Occurrence of primary biliary cirrhosis, CREST syndrome and Sjögren's syndrome in a patient with HTLV-I-associated myelopathy

Journal of the Neurological Sciences, 116 (1993) 47 -51 © 1993 Elsevier Science Publishers B.V. All rights reserved 0022-510X/93/$06.00

47

JNS 03969

Occurrence of primary biliary cirrhosis, CREST syndrome and Sj6gren's syndrome in a patient with HTLV-I-associated myelopathy Yasuo Kuroda a, Mami Fukuoka a, Chiyoko Endo a, Makoto Matsui ~, Kazuhiro Kurohara a, Ryusuke Kakigi a and Osamu Tokunaga b Departments of a Internal Medicine (Section of Neurology) and t, Pathology, Saga Medk:al School, Saga, Japan

(Received 21 August, 1992) (Revised, received 27 October, 1992) (Accepted 2 November, 1992)

Key words: HTLV-I-associated myelopathy; Tropical spastic paraparesis; Primary biliary cirrhosis; CREST syndromc: Sj6gren's syndrome; Chronic graft-versus-host disease

Summary We report the occurrence of three autoimmune diseases (primary biliary cirrhosis, CREST syndrome and Sj6gren's syndrome) in a patient with HTLV-I-associated myelopathy (HAM). The patient had the depressed cell-mediated immune responses but the infiltration of CD8-T cells was found in the cerebrospinal fluid and liver. The clinical and immunological features of this case are similar to those of chronic graft-versus-host disease.

Introduction Human T-lymphotropic virus type I (HTLV-I)-associated myelopathy ( H A M ) / t r o p i c a l spastic paraparesis (TSP) is a chronic inflammatory disorder primarily affecting the spinal cord (Osame et al. 1987; Romfin 1987; Vernant et al. 1987). Although the infiltration of CD8 (cytotoxic/suppressor)-T cells was found in the lesion of H A M / T S P (Moore et al. 1990; Bhigjee et al. 1992), HTLV-I antigens have been hardly detected in the lesions (Moore et al. 1990; Bhigjee et al. 1992), suggesting the implication of an immunopathogenic mechanism in H A M / T S P (Moore et al. 1990). The involvement of an immunopathogenic mechanism in H A M / T S P may also be suggested by its association with autoimmune disorders (Nakagawa et al. 1992) and the therapeutic efficacy of corticosteroids (Osame et al. 1987) and high-dose intravenous gammaglobulin (Kuroda et al. 1991a). We herewith report the occurrence of primary biliary cirrhosis (PBC), limited scleroderma (CREST syndrome) and Sj6gren's syndrome in a patient with H A M / T S P . To our knowledge, this is the first report of H A M / T S P associated with three

Correspondence to: Yasuo Kuroda, M.D., Department of Internal Medicine, Saga Medical School, Nabeshima, Saga 849, Japan. (Fax): 81-0952-32-3026.

autoimmune disorders. In this case the infiltration of CD8-T cells was found in the cerebrospinal fluid (CSF) and the liver. The clinical and immunological features of this case have a similarity to chronic graft-versus-host disease (GVHD).

Case report A 55-year-old woman presented with gait disturbance, urinary urgency and Raynaud's phenomenon at the age of about 40. The gait disturbance had progressively deteriorated and she required a cane at age 50. At age 52, the abnormality in liver function was first pointed out, and subsequent examinations showed that she had cirrhosis of liver, portal hypertension, esophageal varices, and H A M / T S P . Pruritis, bilateral swelling of hands and fingers, difficulty swallowing, and a dry mouth also developed over the following few years. At age 55, she was first admitted to our hospital. There was no history of blood transfusions prior to the diagnosis of H A M / T S P . A serovirological study showed that none of her family members had antibodies (Ab) to HTLV-I. Physical examination on admission showed telangiectasis on her face and lips, and sclerodactily in both hands. Her mentation and cranial nerve functions were normal. Moderate spastic weakness, increased deep tendon reflexes and positive

48

Fig. 1. Liver biopsyshows the infiltration of inflammatorycells in the portal areas and the degeneration of interlobular bile ducts (H&E. × 40).

