Service de Médecine Interne (Pr J-C Piette) and 1 Service d'Hématologie (Pr J-P Vernant), CHU Pitié-Salpétrière, 4783 boulevard de l'hôpital, 75651 Paris cedex 13, France.
Correspondence to: S. Trad, Service de Médecine Interne (Pr J-C Piette), CHU Pitié-Salpétrière,4783 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 [13]. 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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This first case of fatal SSc emerging after HDT including TBI might seem paradoxical, since this regimen has been proposed to treat refractory SSc [13] 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
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