Abstract
Objective. To find an effective, safe immunosuppressive regimen as an alternative to cyclophosphamide (Cy) for the treatment of clinically evident diffuse scleroderma (dSSc)-associated alveolitis of recent onset.
Methods. Five consecutive patients with dSSc and recent-onset alveolitis were enrolled and treated with mycophenolate mofetil (MMF) and small (≤10 mg/day) doses of predinisolone in this open-label trial. One patient with long-standing fibrosing alveolitis was later added to our cohort. Pulmonary function tests [carbon monoxide diffusing capacity (DLCO) and forced vital capacity (FVC)], pulmonary high-resolution computed tomography (HRCT) scans and clinical assessment were performed before and at specified time-points after enrolment. Cases of significant infections, leucopenia and abdominal pain were recorded.
Results. After 4–6 months of MMF therapy, DLCO improved significantly compared with pre-treatment (mean DLCO 75.4% vs 64.2% of predicted value, respectively, P=0.033). Values of FVC also improved, with the difference almost reaching levels of statistical significance (mean FVC 76.2% vs 65.6% of predicted value, P=0.057). Ground glass opacities cleared in three of four patients with recent-onset alveolitis and were reduced in one patient after 6–8 months of treatment. Breathlessness and cough improved by 3 months. A possible treatment failure was seen in one patient. However, in five patients functional and clinical improvement was sustained during the study period. No adverse events were recorded in this ongoing clinical trial.
Conclusion. Our preliminary data suggest that in patients with dSSc and recent, clinically apparent alveolitis, early treatment with MMF and small doses of corticosteroids (CS) may represent an effective, well-tolerated and safe alternative therapy.
Currently, the principal factor adversely influencing survival in patients with diffuse scleroderma (dSSc) is pulmonary involvement. Therefore, early recognition and treatment of dSSc-related lung disease are crucial. There is no consensus on the means employed to assess scleroderma lung disease. Usually, the extent and severity of pulmonary involvement is assessed using pulmonary high-resolution computed tomography (HRCT) and pulmonary function tests (PFT). In particular, abnormalities of diffusing capacity (DLCO) and of forced vital capacity (FVC) have been identified as adverse prognostic markers [1, 2]. Scoring of HRCT is not routinely performed; the best surrogate correlating well with the extent of HRCT-proven lung involvement is the DLCO value [3]. Additionally, declining DLCO values are the single most important adverse prognostic factor [4]. Treatment of scleroderma lung is empirical and at present consists of cyclophosphamide (Cy) usually given in conjunction with corticosteroids (CS). Nevertheless the toxicity of Cy administered intravenously (i.v.) or orally, in particular, is considerable and the use of other than small doses of CS in dSSc patients raises serious concerns [5].
Mycophenolate mofetil (MMF) inhibits inosine monophosphate dehydrogenase interfering with purine biosynthesis. Since MMF is an effective immunosuppressive substance associated with significantly less toxicity than Cy, we prospectively treated six patients with dSSc and lung disease (of recent onset in five) with MMF along with small (≤10 mg prednisolone/day) doses of CS. In this small-scale trial we report that administration of MMF in patients with early, clinically evident scleroderma lung disease improves respiratory symptoms, significantly increases DLCO values, improves FVC and diminishes HRCT-documented early pulmonary lesions. Large-scale studies are necessary to evaluate whether MMF represents an effective and safe therapeutic modality in the treatment of early dSSc-associated pulmonary disease.
Patients and methods
Patients
This is a prospective, single-centre, open-label trial. Between October 2002 and July 2004 we identified and subsequently enrolled into this trial five consecutive patients with dSSc (four female, one male, all Caucasian) with previously non-apparent pulmonary involvement, who developed scleroderma lung during follow-up. We additionally enrolled one male patient (patient 6) with previously established, Cy-resistant, advanced scleroderma lung involvement. Patients were evaluated on an out-patient basis at the Rheumatology Clinic of Patras University Hospital. All participating individuals were at least 18 yr old at the time of enrolment and gave written informed consent according to the Declaration of Helsinki. This work conforms to standards currently applied in Greece.
Clinically significant infection(s), leucopenia [<4000 white blood cells (WBC)/mm3], pregnancy or a history of malignancy were exclusion criteria for enrolment, although none of the patients met any of them. All but the one patient with advanced scleroderma lung (patient 6) had not previously received cytotoxic medications.
