Haematopoietic stem cell transplantation for refractory Takayasu's arteritis

J. C. Voltarelli, M. C. B. Oliveira, A. B. P. L. Stracieri, D. F. Godoi, D. A. Moraes, M. A. Coutinho, K. C. R. Malmegrim and A. C. Santos1

Bone Marrow Transplantation Unit and 1 Division of Radiology, Department of Clinical Medicine, University Hospital (Hospital das Clínicas), School of Medicine of Ribeirão Preto, University of São Paulo, Brazil

Correspondence to: J. C. Voltarelli, Regional Blood Center (Hemocentro), Campus USP, 14051–140, Ribeirão Preto, Brazil. E-mail: jcvoltar{at}fmrp.usp.br

SIR, Takayasu's arteritis is a rare large-vessel vasculitis with a variable natural history. Manifestations range from asymptomatic disease to catastrophic neurological impairment and 5-yr survival is 60–70% in up to 25% of patients with progressive disease. Fifty per cent of patients respond to steroids and 30–50% of non-responders benefit from other forms of immunosuppression [1].

Eleven cases of small- or medium-vessel vasculitis submitted to autologous haematopoietic stem cell transplantation (HSCT) have been reported worldwide [2, 3] and a further two in Brazil [4, 5]. Outcome is variable: 1/1 complete remission (CR) in polyarteritis nodosa, 1/3 CR in Wegener's granulomatosis, 1/3 CR and 1/3 partial remission (PR) in Behçet's disease, 2/3 CR in cryoglobulinaemia and 1/1 PR in an undifferentiated vasculitis. To the best of our knowledge, this is the first case of HSCT for large-vessel arteritis reported in the literature; it was briefly presented at an international meeting [6].

Takayasu's arteritis was diagnosed in June 1990 in a 41-yr-old Brazilian woman presenting with upper and lower limb claudication, dizziness, headache, polyarthritis, malaise, myalgia and occasional fever. There was no kidney or heart involvement. Doppler ultrasound (US) showed biphasic or monophasic pulse waves with slow speed in the abdominal aorta (41 cm/s) and in the upper and lower limbs. The arteriography showed irregularities and stenosis of the abdominal aorta, of both carotid and iliac arteries and of the left subclavian artery. The patient was treated with various immunosuppressive agents, such as steroids (two pulses of 6-methylprednisolone 1 g x 3, and up to 80 mg prednisone per day since diagnosis), oral cyclophosphamide (50 mg/day for 30 days), mycophenolate mofetil (MMF; 2 g/day for 11 months), methotrexate (25 mg/week for 6 months) and chlorambucil (6 mg/day for 3 months), but none of those therapies stopped disease progression. In October 2002, while on MMF and steroids, a magnetic resonance angiogram (MRA) showed narrowing and irregularities in both carotid and subclavian arteries and in the brachiocephalic artery (Fig. 1A). This result was associated with worsening of clinical symptoms and prompted the patient and her physician to choose our experimental protocol of autologous HSCT for refractory autoimmune diseases [4, 5] which was approved by the Committee of Ethics in Research of the University Hospital of the School of Medicine of Ribeirão Preto. An informed consent according to the Declaration of Helsinki was signed. In December 2002 fibromyalgia was also diagnosed.



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FIG. 1. Magnetic resonance angiography images before (A) and 60 days after (B) haematopoietic stem cell transplantation showing correction of the stenosis of the brachiocephalic artery (arrow 1) and reduction in the irregularities of the left carotid artery (arrow 2) and of the left subclavian artery (arrow 3).

 
In March 2003 haematopoietic stem cells were mobilized from the bone marrow with cyclophosphamide (2 g/m2) and granulocyte colony-stimulating factor (G-CSF) (10 µg/kg/day), collected by leucapheresis (two sessions) and frozen in liquid N2. In April 2003 the patient was conditioned with cyclophosphamide (50 mg/kg/day x4) plus rabbit anti-thymocyte globulin (ATG; Tecelac, Biotest, Germany; 4.5 mg/kg divided in five doses and preceded by 125 mg of hydrocortisone), followed by stem cell infusion (3.9 x 106/kg CD34+ cells). Complications during the neutropenic phase included fever of unknown origin, hyperglycaemia, subconjunctival haematoma and emotional liability. Cefepime and teicoplanin were used as empirical treatment for neutropenic fever, acyclovir for prophylaxis of herpes infection and trimethoprim/sulphamethoxazole for prophylaxis of Pneumocystis carinii infection. G-CSF (5 µg/kg/day) was used from day 5 through to neutrophil engraftment which was observed on day 9. On day 14 the patient presented with a skin rash and on day 16 she was discharged from the hospital. Amenorrhoea developed in the pre-transplant period after use of leuprolide and persisted after transplantation. The clinical condition improved rapidly; there was complete resolution of headache, dizziness and malaise while limb claudication was significantly reduced. After transplantation (day 320), arterial pulses of the left lower limbs and of the carotid arteries showed normal shape and speed by Doppler US and the wave speed of abdominal aorta increased to 73 cm/s. There were still stenotic areas in the arteries of the upper limbs and a low-speed biphasic pattern in the wave speed of the right lower limb. In the last clinical follow-up on day 270 the patient presented manifestations only of fibromyalgia and hand paraesthesia. C-reactive protein was 2.4 mg/dl pre-transplant and 0.8 mg/dl on day 147 and day 183. The erythrocyte sedimentation rate was 84 mm/1st h (Westergren method) pre-transplant, and 34 mm/1st h on day 350. Immunophenotyping of peripheral blood lymphocytes showed inversion of the CD4/CD8 ratio, and reduction of CD4 memory cells at day 210 post-transplantation. Pre- and post-transplantation immunoglobulin levels were respectively: IgG 750 and 924 mg/dl, IgA 395 and 110, IgM 426 and 144. In the evaluation of day 60 the MRA of the aortic arch branches showed recovery of the previous brachiocephalic artery stenosis and great improvement in the irregularities of the left carotid artery and the left subclavian artery (Fig. 1B). The patient was off any immunosuppression on day 400.

