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Sclerodermatous chronic graft-versus-host disease
Sclerodermatous chronic graft-versus-host disease Analysis of seven cases Olivier Chosidow, MD,a Martine Bagot, MD,a Jean-Paul Vernant, MD,b Jean-Claude Roujeau, MD,a Catherine Cordonnier, MD,b Mathieu Kuentz, MD,b Janine Wechsler, MD,c Chantal Andre, MD,d Rene Touraine, MD,t and Jean Revuz, MDa
Creteil, France Background: Sclerodermatous chronic graft-versus-host disease is a disabling complication after allogeneic bone marrow transplantation from HLA-identical sibling donors. Only a few series of patients have been reported and the dermatologic features have never been extensively described. Objective: The purpose of the study was to describe clinical and biologic features of chronic sclerodermatous graft-versus-host disease and to compare them with scleroderma. Methods: We reviewed 196 patients grafted between April 1973 and July 1987 with survival times sufficient to be at risk of chronic graft-versus-host disease. Seven had the sclerodermatous form. . Results: Most patients had disseminated sclerosis of the trunk and the proximal portions of the limbs. In two cases, atrophy of the skin was predominant, corresponding with a severe clinical evolution. Periorbital pigmentation was observed as an initial manifestation in three cases. Visceral manifestations resembled those observed in scleroderma but histologic and immunologic studies demonstrated clear differences. Response to therapy was variable. Conclusion: Chronic sclerodermatous graft-versus-host disease may realize two different patterns. Major atrophy is associated with a more severe progression. (J AM ACAD DERMATOL 1992;26:49-55.) Chronic graft-versus-host disease (GVHD) may be a significant problem in patients who undergo allogeneic bone marrow transplantation from an HLA-identical sibling donor. This complication occurs after 100 days in 25% to 45% of patients. l Most patients have lichenoid lesions that may resolve after a few months, whereas sclerodermatous chronic GVHD occurs far less frequently.2 Reports of patients with chronic cutaneous GVHD have indicated only a few with sclerodermatous changes. 2-4 We observed only seven cases among 196 patients who had survival times sufficient to be at risk for chronic GVHD. This report analyzes the clinical and histologic features of these cases.
From the Departments of Dermatology," Haematology,b Histopathology,C and Haematology-Immunology,d Hopital Henri-Mondor. Presented in part to the Societe Fran9aise de Dermatologie, Paris, France, Dec. 14, 1989. Accepted for publication July 3, 1991. Reprint requests: Olivier Chosidow, Department of Dermatology, Hopital Henri-Mondor, Universite Paris XII, 51 Avenue du Man~chal de Lattre de Tassigny, 94010 Creteil, France. tDeceased.
16/1/32152
PATIENTS AND METHODS Between April 1973 and July 1987,270 consecutive patients underwent allogeneic transplants from HLA identical donors in our transplant unit as treatment for acute or chronic leukemias or aplastic anemia. Patients with leukemia received total body irradiation (1000 Tad) after cyclophosphamide (two doses of 60 mg/kg) before receiving the transplant. Patients with aplastic anemia received only cyclophosphamide. Methotrexate was given during the first 100 days in an attempt to prevent GVHD. Of the 270 patients, 196 (72.6%) survived more than 100 days and were theoretically at risk for chronic GVHD, and in 53 (27%) of these patients chronic GVHD developed as previously defined. 2, 5 In seven of these patients the sclerodermatous form developed. They were five male and two female patients with a mean age of 25.8 years (range 16 to 33 years). Three patients underwent bone marrow transplantation for acute leukemia, three for chronic leukemia, and one for aplastic anemia (Table I). Of the six patients with a hematologic malignancy, four were in their first remission or chronic phase, one was in a second remission, and one was in a blastic phase at the time of transplantation. Donors ~ere sex-mismatched in six cases (female donor/male recipient in four cases). One of the female donors had been pregnant. Acute GVHD occurred in five patients (grade I in one
49
Journal of the American Academy of Dermatology
50 Chosidow et al.
Fig. 1. Initial periorbital eruption progressing towards residual hyperpigmentation.
Table I. Bone marrow transplant regimens and donors Recipients
UPN
001 071 107 110
144 146 164
I
Age (yr)
16 32 27 33 28 17 28
I
Sex
M M M
F
M M F
Donors
I
Diagnosis
AA AML CML CML AML ALL CML
Age (yr)
14 35 33
39 23 15
22
I
Sex
F F
F M M F M
BMT conditioning
regimen
GVHD
prophylaxis
Cy Cy, Bel, TBI Cy, TBI Cy, TBI Cy, TBI Cy, TBI Cy, TBI
MTX MTX MTX MTX MTX MTX MTX
Follow-up (yr)
2t 8.5 7.5 7.5 6.5 6t 6
AA, Aplastic anemia; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; Bel, belustine; CML, chronic myeloid leukemia; Cy, cyclophosphamide; MTX, methotrexate; TBI, total body irradiation; UPN, unique patient number (Bone Marrow Transplantation Unit, Hopital HenriMondor). tDeceased.
