S ir , In six patients with systemic sclerosis (SSc) and interstitial lung disease (ILD), Liossis et al . [ 1 ] reported pulmonary function improvements following first-line treatment with mycophenolate mofetil (MMF) for a period of 4–6 months. The improvements of lung diffusion capacity (DLCO), primarily, and to a lesser extent of forced vital capacity (FVC) along with radiological evidence of infiltrate clearing on chest CT lead the authors to conclude that MMF in conjunction with small doses of steroids may be an effective first-line therapy for these patients.
We would like to report our experience with MMF when used not as a first-line drug but as a long-term immunosuppressive agent following treatment with i.v. cyclophosphamide (CYC). Seven patients (age 58± 11 yrs; 6 women) with SSc and ILD received MMF for a period of 18± 7 months. Initially, patients were treated with MMF 500 mg twice daily for a month. A complete blood count at that point, excluding the development of leucopenia, allowed for escalation of the MMF dosage to 2000 mg/day, which was continued thereafter. All patients had completed therapy with i.v. CYC for a period of 3± 1.4 yrs.
Pulmonary function indices before and after treatment with MMF were measured and compared with those obtained in a case-control group of seven patients ( Table 1 ) who had similarly completed treatment with i.v. CYC but received no long-term immunosuppressive therapy following CYC treatment. As shown in the table, the changes in FVC and DLCO did not differ between the two groups.
Changes in pulmonary function of patients treated with or without MMF following initial therapy with intravenous CYC
| MMF | No MMF | P -values | |
|---|---|---|---|
| Gender (F/M) | 6/1 | 6/1 | N/S |
| Age at disease onset (yrs) | 49.6± 10.7 | 49.7± 11.5 | N/S |
| Pulmonary fibrosis on chest CT | 7 (100%) | 7 (100%) | N/S |
| CYC dosages total (gm) | 14.6± 3.89 | 18± 7.88 | N/S |
| Difference in FVC (% predicted) | −2± 11 | −2± 5 | N/S |
| Difference in FVC (L) | −0.6± 0.67 | −0.19± 0.45 | N/S |
| Difference in DLCO (% predicted) | −0.78± 13.5 | −6.46± 15.1 | N/S |
| Difference in DLCO (mmol/min/kPa) | −1.76± 1.43 | −1.5± 0.74 | N/S |
| MMF | No MMF | P -values | |
|---|---|---|---|
| Gender (F/M) | 6/1 | 6/1 | N/S |
| Age at disease onset (yrs) | 49.6± 10.7 | 49.7± 11.5 | N/S |
| Pulmonary fibrosis on chest CT | 7 (100%) | 7 (100%) | N/S |
| CYC dosages total (gm) | 14.6± 3.89 | 18± 7.88 | N/S |
| Difference in FVC (% predicted) | −2± 11 | −2± 5 | N/S |
| Difference in FVC (L) | −0.6± 0.67 | −0.19± 0.45 | N/S |
| Difference in DLCO (% predicted) | −0.78± 13.5 | −6.46± 15.1 | N/S |
| Difference in DLCO (mmol/min/kPa) | −1.76± 1.43 | −1.5± 0.74 | N/S |
N/S, Non–significant.
CYC has emerged as the first-line therapy for ILD in SSc. It produces a small but significant effect on FVC (about 2.5% of predicted), when compared with placebo; this modest effect is maintained for about 1 yr following the discontinuation of treatment [ 2 ]. Thereafter, the annual loss in the FVC may range from two to eight per cent of the predicted value, being greater for patients with more fibrosis on high-resolution CT [ 2 ], as well as during the first 3 yrs from disease onset [ 3 , 4 ]. In the absence of clinical data, the most appropriate long-term immunosuppressive agent to substitute CYC is unknown. Azathioprine combined with low-dose steroids, a regimen commonly used in idiopathic pulmonary fibrosis despite lack of sufficient evidence of survival improvement, could be an alternative selection [ 5 , 6 ].
MMF is primarily used in post-transplant patients to suppress acute and chronic allograft rejection [ 7 ]. It inhibits purine synthesis through de novo pathways and thus decreases the activity of inflammatory cells including T-, B-lymphocytes and macrophages. Over the last decade, MMF has emerged as a useful therapy not only in solid organ transplantation but also in various autoimmune disorders, largely replacing azathioprine.
Our preliminary data are not in conflict with those reported by Liossis et al . [ 1 ] because MMF was used as a maintenance treatment rather than a first-line therapy. In a similar study in which MMF was used as a maintenance therapy following induction with anti-thymocyte globulin, Stratton et al . [ 8 ] detected no pulmonary function improvements in 13 patients with SSc. A recent retrospective study [ 9 ] on 28 patients who received MMF either as initial immunomodulatory or as maintenance agent for ILD related to various connective tissue diseases reported no significant adverse effects and a trend towards pulmonary function stability after a year (median) of follow up.
These recent reports should encourage the launch of controlled studies that will fully define the role of MMF, used either as initial or as long-term immunosuppressive agent, in treating patients with SSc and ILD.
The authors have declared no conflicts of interest.
Acknowledgements
The authors are grateful to Prof. Haralampos M. Moutsopoulos, MD, for his continuous inspiration, guidance and support.
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