Cyclophosphamide for connective tissue disease–associated interstitial lung disease
Sübutlu məlumatların xülasələri
09.03.2018 • Sonuncu dəyişiklik 09.03.2018
Editors
Cyclophosphamide in patients with connective tissue disease–associated interstitial lung disease may provide a small improvement in lung function and in dyspnoea compared to placebo. Mycophenolate may be as good as cyclophosphamide.
The quality of evidence is downgraded by by indirectness (differences between the population and outcomes of interest and those studied: subjects with relatively stable disease were included), and by imprecise results (wide confidence intervals).
Summary
A Cochrane review included 4 studies with a total of 495 subjects with interstitial lung disease and a diagnosis of connective tissue disease (most with systemic sclerosis). Three studies included only participants with systemic sclerosis, and 1 study included participants with systemic sclerosis, dermatomyositis/polymyositis, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Two studies compared cyclophosphamide to placebo (n=195) and 2 studies compared it to mycophenolate (n=300).
There was significant improvement in lung function with cyclophosphamide compared with placebo (post-treatment FVC %: MD 2.83, 95% CI 0.80 to 4.87; 2 studies, n=182) but no significant difference in post-treatment diffusing capacity of the lung for carbon monoxide (DLCO; % MD -1.68, 95% CI -4.37 to 1.02; 2 studies, n=182).
Risk of adverse effects was increased in the cyclophosphamide groups (in particular haematuria, leukopenia, and nausea) leading to a higher rate of withdrawal from cyclophosphamide treatment. There was statistically significant improvement in one-measure of quality of life in one study favouring cyclophosphamide over placebo and clinically and statistically significant improvement in breathlessness in one study favouring cyclophosphamide compared with placebo, with no significant impact on mortality.
There was no significant impact on lung function when cyclophosphamide was compared with mycophenolate at 12 months (FVC % MD -0.82, 95% CI -3.95 to 2.31; 2 studies, n=149; DLCO % MD -1.41, 95% CI -10.40 to 7.58; 2 studies, n=149).
Risk of side effects was increased with cyclophosphamide (in particular leukopenia and thrombocytopenia).
There was no significant impact on health-related quality of life, all-cause mortality, dyspnoea, or cough severity in the cyclophosphamide group compared to mycophenolate.
Subgroup analysis were performed to determine whether severity of lung function, connective tissue disease diagnosis, or radiological pattern had any impact on outcomes. One study reported that cyclophosphamide protected against decreased FVC in individuals with worse fibrosis scores, and also showed that cyclophosphamide may be more effective in those with worse lung function. No association could be made between connective tissue disease diagnosis and outcomes.
One multicenter RCT included 158 subjects with scleroderma, restrictive lung physiology, dyspnea, and evidence of inflammatory interstitial lung disease. Patients received oral cyclophosphamide (CYC) or matching placebo for one year and were followed for an additional year. The mean absolute difference in adjusted 12-month forced vital capacity (FVC) percent predicted between the CYC and placebo groups was 2.53 % (95 % CI 0.28 to 4.79 %), favoring CYC (P<0.03). There were also treatment-related differences in physiological and symptom outcomes, and the difference in FVC was maintained at 24 months. There was a greater frequency of adverse events in the CYC group, but the difference between the two groups in the number of serious adverse events was not significant.
Another RCT randomized 45 subjects to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral azathioprine, or placebo. Primary outcome measures were change in percent predicted FVC and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19% (a trend toward statistical significance, P = 0.08). No improvements in DLCO or secondary outcome measures were identified.
Ədəbiyyat
- Barnes H, Holland AE, Westall GP et al. Cyclophosphamide for connective tissue disease-associated interstitial lung disease. Cochrane Database Syst Rev 2018;(1):CD010908. Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M, Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med 2006 Jun 22;354(25):2655-66. Hoyles RK, Ellis RW, Wellsbury J, Lees B, Newlands P, Goh NS, Roberts C, Desai S, Herrick AL, McHugh NJ, Foley NM, Pearson SB, Emery P, Veale DJ, Denton CP, Wells AU, Black CM, du Bois RM. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum 2006 Dec;54(12):3962-70.