case and grade II-IY in four cases). Two patients had no history of acute GYRD and presented with de novo chronic GYHD. Lichenoid GYHD always preceded sclerodermatous GVHD, which occurred despite steroid therapy. When the chronic sclerodermatous GYHD appeared, all patients had a complete blood cell count, liver function tests, rheumatoid factor, antinuclear antibodies including anticentromere and anti.. .extractable nuclear antigens, antimitochondria, and anti-smooth muscle antibodies. Pulmonary function tests, chest x-rays, esophageal radiocinema or manometry, capillaroscopy, and ophthalmologic examination (Schirmer's test, fluorescein dye staining) were also performed. Clinical evolution was defined as follows: significant improvement was stated when clearly increased mobility and resolving of dermal tightness and contractures were
observed with no occurrence of new lesions. Partial improvement was defined as a slight improvement in these features. RESULTS Sclerodermatous changes began 0.8 to 6 years after transplantation (mean 2.0 years) (Table II).
Cutaneous manifestations
Initial findings. Three patients had a lichenoid periorbital eruption (Fig. 1) that evolved into residual hyperpigmentation 75 to 165 days after transplant. This periorbital eruption was associated with sclerodermatous changes in one patient and was the first manifestation of chronic GVRO in two others. In five patients, sclerodermatous lesions appeared in
Volume 26 Number 1 January 1992
Sclerodermatous chronic GVHD 51
Fig. 2. Pearly-white plaque with atrophy of the skin.
Table II. Cutaneous patterns of chronic sclerodermatous GVHD UPN
001
Onset of clinical sclerodermatous changes (yr) Sclerosis Atrophy of the skin Telangiectasia Pigmentation disorders Erythema Contractures Ulcerations Hair loss Nail involvement Genital involvement Oral involvement
0.8
+ + + +
071
107
110
6
3.5
1.1
+ +
+ +
+
+ +
+
+ +
+ + + + + + +
+
+ +
+ +
+ + + +
+ +
+
+
+
144
146
164
1
1.1
0.9
+ + +
+
+ +
+
+
+. Present; -. absent.
areas of previous injury such as acute or lichenoid GVHD lesions, scars of zoster infection, BeG therapy, or suction blisters. Clinical features of sclerodermatous GVlID Details of the cutaneous manifestations are shown in Table II. Lesions were always disseminated. They presented as guttate or confetti-like lesions, morphea with no lilac ring, and/or deep erythematous and edematous infiltration predominantly on the trunk and the proximal limbs. Reticulated pigmentary disorders were associated with "vitiligo-like" lesions
or leukomelanoderma. In two patients, atrophy of the skin and sclerosis were particularly severe. These patients had multiple pearly-white plaques (Fig. 2), telangiectasia (poikiloderma), diffuse skin ulcerations, contractures, and retractions. One of them had sclerodactyly (Fig. 3). Atrophy of the nails occurred in one case and koilonychia in another. Lichenoid lesions (erosive or not) of the oral mucosa were present in four cases. Histopathologic examination. Skin biopsy specimens were obtained from six patients. Biopsies were
Journal of the American Academy of Dermatology
52 Chosidow et ai.
Fig. 3. Sclerodactyly.
in three cases. The epidermis was normal in two cases but atrophic in four, especially in the two patients with multiple pearly-white plaques. Basal layer vacuolar degeneration, inflammation, and eosinophilic body formation were found in one case. Dermal alterations included fibrosis and destruction of adnexal structures. The papillary and reticular dermis could not be distinguished. Fibrosis extended to the subcutaneous fat in four cases. In a patient with edematous infiltration, a muscle biopsy specimen showed a centripetal fibrosing process of the fascia (with rare mononuclear cells), the interfascicular septa, and the endomysium (Fig. 4). In one case, a skin biopsy spec:imen of the periorbital area was obtained 75 days before generalized sclerodermatous GVHD. It showed vacuolization of basal epidermal cells with a slight lymphohistiocytic infiltrate, free melanin deposits and melanophages, and superficial fibrosis in the papillary dermis (Fig. 5). Extracutaneous manifestations (Table III)
Fig. 4. Histologic appearance of diffuse fasciitis. Centripetal fibrosing process affects fascia, interfascicular septa, and endomysium. *, Fascia; **, muscle. (X30.)
performed I to 50 days after the clinical diagnosis of sclerodermatous chronic GVHD (mean 12.5 days) but in all cases before specific therapy. Sites of the biopsies were the trunk in three cases and the arms
Raynaud's phenomenon was noted in one case. Capillaroscopy was performed in five cases and revealed only nonspecific vascular changes. Reduced lacrimal secretion (xerophthalmia and/or Schirmer's test -< 10 mm in 5 minutes) was noted in six cases. Five patients presented with chronic pulmonary abnormalities with no documented microbiologic cause, including cytomegalovirus. Two patients had obliterative bronchiolitis, defined by chronic cough, dyspnea, and a ratio of forced expiratory volume in 1 second (FEV!) to forced vital capacity (FVC) lower than 70%. This pattern is very suggestive ofchronic GVHD; in one ofthese patients
Volume 26 Number 1 January 1992
Sclerodermatous chronic GVHD 53
Fig. 5. Histologic appearance ofperiorbital pigmentation. Vacuolization ofbasal epidermal cells (arrow) , slight lichenoid lymphohistiocytic infiltrate, free melanin deposits and melanophages, and superficial fibrosis. (X250.)
