Multiple sclerosis and other immunologic

4 *

diseases
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 immu-
nologic 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 dis-
position (58) and immunologic disturbances (63,66)
seem to be relevant. Because of the latter 2 condi-
tions, 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), ul-
cerative colitis (49), iridocyclitis (25, 59) and other
immunologic disturbances (2). We therefore con-
ducted 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 autoanti-
bodies.
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 diagnos-
ed 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.
Test protocol

Material and methods
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 sys-
temic lupus erythematosus or Sjogren syndrome (3,
4, 22) was carefully considered (1, 50). Eighty-five
patients (55 women, 30 men) were classified as clini-
cally 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.
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), antimitochon-
drial 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), anti-
pituitary Ab (human fetal pituitary, PD Dr. W.
Scherbaum, Ulm) - by indirect immunofluore-
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 mi-
crosomal Ab (Wellcome, UK) and rheumatoid fac-
tor (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 appli-
cation of insulin-induced hypoglycemia, protirelin
and gonadorelin and determination of cortisol,
thyroid-stimulating hormone, somatotropin, prolac-
tin, 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 sta-
tistically 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 fe-
male 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 anti-
bodies): 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 possi-
bly 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 ca-
pacity 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 immu-
nologic diseases and/or serum autoantibodies (27
patients) significantlyless often showed the MS typi-
cal 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 coin-
cidence 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 coinci-
dent diseases is reasonable, however, because the
immunologic pathogenesis is in focus here. The re-
sult, 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 com-
pared with the controls. This was significant for the
total number of patients and controls with autoanti-
bodies and for patients and controls with PCA and
with ANA. Autoantibodies are markers of im-
munologic 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 dis-
turbance here. This fits with the increased rate of
immunologic diseases in the MS patients and sup-
ports the above conclusions. Comparing the rates of
coincident immunologic diseases and of autoanti-
bodies 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 95% confidence limits of

MS controls rate of imm. disease
literature present present series in MS (t1 from prevalence
series series (no data in lit.)

Graves' 21326-151828 61101 2/97 1.0-3.0 0.5-0.65

disease 19.171 123.611
Prim. hypo 11326-1 I69 21101 0197 0.04-7.8 0.7-1.5
thyroid. 19. 17, 221 123)
TYPO I 11326-41828 OllOl 0197 0.1-1.2 0.18-0.23
diab. mell. 19, 17) 164)
Addison's 01828-11326 OllOl 0197 0.01-1.8
disease 19. 171
Pernicious 11828-1 142 0/101 0197 0.01-1.8 0.17-0.23
anemia 19,17,241 1141
Prim. bil. 01326-1 1828 OllOl 0197 0-0.6 0.0008-0.0018
cirrhosis 19. 171 121)
Crohn's 01326-11828 OllOl 0197 0-0.6 0.002-0.0035
disease 19. 171 155)
Ulc. colitis 01326-21828 11101 0197 0.03-5.4 0.01-0.04
19. 17) 1551
Rheum. 11255-51828 11101 0197 0.2-1.4 N 1.8-2.2
arthrit. 19, 17. 331 1431
Ank. 01326-1 1828 21101 0197 0.2-7.0 0.11-0.15
spondylit. 19. 171 1161
Uveitis 01 127-14152 0/101 0197 0.7-4.3
16.7,8,10. 11, 15,25,44,47,59)
Alopecia 01326-11828 21101 1/97 0.2-7.0
areata 19, 171
Vitiligo 01326-21828 OllOl 0197 0.03-0.9
19. 17)
Myasthenia 01828-911146 OllOl 0197 0-36 0.005-0.008
gravis 19, 17.32,531 146)
Chron. inflamm. 01326-21828 01101 0197 0.03-0.9
neuropathy 19, 171

Table 1 b

Rate of coincident MS in 95% confidence limits of

samples of immunol. disease MS in samples prevalence
(literature series) of imm. disease (t) of MS

Ulc. colitis 9 1012216 0.16-1.17 0.08-0.1

1491 140, 651
Ank. spondylit. 1 1 121-1 145 0.12-3.5
113. 34, 57)
Chron. uveitis 51255 0.6-4.6 0.05-0.06
1251
Myasthenia 01440-2 194 0.09-1.2
gravis 127.28,29.32,46,51,53,54) 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 Relative 95% confidence limits

MS controls risk (t) of auto-antibody rate
literature present literature present MS versus in MS (t) from prevalence
series series series series controls (age-adj.)

Thyreoglob- 2/110-8/69 0/88 31175-4/50 0/95 1 0.2-6.4 1.2-1.9

Ab (22, 35, 671 1301
Thyroid micro- 4/50-151110 5/88 8/175-6 / 50 2/95 2.1 3.5-15.2 4.1-5.4
sornal Ab 135. 671 1301
TSH recept.-Ab 5/88 3/95 1 .a 1.9-12.8
Islet cell Ab o/aa 0/95 1 0-3.6
Steroid cell Ab 2/88 1 /95 2.1 0.6-8.5
Pituitary Ab 11/33 4/51 9/97 0/41 >1 3.2-21.0
I261
PCA 0/50-7/69 io/aa 4/105-3/50 0/95 2.75 4.9-17.6 3.4-4.5
147. 22, 67) 130)
Intrinsic 0/69 0/88 0/95 1 0-3.6
fact. Ab 1221
SMA 4/69-10126 4/88 1/36-10/30 2/95 2.4 7.7-38.5 1.1-1.7
117,22.31,41,42,45.60l 1301
AMA 0/69-4/105 0/88 1/105 0/95 4.0 0-3.6 0.2-0.5
(17, 22, 451 (301
ANA 0/51-22/27 9/88 0/30-4/20 1/95 2.5 4.1-19.7 1.4-2.2
(2, 17, 19.22.31,38,45,52.60,671 1301
DNA-Ab Oil 1-23/45 6/88 0/200-9/30 2/95 3.2 2.2-12.6
15, 18. 31, 561
RF 0/69-6/30 5/88 0/36-3/30 2/95 2.7 0.1-19.6 1.9-2.6
(22, 42, 45, 67, 681 30
HMA 1 /55 0/60 >1 0.05-9.7

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