aplastic anemia. As the disease was steroid-resistant, the patient underwent allogeneic bone marrow transplan- tation (BMT). Remission of ShS was achieved.
Bone Marrow Transplantation, (1998) 21, 637–639 1998 Stockton Press All rights reserved 0268–3369/98 $12.00
Case report Successful treatment of severe Shulman’s syndrome by allogeneic bone marrow transplantation ˘ ´ ´ ´ P Cetkovsky1, V Koza1, P Cetkovska2 and M Svojgrova1 1
Department of Haematology and Oncology, and 2Department of Dermatology and Venerology, Charles University Hospital, Pilsen ˘ (Plzen), Czech Republic
Summary: We describe a patient with severe Shulman’s syndrome (ShS) (eosinophilic fasciitis). This auto-immune disease involved not only the skin and muscles, but the bone marrow as well – thereby fulfilling the criteria of severe aplastic anemia. As the disease was steroid-resistant, the patient underwent allogeneic bone marrow transplantation (BMT). Remission of ShS was achieved. Eight months later chronic GVHD developed and relapse of ShS (probably induced by GVHD) occurred. He was successfully treated with corticosteroids and the disappearance of GVHD was followed by cessation of the symptoms of ShS. At present (34 months following BMT) he is doing well and displays no signs of ShS or GVHD. This case suggests that an aggressive immunoablative preparative regimen with subsequent allogeneic BMT can result in long-lasting clinical remission of a severe auto-immune disease. Keywords: allogeneic bone marrow transplantation; severe auto-immune disease; Shulman’s syndrome; eosinophilic fasciitis; GVHD; severe aplastic anemia
Shulman’s syndrome (ShS) (eosinophilic fasciitis), the auto-immune disease that appears to be a variant of scleroderma, was described 24 years ago.1 The patients are predominantly middle-aged males who rapidly develop typical induration of the skin. Sclerodermatous changes characteristically occur in the skin of the upper extremities and trunk, usually sparing the hands and fingers. The skin becomes hard and wrinkled and is tightly bound to underlying structures. Raynaud’s phenomenon and sclerosis of internal organs are unusual.1,2 Blood eosinophilia occurs in 70% of cases. The sera of some of these patients have demonstrated the presence of humoral factors (probably autoantibodies) capable of suppressing myeloid and erythroid precursors. Therefore, in a small number of ShS patients, aplastic anemia subsequently develops.3 Extremely rarely, ´ Correspondence: Dr P Cetkovsky, BMT Unit, Department of Haematology and Oncology, Charles University Hospital, alej Svobody 80, 304 60 ˘ Pilsen (Plzen), Czech Republic Received 14 August 1997; accepted 20 October 1997
the hematological findings in the most severe clinical form fulfill the criteria of severe aplastic anemia (SAA). There is no curative treatment for patients with severe auto-immune diseases (SADS; the term coined by Professor A Marmont) and therapy is based on relief of symptoms, suppression of presymptomatic laboratory abnormalities, and prevention of organ damage.2 High-dose chemotherapy with subsequent hematopoietic stem cell transplantation has been proposed recently as the first potentially curative treatment for SADS because it is assumed that a myeloablative preparative regimen can destroy auto-aggressive lymphocyte clones.4–8 We describe a patient suffering from severe, corticosteroid-resistant ShS. He underwent allogeneic BMT and remission of ShS was achieved. During chronic GVHD (cGVHD) relapse of ShS occurred and was successfully treated with corticosteroids. Case report A 43-year-old man suffered from ShS from May 1994. This was characterized by induration of the skin of the upper extremities (sparing the hands and fingers) and the trunk (maximal on the abdomen). Painful contractures and muscle weakness were present involving the muscles of the upper extremities and abdomen. Raynauds’s phenomenon was not found. The changes were associated with constitutional symptoms, such as fatigue, malaise, anorexia and weight loss (15% of the total body weight). In September 1994 examination revealed a normal blood count except for slight transient eosinophilia. When the patient was advised of the possibility of corticosteroid therapy he refused further examination and medical care and sought paramedical aid (alternative medicine). He was admitted to hospital in February 1995 with hemorrhage into the skin (petechiae, ecchymoses and oozing from venipunctures), mucosal surfaces and intracranially. Massive bleeding into gastrointestinal and genitourinary tracts (hematemesis, melena, hematuria) was also present. The blood count was as follows: white blood cells (WBC) 2.1 ⫻ 109/l (neutrophils 23%, eosinophils 28%, plasma cells 2%, lymphocytes 45%, monocytes 2%), hemoglobin (Hb) 43 g/l (reticulocytes less than 50 ⫻ 109/l), platelets 2 ⫻ 109/l. Trephine biopsy of the marrow showed overall hypocellularity (less than 20%).
