Fatal progressive systemic sclerosis following autologous stem cell transplantation and high-dose chemotherapy

S. Trad, Z. Amoura, J. Haroche, L. T. Huong Du Boutin, B. Wechsler, V. Leblond1 and J.-C. Piette

Service de Médecine Interne (Pr J-C Piette) and 1 Service d'Hématologie (Pr J-P Vernant), CHU Pitié-Salpétrière, 47–83 boulevard de l'hôpital, 75651 Paris cedex 13, France.

Correspondence to: S. Trad, Service de Médecine Interne (Pr J-C Piette), CHU Pitié-Salpétrière,47–83 boulevard de l'hôpital, 75651 Paris cedex 13, France. E-mail: tradsalim{at}aol.com

SIR, The prognosis of diffuse systemic sclerosis (SSc) and the lack of effective therapies together with well-defined prognostic factors for early mortality have allowed trials of high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) in severe SSc [1–3]. These trials have suggested that such regimens could improve SSc, especially skin involvement.

We report the first case of fatal diffuse SSc occurring after HDT including total body irradiation (TBI) and ASCT for treatment of a multiple myeloma (MM).

In 1999, a 48-yr-old woman was diagnosed as having a stage III IgG kappa-type MM with hypercalcaemia and diffuse bone lesions. Primary Sjögren's syndrome (SS) had been diagnosed in 1985 on sicca syndrome, arthritis, positive speckled antinuclear antibodies (ANA) (1:640), anti-SSA/Ro and anti-SSB/La antibodies and Chisholm's grade IV on salivary gland biopsy. Clinical and biological features remained unchanged for 14 years. Low-dose steroids were given during the 4 yr preceding diagnosis of MM to control arthritis. During this period, the patient had no Raynaud's phenomenon and anti-Scl70 antibodies were negative.

Following diagnosis of MM, it was decided to perform HDT and ASCT. Induction chemotherapy consisted of vincristine, adriamycin and dexamethasone infusions. The mobilization regimen used methylprednisolone and cyclophosphamide before stem cell apheresis. The conditioning regimen consisted of total body irradiation (TBI) (abdomen 12 Gy, chest 9 Gy and brain 11 Gy) followed by polychemotherapy including lomustine, etoposide, cyclophosphamide and melphalan. Rescue with ASCT was done 2 days after completion of chemotherapy. The patient was discharged 1 month later after ASCT. During the next 2 yr, myeloma was in remission and the course uneventful.

In 2001, 24 months after ASCT, finger swelling occurred with severe Raynaud's phenomenon involving all fingers and toes, with pulpal ulcerations. Nailfold capillary microscopy was unremarkable. The ANA profile remained unchanged, including negative tests for anti-Scl70. No cryoglobulin was detected. Ilomedin, amlodipine and prednisone (10 mg/day) were initiated. Several months later, the patient developed progressive skin sclerosis, dysphagia and dyspnoea. Diffuse SSc was diagnosed. Skin sclerosis extended to the proximal limbs associated with interstitial pulmonary fibrosis (Fig. 1) and a decrease in the diffusing capacity for carbon monoxide. Nailfold capillary microscopy showed major dystrophies and enlarged capillary loops.



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FIG. 1. Chest CT scan at time of diagnosis of multiple myeloma (A) and 35 months after total body irradiation (B). This figure may be viewed in colour as supplementary data at Rheumatology online.

 
In 2002, anti-Scl70 antibody became positive. Concomitant retesting of the 2001 serum was confirmed negative. Interferon gamma (85 mg three times per week) was inefficient. A tamponade required surgical drainage. Biopsy confirmed pericardial fibrosis. The patient died from pulmonary failure 14 months after the onset of SSc. At the time of death the myeloma was still in remission.

