Clin Rheumatol (2003) 22: 393–396 DOI 10.1007/s10067-003-0756-8
O R I GI N A L A R T IC L E
Salvatore DAngelo Æ Giovanna Cuomo Æ Carmen Paone Emiliana Colutta Æ Giovanni La Montagna Gabriele Valentini
Low-dose intravenous cyclophosphamide in systemic sclerosis: a preliminary safety study Received: 11 December 2002 / Accepted: 9 May 2003 / Published online: 23 October 2003 Ó Clinical Rheumatology 2003
Abstract Both oral and intravenous high-dose cyclophosphamide (CYC) regimens are associated with serious side effects when used for the treatment of systemic sclerosis (SSc). The aim of the present trial was to test the safety of low-dose intravenous CYC in patients with SSc. Eight SSc patients, in whom CYC treatment was warranted, were studied at baseline and after 6 months intravenous CYC treatment (500 mg pulses at weeks 0, 1, 2, 6, 10, 14, 18 and 22). Side effects probably related to CYC treatment were carefully investigated. The development of amenorrhea was assessed during the period of treatment and over the following 12 months. The therapy was well tolerated overall. No patient discontinued treatment because of side effects. Leukopenia, premature ovarian failure, hemorrhagic cystitis, microscopic hematuria and liver toxicity were never detected. The most common adverse events were mild and self-limiting nausea and weakness. Our data suggest that low-dose intravenous CYC is relatively safe, at least in the short term. Further studies are needed to assess both the efficacy and the long-term safety. Keywords Low-dose intravenous cyclophosphamide Æ Safety Æ Systemic sclerosis Æ Treatment Abbreviations CYC Cyclophosphamide Æ DLCO Carbon monoxide diffusing capacity Æ FVC Forced vital capacity Æ SSC Systemic sclerosis
Introduction The treatment of systemic sclerosis (SSc) is commonly divided into two broad types: treatment of disease organ manifestations (i.e. scleroderma renal crisis, esophageal involvement, digital ulcerations etc.) and disease-modifying therapy aimed to influence the pathogenetic process [1]. At present no drug or combination of drugs has been shown to be effective as disease-modifying therapy in SSc. Previous studies, however, have pointed out the efficacy of oral (1–2 mg/kg/day) and intravenous (1000 mg/m2 of body surface monthly) cyclophosphamide (CYC) in the treatment of fibrosing alveolitis [2, 3, 4, 5, 6, 7, 8, 9]. However, both oral and intravenous traditional CYC regimens are associated with serious side effects. In 1989, Bombardieri et al. [10] first reported the use of low-dose intravenous CYC pulse treatment in patients with polymyositis. The same therapeutic approach has been used in a significant number of patients with connective tissue diseases and systemic vasculitis [11, 12, 13]. On the whole, these studies have shown that such an approach is comparable in efficacy and better tolerated than other CYC regimens. Because both oral and intravenous CYC treatments have been found to be effective in SSc, but to have a limited use because of a high burden of side effects, particularly hemorrhagic cystitis and ovarian failure [2, 3, 4, 9, 14], we undertook a prospective 6-month trial aiming to test the safety of low-dose intravenous CYC.
Methods S. DAngelo Æ G. Cuomo Æ C. Paone Æ E. Colutta G. La Montagna Æ G. Valentini (&) Rheumatology Unit, Department of Clinical and Experimental Medicine, Second University of Naples, Edificio 3, Via Pansini 5, 80131 Naples, Italy E-mail:
[email protected] Tel.: +39-081-5464487 Fax: +39-081-5666747
SSc patients followed at our Rheumatology Unit, in whom at the time of the usual 6-month evaluation a new disease manifestation and/or a deterioration of a previously present one had occurred, were invited to participate in the present study. The following conditions were considered as either new disease manifestations or deteriorations of previously present ones: increased skin score (at least 20% of the previous value); decreased (at least 20% of the previous value) forced vital capacity (FVC) or carbon monoxide diffusing capacity (DLCO); new appearance of ground-glass or increased extent of
394 fibrotic/reticular pattern abnormalities on high-resolution computed tomography (HRCT) of the chest; appearance of pericarditis or pleuritis; appearance of a new ischemic ulcer. All SSc patients entering the study were investigated in order to define the preliminary ACR (formerly ARA) classification criteria satisfied [15] and the clinical subset according to Giordano et al. [16]. For each patient a written informed consent was obtained according to the Declaration of Helsinki. Exclusion criteria were: i) impaired renal function (creatinine clearance
