Cyclophosphamide in systemic sclerosis: light and shadows.

© Copyright CLINICALAND EXPERIMENTAL RHEUMATOLOGY 2004. Pulmonary interstitial fibrosis (PIF) affects half of all patients with systemic sclerosis (SSc) (1) and accounts for one-third of SSc-related deaths (2). Despite enormous efforts, therapy remains empirical and its efficacy is questionable. D-penicillamine (3) interfero n -γ (4), and cyclophosphamide (5) have been used to halt the progression of PIF. While studies on these regimens have reported encouraging results, patients still die from respiratory failure due to PIF. For instance, D-penicillamine was shown to have beneficial effects for SSc lung disease, as detected by increased values of DLCO/lung volumes (3), but hardly anyone believes in this therapy today. This is probably a reflection of the weak design and lack of methodological credibility of most studies performed in SSc. There are several reasons for this situation. First, the natural history of the disease is not well known, and therefore slow disease progression due to the disease itself could be spuriously considered as stabilization due to the therapy for some patients, while for patients with an unfavourable disease profile at entry regression-to-the-mean is a problem in uncontrolled studies (6). Second, the duration of follow-up in patients receiving a therapeutic intervention under evaluation is usually short. Third, the small numbers of patients per cohort do not favour the adoption of randomized controlled studies, and whenever such studies are undertaken, small sample sizes are the rule (7). Finally, surrogate markers are used for the response instead of hard clinical outcomes, and these surrogates have their limitations. Nevertheless these surrogate markers probably represent very early changes of lung function, in a time point when the involvement of the lung can regress without serious consequences for the health of the individual. Therefore these markers have been proposed for future studies in the Portonovo Conference on the evaluation of patients with systemic scleroderma (8). At the same time, very little progress has been made at the basic science level to suppress fibrotic processes. Airo et al. in this issue of the journal (9) report their experience with intravenous cyclophosphamide therapy for SSc PIF in a retrospective, observational study. They also attempted to enhance their findings by reviewing five other relevant studies (10-14). However, they were not able to adopt a standard protocol and use standardized individual level data from all the previous cohorts. Pooling was performed on the data of 3 of the 6 studies. The endpoint of the study by Airo et al. was alterations in lung function tests after 6 months (9). The regimen used was cyclophosphamide 750 mg pulses combined with methylprednisolone 125 mg pulses every 3 weeks and the results were promising. Despite the small numbers, lack of prospective or even retrospective control subjects, and the limitations of retrospective evaluation, practically all the studies reporting the results of cyclophosphamide therapy in SSc PIF have suggested that cyclophosphamide may be more or less efficacious for PIF. However, the outcomes have not been the same between studies, the prednisolone dose differs significantly between them, and the baseline characteristics of the patients are considerably different across studies. For instance, the patients in the study of Pakas et al. (12) had considerably advanced disease at the initiation of treatment, while the patients in the study by Giacomelli et al. (14) had initial FVC levels within normal range. While the results are promising, the need for caution cannot be overstated. There are several issues regarding the definition of the disease and outcomes thereof that have to be considered in future studies (15). First, what is the histopathologic subset of fibrosing alveolitis in patients with SSc? It is well known today that non-specific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP) are two histopathologic types with different outcomes, and they may coexist in patients with scleroderma lung disease but to a different extent from one patient to another (16). Second, is PIF clinically significant? Pulmonary function tests and dyspnea scoring are the only widely available means of determining wheEDITORIAL Clinical and Experimental Rheumatology 2004; 22: 551-552.