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Treatment of systemic sclerosis with autologous haemopoietic stem cell transplantation
THE LANCET
Treatment of systemic sclerosis with autologous haemopoietic stem cell transplantation A Tyndall, C Black, J Finke, J Winkler, R Mertlesmann, H H Peter, A Gratwohl
Systemic sclerosis (scleroderma) is an autoimmune connective tissue disease with an often progressive and fatal course involving skin and vital organs. There is no definitive treatment. The pathology is complex, but a substantial immunological component is implied by the consistent finding of T-cells of the α/β subset producing interleukin-2 in biopsy specimens of involved organs.1 In addition, some success has been noted following immunosuppression of the lung involvement with cyclophosphamide.2 We report a case treated with immune ablation followed by autologous haemopoietic stem cell transplantation (HSCT) with apparent early (followup 6 months) response. A 37-year-old woman developed Raynaud’s phenomenon in the hands 5 years ago. 2 years later, during the third trimester of her only pregnancy, she developed skin thickening and joint stiffness which rapidly progressed after parturition such that 6 months later she had diffuse skin involvement with pigmentation changes (skin score 41), myositis, and high resolution computed tomographic evidence of fibrosing alveolitis (plain radiographs normal). Lung function tests showed mild restriction (probably external) but normal diffusion capacity (TLCO). No doppler-echo evidence of pulmonary hypertension was found, and systemic blood pressure remained normal. Antinuclear antibody was positive (titre 5120) with a fine, speckled, diffuse, and nucleolar pattern, and Scl 70 antibody was positive at a titre above 1000 by ELISA. Other laboratory values were normal, including serum creatinine and urinalysis. Despite initial symptomatic improvement on prednisone 25 mg, felodipine, and penicillamine, the skin involvement progressed and after 6 months penicillamine-induced glomerulonephritis developed (biopsy proven with no signs of systemic sclerosis renal changes). TLCO dropped to 18·9 mL/min per mm Hg (67% normal). After extensive cross consultation, ethics committee approval and informed consent were obtained for intensive immunoablation followed by autologous HSCT, which was carried out in May, 1996. Priming was done with two doses of cyclophosphamide 2 g/m2 and daily granulocyte colonystimulating factor 5 mg/kg subcutaneously. On day 10 7·4⫻108 per kg body weight nucleated cells were harvested from peripheral blood, of which 32·8⫻106 per kg were CD34 positive (stem and precursor cells) and 220⫻106 per kg CD3 cells. The transplant product was purged with positive CD34 selection (Ceprate R) and T-cell depletion with CD3 antibody (Miltenyi). This yielded a final product of 8·2⫻106 per kg body weight CD34 cells and 0·04⫻106 per kg body weight CD3 cells. Conditioning (haematological ablation) was with four doses of cyclophosphamide 50 mg/kg over 4 days, inducing an aplastic period of 10 days. She was discharged on day 14 after conditioning with full haematological reconstitution. Complications were mild self-limiting haemorrhagic cystitis and an episode of herpes zoster, responding to acyclovir. 6 weeks after HSCT she began to feel slightly stronger with less skin tightness, though the skin severity score remained unchanged at 41 points.3 At 6 months there was subjective improvement with more energy, minimum joint stiffness and pain, and less skin tightness. The skin score was reduced by seven points to 34. The pigmentation changes were disappearing and there were no further ischaemic lesions of the finger tips. Repeat lung function tests showed no deterioration and no pulmonary hypertension was detected. Antinuclear
254
antibody titre was reduced to 320 and Scl 70 to 200. Current medication is prednisone 5 mg and felodipine 10 mg daily. The extent and duration of this clinical and serological improvement is difficult to predict, but 12 and 24 month follow-up is planned. This case is of a growing number of patients with serious autoimmune disease being treated and recorded under a combined European Group for Blood and Marrow Transplantation and European League Against Rheumatism programme.4,5 1
2
3
4
5
Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992; 166: 255–63. Steen VD, Lanz J Jr, Conte C, et al. Therapy for severe intestinal lung disease in systemic sclerosis: a retrospective study. Arthritis Rheum 1994; 37: 1290–96. Kahaleh MB, Sultany GL, Smith EA, Huffstutter JE, Loadholt CB, LeRoy EC. A modified sclerodermal skin scoring method. Clin Exp Rheumatol 1986; 4: 367–69. Marmont A, Tyndall A, Gratwohl A, Vischer T. Haemopoietic precursor-cell transplants for autoimmune diseases. Lancet 1995; 345: 978. Tyndall A, Gratwohl A. Consensus statement: blood and marrow stem cell transplants in autoimmune diseases. Bone Marrow Transplant (in press).