Haematopoietic stem cell transplantation has been employed since 1996 for isolated refractory autoimmune diseases; more than 500 autologous transplants have been registered at the EBMT/EULAR data base in Basel [7] and about 150 have been performed in North and South America [8, 9]. Neurological diseases such as multiple sclerosis, and rheumatic diseases such as systemic lupus erythematosus, systemic sclerosis and adult and juvenile rheumatoid arthritis are currently the main indications for HSCT. Many other autoimmune diseases, including small- and medium-vessel arteritis [2, 3], have been successfully treated with autologous HSCT, but this is the first case of a large-vessel arteritis submitted to this treatment.

The mechanisms of therapeutic benefit of HSCT in autoimmune disease are currently under investigation and may include immunosuppression induced by high-dose chemotherapy and immunotherapy, tolerance induced by autologous stem cells or tissue repair mediated by transdifferentiated stem cells [9]. In the present case, inhibition of inflammatory activity is likely to be a consequence of immunosuppression by cyclophosphamide and ATG, but the surprisingly fast improvement in artery structure and function might be due to angiogenic properties of HSC, as hypothesized in HSCT for systemic sclerosis [10].

Although our patient still has a short follow-up and some arterial abnormalities, the encouraging results suggest that high-dose chemo/immunotherapy associated with HSCT can modify the clinical course of severe and refractory large-vessel vasculitis.

We are grateful to the multiprofessional team of the Bone Marrow Transplantation Unit of the University of São Paulo Hospital at the Campus of Ribeirão Preto for superb care of the patient, to the referring physicians Maria Tereza M. Santos and Sergio S. Komessu, and to FAEPA-HCFMRP, FUNDHERP, FAPESP, Ministry of Health, CNPq and FINEP for financial support.

The authors have declared no conflicts of interest.

References

  1. Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: a review. J Clin Pathol 2002;55:481–6.[Abstract/Free Full Text]
  2. Bacon PA, Carruthers D. New therapeutic aspects: hematopoietic stem cell transplantation. Best Practice Res Clin Rheumatol 2001; 15:299–13.[CrossRef][ISI]
  3. Fiehn C, Hensel M. High dose chemotherapy with hematopoietic stem cell transplantation in primary systemic vasculitis, Behçet's disease and Sjogren's syndrome. In: Burt RK, Marmont A (eds). Stem Cell Therapy for Autoimmune Diseases. Georgetown, TX: Landes Bioscience USA, 2004;411–18.
  4. Voltarelli JC. Hematopoietic stem cell transplantation for autoimmune diseases in Brazil: current status and future prospectives. Rev Bras Hematol Hemoter 2002;24:206–11.
  5. Voltarelli JC, Ouyang J. Hematopoietic stem cell transplantation for autoimmune diseases in developing countries: current status and future prospectives. Bone Marrow Transplant 2003;32:S69–S72.[CrossRef][ISI][Medline]
  6. Voltarelli JC, Oliveira MCB, Stracieri APBL, Godoi DF, Moraes DA, Coutinho MA. Autologous hematopoietic stem cell transplantation for Takayasu's arteritis: report of the first case of the literature. Biol Blood Marrow Transplant 2004;10(Suppl 1):62.
  7. Tyndall A, Koike T. High dose immunoablative therapy with hematopoietic stem cell support in the treatment of severe autoimmune disease: current status and future direction. Intern Med 2002;41:608–12.[ISI][Medline]
  8. Voltarelli JC, Stracieri AB, Rodrigues MC et al. Outcome of autologous HSCT for severe and refractory autoimmune diseases in Brazil. Bone Marrow Transplant 2004;33:S145.
  9. Burt RK, Slavin S, Burns WH, Marmont A. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure? Blood 2002;99:768–84.[Abstract/Free Full Text]
  10. Burt RK, Oyama Y, Traynor A et al. Hematopoietic stem cell transplantation for systemic sclerosis with rapid improvement in skin scores: is neoangiogenesis occurring? Bone Marrow Transplant 2003;32:S65–S67.[CrossRef][ISI][Medline]
Accepted 8 June 2004





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