What is the Incidence of Bladder Toxicity from Cyclophosphamide in the Treatment of Rheumatic Diseases?

Monach et al. performed a detailed literature review of studies published between the 1970s and 2000 concerning bladder toxicity related to CYC. They found the rates of bladder toxicity from IV CYC regimens used in rheumatology to be quite low when compared with rates seen in the cancer literature, perhaps due to the finding that rheumatology regimens usually resulted in less overall CYC total dosing. Also, within rheumatic diseases, they found rates of bladder toxicity to be very low in patients given IV therapy, perhaps due to less total dose when CYC is used IV and/or lack of capture of bladder toxicity data in studies using IV therapy. They report the incidence of CYC-related cystitis from a number of studies using daily oral CYC (doses from 1-5 mg/kg/day), ranging from 7% to 41%, although each study may have defined cystitis differently, ranging from hematuria only to cystoscopy-diagnosed disease. The authors also report rates of bladder cancer ranging from 0% to 8%, with latency periods of diagnosis of cancer from 1 to 23 years. Of note, rates of bladder cancer appeared higher in smokers.

Regarding prevention of bladder toxicity, mesna (2-mercatpoethanesulfonic acid), is thought to decrease the incidence of cystitis and bladder cancer by counteracting the toxic effects of acrolein though data are inconclusive. The authors discuss their surprise over the relative paucity of data regarding mesna use in rheumatologic-related CYC dosing, especially given the recommendations in several rheumatology texts advocating use of mesna.

In this data review authors conclude that in rheumatic diseases, oral CYC is associated with higher risk for bladder toxicity when compared with IV use. They believe that patients with rheumatic diseases requiring CYC should be counseled that indications for mesna use are not strongly evidence-based, but that if patients need CYC for prolonged therapy (e.g. more than 4 months) mesna should be considered. Recommendations regarding appropriate long-term screening for bladder toxicity/cancer in patients who have received CYC are not provided.

If mesna is used, it can be dosed IV at approximately 20% of the CYC dose. For example, if 1000 mg of CYC is given, then a total dose of 200 mg of mesna is given, divided into 3 doses (usually dosed 30 minutes prior and then 4 and 8 hours after CYC administration). For oral dosing of mesna, typically a total of 40% of the CYC dose is used, again divided into 3 doses (the first approximately 2 hours prior to CYC, to allow time for absorption, and again at 4 and 8 hours after CYC dosing). If a patient is on daily oral CYC, the mesna needs to be continued daily; if a patient is on monthly IV CYC, the mesna may be dosed only on the day of CYC infusion.

Reference:

1. Monach PA, et al. Incidence and Prevention of Bladder Toxicity from Cyclophosphamide in the Treatment of Rheumatic Diseases: A Data-Driven Review. Arthritis Rheum.2010;62:9–21
   

E. All of the above

Multiple epidemiologic studies support an association between psoriasis and components of the metabolic syndrome. Children may also be affected by the relationship between psoriasis and metabolic syndrome. Population-based studies have found increased rates of components of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes) in children with psoriasis. Psoriasis is associated with increased risk for the development of atherosclerotic vascular disease including cardiovascular, cerebrovascular, and peripheral vascular disease.¹ Multiple studies have found an increased risk for malignancy in patients with psoriasis, The highest detected risks were for pancreatic cancers (incidence rate ratio [IRR] 2.20, 95% CI 1.18-4.09) and lymphohematopoietic malignancies (IRR 1.81, 95% CI 1.35-2.42).² Compared with the general population, autoimmune disease may be more likely to occur in individuals with psoriasis. In a retrospective cohort study that included approximately 23,000 patients with psoriasis, an increased risk for multiple autoimmune diseases was detected, with the greatest risk increase observed for alopecia areata (odds ratio 2.2, 95% CI 2.0-3.0), followed by celiac disease, systemic sclerosis, Crohn’s disease, vitiligo, and other disorders.³

References

1. Kaye JA, Li L, Jick SS. Incidence of Risk Factors for Myocardial Infarction and Other Vascular Diseases in Patients with Psoriasis. Br J Dermatol. 2008;159:895.
2. Brauchli YB, Jick SS, Miret M, et al. Psoriasis and Risk of Incident Cancer: An Inception Cohort Study with a Nested Case-Control Analysis. J Invest Dermatol. 2009;129:2604.
3. Wu JJ, Nguyen TU, Poon KY, et al. The Association of Psoriasis with Autoimmune Diseases. J Am Acad Dermatol. 2012;67:924.