Departments of Rheumatology (A Tyndall) and Haematology, Felix Platter Spital, 4055 Basel, Switzerland; Departments of Haematology and Rheumatology/Immunology Clinic, University Clinic, Freiburg, Germany; and Department of Rheumatology, Royal Free Hospital, London, UK
Leptospirosis presenting as haemorrhagic fever in visitor to Africa Jean-Jacques Monsuez, Rachid Kidouche, Bernard Le Gueno, Daniele Postic
During a 1-month stay in the Ivory Coast, a 35-year-old French woman joined a tour to a rural area where she had contact with cattle, sheep, and monkeys. She took meals with a farming family but did not bathe in a river. When she returned to France, 15 days later, she was admitted to hospital with a fever of 39ºC, neckache, headache, vomiting, and abdominal pain. Physical examination was normal apart from a mild tenderness over her liver. There was no anaemia or leucocytosis. Other routine laboratory investigations were normal as was a chest radiograph and abdominal ultrasound. Blood, urine, and stool cultures remained unremarkable. Malaria and amoebic liver abscess were ruled out by stained blood smears and serology, respectively. Cerebrospinal fluid was also normal. 2 days after admission, she had bleeding from her nose, ears, and macroscopic vagina, and haematuria. There were no coagulation factors disorders nor thrombocytopenia. Although fever slightly decreased with ampicillin, ciprofloxacin, and gentamycin, an African haemorrhagic fever (AHF) was suspected and the patient was isolated for 10 days until two serological tests remained negative for dengue, Ebola, Lassa, and Rift Valley Fever viruses as well as for arboviruses (alphavirus, flavivirus, bunyavirus, and phleboviruses). No AHF virus was isolated on Vero and C6 36 viral cultures. Subsequently, the patient seroconverted for Leptospira with appearance of IgM class antibodies (Elisa 1/1600) and a positive microagglutination test for L canicola (1/200) and L patoc (1/200). Bleeding complications and fever resolved and she recovered with ampicillin. Recognition of leptospirosis as a cause of unexplained haemorrhagic fever in patients returning from African countries may have clinical implications because leptospirosis has recently been reported in patients who travelled to tropical areas, including Africa.1 The recent outbreak of
Vol 349 • January 25, 1997
Treatment of systemic sclerosis with autologous haemopoietic stem cell transplantation A Tyndall, C Black, J Finke, J Winkler, R Mertlesmann, H H Peter, A Gratwohl
Systemic sclerosis (scleroderma) is an autoimmune connective tissue disease with an often progressive and fatal course involving skin and vital organs. There is no definitive treatment. The pathology is complex, but a substantial immunological component is implied by the consistent finding of T-cells of the α/β subset producing interleukin-2 in biopsy specimens of involved organs.1 In addition, some success has been noted following immunosuppression of the lung involvement with cyclophosphamide.2 We report a case treated with immune ablation followed by autologous haemopoietic stem cell transplantation (HSCT) with apparent early (followup 6 months) response. A 37-year-old woman developed Raynaud’s phenomenon in the hands 5 years ago. 2 years later, during the third trimester of her only pregnancy, she developed skin thickening and joint stiffness which rapidly progressed after parturition such that 6 months later she had diffuse skin involvement with pigmentation changes (skin score 41), myositis, and high resolution computed tomographic evidence of fibrosing alveolitis (plain radiographs normal). Lung function tests showed mild restriction (probably external) but normal diffusion capacity (TLCO). No doppler-echo evidence of pulmonary hypertension was found, and systemic blood pressure remained normal. Antinuclear antibody was positive (titre 5120) with a fine, speckled, diffuse, and nucleolar pattern, and Scl 70 antibody was positive at a titre above 1000 by ELISA. Other laboratory values were normal, including serum creatinine and urinalysis. Despite initial symptomatic improvement on prednisone 25 mg, felodipine, and penicillamine, the skin involvement progressed and after 6 months penicillamine-induced glomerulonephritis developed (biopsy proven with no signs of systemic sclerosis renal changes). TLCO dropped to 18·9 mL/min per mm Hg (67% normal). After extensive cross consultation, ethics committee approval and informed consent were obtained for intensive immunoablation followed by autologous HSCT, which was carried out in May, 1996. Priming was done with two doses of cyclophosphamide 2 g/m2 and daily granulocyte colonystimulating factor 5 mg/kg subcutaneously. On day 10 7·4⫻108 per kg body weight nucleated cells were harvested from peripheral blood, of which 32·8⫻106 per kg were CD34 positive (stem and precursor cells) and 220⫻106 per kg CD3 cells. The transplant product was purged with positive CD34 selection (Ceprate R) and T-cell depletion with CD3 antibody (Miltenyi). This yielded a final product of 8·2⫻106 per kg body weight CD34 cells and 0·04⫻106 per kg body weight CD3 cells. Conditioning (haematological ablation) was with four doses of cyclophosphamide 50 mg/kg over 4 days, inducing an aplastic period of 10 days. She was discharged on day 14 after conditioning with full haematological reconstitution. Complications were mild self-limiting haemorrhagic cystitis and an episode of herpes zoster, responding to acyclovir. 