-4/105 0/51-22/27
0/88
1/105
0/95
4.0
0-3.6
9/88
0/30-4/20
1/95
2.5
4.1-19.7
Oil 1-23/45
0.2-0.5 (301
1.4-2.2 1301
(2, 17, 19.22.31,38,45,52.60,671
DNA-Ab
1.1-1.7 1301
(17, 22, 451
ANA
3.4-4.5 130)
0/88
117,22.31,41,42,45.60l
AMA
4.1-5.4 1301
147. 22, 67)
Intrinsic fact. Ab SMA
1.2-1.9 1301
135. 671
I261
PCA
controls literature series
6/88
0/200-9/30
2/95
3.2
2.2-12.6
5/88
0/36-3/30
2/95
2.7
0.1-19.6
15, 18. 31, 561
RF
0/69-6/30
HMA
1 /55
another statistical estimate of the coincidence rates. An overview over all available studies (Tables 1,2) also points to an increased rate of immunologic diseases and autoantibodies in MS. Because of the relatively small sample size of most series, including ours, the patient selection, and the use of prevalences from different populations, the above conclusions may be regarded with caution. On the other hand, the comparison of our MS group with an independent control group and the independence of our patient selection from the occurrence of other immunologic diseases support the validity of this series. An increased coincidence of MS with immunologic diseases, just as that among these diseases, leads to the question of common pathogenetic factors. They are not known, but should lie in genetic disposition (62). A search for genetic subgroups, as indicated by the HLA phenotypic differences in our sample, and identification of HLA subtypes more closely correlated to the diseases, should give further insight. Acknowledgement The financial support of the HLA typing by the Sanitatsrat Dr. med. Arthur Arnstein-Stiftung, Berlin, is gratefully recognized.
40
1.9-2.6 30
(22, 42, 45, 67, 681
0/60
>1
0.05-9.7
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