Table III. Extracutaneous manifestations
UPN 001
Vascular Raynaud's phenomenon Ophthalmologic Reduced lacrimal secretion Pulmonary Chest x-ray abnormalities Pulmonary function test Diffusion capacity (CO) Esophageal Dysphagia Radiocinema or manometry Hepatic Cirrhosis Intestinal Enteropathy Immunologic Rheumatoid factor Antinuclear autoantibodies Anticentromere Anti-Scl-70 Antimitochondria Anti-smooth muscle
071
107
110
144
+
+
146
164
+ + NI ND
+ +
+ + (0)
NI
+ + (0)
+
ND
+
+ (R) +
+
+ +
+ +
+ + + ND ND ND ND
ND
+
ND
+
+ +
ND
+ ND NI
+
+
ND, Not done; NJ, not interpretable; (0), obstructive; (R), restrictive; UPN, unique patient number.
the diagnosis of obliterative bronchiolitis was confirmed by bronchial biopsy specimens. The three remaining patients had either a severe restrictive ventilatory defect and septal dense fibrosis with
fiberoptic biopsy specimens or a decreased diffusion capacity. These patterns may be related to chronic GVHD, but may also be induced by irradiation or chemotherapy. Esophageal involvement was foood
54 Chosidow et at. in one case (with decreased esophageal peristalsis on cineradiography) and cirrhosis was present in two. In one patient, enteropathy with diarrhea and malabsorption was documented and related to lymphocytic infiltration and fibrosis of the intestinal submucosa. Patient sera were tested at various times for several autoantibodies, with concordant results. Two patients had antinuclear antibodies (1 :200 and 1:1000) (normal <1:10) with speckled pattern and five patients had anti-smooth muscle antibodies (1:10 in one patient, 1:50 in three, and 1:100 in one) (normal < 1: 10). No antibodies against centromere antigens or DNA topoisomerase I (Sc1-70) were found (in 6 and 5 patients tested, respectively).
Therapy and course All patients initially received a combination of prednisone (0.5 to 1 mg/kg/day) and azathioprine (50to 150mg/day) or cyclophosphamide (50 to 100 mg/day) for 3 to 12 months. The two patients with the severe atrophic form died, 2 and 6 years after BMT: the first of septicemia and the other of severe malnutrition. In this last patient no significant improvement was seen after thalidomide (2 mg/ kg/day) given for 5 months. The remaining five patients are alive. Three had a favorable course that persisted after discontinuation of the therapy; the resolution of the periorbital eruption was associated with overall clinical improvement in two of these patients. The two other patients had persistent lesions that justified further treatment. One patient received alternating-day cyclosporine (6 mg/kg every 12 hours every other day) and prednisone (1 mg/kg every other day) for 6 months and showed rapid improvement. One patient received cyclosporine (2 mg/kg every 12 hours) for 6 months with partial improvement. DISCUSSION
We report seven cases of generalized sclerodermatous chronic GVHD after bone marrow transplantation from an HLA identical sibling donor. This complication occurred in only 3.6% of the 196 patients at risk of chronic GVHD observed during a 14-year period in our bone marrow transplant unit. Fewseries ofpatients with chronic cutaneous GVHD have been reported and only a few of these cases presented with sclerodermatous changes. 2-4 The cutaneous features of these patients have never before been described in detail. In our series, sclerodermatous changes always began on previous lesions of
Journal of the American Academy of Dermatology
acute or lichenoid GVHD or on zoster Or suction blister scars, as already reported. 5, 7, 8 Various types of cutaneous injury may trigger the formation of sclerodermatous GVHD lesions. Hyperpigmentation ofthe periorbital area has been observed in some cases. 1 In our series, it occurred 75 to 165 days after the graft and may be a predictive sign of extensive sclerodermatous GVHD. Improvement coincided in two patients with the resolution of this periorbital pigmentation. However, the incidence of periorbital hyperpigmentationin patients withlichenoid GVHD in whom sclerodermatous chronic lesions do not develop is unknown. In five patients, cutaneous lesions presented as inflammatory guttate sclerosis and/or edematous infiltration associated with hyperpigmented lesions. These patients had a favorable outcome. Two patients initially presented with extensive sclerotic lesions associated with multiple atrophic pearly~white plaques and ulcerations. The outcome was fatal in both cases. This sclerotic pattern may therefore be a marker of severe chronic GVHD. Results of experimental studies strongly support an autoimmune pathophysiology of chronic GVHD. The normal ability of the thymus to delete autoreactive T cells and to induce tolerance may be impaired. These autoreactive T cells produce unusual patterns of cytokines such as interleukin 4 and interferon gamma and can stimulate the production of collagen by fibroblasts. 9 Because chronic GVHD resembles some connective tissue diseases, such as systemic scleroderma and lupus erythematosus, it may be considered a model for pathogenetic studies. 10 Some authors have hypothesized that both diseases, systemic scleroderma and sclerodermatous chronic GVHD, might be closely related because both are associated with Sjogren's syndrome, pulmonary and esophageal involvement, and immunologic disorders. 1 1, 12 Hepatic involvement in GVHD may resemble primary biliary cirrhosis. 13 Raynaud's phenomenon is rare but may occur. However, differences between systemic scleroderma and sclerodermatous GVHD merit further discussion. ( 1) The initial location of the sclerosis is clearly the reticular dermis in scleroderma. In our cases, the initial site of the lesion was difficult to appreciate because the sclerosis rapidly involved the entire dermis. Electron microscopy and immunohistologic studies have revealed several differences. In sclerodermatous GVHD, the staining for procollagen I and III and collagen III was not more intense than in normal