6 weeks after HSCT she began to feel slightly stronger with less skin tightness, though the skin severity score remained unchanged at 41 points.3 At 6 months there was subjective improvement with more energy, minimum joint stiffness and pain, and less skin tightness. The skin score was reduced by seven points to 34. The pigmentation changes were disappearing and there were no further ischaemic lesions of the finger tips. Repeat lung function tests showed no deterioration and no pulmonary hypertension was detected. Antinuclear
254
antibody titre was reduced to 320 and Scl 70 to 200. Current medication is prednisone 5 mg and felodipine 10 mg daily. The extent and duration of this clinical and serological improvement is difficult to predict, but 12 and 24 month follow-up is planned. This case is of a growing number of patients with serious autoimmune disease being treated and recorded under a combined European Group for Blood and Marrow Transplantation and European League Against Rheumatism programme.4,5 1
2
3
4
5
Prescott RJ, Freemont AJ, Jones CJ, Hoyland J, Fielding P. Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992; 166: 255–63. Steen VD, Lanz J Jr, Conte C, et al. Therapy for severe intestinal lung disease in systemic sclerosis: a retrospective study. Arthritis Rheum 1994; 37: 1290–96. Kahaleh MB, Sultany GL, Smith EA, Huffstutter JE, Loadholt CB, LeRoy EC. A modified sclerodermal skin scoring method. Clin Exp Rheumatol 1986; 4: 367–69. Marmont A, Tyndall A, Gratwohl A, Vischer T. Haemopoietic precursor-cell transplants for autoimmune diseases. Lancet 1995; 345: 978. Tyndall A, Gratwohl A. Consensus statement: blood and marrow stem cell transplants in autoimmune diseases. Bone Marrow Transplant (in press).
Departments of Rheumatology (A Tyndall) and Haematology, Felix Platter Spital, 4055 Basel, Switzerland; Departments of Haematology and Rheumatology/Immunology Clinic, University Clinic, Freiburg, Germany; and Department of Rheumatology, Royal Free Hospital, London, UK
Leptospirosis presenting as haemorrhagic fever in visitor to Africa Jean-Jacques Monsuez, Rachid Kidouche, Bernard Le Gueno, Daniele Postic
During a 1-month stay in the Ivory Coast, a 35-year-old French woman joined a tour to a rural area where she had contact with cattle, sheep, and monkeys. She took meals with a farming family but did not bathe in a river. When she returned to France, 15 days later, she was admitted to hospital with a fever of 39ºC, neckache, headache, vomiting, and abdominal pain. Physical examination was normal apart from a mild tenderness over her liver. There was no anaemia or leucocytosis. Other routine laboratory investigations were normal as was a chest radiograph and abdominal ultrasound. Blood, urine, and stool cultures remained unremarkable. Malaria and amoebic liver abscess were ruled out by stained blood smears and serology, respectively. Cerebrospinal fluid was also normal. 2 days after admission, she had bleeding from her nose, ears, and macroscopic vagina, and haematuria. There were no coagulation factors disorders nor thrombocytopenia. Although fever slightly decreased with ampicillin, ciprofloxacin, and gentamycin, an African haemorrhagic fever (AHF) was suspected and the patient was isolated for 10 days until two serological tests remained negative for dengue, Ebola, Lassa, and Rift Valley Fever viruses as well as for arboviruses (alphavirus, flavivirus, bunyavirus, and phleboviruses). No AHF virus was isolated on Vero and C6 36 viral cultures. Subsequently, the patient seroconverted for Leptospira with appearance of IgM class antibodies (Elisa 1/1600) and a positive microagglutination test for L canicola (1/200) and L patoc (1/200). Bleeding complications and fever resolved and she recovered with ampicillin. Recognition of leptospirosis as a cause of unexplained haemorrhagic fever in patients returning from African countries may have clinical implications because leptospirosis has recently been reported in patients who travelled to tropical areas, including Africa.1 The recent outbreak of
Vol 349 • January 25, 1997