Babinski's reflexes were found symmetrically in her lower limbs. Muscle atrophy was not noted. The vibration perception was mildly impaired in her lower limbs. Urinary urgency and difficulty of urination were also present. The white blood cell count was 1900/lzl with 34% lymphocytes and 0 to 1% adult T-cell leukemia (ATL)-cells. The erythrocyte sedimentation rate was 60 m m / h . Serum IgG was 2515 m g / d l (normal: 1000-2100 mg/dl), IgA 364 m g / d l (110-390 m g / d l ) and IgM 660 m g / d l (60-340 mg/dl). Anti-DNA Ab, anticentromere Ab and antimitochondrial Abs were positive at a titer of 1 : 80, 1 : 1280 and 1 : 320, respectively. Serum GOT, LDH, alkaline phosphatase and y - G T P levels were elevated more than twofolds of the normal values. Hepatitis B and C serologic studies were negative. The cirrhosis of liver was found on CT. A liver biopsy showed chronic portal inflammation, stellate fibrosis, and degeneration of interlobular bile ducts (Fig. 1). The immunohistochemical staining of the liver biopsy specimens with an Ortho O K series of monoclonal Abs showed that more than 80% of the infiltrating cells were CD8-T cells (Fig. 2). Impairment of lacrimal and salivary secretions was demonstrated by Schirmer's test (2 mm for 5 min, bilaterally) and gum test (4 ml for 10 min), respectively. Sialography showed dilatation and cavitation of the ducts and extravasation of contrast media. Skin biopsy of the left fifth finger showed thick compact collagen bundles in dermis, decreased skin appendages and mild lymphocytic infiltration. Serum and CSF IgG-Abs to HTLV-I were positive at a titer of 1 : 32,768 and 1 : 256, respectively (particle agglutination method). IgM-Ab to HTLV-I was also detected in serum by Western immunoblots. Southern blotting analysis of the proviral D N A integrated in the peripheral blood lymphocytes (PBLs) showed discrete, broad bands larger than 9 kb, indicating polyclonal

Fig. 2. Immunohistochemical staining of the biopsied liver sample with an OK series of monoclona antibodies shows the predominant infiltration of CD8-cells in the lesion ( × 80). integration of the proviruses in the PBL-DNA. MRI showed Atrophy of thoracic cord (Fig. 3). The CSF was clear with less than 1 cell//xl and an IgG level of 7.9 m g / d l (normal: < 4.5 mg/dl). The skin reaction to PPD was negative. The proliferative response of PBLs

Fig. 3. Diffuse atrophy of the thoracic cord is shown on MRI.

49 to phytohemagglutinin (PHA) was assayed with a flow fluorocytometric method (Kuroda and Takashima 1990). The percentage of proliferating PBLs after 3 days of culture with P H A was 36% (normal: 47 _+ 5%). The proportion of peripheral blood T-cell subsets was normal: CD3 T-cells 61%, CD4 T-cells 41%, and CD8 T-cells 22%. An analysis of CSF T-cell subsets by a direct immunofluorescent method using a flow cytometry showed that 96% of CSF cells were CD3 T-cells, 50% were CD4 T-cells and 33% were CD8 T-cells; an increase in CD8 T-cells in the CSF was noted when compared with the data of multiple sclerosis (MS): the mean _+ S.D. for 10 active MS patients was 18 + 11% and that for 9 stable MS patients was 19 _+ 4% (Kuroda and Shibasaki 1987).

Discussion

The findings of progressive spastic paraparesis, anti-HTLV-I Abs in serum and CSF, increased CSF IgG and thoracic cord atrophy on MRI suggested that the patient had clinically definite H A M / T S P . The liver biopsy findings and positive antimitochondrial Abs showed that she also had PBC. The findings of sclerodactily, anticentromere Ab, Raynaud's phenomenon, telangiectasia and difficulty in swallowing also confirmed the diagnosis of C R E S T syndrome, and the clinical features of keratoconjunctivitis sicca and the sialographic finding confirmed the existence of Sj6gren's syndrome in our case. The association of Sj6gren's syndrome with H A M / T S P has been reported (Vernant et al. 1988; Nakagawa et al. 1992). Nakagawa et al. (1992) found the occurrence of Sj6gren's syndrome in 10, anterior uveitis in 3 and polymyositis in 3 among 196 H A M / T S P patients. Hashiguchi et al. (1989) also reported 18 cases of H A M / T S P presenting with skin manifestations of chronic inflammatory nature. We found rheumatoid arthritis in 3, acute polymyositis in 1, and anterior uveitis responding to corticosteroids in 3 of our 26 H A M / T S P patients (unpublished data). In all these patients, symptoms of HAM preceded the occurrence of autoimmune diseases. We also detected rheumatoid factor, antinuclear Ab and anti-DNA Ab in serum in 57%, 20% and 14%, respectively, of our 26 H A M / T S P patients (unpublished data). Thus, the findings indicate that the association of autoimmune diseases with H A M / T S P may not be accidental. Of particular interest in our case is its association with PBC because PBC has a number of similarities to H A M / T S P . Immunologically, the occurrence of autoimmune diseases, the anergy of skin reaction to dinitrochlorobenzene (DNCB) and the suppression of in vitro lymphoproliferative responses to mitogens were observed in both conditions (Epstein et al. 1980; Pow-

