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`acylcarnitine in secondary carnitine deficiency. Neurology
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`1984;34:977-979.
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`33. Zaccara G, Paganini M, Campostrini R, et al. Effect of associated
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`antiepileptic treatment on valproate-induced hyperammonemia.
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`Ther Drug Monit 1985;7:185-190.
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`34. Haidukewych D, John G, Zielinski JJ, Rodin EA. Chronic val-
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`proic acid therapy and incidence of increases in venous plasma
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`ammonia. Ther Drug Monit 1985;71290-294.
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`35. Warter JM, Marescaux C, Brandt C. et al. Sodium valproate
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`associated with phenobarbital: efl‘ects of ammonia metabolism in
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`humans. Epilepsia 1983;24:628—633.
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`36. Marescaux C, Warter JM, Brandt C, et al. Adaptation of hepatic
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`ammonia metabolism after chronic valproate administration in
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`epileptics treated with phenytoin. Eur Neurol 1985;24:191-195.
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`BEEEJE]
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`Autoimmunity in multiple sclerosis
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`Jacques De Keyser, MD
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`Article abstract—Multiple sclerosis reportedly coexists with disorders of autoimmune origin. The prevalence with which such
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`disorders occur in the MS population has not been adequately investigated. We reviewed the medical records of 828 patients with
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`definite MS and found that 4.8% had a past or present associated disorder in which autoimmune mechanisms presumably play a
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`role. The cumulative prevalence of these disorders was no higher than that estimated for the general population. Serum from 105
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`patients, without clinical evidence of an associated autoimmune disorder, was tested for the presence of antinuclear, thyroid,
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`parietal cell, smooth muscle, and mitochondrial antibodies. A significantly higher prevalence (p < 0.01) of generally low titers of
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`one or more autoantibodies was found in serum from the MS group, compared with a control group of 105 patients with other
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`neurologic disorders. The increased frequency of serum autoantibodies probably reflects the existence of a nonspecific B cell
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`overactivity in MS.
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`NEUROLOGY 1988;38:371—374
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`Extensive evidence indicates that immune mechanisms
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`are disturbed in multiple sclerosis. However, it is un-
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`clear whether these abnormalities play a primary role in
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`its pathogenesis or represent only an epi-
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`phenomenon.“3 The autoimmune hypothesis of MS is
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`based mainly on the pathologic similarity of the disease
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`with chronic relapsing experimental allergic encepha-
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`lomyelitis.‘
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`MS in most, but not all, ethnic groups has been
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`linked with particular HLA antigens,2 and studies of
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`peripheral blood T cell subpopulations in MS pa-
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`tients demonstrated reductions in the number of T
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`suppressor cells.*'*7 An association with specific HLA
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`antigens, which are concerned with the control of the
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`immune response, as well as alterations in the balance
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`of the immunoregulatory T cell subpopulations, have
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`been noted in a variety of autoimmune disorders?10
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`Autoimmune diseases tend to occur in combina-
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`tion. The finding that a disease is more frequently
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`associated with recognized autoimmune disorders
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`than would be expected by chance may thus provide
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`an indication that the disease itself has an autoim-
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`mune basis. A classic example is myasthenia gravis.
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`Before acetylcholine receptors were discovered, my-
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`asthenia gravis was postulated to have an autoim-
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`mune pathogenesis,” based on associations with
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`other autoimmune disorders.
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`MS has been reported in combination with disorders
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`of autoimmune origin (see “Discussion”). However,
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`most of these proposed associations are based on case
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`reports. The prevalence of putative autoimmune disor-
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`ders in the MS population has not been fully investi-
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`gated. The purpose of this study was to find out if there
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`is evidence for more generalized autoimmune reactions
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`in MS.
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`Patients and methods. We reviewed the medical records
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`ofpatients who attended the National Hospital for Nervous
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`Diseases (London), between 1979 and 1984, with clinically
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`or laboratory-supported definite MS, as defined by Poser et
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`al.” The study population consisted of 828 patients (537
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`females and 291 males) ranging in age from 12 to 79 years.
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`We screened the records for past or present associated dis-
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`orders in which autoimmune mechanisms are considered to
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`play a role.