Assessment of pulmonary involvement
All patients with dSSc are evaluated with PFT and HRCT at the time of diagnosis and at regular time intervals on follow-up. Development of scleroderma alveolitis was assessed using the following algorithm based upon clinical, functional and imaging studies. Patients with dSSc with previously normal PFT and HRCT reporting a recent onset of breathlessness and/or dyspnoea on exertion (DOE) and/or dry cough and/or who developed previously non-existent inspiratory crackles on chest auscultation underwent a new PFT evaluation. The two parameters analysed for the purposes of this study were DLCO and FVC. To exclude a cardiac- or pulmonary hypertension-related decrease of DLCO all patients underwent Doppler echocardiographic evaluation before enrolment. All patients had normal (>60%) left-ventricular ejection fraction values. None of the patients, except patient 1, had evidence of pulmonary hypertension on the basis of cardiac ultrasound. For patient 1 pulmonary hypertension was excluded with right-sided cardiac catheterization. Patients with clinical evidence of pulmonary affliction and/or a recent decrease in FVC and/or DLCO were additionally evaluated using a new chest HRCT. Identification of 'ground-glass' opacities on HRCT was considered as evidence of early lung involvement and was used as an inclusion criterion.
MMF treatment
Initially, patients were treated with MMF (CellCept, Roche), 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 additionally received 7.5–10 mg prednisolone/day (median 10 mg). Monitoring for possible MMF side-effects included signs of infection such as fever, productive cough, headache, diarrhoea, dysuria and also any abdominal pain at each follow-up visit every 3 months.
Study end points
To assess the effectiveness of MMF therapy, we aimed at an improvement in DLCO and/or FVC and/or the extent of ‘ground-glass’ opacities found on HRCT. To evaluate the safety of MMF treatment, adverse events such as clinically significant infections and leucopenia were recorded. An improvement of breathlessness and/or DOE was a secondary end point.
Statistical analysis
The paired two-tailed Student's t-test was employed to analyse data. P values ≤0.05 were considered as statistically significant.
Results
Patient characteristics
Five out of our six patients with dSSc developed clinical, functional and imaging evidence of recent-onset pulmonary involvement. At enrolment, all patients had DOE, five out of six patients reported a dry, irritating cough and all had developed novel, fine, end-inspiratory crackles on auscultation at the lung bases bilaterally. Demographics, clinical parameters as well as the serological profile of the patients are depicted in Table 1.
Demographic, clinical and serological characteristics of patients at onset of treatment with MMF
| Pt | Sex | Age (yr) | dSSc duration (yr) | DOE | Dry cough | Crackles | Raynaud's | Digital ulcers | ANA titre | Anti-Scl-70 |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 54 | 1.5 | + | + | + | + | + | 1:640 | + |
| 2 | M | 52 | 2.5 | + | – | + | + | – | 1:1280 | + |
| 3 | F | 63 | 1.5 | + | + | + | + | – | 1:1280 | + |
| 4 | F | 57 | 3 | + | + | + | + | – | 1:640 | + |
| 5 | F | 18 | 2 | + | + | + | + | + | 1:640 | + |
| 6 | M | 32 | 10 | + | + | + | + | + | 1:640 | + |
| Pt | Sex | Age (yr) | dSSc duration (yr) | DOE | Dry cough | Crackles | Raynaud's | Digital ulcers | ANA titre | Anti-Scl-70 |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 54 | 1.5 | + | + | + | + | + | 1:640 | + |
| 2 | M | 52 | 2.5 | + | – | + | + | – | 1:1280 | + |
| 3 | F | 63 | 1.5 | + | + | + | + | – | 1:1280 | + |
| 4 | F | 57 | 3 | + | + | + | + | – | 1:640 | + |
| 5 | F | 18 | 2 | + | + | + | + | + | 1:640 | + |
| 6 | M | 32 | 10 | + | + | + | + | + | 1:640 | + |
dSSc, diffuse systemic sclerosis; DOE, dyspnoea on exertion; ANA, antinuclear antibodies; +, present, –, absent.
