Effects of 1-Year Treatment with Cyclophosphamide on Outcomes at 2 Years in Scleroderma Lung Disease

Tashkin, Donald P.; Elashoff, Robert M.; Clements, Philip J.; Roth, Michael D.; Fürst, Daniel E.; Silver, Richard M.; Goldin, Jonathan G.; Arriola, Edgar; Strange, Charlie; Bolster, Marcy B.; Seibold, James R.; Riley, David; Hsu, Vivien; Varga, John; Schraufnagel, Dean E.; Theodore, Arthur C.; Simms, Robert W.; Wise, Robert A.; Wigley, Fred; White, Barbara; Steen, Virginia D.; Read, Charles A.; Mayes, Maureen D.; Parsley, Ed; Mubarak, Kamal K.; Connolly, M. Kari; Golden, Jeffrey A.; Olman, Mitchell A.; Fessler, Barri J.; Rothfield, Naomi F.; Metersky, Mark L.; Khanna, Dinesh; Li, Ning; Li, Gang

doi:10.1164/rccm.200702-326oc

Cited by 415 publications

(278 citation statements)

References 31 publications

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“…A recent placebo-controlled, double-blind study showed a statistically significant but modest (2.53%) beneficial effect of oral cyclophosphamide on lung function, as measured by forced vital capacity (FVC) (3). This small effect was not persistent at 1 year of followup (4), although the patients who had received cyclophosphamide still demonstrated a benefit in the dyspnea score.…”

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confidence: 99%

Randomized, prospective, placebo‐controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis

Seibold

Denton

Fürst

et al. 2010

Arthritis & Rheumatism

119

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Objective. Endothelin is implicated as a participatory pathway in systemic sclerosis (SSc). We tested this hypothesis in a 12-month trial of bosentan, a nonselective endothelin receptor antagonist, as a therapy for SSc-related interstitial lung disease (ILD).Method. Patients with SSc and significant ILD were recruited to this prospective, double-blind, randomized, placebo-controlled, parallel group study. The inclusion criteria were designed to select a cohort enriched for patients with active and progressive disease. Exclusion factors included significant pulmonary hypertension. Patients with a diffusing capacity for carbon monoxide of <80% predicted and a 6-minute walk distance of 150-500 meters or a 6-minute walk distance of >500 meters with a decrease in oxygen saturation received bosentan or placebo. The primary efficacy end point was a change in the 6-minute walk distance from baseline up to month 12. Secondary end points included time to death or worsening results of pulmonary function tests (PFTs). The safety and tolerability of bosentan were also assessed.Results. Among the 163 patients, 77 were randomized to receive bosentan, and 86 were randomized to receive placebo. No significant difference between treatment groups was observed for change in the 6-minute walk distance up to month 12. No deaths occurred in this study group. Forced vital capacity and diffusing capacity for carbon monoxide remained stable in the majority of patients in both groups. Significant worsenClinicalTrials.gov identifier: NCT00070590.

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confidence: 99%

Randomized, prospective, placebo‐controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis

Seibold

Denton

Fürst

et al. 2010

Arthritis & Rheumatism

119

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“…All patients fulfilled the 2013 classification criteria (van den Hoogen et al 2013). The follow-up period was defined as the time from the initial manifestation of SSc-related symptoms to either the date of death or the latest visit to our hospital.…”

Section: Methodsmentioning

confidence: 99%

“…However, no agents have been proven to effectively control ILD . Cyclophosphamide was demonstrated to stabilize lung function in a randomized controlled trial, but its beneficial effect disappeared at 24 months (Tashkin et al 2006;Tashkin et al 2007). Moreover, acute exacerbation of ILD (AE-ILD) occurs at a 1-year frequency of 1.25%-3.3% and at a lifetime incidence of 7.2%, with a high mortality rate in patients with connective tissue disease (Park et al 2007;Suda et al 2009).…”

Section: Introductionmentioning

confidence: 99%

High Prevalence of Acute Exacerbation of Interstitial Lung Disease in Japanese Patients with Systemic Sclerosis

Tomiyama

Watanabe

Ishii

et al. 2016

Tohoku J. Exp. Med.