ell et al. 1987; Kuroda and Takashima 1990; Jacobson et al. 1990; Kuroda et al., 1991). Failure of immuno response to convert from IgM to IgG Ab synthesis was reported in PBC (Epstein et al. 1980). Likewise, we found the persistence of IgM-Ab to HTLV-I in serum in the majorities of HAM cases (Kuroda and Takashima 1990). Clinically, both are characterized by the insidious onset and slow rate of progression. Pathologically, it was shown that CD8 T-cells predominated in the liver of PBC (Pape et al. 1983; Yamada et al. 1986; Meuer et al. 1988) and in the spinal cord of H A M / T S P (Moore et al. 1990; Bhigjee et al. 1991). In the present case, we found the predominant infiltration of CD8 T-cells in the liver and the increase in CD8 T-cells in the CSF. Matsui et al. (1989) have also shown that CD8 T-ceils increased in the CSF of HAM. Although the pathogenesis of PBC and H A M / T S P remains undetermined, Epstein et al. (1980) proposed a hypothesis of chronic GVHD-Iike disease for PBC. Chronic G V H D occurs in patients with leukemia following irradiation and bone marrow transplantation, in recipients of an allograft during immunosuppressive treatment, in patients with aplastic anemia after bone marrow transplantation, and in irradiated or immunocompromised mice after injection of allogeneic lymphoid cells (Shu[man et al. 1980; Jaffee and Claman 1983; Vierling and Fennell 1985; Shulman ct al. 1988). Clinical features resembling PBC, scleroderma, CREST syndrome or Sj6gren's syndrome most commonly develop in both human and experimental chronic GVHDs (Epstein et al. 1980; Shulman et al. 1980). Hepatic chronic G V H D has been shown to be caused by the cytotoxic T-cell response to the bile-duct epithelial cells (Vierling and Fennell 1985; Shulman et al. 1988; Saitoh et al. 1989), which is similar to the immunohistologic findings in PBC (Pape et al. 1983; Yamada et al. 1986; Meuer et al. 1988). Epstein et al. (1980) assume that the presence of major histocompatibility complex (MHC) antigens in high density on the bile duct epithelial cells may be responsible for the occurrence of hepatic chronic G V H D and PBC. Patients and experimental animals with chronic G V H D have also been shown to produce multiple autoantibodies and to have immune response failure to convert IgM to IgG Ab synthesis, the impairment of skin reaction to DNCB and the suppressed lymphoproliferative response to PHA (Epstein et al. 1980; Lum 1987) like patients with PBC or H A M / T S P . We therefore assume that a chronic GVHD-like mechanism may also be involved in H A M / T S P . In addition to the immunologic and histologic similarities between chronic G V H D and H A M / T S P there are reports of the occurrence of H A M / T S P in recipients of an allograft (Gout et al. 1990; Kuroda et al. 1992) and a patient with aplastic anemia receiving blood transfusions (Kuroda et al. 1992). Osame et al. (1990) have shown that about 20%

5(I

of Japanese HAM/TSP patients had a history of blood transfusion and that 50% of these patients developed HAM within 3.3 years after blood transfusion; this latent period is quite short when compared with that of HAM infected with HTLV-I by the route of motherto-child transmission. So far no known case of ATL definitely infected with HTLV-I by transfusion has been reported (Okochi and Sato 1989), and the mechanism involved in the frequent, rapid occurrence of HAM/TSP by that infection route remains unknown. We assume that, in addition to a large amount of the virus inoculum (Osame et al. 1990), the generation of chronic GVHD by transfusion (Epstein et al. 1980; Saito et al. 1989; Vierling et al. 1989) may also contribute to its rapid development. Recently, Habeshaw et al. (1992) found a molecular homology between class II MHC antigens and human immunodefiency virus (HIV) envelope glycoproteins and suggested the implication of chronic GVHD-like mechanism in the development of HIV-associated diseases. Findings in H A M / T S P such as the depressed cell-mediated immunity, frequent association with autoimmune disorders, its rapid development in recipients of allograft or blood, and infiltration of cytotoxic T cells in the lesion suggest the possibility that HTLV-I infection may also generate a mechanism resembling chronic GVHD, which we assume to be deeply involved in the development of HAM/TSP.

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