Improvement of DLCO, FVC and clinical symptoms
Pulmonary function tests were repeated after 4–6 months of MMF treatment. All five patients with early onset scleroderma lung as well as the additional patient with established, advanced pulmonary involvement displayed an improvement of DLCO compared with pre-treatment values. Increases in DLCO values were statistically significant (pre-treatment mean DLCO 64.2% of predicted vs post-treatment mean DLCO 75.4% of predicted, P = 0.033).
Values for FVC also improved in all but one patient with early onset lung disease. Differences almost reached the level of statistical significance (pre-treatment mean FVC 65.6% of predicted vs post-treatment mean FVC 76.2% of predicted, P = 0.057). Results of the PFT studies are shown in Table 2. Within the first 3 months following initiation of MMF treatment, clinical symptoms from the respiratory tract improved in all five patients with recent-onset alveolitis. The respiratory symptoms of patient 6 remained unchanged despite his reportedly improved general well-being. In four patients PFT were re-evaluated at additional time points during this ongoing trial. Values of DLCO and FVC for patient 1 kept improving at 12 months (80% and 92% of predicted values, respectively) and at 24 months (84% and 96% of predicted values, respectively). Patients 2 and 6 underwent PFT studies after 10–12 months of MMF treatment, and DLCO as well as FVC values at that time point retained the initial benefits recorded at 6 months’ post-treatment. Patient 3 declined to perform PFT before treatment initiation. She underwent PFT studies after 6 and 12 months of treatment. Her DLCO values were 77% and 85% of predicted respectively. Even though pre-treatment values are not available and safe conclusions cannot be drawn, it can be assumed that MMF treatment was of benefit for the period between 6 and 12 months of follow-up.
Effects of MMF treatment at 6 months on DLCO, FVC and ‘ground glass’ HRCT pattern
| Pt | DLCO (%pr) 0 mo | DLCO (%pr) 4–6 mo* | FVC (%pr) 0 mo | FVC (%pr) 4–6 mo** | ‘Ground-glass’ at onset of MMF treatment | ‘Ground-glass’ after 6–8 months on MMF |
|---|---|---|---|---|---|---|
| 1 | 66 | 78 | 71 | 90 | + | ↓ |
| 2 | 75 | 97 | 74 | 97 | + | – |
| 3 | NA | NA | NA | NA | + | – |
| 4 | 85 | 99 | 71 | 80 | + | NA |
| 5 | 69 | 70 | 80 | 79 | + | – |
| 6 | 26 | 33 | 32 | 39 | Fibrosis | Fibrosis |
| Pt | DLCO (%pr) 0 mo | DLCO (%pr) 4–6 mo* | FVC (%pr) 0 mo | FVC (%pr) 4–6 mo** | ‘Ground-glass’ at onset of MMF treatment | ‘Ground-glass’ after 6–8 months on MMF |
|---|---|---|---|---|---|---|
| 1 | 66 | 78 | 71 | 90 | + | ↓ |
| 2 | 75 | 97 | 74 | 97 | + | – |
| 3 | NA | NA | NA | NA | + | – |
| 4 | 85 | 99 | 71 | 80 | + | NA |
| 5 | 69 | 70 | 80 | 79 | + | – |
| 6 | 26 | 33 | 32 | 39 | Fibrosis | Fibrosis |
DLCO, carbon monoxide diffusing capacity; FVC, forced vital capacity; %pr, percentage of predicted values; NA, not available; +, present; –, absent; ↓, decreased; mo, months of treatment with MMF; 0 mo, at onset of treatment with MMF.
*P = 0.033; **P = 0.057.
These results demonstrate that treatment with MMF improved the critical parameters of PFT studies. The MMF-induced significant increases of DLCO at 6 months of treatment and the initial benefits were maintained for at least 1 yr with ongoing treatment. The FVC also increased following MMF treatment, and respiratory symptoms improved as early as 3 months after treatment.
Improvement of ‘ground-glass’ pattern on chest HRCT
In four out of five patients with recent-onset dSSc-related lung disease MMF treatment resulted in the disappearance of ‘ground-glass’ opacities that were uniformly present at enrolment, after 6–8 months of treatment (Table 2 and Fig. 1). A reduction in the extent of alveolitis was evident in one patient. Patient 6 had established fibrosis and a ‘honeycombing’ pattern on pre-treatment chest HRCT, findings that persisted on repeat HRCT following 6 months of MMF treatment.