Volume 26 Number 1 January 1992
skin but a zone three times thicker was stained in the papillary dermis. In contrast, abnormal staining of collagen III in the reticular dermis has been found in scleroderma. 14 (2) Visceral involvement associated with systemic scleroderma is difficult to evaluate in chronic GVHD patients in whom several factors may induce organ damage. For example, interstitial pneumonia may be related to radiation or chemotherapy toxicity, infection, lymphoid interstitial pneumonia,15 or bronchiolitis. 16 In the esophagus chronic GVHD lesions, unlike those of scleroderma, show submucosal fibrosis with no muscle or neuronal involvement,17 (3) Antibody patterns in chronic GVHD patients differ from those in connective tissue diseases. IS, 19 In our series we did not find antinucleolar, anticentromere or anti-Scl-70 antibodies. Thus sclerodermatous chronic GVHD appears to be a distinct clinical entity. Response to therapy in our patients was variable. Combined immunosuppression (azathioprine and prednisone) was effective in three patients. Alternating-day cyclosporine and prednisone induced a good response in another patient. This treatment is known to improve survival in patients with severe chronic GVHD.20 Thalidomide has also been reported to cause improvement in sclerodermatous GVHD21; however, we did not observe significant improvement with this drug in one of our patients. All treatments were ineffective in both patients with severe atrophic chronic sclerodermatous GVHD. REFERENCES 1. Sullivan KM, Shulman HM, Stmb R, et al. Chronic graftversus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 1981;57:267-70. 2. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980;69:204-17. 3. Herzog P, Clements PJ, Roberts NK, et al. Progressive systemic sclerosis like syndrome after bone marrow transplantation. J Rheumatol 1980;7:56-64. 4. Graze PR, Gale RP. Chronic graft versus host disease: a syndrome ofdisordered immunity. Am J Med 1979;66:61120.
Sclerodermatous chronic GVHD 55 5. Shulman HM, Sale GE, Lerner KG, et al. Chronic cutaneous graft-versus-host disease in man. Am J Pathol 1978;92:545-70. 6. Deeg HJ, Storb R. Acute and chronic graft-versus-host disease: clinical manifestations, prophylaxis and treatment. JNCI 1986;76:1325-8. 7. Fenyk JR, Smith CM, Warkentin PI, et al. Sclerodermatous graft-versus-host disease limited to an area of measles exanthem. Lancet 1978;1:472-3. 8. Urbano-Marquez A, Estruch R, Grau JM, et al. Inflammatory myopathy associated with chronic graft-versus-host disease. Neurology 1986;36:1091-3. 9. Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324:667-74. 10. Roujeau J-C, Revuz J, Touraine R. Graft-versus-host reactions. In: Rook A, Kamiya N, eds. Recent advances in dermatology. New York: Churchill Livingstone, 1980:13157. 11. Graham-Brown RAC, Sarkani 1. Scleroderma-like changes due to chronic graft-versus-host disease. Clin Exp DermatoI1983;8:531-8. 12. Lawley TJ, Peck GL, Moutsopoulos HM, et al. Scleroderma, Sjogren-like syndrome and chronic graft-versushost disease. Ann Intern Med 1977;87:707-9. 13. Epstein 0, Thomas HC, Sherlock S. Primary biliary cirrhosis is a dry gland syndrome with features of chronicgraft-versus-host disease. Lancet 1980;1:1166-8. 14. Janin-Mercier A, Devergie A, Van Cauwenberg D, et al. Immunohistologic and ultrastructural study of the sclerotic skin in chronic graft-versus-host disease in man. Am J PathoI1984;115:296-306. 15. Perreault C, Cousineau S, D'Angelo G, et al. Lymphoid interstitial pneumonia after allogeneic bone marrow transplantation. Cancer 1985;55:1-9. 16. Hyland RH, Chan CK, Hutcheon MA, et al. Bronchiolitis in allogeneic bone marrow transplant recipients. Int J Cell Clan 1986;4(suppl 1 ):203-5. 17. McDonald GB, Sullivan KM, Schuffier MD, et al. Esophageal abnormalities in chronic graft-versus-host disease in humans. Gastroenterology 1981;80:914-21. 18. Rouquette-Gally AM, Boyeldieu D, Gluckman E, et al. Auto-immunity in 28 patients after allogeneic bone marrow transplantation: comparison with Sjogren syndrome and scleroderma. Br J Haematol1987;66:45-7. 19. Dighiero G, Intrator L, Cordonnier C, et al. High levels of anti-cytoskeleton autoantibodies are frequently associated with chronic GVHD. Br J Haematol 1987;67:301-5. 20. Sullivan KM, Witherspoon RP, Storb R, et al. Alternatingday cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease. Blood 1988;72:555-61. 21. Heney D, Lewis 11, Bailey Cc. Thalidomide for chronic graft-versus-host disease in children [Letter]. Lancet 1988;2:1317.
