Sjogren-Type Syndrome After Allogeneic Bone-Marrow Transplantation ALOIS A. GRATWHOL, M.D.; HARALAMPOS M. MOUTSOPOULOS, M.D.; THOMAS M. CHUSED, M.D.; MASASHI AKIZUKI, M.D.; ROBERT O. WOLF, D.D.S.; JAMES B. SWEET, D.D.S., M.S.; and ALBERT B. DEISSEROTH, M.D.; Bethesda, Maryland

Four patients, treated for hematologic disorders with bonemarrow transplants from HLA-identical siblings, spontaneously complained of dry eyes 8 to 12 months after transplantation. Four allograft recipients and two recipients of autologous bone-marrow transplants were evaluated for xerophthalmia and xerostomia. Three allogeneic marrow recipients had evidence of keratoconjunctivitis sicca, and two had decreased parotid gland function. All four allograft recipients had minor salivary gland histopathology identical to that of Sjogren's syndrome. The severity of symptoms and histologic lesions corresponded with the severity of chronic graft-versus-host disease. In addition, one patient developed sclerodermatous skin changes, another had discoid lupus erythematosus, and two patients had laboratory evidence of cholestasis. None of the patients had autoantibodies but all had hypergammaglobulinemia. In contrast, none of the recipients of autologous bone marrow had clinical, laboratory, or histologic findings resembling Sjogren's syndrome.

B O N E - M A R R O W T R A N S P L A N T A T I O N from HLA-identical siblings has been used recently to treat hematologic disorders unresponsive to conventional therapy (1). Graft-versus-host disease, the major complication of such treatment, is the reaction of transplanted immunocompetent cells to the recipient's tissue antigens. Acute graftversus-host disease primarily involves the skin, liver, and gastrointestinal tract. Because it often has a fatal outcome, few patients survive to the chronic phase. The sequelae of chronic graft-versus-host disease are poorly known in man, and the study of bone-marrow transplant patients offers a unique opportunity to define them. Two National Institutes of Health patients with chronic graft-versus-host disease resulting from allogeneic bone-marrow transplantation spontaneously complained of dry eyes. We therefore evaluated all bone-marrow recipients for evidence of xerophthalmia and xerostomia. • F r o m the Experimental Hematology Section, Pediatric Oncology Branch, National Cancer Institute; the Clinical Immunology Section, Laboratory of Microbiology and Immunology, Laboratory of Oral Medicine a n d Dental Services Section, National Institute of Dental Research; and the Arthritis Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes oi Health; Bethesda, Maryland.

Annals of Internal Medicine 87:703-706, 1977

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A b n o r m a l i t i e s closely r e s e m b l i n g S j o g r e n ' s s y n d r o m e w e r e f o u n d in four r e c i p i e n t s of a l l o g e n e i c b o n e m a r r o w b u t n o t in t w o r e c i p i e n t s of a u t o l o g o u s b o n e m a r r o w . These data provide direct evidence that h u m a n chronic graft-versus-host disease p r o d u c e s changes resembling t h o s e seen in s p o n t a n e o u s a u t o i m m u n e disease. Subjects and Methods PATIENTS

All living recipients of allogeneic bone-marrow transplants at the National Cancer Institute were studied except one who refused follow-up (Table 1). All patients were studied between 14 and 19 months post-transplantation, when they were clinically stable, not receiving immunosuppresive agents, and without signs of infection. Identical twins were not available as donors. Selection of donors was based upon the presence of absolute compatibility at the H L A - A and B loci. Also, donor recipient pairs were shown to be nonreactive in mixed lymphocyte cultures (done by Dr. Paul Terasaki, U C L A School of Medicine, Los Angeles, California). Complete post-transplantation chimerism was established in Patients 1 and 2 through donor-recipient sex differences, in Patient 3 on the basis of donor-recipient A B O erythrocyte antigenic differences, and in Patient 4 through donor-recipient M N erythrocyte antigenic differences. Details of the grafting procedure, patient and donor selection, and post-transplantation care have been described (3). T h e patient with acute leukemia was prepared for transplantation with combination chemotherapy (BCNU [bis-chloroethyl-nitroso-urea] 200 mg/m 2 body surface area X l ; Ara-C [cytosine arabinoside] 100 mg/m 2 body surface area X8; cyclophosphamide 45 m g / k g body weight X4; 6thioguanine 100 mg/m 2 body surface area, X8) and three patients with aplastic anemia with cyclophosphamide and procarbazine (cyclophosphamide, 50 m g / k g body weight X4; procarbazine, 12.5 m g / k g body weight X3). Despite prophylactic antithymocyte-globulin (Upjohn Co., Kalamazoo, Michigan) and immunosuppression with methotrexate post-transplantation (4), all four patients developed moderate-to-severe acute graft-versus-host disease (Table 1). Skin and liver biopsies in three patients were compatible with the clinical diagnosis of graft-versus-host disease. T h e three patients with grade four progressive graft-versus-host disease were given additional antithymocyteglobulin. All four had severe infections in their post-transplantation course. At the time of study, all patients had evidence of chronic graft-versus-host disease (Table 1). Additionally two patients with Burkitt's lymphoma were evaluated for the presence of xerophthalmia and xerostomia 11 to 21 months after receiving high-dose levels of the combination chemotherapy and transfusion of their previously cryopreserved autologous bone marrow (Table 1). 703