BMT in Shulman’s syndrome ´ P Cetkovsky et al
638
The symptoms of ShS were worse than in September 1994: the painful contractures, muscle weakness and sclerodermatous process had progressed. Deep biopsy of the skin was not carried out due to the risk of bleeding because of the profound refractory thrombocytopenia, and only a regular skin biopsy was performed. Histopathological findings showed dermal sclerosis with inflammation and fibrosis of the fat, with calcinosis. Antinuclear antibodies (ANA) including extractable nuclear entigens (ENA) were negative, and serum immune complexes were within normal limits. As high-dose methylprednisolone (MP) treatment was unsuccessful and the blood count did not improve, he underwent allogeneic BMT with his HLA-identical sister as a donor in April 1995. Conditioning consisted of CY 200 mg/kg for 4 days. Twenty-four hours after conditioning he received 2.56 ⫻ 108 nucleated cells/kg. No growth factors were used during the post-transplant period. CyA and ‘short’ MTX were used as GVHD prophylaxis. The granulocyte count reached 0.5 ⫻ 109/l on day ⫹17, and platelets 50 ⫻ 109/l on day ⫹14, complete chimerism was confirmed (evaluation of the chimerism was performed by twostep PCR amplification of hypervariable region MCT 118 and single-step PCR assay for sex identification:amelogenin gene). His clinical course was uneventful. The signs of ShS completely disappeared from day ⫹29. He was discharged on day ⫹34 with a WBC of 3.7 ⫻ 109/l (66% neutrophils, 20% lymphocytes, and 14% monocytes), Hb of 117 g/l and platelets of 241 ⫻ 109/l without any signs of ShS. Control examination of a biopsy specimen revealed no sclerodermic changes and the calcinosis had also completely disappeared. The post-transplant course was uneventful until August 1995, when elevated liver function tests were noted. Liver biopsy (September 1995) showed drug-induced hepatopathy. CyA was stopped, GVHD prophylaxis with MP was started and the liver tests improved. In October 1995 he developed Listeria monocytogenes meningitis and he was therefore treated with ampicillin and aminoglycoside, and the prophylactic MP was stopped. In December 1995, because of limited mucocutaneous (skin biopsy showed lichenoid cGVHD changes) and liver cGVHD, therapy with MP was again initiated. During the period of cGVHD some of the clinical signs of ShS returned (weakness and painful contractures in the muscles of the upper extremities and abdomen). After treatment with MP, the cGVHD fully resolved and the symptoms of ShS also disappeared within 6 weeks. MP was discontinued in May 1996 and cessation of the immunosuppressive therapy did not result in a relapse of cGVHD and/or ShS. He is doing well with no signs of cGVHD for more than 34 months after BMT, on no therapy. He also has no clinical signs of ShS and histological examination of the skin and immunologic parameters are within normal limits. At present, his blood count shows a WBC of 8.9 ⫻ 109/l, Hb 151 g/l, and platelets of 222 ⫻ 109/l. Discussion SADS represents a small subset of patients with autoimmune diseases who have a high risk of early mortality due to the rapidly progressive disease which is incurable
with conventional therapy. Remission from SADS, before development of irreversible organ damage, can probably be achieved with myeloablative treatment and BMT.4–8 In the autologous BMT setting,9 therapeutic interventions aim to restore the function of the immune system to its major role in the prevention rather than production of disease.2 A recently published study noted persistence or rapid recurrence of SADS after unmanipulated autologous BMT9 and so T cell depletion seems to be necessary. In allogeneic BMT, the replacement of defective lymphopoiesis by donor lymphohematopoietic stem cells can result in long-lasting