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Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by extensive fibrosis and autoantibodies. Its clinical manifestations are diverse and include Raynaud's phenomenon, gastrointestinal dysmotility, interstitial lung disease (ILD), pulmonary hypertension, and renal crisis. Among these, ILD is the primary cause of SSc-related death. It has been considered that acute exacerbation of ILD (AE-ILD) is not common in patients with SSc; however, little is known about the prevalence of AE-ILD in Japanese patients with SSc. In this study, we aimed to clarify the prevalence, clinical characteristics, and prognosis of patients with SSc who developed AE-ILD and to identify predictive factors for AE-ILD in our Japanese cohorts. Clinical data of patients who visited our department from 1990 to 2014 and fulfilled the 2013 classification criteria for SSc were retrospectively reviewed. A total of 139 patients were enrolled. The mean age of onset was 49.1 years, and 113 (81.3%) patients were female; 116 (83.5%) had limited cutaneous involvement, and the overall 10-year survival rate was 92.0%. Among 66 (47.5%) patients with ILD, 13 (9.4%) developed AE-ILD. Patients with AE-ILD had a significantly higher incidence of overlap with polymyositis (PM) or dermatomyositis (DM) and lower prevalence of anticentromere antibodies with higher mortality rate compared with those without AE-ILD. Multivariate Cox regression analysis identified that an overlap with PM or DM was the most significant predictive factor for AE-ILD. Our study results suggest that Japanese patients with SSc, particularly patients overlapped with PM or DM, have a high risk of AE-ILD.

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“…At present, only daily oral or pulse intravenous cyclophosphamide (CYC) have been shown in large randomized, doubleblinded, placebo-controlled trials to alter the course of SSc-ILD (2)(3). While highlighting that SSc-ILD is treatable, the overall magnitude of the response to CYC in these studies was modest and the beneficial effects appeared to fade within a year after stopping treatment (2)(3)(4). When these features are combined with the potential toxicity associated with CYC (5), there has been considerable controversy about whether all patients with SSc-ILD should be treated or whether therapy should be reserved for patients at the greatest risk for progression or deterioration (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Predicting Treatment Outcomes And Responder Subsets In Scleroderma-Related Interstitial Lung Disease

Roth¹,

Tseng²,

Clements³

et al. 2011

B102. Interstitial Lung Disease: Novel Management and Outcome Strategies

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Objectives-To identify baseline characteristics of patients with Scleroderma-Related Interstitial Lung Disease (SSc-ILD) which predict the most favorable response to a 12-month treatment with oral cyclophosphamide (CYC).Methods-Regression analyses were retrospectively applied to the Scleroderma Lung Study data in order to identify baseline characteristics that correlated with the absolute change in %-predicted Forced Vital Capacity (FVC) and the placebo-adjusted change in %-predicted FVC over time (the CYC treatment effect).Results-Completion of the CYC arm of the Scleroderma Lung Study was associated with a placebo-adjusted improvement in %-predicted FVC of 2.11% at 12 months which increased to 4.16% when patients were followed for another 6 months (p=0.014). Multivariate regression analyses identified the maximal severity of reticular infiltrates on baseline high-resolution computerized tomography (HRCT), the modified Rodnan Skin Score (mRSS), and Mahler's Baseline Dyspnea Index (BDI) as independent correlates of treatment response. When patients were stratified based on whether 50% or more of any lung zone was involved by reticular infiltrates on HRCT and/or the presence of a mRSS of at least 23, a subgroup emerged with an average CYC treatment effect of 4.73% at 12 months and 9.81% at 18 months (p<0.001). Conversely, there was no treatment effect (−0.58%) in patients with less severe HRCT findings and a lower mRSS.

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Effects of 1-Year Treatment with Cyclophosphamide on Outcomes at 2 Years in Scleroderma Lung Disease

Cited by 415 publications

References 31 publications

Randomized, prospective, placebo‐controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis

Randomized, prospective, placebo‐controlled trial of bosentan in interstitial lung disease secondary to systemic sclerosis

High Prevalence of Acute Exacerbation of Interstitial Lung Disease in Japanese Patients with Systemic Sclerosis

Predicting Treatment Outcomes And Responder Subsets In Scleroderma-Related Interstitial Lung Disease

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