CLINICAL EVALUATION FOR SJOGREN'S SYNDROME AND LABORATORY TESTS

Medical history and physical examination were done for each patient with particular attention to symptoms and signs of Sjogren's syndrome. Complete blood count, determination of erythrocyte sedimentation rate, quantitative serum levels of immunoglobulins, fluorescent antinuclear antibodies, antibodies to double-stranded DNA, bentonite flocculation test for rheumatoid factor, serum complement (C3) levels, and renal and liver function tests were done in all patients. In addition, all sera were tested for antibodies to Ha, a specific extractable nuclear antigen, antibodies to which are frequently found in Sjogren's syndrome (5). All patients had an ophthalmological assessment including slit-lamp examination, Schirmer's test, and fluorescein staining (6). Parotid gland function was evaluated by salivary flow rate and salivary gland scintigraphy (7). Lip biopsies were done in all patients and slides were scored by three observers from 0 (normal) to 4 + , according to the degree of lymphocytic infiltration and salivary gland destruction (8). Informed consent was obtained from all patients or their legal guardians. Results

Allogeneic Bone-Marrow Recipients 1, 2, and 4 developed clinical complaints ranging from minor grittiness to severe dryness of the eyes and mouth, beginning 8 to 12

months after transplantation (Table 1). All three had objective evidence of keratoconjunctivitis sicca, and two had decreased parotid gland function. None of the patients had major salivary gland enlargement, arthralgias, or arthritis. All had varying degrees of histologic changes of minor salivary glands similar to those of Sjogren's syndrome (Figure 1). In general, the severity of symptoms and histologic lesions corresponded with the severity of the chronic graft-versus-host disease (Table 1). Patient 4 had skin changes resembling scleroderma with atrophic epidermis, indurated skin of the distal extremities, finger-tip ulcerations, and distal phalanges softtissue calcifications. N o esophageal motility changes or Raynaud's phenomena were observed. Patients 1 and 2 had laboratory evidence of cholestatic liver disease. Patient 1 also developed a skin lesion resembling discoid lupus erythematosus, which was confirmed by skin biopsy. None of the patients had a positive rheumatoid factor, antinuclear antibodies, antibodies to double-stranded D N A , or antibodies to Ha. All showed elevated erythrocyte sedimentation rates and elevated IgG and IgM, but normal IgA levels.

Table 1. Clinical Characteristics of Patients and Evaluation for Sjogren's Syndrome

Characteristics 1 Age, (years) Sex Race Diagnosis before transplantation Time of study (months after transplantation) Acute graft-versus-host disease* Skin Liver Gastrointestinal tract Overall grade Chronic graft-versus-host disease * Skin Liver Gastrointestinal tract Onset of symptoms (months after transplantation) Dry eyes Dry mouth Schirmer's test (mm/5 miri) right eye/left eye Corneal ulcerations Parotid flow (ml/5 min) Parotid scan

December

Male White

Male White

Male White

Aplastic anemia

Aplastic anemia

Aplastic anemia

Acute myelogenous leukemia

5

6

11 Female White

18 Male White

Burkitt's lymphoma

Burkitt's lymphoma

19

18

14

17

11

21

+ ++++ ++++ ++++

++++ +++ ++++ ++++

+ ++ + ++

++++ ++ ++++ ++++

— — —

— — —

—

Sclerodermatous lesions Elevated alkaline phosphatase Mild oral vasculitic lesions f

—

—

Discoid lupus Lichen planus erythematosus Cholestatic Cholestatic liver disease liver disease Mild oral Severe oral vasculitic vasculitic lesions f lesions f 12 —

11 —

0/0

4/2

+ 2.2

+

Normal 2+

1977

25

20

18

Male Black

1.4 Abnormal (class 3) 4+

— Mild oral vasculitic lesions f — — 20/20 — 1.9 Normal 1+

* Reference 1. t Biopsy of these lesions was compatible with graft-versus-host disease and vasculitis.

