Mycophenolate mofetil as a therapeutic agent for interstitial lung diseases in systemic sclerosis.

Systemic sclerosis (SSc) is an intractable disease that causes fibrosis in all organs. Approximately 40% of patients with SSc have some degree of interstitial lung disease (ILD). One third of patients with SSc and ILD, approximately 15% of all patients, have pulmonary lesions, which slowly progress to respiratory failure resistant to corticosteroid and other treatments. A randomized controlled trial conducted in the United States indicated that one year of treatment with oral cyclophosphamide in patients with SSc-ILD had a significant but modest beneficial effect on lung function, dyspnea, thickening of the skin, and health-related quality of life. However, all the effects, except for a sustained impact on dyspnea, disappeared approximately one year after stopping oral administration of cyclophosphamide. A randomized controlled trial using cyclophosphamide and mycophenolate mofetil (MMF) was then held in the United States for 142 patients with SSc-ILD. Treatment of SSc-ILD with MMF for two years or cyclophosphamide for one year both resulted in significant improvements in lung function over the 2-year course of the study. Leukopenia and thrombocytopenia occurred less often in patients administered MMF than in those administered cyclophosphamide. MMF is currently not approved for the treatment of SSc-ILD in Japan. Both MMF and cyclophosphamide were effective against ILD associated with SSc and, in particular, MMF was useful in terms of tolerability. When MMF is approved, it should be positioned as one of the first treatment options for SSc-ILD, which will further enhance the treatment of this disease in Japan.

Ueda T ，Sakagami T ，Kikuchi T ，Takada T ... -  《-》

Cyclophosphamide versus mycophenolate mofetil in scleroderma interstitial lung disease (SSc-ILD) as induction therapy: a single-centre, retrospective analysis.

Shenoy PD ，Bavaliya M ，Sashidharan S ，Nalianda K ，Sreenath S ... -  《-》

Use of mycophenolate mofetil for systemic sclerosis and systemic sclerosis-associated interstitial lung disease: Information from a Japanese hospital claims database.

Limited information is available on patients with systemic sclerosis (SSc) or SSc-associated interstitial lung disease (SSc-ILD) receiving mycophenolate mofetil (MMF) in Japan. The dose, treatment duration, and patient characteristics of SSc and SSc-ILD patients receiving MMF were investigated. We used data from a Japanese hospital claims database (2008-2020). Data on 486 SSc patients ≥18 years old receiving MMF were captured; 314 had SSc complicated with ILD. The most common initial daily doses were 1000 mg (SSc, 39.5%; SSc-ILD, 38.1%) and 500 mg (SSc, 36.6%; SSc-ILD, 34.6%). The most common maximum daily doses were 1000 mg (SSc, 33.3%; SSc-ILD, 34.9%), 1500 mg (SSc, 24.4%; SSc-ILD, 23.1%), and 2000 mg (SSc, 23.8%; SSc-ILD, 24.4%). Doses ranged from 250 to 3000 mg/day and were similar for SSc and SSc-ILD patients. Over 27% of patients received treatment for >1 year. There was a gradual decrease in steroid doses during MMF treatment. Our study suggests that the off-label use of MMF for SSc and SSc-ILD has been increasing annually since 2015 in Japan. The doses used in patients with SSc and SSc-ILD were similar to the approved doses of MMF for lupus nephritis in Japan.

Funatogawa T ，Narita Y ，Tamura A ，Mii K ，Sugitani Y ，Uchida T ... -  《-》

Mycophenolate Mofetil Versus Placebo for Systemic Sclerosis-Related Interstitial Lung Disease: An Analysis of Scleroderma Lung Studies I and II.

To compare mycophenolate mofetil (MMF) with placebo for the treatment of systemic sclerosis (SSc)-related interstitial lung disease (ILD). We included participants enrolled in the placebo arm of Scleroderma Lung Study (SLS) I and the MMF arm of SLS II. SLS I randomized participants to receive either oral cyclophosphamide (CYC) or placebo for 1 year, while SLS II randomized participants to receive either MMF for 2 years or oral CYC for 1 year followed by 1 year of placebo. Eligibility criteria for SLS I and SLS II were nearly identical. The primary outcome was % predicted forced vital capacity (FVC), and key secondary outcomes included % predicted diffusing capacity for carbon monoxide (DLco), the modified Rodnan skin thickness score (MRSS), and dyspnea. Joint models were created to evaluate the treatment effect on the course of these outcomes over 2 years. At baseline, the MMF-treated group in SLS II (n = 69) and the placebo-treated group in SLS I (n = 79) had similar percentages of men and women and similar disease duration, SSc subtype, extent of skin disease, and % predicted FVC. MMF-treated patients in SLS II were slightly older (mean ± SD age 52.6 ± 9.7 years versus 48.1 ± 12.4 years; P = 0.0152) and had higher % predicted DLco (mean ± SD 54.0 ± 11.1 versus 46.2 ± 13.3; P = 0.0002) than placebo-treated patients in SLS I. After adjustment for baseline disease severity, treatment with MMF in comparison with placebo was associated with improved % predicted FVC (P < 0.0001), % predicted DLco (P < 0.0001), MRSS (P < 0.0001), and dyspnea (P = 0.0112) over 2 years. Although there are inherent limitations in comparing participants from different trials, treatment with MMF was associated with improvements in physiologic outcomes and dyspnea compared with placebo, even after accounting for baseline disease severity. These results further substantiate the use of MMF for the treatment of SSc-related ILD.

Volkmann ER ，Tashkin DP ，Li N ，Roth MD ，Khanna D ，Hoffmann-Vold AM ，Kim G ，Goldin J ，Clements PJ ，Furst DE ，Elashoff RM ... -  《-》

Interstitial lung disease in systemic sclerosis.

Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc) and mainly encountered in patients with diffuse disease and/or anti-topoisomerase 1 antibodies. ILD develops in up to 75% of patients with SSc overall. However, SSc-ILD evolves to end-stage respiratory insufficiency in only a few patients. Initial pulmonary function tests (PFT) with measurement of carbon monoxide diffusing capacity, together with high-resolution computed tomography, allows for early diagnosis of SSc-ILD, before the occurrence of dyspnea. Unlike idiopathic ILD, SSc-ILD corresponds to non-specific interstitial pneumonia in most cases, whereas usual interstitial pneumonia is less frequently encountered. Therefore, the prognosis of SSc-ILD is better than that for idiopathic ILD. Nevertheless, ILD represents one of the two main causes of death in SSc patients. To detect SSc-ILD early, PFT must be repeated regularly, every 6 months to 1 year, depending on disease worsening. Conversely, broncho-alveolar lavage is not needed to evaluate disease activity in SSc-ILD but may be of help in diagnosing opportunistic infection. The treatment of SSc-ILD is not well established. Cyclophosphamide, which has been used for 20 years, has recently been evaluated in two prospective randomized studies that failed to demonstrate a major benefit for lung function. Open studies reported mycophenolate mofetil, azathioprine and rituximab as alternatives to cyclophosphamide. On failure of immunosuppressive agent treatment, lung transplantation can be proposed in the absence of other major organ involvement or severe gastro-esophageal reflux.

Bussone G ，Mouthon L 《-》