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`Serum from 105 MS patients without clinical evidence
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`of an associated autoimmune disorder was analyzed for the
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`presence of antinuclear, thyroid, parietal cell, smooth mus-
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`cle, and mitochondrial antibodies. None of these patients
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`had been selected on clinical grounds, but the presence of
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`autoantibodies was assessed as part of an initial routine
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`evaluation before the diagnosis of MS was established. A
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`control group consisted of patients with other neurologic
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`disorders, matched for age and sex to the patients with MS,
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`From the Department of Neurology, National Hospital for Nervous Diseases. London, UK.
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`Supported by the British Council.
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`Received April 22, 1987. Accepted for publication in final form July 2. 1987.
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`Address correspondence and reprint requests to Dr. De Keyser, Department of Neurology, Akademisch Ziekenhuis, Vrije Universiteit Brussel, Laarbeeklaan 101,
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`B- 1090 Brussels, Belgium.
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`Page 1 of 4
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`Biogen Exhibit 2114
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`
`
`March 1988 NEUROLOGY 38 371
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`
`
`
`Mylan v. Biogen
`IPR 2018-01403
`
`Page 1 of 4
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`Biogen Exhibit 2114
`Mylan v. Biogen
`IPR 2018-01403
`
`

`

`Table 1. Associated disorders with autoimmune
`character
`
`Table 2. Autoantibodies in MS patients and controls‘
`
`Associated disorders
`
`Rheumatic
`Rheumatoid arthritis
`Ankylosing spondylitis
`Polymyalgia rheumatica
`Gastrointestinal
`Ulcerstive colitis
`Celiac disease
`Primary biliary cirrhosis
`Chronic atrophic gastritis
`Dermatologic
`Vitiligo
`Alopecia universalis
`Cutaneous lupus
`erythemstosus
`Endocrine
`Type I diabetes mellitus
`Hyperthyroidism
`Primary hypothyroidism
`Neurologic
`Chronic inflammatory
`neuropathy
`Total
`
`No. of
`pta
`
`Prevalence
`(‘70)
`
`Estimated
`prevalence
`(7°)
`
`13‘3
`0.1399
`0.5“”
`
`(1.0839
`0.03‘l
`0.014”
`
`5
`
`41'
`
`0.6
`0.12
`0.12
`
`0.24
`0.12
`0.12
`0.12
`
`0.24
`0.12
`0.12
`
`0.48
`1.8
`0.48
`
`0.24
`
`4.92
`
`1 One patient suffered from rheumatoid arthritis and hyperthyroidism.
`
`' 1n the population aged 50 years or older.
`
`who had been admitted during the same period. Patients with
`overt autoimmune disease were not included. The mean age
`for the patients with MS was 35 years; controls had a mean age
`of 39 years. The controls suffered from the following condi-
`tions: cerebrovascular disorders (19), movement disorders
`(11). headache and other pain syndromes (41). functional dis-
`orders (20), idiopathic epilepsy (8), nerve entrapment (4), and
`positional vertigo (2). Indirect immunofluorescence was used
`to screen serum diluted at 1:10 for antibodies reactive with
`cell nuclei. gastric parietal cells, smooth muscle, and mito-
`chondria. Rat kidney, stomach, and liver (Biodiagnostics
`Ltd.) were the receptive substrates. All serum positive at
`1:10 was further titrated. Thyroglobulin and microsomal
`antibodies were analyzed by a Thymune-M kit (Wellcome
`Diagnostic) and titers of, respectively, a 1:10 and Z 1:100
`were considered positive. The 12 test was used for statistical
`analysis.
`
`Results. Associated autoimmune disorders. Forty pa-
`tients (4.8%) had a past or present disorder in which
`autoimmune mechanisms were believed to be impli-
`cated. A list is given in table 1.
`Rheumatoid arthritis was diagnosed in five patients;
`in one this was associated with Sjogren’s syndrome, and
`one had previously been treated with 13‘1 for hyper-
`thyroidism. One patient had longstanding ankylosing
`spondylitis, and a 50-year-old woman was in remission
`of polymyalgia rheumatica after prolonged treatment
`with corticosteroids.
`
`Two patients developed a chronic inflammatory de-
`myelinating neuropathy after the clinical onset of MS.
