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).
A Cochrane review [Abstract] 1 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.
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