Creteil, France Background: Sclerodermatous chronic graft-versus-host disease is a disabling complication after allogeneic bone marrow transplantation from HLA-identical sibling donors. Only a few series of patients have been reported and the dermatologic features have never been extensively described. Objective: The purpose of the study was to describe clinical and biologic features of chronic sclerodermatous graft-versus-host disease and to compare them with scleroderma. Methods: We reviewed 196 patients grafted between April 1973 and July 1987 with survival times sufficient to be at risk of chronic graft-versus-host disease. Seven had the sclerodermatous form. . Results: Most patients had disseminated sclerosis of the trunk and the proximal portions of the limbs. In two cases, atrophy of the skin was predominant, corresponding with a severe clinical evolution. Periorbital pigmentation was observed as an initial manifestation in three cases. Visceral manifestations resembled those observed in scleroderma but histologic and immunologic studies demonstrated clear differences. Response to therapy was variable. Conclusion: Chronic sclerodermatous graft-versus-host disease may realize two different patterns. Major atrophy is associated with a more severe progression. (J AM ACAD DERMATOL 1992;26:49-55.) Chronic graft-versus-host disease (GVHD) may be a significant problem in patients who undergo allogeneic bone marrow transplantation from an HLA-identical sibling donor. This complication occurs after 100 days in 25% to 45% of patients. l Most patients have lichenoid lesions that may resolve after a few months, whereas sclerodermatous chronic GVHD occurs far less frequently.2 Reports of patients with chronic cutaneous GVHD have indicated only a few with sclerodermatous changes. 2-4 We observed only seven cases among 196 patients who had survival times sufficient to be at risk for chronic GVHD. This report analyzes the clinical and histologic features of these cases.
From the Departments of Dermatology," Haematology,b Histopathology,C and Haematology-Immunology,d Hopital Henri-Mondor. Presented in part to the Societe Fran9aise de Dermatologie, Paris, France, Dec. 14, 1989. Accepted for publication July 3, 1991. Reprint requests: Olivier Chosidow, Department of Dermatology, Hopital Henri-Mondor, Universite Paris XII, 51 Avenue du Man~chal de Lattre de Tassigny, 94010 Creteil, France. tDeceased.
16/1/32152
PATIENTS AND METHODS Between April 1973 and July 1987,270 consecutive patients underwent allogeneic transplants from HLA identical donors in our transplant unit as treatment for acute or chronic leukemias or aplastic anemia. Patients with leukemia received total body irradiation (1000 Tad) after cyclophosphamide (two doses of 60 mg/kg) before receiving the transplant. Patients with aplastic anemia received only cyclophosphamide. Methotrexate was given during the first 100 days in an attempt to prevent GVHD. Of the 270 patients, 196 (72.6%) survived more than 100 days and were theoretically at risk for chronic GVHD, and in 53 (27%) of these patients chronic GVHD developed as previously defined. 2, 5 In seven of these patients the sclerodermatous form developed. They were five male and two female patients with a mean age of 25.8 years (range 16 to 33 years). Three patients underwent bone marrow transplantation for acute leukemia, three for chronic leukemia, and one for aplastic anemia (Table I). Of the six patients with a hematologic malignancy, four were in their first remission or chronic phase, one was in a second remission, and one was in a blastic phase at the time of transplantation. Donors ~ere sex-mismatched in six cases (female donor/male recipient in four cases). One of the female donors had been pregnant. Acute GVHD occurred in five patients (grade I in one
49
Journal of the American Academy of Dermatology
50 Chosidow et al.
Fig. 1. Initial periorbital eruption progressing towards residual hyperpigmentation.
Table I. Bone marrow transplant regimens and donors Recipients
UPN
001 071 107 110
144 146 164
I
Age (yr)
16 32 27 33 28 17 28
I
Sex
M M M
F
M M F
Donors
I
Diagnosis
AA AML CML CML AML ALL CML
Age (yr)
14 35 33
39 23 15
22
I
Sex
F F
F M M F M
BMT conditioning
regimen
GVHD
prophylaxis
Cy Cy, Bel, TBI Cy, TBI Cy, TBI Cy, TBI Cy, TBI Cy, TBI
MTX MTX MTX MTX MTX MTX MTX
Follow-up (yr)
2t 8.5 7.5 7.5 6.5 6t 6
AA, Aplastic anemia; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; Bel, belustine; CML, chronic myeloid leukemia; Cy, cyclophosphamide; MTX, methotrexate; TBI, total body irradiation; UPN, unique patient number (Bone Marrow Transplantation Unit, Hopital HenriMondor). tDeceased.
case and grade II-IY in four cases). Two patients had no history of acute GYRD and presented with de novo chronic GYHD. Lichenoid GYHD always preceded sclerodermatous GVHD, which occurred despite steroid therapy. When the chronic sclerodermatous GYHD appeared, all patients had a complete blood cell count, liver function tests, rheumatoid factor, antinuclear antibodies including anticentromere and anti.. .extractable nuclear antigens, antimitochondria, and anti-smooth muscle antibodies. Pulmonary function tests, chest x-rays, esophageal radiocinema or manometry, capillaroscopy, and ophthalmologic examination (Schirmer's test, fluorescein dye staining) were also performed. Clinical evolution was defined as follows: significant improvement was stated when clearly increased mobility and resolving of dermal tightness and contractures were
observed with no occurrence of new lesions. Partial improvement was defined as a slight improvement in these features. RESULTS Sclerodermatous changes began 0.8 to 6 years after transplantation (mean 2.0 years) (Table II).