`They are described in detail by Thomas et al13 (cases 1
`and 3).
`372 NEUR OGY
`age 131'
`
`1988
`
`MS patients
`(a = 106)
`
`Control-
`(a - 105)
`
`pt
`
`
`
`Organ-specific antibodies
`Thyroid (thyroglobulin
`and/or microsomal)
`Parietal cell
`Total
`Non-organ-specific antibodies
`Antinuclear
`Smooth muscle
`Mitochondrial
`Total
`Total patients with one or
`more autoantibodies
`
`4
`
`11
`15
`
`20
`8
`4
`32
`48 (41%)
`
`2
`
`4
`6
`
`8
`10
`1
`19
`24 (23%)
`
`<0.05
`< 0.01
`
`' Only patients who did not have clinical evidence of associated
`autoimmune disease are included.
`1‘ 12 test.
`
`Two patients had a history of ulcerative colitis; one
`was in remission for many years, and the other was
`under treatment with sulfasalazine and prednisolone.
`One patient suffered from celiac disease, one had
`chronic autoimmune atrophic gastritis with vitamin
`B12 malabsorption, and in another primary biliary cir-
`rhosis was diagnosed by liver biopsy.
`Vitiligo was present in two patients; in one this was
`familial. One patient suffered from alopecia universalis
`with no regrowth of body hair for a follow-up period of 2
`years. Cutaneous lupus erythematosus was diagnosed
`by skin biopsy in one patient in whom there was no
`evidence of systemic involvement.
`Thirty patients had evidence of past or present thy-
`roid disease. We excluded those who had undergone
`surgical treatment for an adenoma (2), cyst (2), or un-
`known reason (2), and those with a goiter in whom
`available data were insufficient to suspect an autoim-
`mune etiology (5). Hyperthyroidism occurred in 15
`(7 had undergone partial thyroidectomy, and 8 had been
`treated medically with "“1 or antithyroid drugs). Pri-
`mary “idopathic” hypothyroidism was present in four
`patients. Ten were treated for diabetes mellitus, but
`only four suffered from the insulin-dependent form
`(type I diabetes mellitus).
`The estimated prevalences for most of these disor-
`ders (the prevalence for some is not well established) are
`also shown in table 1. The cumulative prevalence of the
`putative autoimmune disorders in the MS group
`(4.92%) was no higher than that expected for the gen-
`eral population (5.12%).
`Autoantibodies. Table 2 shows the prevalence of se-
`rum autoantibodies in the 105 MS and 105 control
`
`patients, of whom none had clinical evidence of associ-
`ated autoimmune disease. There was a significantly
`higher prevalence of organ-specific as well as non-
`organ-specific antibodies in the MS group than in con-
`trols. Forty-one percent of the MS patients had one or
`more circulating autoantibodies as compared with 23%
`in the control group (p < 0.01). While only titers equal
`to or greater than 1:10 were accepted as positive, the
`
`

`

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`levels of antinuclear antibodies were low in both groups.
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`The highest titer detected in the MS patients was 1 : 160,
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`and in controls 1:80. Similarly, the titers of smooth
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`muscle cell, and mitochondrial and parietal cell (with
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`the exceptition of four patients) antibodies were low
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`(not greater than 1: 10). Four patients (three of the MS
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`and one of the control group) had higher titers of pari-
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`etal cell antibodies. All four had normal hematologic
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`and vitamin B12 values. The patients with thyroid anti-
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`bodies were euthyroid.
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`Discussion. The present study shows that 4.8% of
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`patients with MS had an associated disorder in which
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`autoimmune mechanisms are generally believed to play
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`a role. However, the cumulative prevalence of these
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`disorders is no higher than that expected for the general
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`population and is considerably lower than that reported
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`for myasthenia gravis (11%).“
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`Thyroid disease, rheumatoid arthritis, hypothyroid-
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`ism and insulin-dependent diabetes mellitus were most
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`commonly encountered. However, these diseases also
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`occur with a higher frequency than the others in the
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`general population, and their prevalence in the MS
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`group did not differ significantly from their expected
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`prevalence. The prevalence in the MS group of some of
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`the more uncommon disorders, such as primary biliary
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`cirrhosis, may well appear to be statistically significant.