This first case of fatal SSc emerging after HDT including TBI might seem paradoxical, since this regimen has been proposed to treat refractory SSc [1–3] and improvement in SSc has been observed after polychemotherapy for coexisting MM [4]. However, converging data have pointed out the deleterious influence of external radiotherapy on the course of scleroderma, and there is the suggestion of a possible role for TBI in the emergence of SSc in our case report. In a prospective study, O'Dell et al. [5] found that total lymphoid irradiation might accelerate pulmonary deterioration in SSc, and seven cases of de novo SSc emerging after radiotherapy have been reported [6, 7], suggesting a possible role of TBI in the emergence of SSc. This low number might suggest a chance association, but we favour the opposite hypothesis of an overlooked ‘aetiological’ role of irradiation, due to (1) our recent observation of an additional similar case not included in our prior report [7] and (2) the very close temporal relationship between irradiation and onset of SSc, occurring within a couple of months [6, 7]. The 2-yr delay between TBI and onset of SSc observed in this report might be due to the high immunosuppressive effect of HDT.

Post-irradiation localized scleroderma skin changes occurring in non-irradiated areas have also been described in up to 26% of reported cases [8], suggesting that the consequences of irradiation might extend beyond ‘local’ phenomena. Irradiation is known to induce increased collagen production, telangiectasia and chromosomal aberrations, all injuries which exist in SSc. Release of circulating neo-antigens affecting fibroblast or endothelial proteins has been proposed as a possible trigger for the immune system [8]. Moreover, SSc patients have a high susceptibility to irradiation. A high frequency of TBI-induced acute interstitial pneumonitis has been reported in SSc treated by ASCT and TBI [2, 3] and complications of irradiation are more frequent in SSc than in other collagen vascular diseases [9].

A possible relationship of SSc with radiotherapy requires possible confounding factors to be ruled out. First, various malignancies have been reported in association with SSc [10], but MM is extremely rare in this setting after exclusion of SSc mimickers (POEMS syndrome, scleromyxoedema). Second, among all drugs used in HDT, none has been shown to induce SSc, unlike bleomycin or paclitaxel.

In conclusion, de novo SSc may occur following external radiotherapy including TBI. Further studies are needed to determine the relevance of this finding and the possible role of prior autoimmune background. Because HDT including TBI is increasingly being used in treatment of refractory SSc, due to its potential risks TBI should probably be avoided in the conditioning regimen preceding ASCT.

The authors have declared no conflicts of interest.

References

  1. Binks M, Passweg JR, Furst D et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis 2001;60:577–84.[Abstract/Free Full Text]
  2. McSweeney PA, Nash RA, Sullivan KM et al. High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes. Blood 2002;100:1602–10.[Abstract/Free Full Text]
  3. Farge D, Passweg J, Van Laar JM et al. Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/EULAR Registry. Ann Rheum Dis 2004;63:974–81.[Abstract/Free Full Text]
  4. Bachleitner-Hofmann T, Machold K, Knobler R, Drach J, Grumbeck E, Gisslinger H. Marked and sustained improvement of systemic sclerosis following polychemotherapy for coexistent multiple myeloma. Clin Exp Rheumatol 2002;20:85–8.[ISI][Medline]
  5. O'Dell JR, Steigerwald JC, Kennaugh RC, Hawkins R, Holers VM, Kotzin BL. Lack of clinical benefit after treatment of systemic sclerosis with total lymphoid irradiation. J Rheumatol 1989;16:1050–4.[ISI][Medline]
  6. Aref I, Cross P, Nair B. Case report: severe fibrosis in a patient with scleroderma and previous radiotherapy—a case report and literature review. Br J Radiol 1996;69:1055–6.[Abstract]
  7. Darras-Joly C, Wechsler B, Bletry O, Piette JC. De novo systemic sclerosis after radiotherapy: a report of 3 cases. J Rheumatol 1999;26:2265–7.[ISI][Medline]
  8. Ullen H, Bjorkholm E. Localized scleroderma in a woman irradiated at two sites for endometrial and breast carcinoma: a case history and a review of the literature. Int J Gynecol Cancer 2003;13:77–82.[CrossRef][ISI][Medline]
  9. Morris MM, Powell SN. Irradiation in the setting of collagen vascular disease: acute and late complications. J Clin Oncol 1997;15:2728–35.[Abstract/Free Full Text]
  10. Hill CL, Nguyen AM, Roder D, Roberts-Thomson P. Risk of cancer in patients with scleroderma: a population based cohort study. Ann Rheum Dis 2003;62:728–31.[Abstract/Free Full Text]
Accepted 8 March 2005





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