Treatment with MMF reduces the extent of ‘ground-glass’ opacities in patients with dSSc-associated alveolitis. Representative examples from the pulmonary CT scanning studies in two patients (patients 2 and 3) evaluated before and after 8 months of treatment with MMF (2 g/day).
Treatment with MMF reduces the extent of ‘ground-glass’ opacities in patients with dSSc-associated alveolitis. Representative examples from the pulmonary CT scanning studies in two patients (patients 2 and 3) evaluated before and after 8 months of treatment with MMF (2 g/day).
MMF treatment failures and adverse events
Because patients improved clinically, functionally and radiologically, treatment with MMF is still ongoing in five out of six patients (range 12–33 months, median 16 months). No cases of clinically significant infection and/or leucopenia have been recorded during MMF treatment. No patient developed abdominal pain justifying discontinuation of MMF or a dosage reduction. Patient 5 failed to meet her scheduled appointments and visited our clinic after 10 months of MMF treatment with clinical and radiological evidence of pleuritis. Despite her initially improving DLCO, her PFT subsequently declined (at 10 months FVC = 78% and DLCO = 64% of predicted. At 16 months FVC = 64% and DLCO = 48% of predicted). On the basis of declining PFT values the patient was withdrawn from the trial, and under gonadal protection treatment she received monthly i.v. pulses of Cy. Pulmonary function test values stabilized a few months following this. These data suggest that MMF treatment is well-tolerated and safe.
Discussion
Diffuse scleroderma-associated fibrosing alveolitis, a major determinant of disease prognosis, is currently treated empirically with Cy. We designed this trial in an effort to identify alternative immunosuppressive regimens that would be effective and would not share the potentially toxic profile of Cy. A small number of previous studies have reported that administration of Cy improved parameters of PFT and reduced the extent of fibrosing alveolitis on HRCT.
A recent study reported a significant benefit in PFT values and HRCT-documented alveolitis in a subgroup of patients receiving pulsed i.v. Cy along with high doses of CS, but not in patients treated with i.v. Cy in conjunction with low doses of CS, similar to those used by us [6]. Another study employed i.v. Cy combined with high-dose i.v CS. The HRCT score and skin disease improved but the PFT values declined 6 months after completion of treatment [7]. In another study all parameters of pulmonary function and HRCT improved following i.v. pulses of Cy and low-dose CS [8]. Similarly to our trial, the authors reported a significant benefit for DLCO and an improvement in FVC that did not reach significance. The effects of orally administered Cy given in conjunction with moderate doses of CS were evaluated in a recent study. Patients with early dSSc, not specifically with early dSSc-associated lung involvement, were enrolled and treated with Cy administered per os. A series of clinical and laboratory parameters were evaluated along with PFT, and all improved after treatment [9].
Since T cells appear to play an important role in the pathogenesis of scleroderma [10], and the major metabolite of MMF, mycophenolic acid, via inhibition of inosine monophosphate, inhibits T-cell proliferation and downstream effects on intracellular adhesion to endothelial cells [11] it is not unlikely that a beneficial effect of this drug might be expected. MMF in conjunction with antithymocyte globulin has been previously studied in patients with scleroderma resulting in significant improvement of skin score but no improvement of PFT [12]. Although we did not formally score skin disease, our experience with MMF in our patients is in agreement with this report.
In our short-term, ongoing, single-centre, uncontrolled, open-label trial, we enrolled patients with previously unapparent pulmonary involvement who developed symptoms of breathlessness and/or dry cough during follow-up. Even though it is thought that pulmonary involvement can be clinically silent despite abnormalities in functional and/or imaging studies, most of our patients had undergone such studies at previous time points (predominantly upon diagnosis of disease) and evidence of lung disease were not present before the onset of symptoms. Based on DLCO values, our group had mild to moderate lung disease. Nevertheless, it was clinically apparent. Furthermore, the moderately decreased pre-treatment DLCO values may reflect earlier stages of scleroderma lung.
Even though the number of patients with dSSc enrolled in this trial is small, the results with MMF treatment are encouraging. MMF was effective, producing significant improvements in DLCO, HRCT and respiratory symptoms, improved the quality of life of our patients, was well tolerated and safe at the dosage studied, and may represent an alternative to treatment of pulmonary involvement with Cy in the context of dSSc. Further randomized multicentre studies are needed to address these issues.
The authors have declared no conflicts of interest.
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