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`However, the fact that this occurred in only one out of
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`828 patients makes such associations clinically insig-
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`nificant.
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`A similar study by Baker et al15 identified only nine
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`cases out of 328 patients with MS (2.7%) who had an
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`associated autoimmune disease. They found four cases
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`with thyroid disease (one of whom also suffered from
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`chronic atrophic gastritis), two with rheumatoid arthri-
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`tis, one with pemphigus vulgaris, one with autoimmune
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`Addison’s disease, and another with chronic atrophic
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`gastritis. None of the previously reported associations
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`in case studies, including myasthenia gravis,“19 sys-
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`temic lupus erythematosus,”22 bullous pemphigoid,23
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`eosinophilic vasculitis,24 and chronic idiopathic throm-
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`bocytopenic purpura25 were represented in the present
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`as well as in Baker’s series.
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`Rang et al26 reported an unexpectedly high incidence
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`of MS in females with ulcerative colitis who had under-
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`gone total colectomy and terminal ileostomy. A number
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`of cases of MS developing in patients with ankylosing
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`spondylitis have been described.“29 We found only two
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`patients with ulcerative colitis and one with ankylosing
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`spondylitis, which does not support a strong association
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`between MS and these two disorders.
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`Particularly intriguing is the concurrence of a
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`chronic inflammatory demyelinating neuropathy
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`with MS. A number of cases with the chronic as well
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`as with the acute form of inflammatory demyelinating
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`neuropathy have been reported.13~3°‘32 The two cases
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`included in this study are described in the recent
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`paper by Thomas et a1,la who collected four other
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`similar cases.
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`In contrast with the lack of a significant association
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`with autoimmune disorders is the finding that serum
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`from MS patients contained significantly more organ-
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`Page 3 of 4
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`specific as well as non-organ-specific antibodies than
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`controls. The increase was mainly due to a higher fre-
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`quency of parietal cell and antinuclear antibodies. How—
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`ever, the titers of all these antibodies were generally low.
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`These data agree with the findings of Dore-Duffy et a],33
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`that significantly more patients with MS than controls
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`have low levels of antinuclear antibodies in their serum.
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`In addition, Kiessling and Pflughaupt34 reported a
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`higher incidence of microsomal thyroid antibodies in
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`MS patients, although thyroid function was not dis-
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`turbed to a greater degree than in other forms of chronic
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`disease.35
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`T cells seem to play a crucial role in the regulation
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`of humoral immune responses by acting as poten-
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`tiators (T helper cells) or inhibitors (T suppressor
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`cells) of the immunoglobulin production by B cells.
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`Tolerance for self-antigens is brought about through
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`the action of T suppressor cells.“'10 Impaired T sup-
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`pressor cell function is thus one of the proposed mech-
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`anisms for the generation of autoimmune responses.
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`Reductions in circulating T suppressor cells occur in
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`MS patients,”7 but whether these changes contribute
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`to the pathogenesis of the disease or represent only
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`secondary effects of the disease process is not clear?”-9
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`A decline in T suppressor cells could theoretically
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`account for the higher frequency of low levels of vari-
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`ous autoantibodies in the MS serum. The findings
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`that MS patients and their siblings tend to have in-
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`creased serum antibody titers against a variety of
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`viruses?“-37 also points to the existence of a possibly
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`genetically determined, nonspecific B cell overac-
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`tivity in MS. However, the role of the T suppressor
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`cells in causing this B cell overactivity is uncertain;
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`reconstitution experiments with T and B cells from
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`MS patients and controls suggest that this B cell
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`overactivity cannot entirely be explained by a defect
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`in T suppressor activity.38 Further study is required to
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`achieve a full understanding of the immune dysfunc-
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`tion in MS. Numerical abnormalities of T suppressor
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`cells alone probably cannot lead to overt autoimmune
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`disease“); this may explain why MS is no more fre-
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`quently associated with autoimmune disorders than
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`might be expected by chance.
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`Acknowledgments
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`I would like to thank Dr. P. Rudge from the National Hospital for
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`Nervous Diseases (London) for helpful suggestions and advice, and
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`the British Council for financial support.
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`374 NEURQQE§34 Well 1988
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`Page 4 of 4
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