clinical remissions of SADS due to a newly developed immune system.4–8 However, complete ablation of the immune system, inhibiting an auto-immune process cannot completely suffice to control SADS, as self-antigen as well as antigen-presenting cells can remain in the patient.8 New histological and immunological findings have shown that cGVHD is of auto-immune origin. Since classical auto-immune diseases and cGVHD have closely related pathogeneses – autoaggressive T lymphocytes and autoantibodies – cGVHD could theoretically worsen the post-transplant remission status of SADS. It may be the reason why in our patient some clinical signs of ShS returned during the period of cGVHD. MP was started and the cGVHD completely resolved. Probably due to early initiation of corticosteroid therapy, the patient did not develop the clinical picture of severe ShS and the symptoms of ShS disappeared within 6 weeks. Later cessation of the immunosuppressive therapy did not result in a relapse of either ShS or cGVHD. The relationship between post-transplant relapse of theoretically cured SADS and cGVHD requires investigation. The majority of cases of SAA appear to be of autoimmune origin. Of all the auto-immune diseases, only SAA is routinely treated with allogeneic BMT (for older patients or those without compatible donors alternative therapy is used: ATG and/or CyA). Delay in starting conventional treatment (due to the patient refusing medical care) was the probable reason why the ShS had no classical benign clinical course and progressed to SADS with severe inhibition of hematopoiesis (fulfilling the diagnostic criteria for SAA). Because the disease was refractory to high-dose MP therapy, he underwent potentially curative allogeneic BMT. Successful treatment of ShS associated with SAA using ATG and CyA has already been reported10 but to our knowledge there have been no previous reports of severe ShS treated with allogeneic BMT. Acknowledgements The bone marrow transplantation program for SAA patients at the BMT Unit in Pilsen is partly supported by grant No. 2993–4 from IGA of the Ministry of Health of The Czech Republic.
References 1 Shulman LE. Diffuse fasciitis with hypergammaglobulinemia and eosinophilia. J Rheumatol 1974; 1 (Suppl. 1): 46 (Abstr.). 2 Condemi JJ. The autoimmune disease. JAMA 1987; 258: 2920–2929.
BMT in Shulman’s syndrome ´ P Cetkovsky et al
3 Shulman LE, Hoffman R, Dainiak N et al. Antibody-mediated aplastic anemia and thrombocytopenic purpura in diffuse eosinophilic fasciitis. Clin Res 1979; 27: 514A. 4 van Bekkum DW, Marmont A, Tyndall A et al. Severe autoimmune disease: a new target for bone marrow transplantation. Stem Cells 1996; 14: 460–472. 5 van Gelder M, van Bekkum DW. Treatment of relapsing experimental autoimmune encephalomyelitis in rats with allogeneic bone marrow transplantation from a resistant strain. Bone Marrow Transplant 1995; 16: 343–351. 6 Marmont AM, van Bekkum DW. Stem cell transplantation for severe autoimmune disease: new proposal but still unanswered questions. Bone Marrow Transplant 1995; 16: 497–498.
7 Brinch L, Evensen SA, Tjonnfjord GE, Sorum Z. Long-term remission of Crohn’s disease after AML treatment and allogeneic marrow transplantation. Bone Marrow Transplant 1997; 19: (Suppl. 1): S206 (Abstr. P820). 8 Burt RK, Burns W, Hess A. Bone marrow transplantation for multiple sclerosis. Bone Marrow Transplant 1995; 16: 1–6. 9 Euler HH, Marmont AM, Bacigalupo A et al. Early recurrence of autoimmune disease after unmanipulated autologous stem cell transplantation. Blood 1996; 88: 3621–3625. 10 Debusscher L, Bitar N, De Maubeuge J et al. Eosinophilic fasciitis and severe aplastic anemia: favorable response to either antithymocyte globulin or cyclosporine A in blood and skin disorders. Transplant Proc 1988; 20 (Suppl. 4): 310–313.
639
