The blind, randomized, controlled trials identified in the review included patients given cyclophosphamide, as well as patients prescribed other drugs or placebo. The duration of treatment with cyclophosphamide was limited to 12 months due to concerns of adverse events. One trial found a clinically and statistically significant improvement in breathlessness in patients taking cyclophosphamide compared with controls. In particular, cyclophosphamide appeared to protect against decreased FVC among patients with worse fibrosis scores. Another trial found a statistically significant improvement measure of quality of life in patients treated with cyclophosphamide when compared with placebo controls. However, many participants withdrew from these trials due to adverse events, treatment failure and participant preference. In particular, patients in the cyclophosphamide treatment groups experienced leukopenia, neutropenia, thrombocytopenia, anemia and nausea.
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Shervin Assassi, MD, a rheumatologist at McGovern Medical School at The University of Texas Health Science Center, Houston, spoke with The Rheumatologist about the findings. While noting that in the U.S. mycophenolate is typically prescribed to these patients, he adds that, “It is reasonable to ask what the evidence is to support that decision.” Given prescription practices in the U.S., he thinks that the two randomized control trials that compared cyclophosphamide with mycophenolate were of greatest interest. One of the trials was written and published in Chinese and the other is the well-known Scleroderma Lung Study II published in 2016.2
“Both cyclophosphamide and mycophenolate have comparable effects, but mycophenolate is thought to be safer,” explains Dr. Assassi. “At this point, we are using mycophenolate based on the results of the 2016 study.”
Call for More Research
The authors concluded the review by suggesting clinical practice guidelines advise clinicians to consider individual patient characteristics when determining treatment. In particular, they suggest that patients with minor or subclinical disease are unlikely to benefit from cyclophosphamide and are likely to experience adverse effects from treatment. Dr. Assassi agrees, noting that “one third of the patients don’t respond to immunosuppression.”
Thus, a great need exists to find biomarkers that can be used to identify these patients. The current evidence would suggest that histological subtype and disease duration cannot be used to predict responsiveness to treatment.
The review described the evidence as low quality due to the limited number of studies in the field. The authors suggest future studies on the use of cyclophosphamide should be adequately empowered to compare outcomes within different subgroups. They suggest the groups should be large enough to stratify the extent of pulmonary infiltrates as determined by high-resolution computed tomography, as well as skin involvement in patients with SSc. This suggestion is due to the fact that patients with rapidly progressive fibrotic disease may be in the best position to benefit from cyclophosphamide treatment and these patients are not well represented in the current literature. The authors also identify the need for studies on other forms of connective tissue disease. Unfortunately, since these are rare diseases, it will be difficult to perform large studies.