Cutaneous manifestations
Initial findings. Three patients had a lichenoid periorbital eruption (Fig. 1) that evolved into residual hyperpigmentation 75 to 165 days after transplant. This periorbital eruption was associated with sclerodermatous changes in one patient and was the first manifestation of chronic GVRO in two others. In five patients, sclerodermatous lesions appeared in
Volume 26 Number 1 January 1992
Sclerodermatous chronic GVHD 51
Fig. 2. Pearly-white plaque with atrophy of the skin.
Table II. Cutaneous patterns of chronic sclerodermatous GVHD UPN
001
Onset of clinical sclerodermatous changes (yr) Sclerosis Atrophy of the skin Telangiectasia Pigmentation disorders Erythema Contractures Ulcerations Hair loss Nail involvement Genital involvement Oral involvement
0.8
+ + + +
071
107
110
6
3.5
1.1
+ +
+ +
+
+ +
+
+ +
+ + + + + + +
+
+ +
+ +
+ + + +
+ +
+
+
+
144
146
164
1
1.1
0.9
+ + +
+
+ +
+
+
+. Present; -. absent.
areas of previous injury such as acute or lichenoid GVHD lesions, scars of zoster infection, BeG therapy, or suction blisters. Clinical features of sclerodermatous GVlID Details of the cutaneous manifestations are shown in Table II. Lesions were always disseminated. They presented as guttate or confetti-like lesions, morphea with no lilac ring, and/or deep erythematous and edematous infiltration predominantly on the trunk and the proximal limbs. Reticulated pigmentary disorders were associated with "vitiligo-like" lesions
or leukomelanoderma. In two patients, atrophy of the skin and sclerosis were particularly severe. These patients had multiple pearly-white plaques (Fig. 2), telangiectasia (poikiloderma), diffuse skin ulcerations, contractures, and retractions. One of them had sclerodactyly (Fig. 3). Atrophy of the nails occurred in one case and koilonychia in another. Lichenoid lesions (erosive or not) of the oral mucosa were present in four cases. Histopathologic examination. Skin biopsy specimens were obtained from six patients. Biopsies were
Journal of the American Academy of Dermatology
52 Chosidow et ai.
Fig. 3. Sclerodactyly.
in three cases. The epidermis was normal in two cases but atrophic in four, especially in the two patients with multiple pearly-white plaques. Basal layer vacuolar degeneration, inflammation, and eosinophilic body formation were found in one case. Dermal alterations included fibrosis and destruction of adnexal structures. The papillary and reticular dermis could not be distinguished. Fibrosis extended to the subcutaneous fat in four cases. In a patient with edematous infiltration, a muscle biopsy specimen showed a centripetal fibrosing process of the fascia (with rare mononuclear cells), the interfascicular septa, and the endomysium (Fig. 4). In one case, a skin biopsy spec:imen of the periorbital area was obtained 75 days before generalized sclerodermatous GVHD. It showed vacuolization of basal epidermal cells with a slight lymphohistiocytic infiltrate, free melanin deposits and melanophages, and superficial fibrosis in the papillary dermis (Fig. 5). Extracutaneous manifestations (Table III)
Fig. 4. Histologic appearance of diffuse fasciitis. Centripetal fibrosing process affects fascia, interfascicular septa, and endomysium. *, Fascia; **, muscle. (X30.)
performed I to 50 days after the clinical diagnosis of sclerodermatous chronic GVHD (mean 12.5 days) but in all cases before specific therapy. Sites of the biopsies were the trunk in three cases and the arms
Raynaud's phenomenon was noted in one case. Capillaroscopy was performed in five cases and revealed only nonspecific vascular changes. Reduced lacrimal secretion (xerophthalmia and/or Schirmer's test -< 10 mm in 5 minutes) was noted in six cases. Five patients presented with chronic pulmonary abnormalities with no documented microbiologic cause, including cytomegalovirus. Two patients had obliterative bronchiolitis, defined by chronic cough, dyspnea, and a ratio of forced expiratory volume in 1 second (FEV!) to forced vital capacity (FVC) lower than 70%. This pattern is very suggestive ofchronic GVHD; in one ofthese patients
Volume 26 Number 1 January 1992
Sclerodermatous chronic GVHD 53
Fig. 5. Histologic appearance ofperiorbital pigmentation. Vacuolization ofbasal epidermal cells (arrow) , slight lichenoid lymphohistiocytic infiltrate, free melanin deposits and melanophages, and superficial fibrosis. (X250.)
