Rheumatology Advance Access originally published online on September 23, 2008
Rheumatology 2008 47(11):1734-1735; doi:10.1093/rheumatology/ken367
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Paraneoplastic scleroderma secondary to hairy cell leukaemia successfully treated with cladribine
1Department of Rheumatology, Bristol Royal Infirmary, Bristol, 2Centre for Rheumatology, Royal Free Hospital, London and 3Bristol Haematology and Oncology Centre, United Bristol Healthcare Trust, Bristol, UK
Correspondence to: M. Juarez, Department of Rheumatology, The Courtyard, Old Building, Bristol Royal Infirmary, Bristol BS2 8HW, UK. E-mail: mariajuarezp{at}gmail.com
SIR, We read with interest the report by Sfikakis et al. on the use of imatinib in refractory dcSSc [1]. We would like to share our own experience. We report a 55-yr-old man with rapidly progressive scleroderma associated with hairy cell leukaemia (HCL). The progression of scleroderma was stopped by treating the underlying malignancy with cladribine (2-chlorodeoxyadenosine).
The patient presented with a 2-month history of severe ankle pain, swollen hands, dyspnoea and fatigue. Physical examination was unremarkable. Baseline tests revealed a pancytopenia and he was referred to haematology. Peripheral blood count showed mononuclear cells with morphology suggestive of HCL. Flow cytometry showed a population of B cell expressing CD22, CD20, CD25, CD103 and CD11C. Bone marrow aspirate confirmed the diagnosis (Fig. 1). Chemotherapy was deferred until peripheral blood count dropped to treatment threshold. However, his dyspnoea worsened and he developed RP. Investigations included CXR (normal), echocardiogram (normal) and blood tests showing positive ANA reactivity with anti-topoisomerase-1 antibodies. This prompted a review by rheumatology at which point the patient complained of persistent swelling, stiffness and RP in his hands, difficulty in opening his mouth, early satiety and regurgitation, dyspnoea on minimal exertion and severe fatigue. Examination revealed abnormal nail-fold capillaries, active RP, poor grip strength and diffuse thickening of the skin in hands, forearms and feet. Mouth aperture was reduced. A diagnosis of dcSSc was made 3 months after the diagnosis of HCL. The severity and rapid progression of scleroderma occurring in the context of recently diagnosed HCL suggested a paraneoplastic origin. Although a conservative approach to management of HCL would otherwise have been taken, it was decided to treat the patient with cladribine due to his concurrent scleroderma. This resulted in total remission (bone marrow <1% hairy cells), almost complete resolution of skin sclerosis and overall symptomatic improvement. RP remained but was controlled by oral vasodilators. To date, HCL remains in remission and the progression of scleroderma has stopped.
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Paraneoplastic scleroderma has been reported in small numbers in association with carcinomas of breast [2], ovary, uterus [3] and prostate [4]; metastatic melanoma and bronchial carcinomas; HCL [5] and other lymphomas. The definition of paraneoplastic scleroderma is supported by a close temporal relationship between the presentation of scleroderma and malignancy [2–5], scleroderma following the progression of the malignancy [3, 5] and a much more rapid and severe progression of scleroderma than usual [2, 4]. These observations are also present in the case we report.
Although some case series have highlighted the atypical features of scleroderma occurring in the context of malignancy, such as absence of hallmark autoantibodies or disproportionate palmar fibrosis [6], our case illustrates that the clinical and laboratory features may on occasions be indistinguishable from idiopathic scleroderma. The only unusual feature in this case is male gender, as 80% of the cases of SSc occur in women. The mechanism of interrelationship between scleroderma and malignancy has not been proven but most hypothesis favour imbalance of the immune system: it is postulated that a humoral or cell-mediated immune process initiated by the malignancy may be responsible for the development of scleroderma [2, 4, 5]. HCL is an indolent form of B-cell lymphoma. Hairy cells produce fibronectin and cytokines such as fibroblast growth factor, TGF-β and TNF-
. The first three have been deemed responsible for bone marrow fibrosis whilst the latter is thought to cause marrow inhibition [7]. Activated fibroblasts are recognized as the effector cells responsible for the fibrotic changes in scleroderma. Their activation and regulation results from complex cell–cell, cell–cytokine and cell–matrix interactions mediated by a variety of cytokines and growth factors [8]. TGF-β promotes extracellular matrix synthesis and myofibroblast differentiation and is implicated as a key driver of the activated scleroderma fibroblast phenotype [9]. Interestingly, TGF-β and other cytokines are produced in excess in HCL. Given that the interplay between a number of cytokines and growth factors is thought to underlie the pathogenesis of both conditions, it is reasonable, although purely speculative, to infer that both pathologies may have common pathogenic links.
Cladribine is a purine analogue with cytotoxic effects in proliferating and quiescent hairy cells [10]. Death of hairy cells will result in interruption of the production of TGF-β and other cytokines, which may explain why treatment of HCL halted the progression of scleroderma in our case. This shows parallelism with recent publications on the use of imatinib (a tyrosine kynase inhibitor that interferes with TGF-β and PDGF signalling) in refractory dcSSc [1] and suggests that these may be promising new targeted therapies for scleroderma.
Clinicians should retain a high index of suspicion for an underlying malignancy in patients presenting with scleroderma even when age of onset and clinical features are unremarkable.
Disclosure statement: M.J. has received sponsorship to attend an education meeting (EULAR annual meeting, June 2008) from Pfizer. R.M. has received sponsorship from Wyeth, MSD and Schering-Plough to attend educational conferences. The other authors have declared no conflicts of interest.
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