704

4

3

2

22

Lip biopsy

Patients with Autologous Bone-Marrow Transplants

Patients with Allogeneic Bone-Marrow Transplants

• Annals of Internal Medicine • Volume 87 • Number

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6

8 9 0/0

+ 0.9 Not done 4+

— —

—

— —

— —

32/26 — 1.6 Normal 0

29/32 — 2.8 Normal 0

Figure 1 . Histology of the minor salivary gland, a. Patient 3, showing periductural infiltrate with intact acinar architecture ( 1 + ) . b. Patient 4, showing severe infiltration and acinar destruction (4 + ) .

In contrast, neither of the recipients of autologus bone marrow had clinical or histologic findings resembling Sjogren's syndrome (Table 1). Discussion

These data present clinical and histologic evidence of a Sjogren-like syndrome following graft-versus-host disease in recipients of allogeneic bone marrow. The association of this syndrome with chronic graft-versus-host disease suggests that graft-versus-host disease is its cause. The onset of lymphoid infiltration in these patients cannot be dated, but in spontaneous Sjogren's syndrome secretorytissue lymphocytic infiltration precedes loss of function, and 5 to 10 years may elapse between onset of symptoms and total loss of function. Like most spontaneous Sjogren's syndrome cases, eye involvement preceded oral manifestations in these patients. The rate of progression appears more rapid in graft-versus-host disease than in spontaneous disease. Sjogren's syndrome is a chronic inflammatory disease occurring predominantly in middle-aged women, characterized by xerophthalmia and xerostomia, and is often associated with rheumatoid arthritis or another connective-tissue disease. The diagnosis is confirmed by the characteristic lymphoid infiltration of the minor salivary glands on lip biopsy (9). The pathogenetic mechanism is unknown but individuals with HLA-B8 or H L A - D W 3 are significantly more susceptible to the disease (10-12), suggesting that an immune-response gene may be involved. Spontaneous Sjogren's syndrome has been associated with connective-tissue diseases such as scleroderma, systemic lupus erythematosus, and primary biliary cirrhosis (13). One patient with chronic graft-versus-host diseaseinduced Sjogren's-like syndrome developed sclerodermatous skin lesions, one developed discoid lupus erythematosus and cholestatic liver disease, and a third developed cholestatic liver disease alone. The association of chronic graft-versus-host disease in man with this Sjogren's-like syndrome, and the additional manifestations resembling autoimmune diseases, extends observations made in ani-

mals. In animal models, chronic graft-versus-host disease can produce such autoimmune diseases as hemolytic anemia, thrombocytopenia and granulocytopenia, polyarthritis, carditis, immune-complex glomerulonephritis, and skin lesions similar to systemic lupus erythematosus or scleroderma (14-16). The immunologic reaction of competent donor lymphocytes against host tissue antigens is the basic mechanism leading to graft-versus-host disease. It is unknown why the primary target organs in acute graft-versus-host disease are the skin, liver, and gastrointestinal tract. These organs may be involved to different degrees in different patients (17). Differences in tissue antigens, the extent of their expression, differential donor lymphocytes reactivity, variations in lymphocyte-homing patterns or susceptibility differences to immunologic injury may account for this observation. Other organ involvement has been described but the relation to graft-versus-host disease is uncertain (18). Cell surface-antigen alteration in the target organ or loss of self-tolerance by the immune system are the two proposed mechanisms leading to autoimmune diseases (19). In patients with chronic graft-versus-host disease the target organs are presumably normal, and the autoimmune-like disease that develops is due to recognition of host antigens by donor lymphocytes. The similarity of clinical and histologic findings of graft-versus-host disease-induced Sjogren's syndrome to the spontaneous disease suggests that both disorders have a final common pathway. It is very interesting that unlike spontaneous Sjogren's syndrome none of these patients developed autoantibodies. Further investigation of allogeneic bone-marrow recipients may increase our knowledge of pathogenetic mechanisms in such diseases as Sjogren's syndrome, scleroderma, and lupus erythematosus. ACKNOWLEDGMENTS: The authors thank all those physicians who contributed to the transplantation effort of the National Cancer Institute, particularly Drs. R. G. Graw, Jr., and F. R. Appelbaum, as well as Drs. R. Siraganian, J. L. Decker, and J. Longstreth for critical review of the manuscript, and Mrs. D. Light for secretarial assistance. Received 18 April 1977; revision accepted 7 September 1977. Gratwhol eta/.

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• Sjogren-Type Syndrome

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• Requests for reprints should be addressed to Haralampos M. Moutsopoulos, M.D.; Building 10, Room 2B-10, National Institutes of Health; Bethesda, MD 20014.

9. BLOCH KJ, BUCHANAN WW, W O H L MJ, B U N I M JJ: Sjogren's syn-

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G E R S H W I N ME, TERASAKI PI, G R A W R, C H U S E D TM: Increased fre-

quency of HL-A 8 in Sjogren's syndrome. Tissue Antigens 1975

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