Table III. Extracutaneous manifestations
UPN 001
Vascular Raynaud's phenomenon Ophthalmologic Reduced lacrimal secretion Pulmonary Chest x-ray abnormalities Pulmonary function test Diffusion capacity (CO) Esophageal Dysphagia Radiocinema or manometry Hepatic Cirrhosis Intestinal Enteropathy Immunologic Rheumatoid factor Antinuclear autoantibodies Anticentromere Anti-Scl-70 Antimitochondria Anti-smooth muscle
071
107
110
144
+
+
146
164
+ + NI ND
+ +
+ + (0)
NI
+ + (0)
+
ND
+
+ (R) +
+
+ +
+ +
+ + + ND ND ND ND
ND
+
ND
+
+ +
ND
+ ND NI
+
+
ND, Not done; NJ, not interpretable; (0), obstructive; (R), restrictive; UPN, unique patient number.
the diagnosis of obliterative bronchiolitis was confirmed by bronchial biopsy specimens. The three remaining patients had either a severe restrictive ventilatory defect and septal dense fibrosis with
fiberoptic biopsy specimens or a decreased diffusion capacity. These patterns may be related to chronic GVHD, but may also be induced by irradiation or chemotherapy. Esophageal involvement was foood
54 Chosidow et at. in one case (with decreased esophageal peristalsis on cineradiography) and cirrhosis was present in two. In one patient, enteropathy with diarrhea and malabsorption was documented and related to lymphocytic infiltration and fibrosis of the intestinal submucosa. Patient sera were tested at various times for several autoantibodies, with concordant results. Two patients had antinuclear antibodies (1 :200 and 1:1000) (normal <1:10) with speckled pattern and five patients had anti-smooth muscle antibodies (1:10 in one patient, 1:50 in three, and 1:100 in one) (normal < 1: 10). No antibodies against centromere antigens or DNA topoisomerase I (Sc1-70) were found (in 6 and 5 patients tested, respectively).
Therapy and course All patients initially received a combination of prednisone (0.5 to 1 mg/kg/day) and azathioprine (50to 150mg/day) or cyclophosphamide (50 to 100 mg/day) for 3 to 12 months. The two patients with the severe atrophic form died, 2 and 6 years after BMT: the first of septicemia and the other of severe malnutrition. In this last patient no significant improvement was seen after thalidomide (2 mg/ kg/day) given for 5 months. The remaining five patients are alive. Three had a favorable course that persisted after discontinuation of the therapy; the resolution of the periorbital eruption was associated with overall clinical improvement in two of these patients. The two other patients had persistent lesions that justified further treatment. One patient received alternating-day cyclosporine (6 mg/kg every 12 hours every other day) and prednisone (1 mg/kg every other day) for 6 months and showed rapid improvement. One patient received cyclosporine (2 mg/kg every 12 hours) for 6 months with partial improvement. DISCUSSION
We report seven cases of generalized sclerodermatous chronic GVHD after bone marrow transplantation from an HLA identical sibling donor. This complication occurred in only 3.6% of the 196 patients at risk of chronic GVHD observed during a 14-year period in our bone marrow transplant unit. Fewseries ofpatients with chronic cutaneous GVHD have been reported and only a few of these cases presented with sclerodermatous changes. 2-4 The cutaneous features of these patients have never before been described in detail. In our series, sclerodermatous changes always began on previous lesions of
Journal of the American Academy of Dermatology
acute or lichenoid GVHD or on zoster Or suction blister scars, as already reported. 5, 7, 8 Various types of cutaneous injury may trigger the formation of sclerodermatous GVHD lesions. Hyperpigmentation ofthe periorbital area has been observed in some cases. 1 In our series, it occurred 75 to 165 days after the graft and may be a predictive sign of extensive sclerodermatous GVHD. Improvement coincided in two patients with the resolution of this periorbital pigmentation. However, the incidence of periorbital hyperpigmentationin patients withlichenoid GVHD in whom sclerodermatous chronic lesions do not develop is unknown. In five patients, cutaneous lesions presented as inflammatory guttate sclerosis and/or edematous infiltration associated with hyperpigmented lesions. These patients had a favorable outcome. Two patients initially presented with extensive sclerotic lesions associated with multiple atrophic pearly~white plaques and ulcerations. The outcome was fatal in both cases. This sclerotic pattern may therefore be a marker of severe chronic GVHD. Results of experimental studies strongly support an autoimmune pathophysiology of chronic GVHD. The normal ability of the thymus to delete autoreactive T cells and to induce tolerance may be impaired. These autoreactive T cells produce unusual patterns of cytokines such as interleukin 4 and interferon gamma and can stimulate the production of collagen by fibroblasts. 9 Because chronic GVHD resembles some connective tissue diseases, such as systemic scleroderma and lupus erythematosus, it may be considered a model for pathogenetic studies. 10 Some authors have hypothesized that both diseases, systemic scleroderma and sclerodermatous chronic GVHD, might be closely related because both are associated with Sjogren's syndrome, pulmonary and esophageal involvement, and immunologic disorders. 1 1, 12 Hepatic involvement in GVHD may resemble primary biliary cirrhosis. 13 Raynaud's phenomenon is rare but may occur. However, differences between systemic scleroderma and sclerodermatous GVHD merit further discussion. ( 1) The initial location of the sclerosis is clearly the reticular dermis in scleroderma. In our cases, the initial site of the lesion was difficult to appreciate because the sclerosis rapidly involved the entire dermis. Electron microscopy and immunohistologic studies have revealed several differences. In sclerodermatous GVHD, the staining for procollagen I and III and collagen III was not more intense than in normal
Volume 26 Number 1 January 1992
skin but a zone three times thicker was stained in the papillary dermis. In contrast, abnormal staining of collagen III in the reticular dermis has been found in scleroderma. 14 (2) Visceral involvement associated with systemic scleroderma is difficult to evaluate in chronic GVHD patients in whom several factors may induce organ damage. For example, interstitial pneumonia may be related to radiation or chemotherapy toxicity, infection, lymphoid interstitial pneumonia,15 or bronchiolitis. 16 In the esophagus chronic GVHD lesions, unlike those of scleroderma, show submucosal fibrosis with no muscle or neuronal involvement,17 (3) Antibody patterns in chronic GVHD patients differ from those in connective tissue diseases. IS, 19 In our series we did not find antinucleolar, anticentromere or anti-Scl-70 antibodies. Thus sclerodermatous chronic GVHD appears to be a distinct clinical entity. Response to therapy in our patients was variable. Combined immunosuppression (azathioprine and prednisone) was effective in three patients. Alternating-day cyclosporine and prednisone induced a good response in another patient. This treatment is known to improve survival in patients with severe chronic GVHD.20 Thalidomide has also been reported to cause improvement in sclerodermatous GVHD21; however, we did not observe significant improvement with this drug in one of our patients. All treatments were ineffective in both patients with severe atrophic chronic sclerodermatous GVHD. REFERENCES 1. Sullivan KM, Shulman HM, Stmb R, et al. Chronic graftversus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 1981;57:267-70. 2. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in man: a long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980;69:204-17. 3. Herzog P, Clements PJ, Roberts NK, et al. Progressive systemic sclerosis like syndrome after bone marrow transplantation. J Rheumatol 1980;7:56-64. 4. Graze PR, Gale RP. Chronic graft versus host disease: a syndrome ofdisordered immunity. Am J Med 1979;66:61120.
Sclerodermatous chronic GVHD 55 5. Shulman HM, Sale GE, Lerner KG, et al. Chronic cutaneous graft-versus-host disease in man. Am J Pathol 1978;92:545-70. 6. Deeg HJ, Storb R. Acute and chronic graft-versus-host disease: clinical manifestations, prophylaxis and treatment. JNCI 1986;76:1325-8. 7. Fenyk JR, Smith CM, Warkentin PI, et al. Sclerodermatous graft-versus-host disease limited to an area of measles exanthem. Lancet 1978;1:472-3. 8. Urbano-Marquez A, Estruch R, Grau JM, et al. Inflammatory myopathy associated with chronic graft-versus-host disease. Neurology 1986;36:1091-3. 9. Ferrara JLM, Deeg HJ. Graft-versus-host disease. N Engl J Med 1991;324:667-74. 10. Roujeau J-C, Revuz J, Touraine R. Graft-versus-host reactions. In: Rook A, Kamiya N, eds. Recent advances in dermatology. New York: Churchill Livingstone, 1980:13157. 11. Graham-Brown RAC, Sarkani 1. Scleroderma-like changes due to chronic graft-versus-host disease. Clin Exp DermatoI1983;8:531-8. 12. Lawley TJ, Peck GL, Moutsopoulos HM, et al. Scleroderma, Sjogren-like syndrome and chronic graft-versushost disease. Ann Intern Med 1977;87:707-9. 13. Epstein 0, Thomas HC, Sherlock S. Primary biliary cirrhosis is a dry gland syndrome with features of chronicgraft-versus-host disease. Lancet 1980;1:1166-8. 14. Janin-Mercier A, Devergie A, Van Cauwenberg D, et al. Immunohistologic and ultrastructural study of the sclerotic skin in chronic graft-versus-host disease in man. Am J PathoI1984;115:296-306. 15. Perreault C, Cousineau S, D'Angelo G, et al. Lymphoid interstitial pneumonia after allogeneic bone marrow transplantation. Cancer 1985;55:1-9. 16. Hyland RH, Chan CK, Hutcheon MA, et al. Bronchiolitis in allogeneic bone marrow transplant recipients. Int J Cell Clan 1986;4(suppl 1 ):203-5. 17. McDonald GB, Sullivan KM, Schuffier MD, et al. Esophageal abnormalities in chronic graft-versus-host disease in humans. Gastroenterology 1981;80:914-21. 18. Rouquette-Gally AM, Boyeldieu D, Gluckman E, et al. Auto-immunity in 28 patients after allogeneic bone marrow transplantation: comparison with Sjogren syndrome and scleroderma. Br J Haematol1987;66:45-7. 19. Dighiero G, Intrator L, Cordonnier C, et al. High levels of anti-cytoskeleton autoantibodies are frequently associated with chronic GVHD. Br J Haematol 1987;67:301-5. 20. Sullivan KM, Witherspoon RP, Storb R, et al. Alternatingday cyclosporine and prednisone for treatment of high-risk chronic graft-v-host disease. Blood 1988;72:555-61. 21. Heney D, Lewis 11, Bailey Cc. Thalidomide for chronic graft-versus-host disease in children [Letter]. Lancet 1988;2:1317.