Infections have been reported in patients with IBD treated with cyclosporine (CsA). Since CsA is indicated in the treatment of severe UC [117], and patients who respond to intravenous CsA are then treated with outpatient oral therapy while initiating another immunosuppressive agent, the combination immunosuppression likely increases this risk of infection.

In the original randomized controlled trial assessing the efficacy of CsA for severe ulcerative colitis, 11 patients were followed until hospital discharge or colectomy, and no infections were reported [117]. However, in a larger chart review of 111 patients with IBD treated with CsA, 25 infections were reported in 23 (20 %) patients [118]. 16 (73 %) were mild infections, and 7 infections were determined to be serious. These included one case of Pneumocystis jiroveci (carinii) pneumonia and three cases of catheter-related sepsis. Another retrospective chart review was performed in 86 Belgian patients with IBD treated with CsA between 1992 and 2000 with a mean follow-up of 773 days [119]. Infections were reported in 16 (18.6 %) patients. Three (3.5 %) died of opportunistic infections (one case of Pneumocystis jiroveci pneumonia and two cases of Aspergillus fumigatus pneumonia). There were eight cases of catheter-related sepsis, and two cases of anal abscess. The several cases of Pneumocystis jiroveci reported in these case series are noteworthy as this is an uncommon complication of other medical therapies for ulcerative colitis. As such, routine prophylaxis against Pneumocystis pneumonia is often used for patients treated with CsA.

Estimating the risk of lymphoma associated with CsA use in IBD is limited by the small number of patients exposed to these drugs and confounding by concomitant immunosuppressive use.

The organ transplant literature provides the most information relating to CsA and lymphoma risk. The largest study that estimated lymphoma risk of CsA in an organ transplant population comes from the Collaborative Transplant Study database, an international database of solid organ transplant patients [120]. Among cadaver kidney transplant recipients, the relative risk of lymphoma was higher among patients exposed CsA compared with a normal population matched by age, sex, and geographic region, but this relative risk was not significantly different than the relative risk of lymphoma in kidney transplant patients treated with steroids and azathioprine (RR 12.7 vs. 14.3, p-value 0.91). A 1998 study examined the outcomes of different CsA doses by randomizing 231 patients 1-year post kidney transplant to normal- or low-dose CsA. After a 66-month follow-up period, four lymphoproliferative disorders were diagnosed, three of which occurred in the normal-dose group and one in the low-dose group [121]. In 1989, Cockburn and Krupp [122] detailed the malignancies including lymphoma or other lymphoproliferative disease reported to the Sandoz Drug Monitoring Center. There were 186 neoplasms among CsA recipients reported, and the largest percentage of malignancies reported were lymphomas or leukemia (29 %). They also reported the results of postmarketing surveillance of 4,040 renal transplant recipients who received at least one dose of CsA. These patients were followed for up to 7 years, and the lymphoma risk was estimated to be 28 times that of the normal population.

In the IBD literature, there are at least three cases of non-Hodgkin’s lymphoma reported among CsA-exposed patients. In a retrospective study of 782 patients with IBD followed at St. James’s Hospital in Dublin from 1990 to 1999, there were four cases of non-Hodgkin’s lymphoma [71]. The patients were all exposed to immunosuppressants, and one of these patients had received 5 months of methotrexate followed by 12 months of CsA prior to a colectomy that revealed diffuse large B-cell lymphoma. A case of rectal diffuse large B-cell lymphoma was reported in a patient with UC and pyoderma gangrenosum treated with 4 years of CsA and low-dose prednisone [123]. Another patient with UC treated with exposure to prednisone, CsA, 6-mercaptopurine, and infliximab developed an EBV-positive non-Hodgkin’s lymphoma of the ileal pouch [124].

Skin cancer appears to be the most frequent malignancy other than lymphoproliferative disease reported among users of CsA. Again, this evidence comes largely from the dermatologic and transplant literature. Cockburn and Krupp [122] reported that of the 186 neoplasms reported by 1989 to the Sandoz Drug Monitoring Center for CsA, 58 (39 %) were skin cancers. Among these cases, Kaposi’s sarcoma was the most commonly reported skin cancer (45 %), followed by basal cell (29 %) and squamous cell skin cancer (26 %). Cockburn [122] also studied the malignancies reported among 4,040 renal transplant patients who received CsA and were followed post transplant. They estimated the risk of skin cancer in this population to be seven times that of the normal population.

The major difference between CsA treatment for transplant recipients and patients with ulcerative colitis is the duration of therapy. While there is clear evidence of an increased risk of malignancy among transplant recipients, it is difficult to quantitatively translate this for patients with ulcerative colitis who typically receive less than 6 months of therapy. Nonetheless, because the risk of cancer appears to be correlated with the degree of immunosuppression, there is a rationale to try to minimize the period of time that patients are simultaneously treated with CsA, steroids, and thiopurines.

Nephrotoxicity due to CsA is well defined in the solid organ transplantation population, including kidney, liver, heart, and lung transplants [125–128]. CsA can cause both acute and chronic kidney injury [126–129]. CsA is thought to cause acute kidney injury (AKI) by reducing renal blood flow due to vasoconstriction of the afferent arteriole, thus leading to a decrease in the glomerular filtration rate and an increase in the serum creatinine. The vasoconstriction is thought to be mediated by a number of factors, including endothelin, thromboxane A2, inhibition of nitric oxide synthase, and activation of the sympathetic nervous system [130]. Fortunately, this form of nephrotoxicity is reversible and often appears to be associated with the dose of CsA used. CsA therapy can also lead to CKD by causing interstitial fibrosis and tubular nephropathy, which tends to develop after 6–12 months of therapy. It is thought that intrarenal activation of the renin-angiotensin system may play a role in the development of CsA-induced CKD [131]. Unfortunately, this form of nephrotoxicity is not reversible and constitutes the major limitation of the use of CsA in the transplantation population.

In contrast to the transplantation world, nephrotoxicity due to CsA in the IBD population is less well described. In IBD, CsA is used most often to induce remission in patients with severely active ulcerative colitis. In the acute setting, three randomized controlled trials of intravenous (IV) CsA for induction of remission in patients with severely active ulcerative colitis have been published [117, 132, 133]. The first study, by Lichtiger et al., in which 20 patients refractory to IV corticosteroids were treated with IV CsA or placebo, found that none of the patients had nephrotoxicity [117]. The second study, by D’Haens et al., comparing IV CsA to IV corticosteroids in 30 patients, reported a significant decrease in renal function, as measured by inulin clearance, after 8 days of CsA treatment; however, renal function returned to normal in these patients after CsA was discontinued [132]. Of note, patients treated with corticosteroids did not experience a reduction in renal function. The third study, by Van Assche et al., compared the efficacy of IV CsA at daily doses of 4 mg/kg versus 2 mg/kg in 73 patients and observed an increase in serum creatinine of 10 % or more in 18 % of patients treated with 4 mg/kg and 17 % of patients treated with 2 mg/kg; of note, no patient had a serum creatinine increase of 30 % or greater [133].

While these data in the acute setting are useful, patients treated with IV CsA for 7–14 days then remain on oral CsA typically at 8 mg/kg daily (with dose adjustment to maintain trough serum levels of 150–300 ng/mL) after hospital discharge for 3–9 months while bridging to thiopurine therapy and weaning corticosteroids. Long-term retrospective follow-up data of UC patients treated with CsA at tertiary care medical centers represent the best information we have to date regarding the nephrotoxicity of CsA in IBD patients. At least five such long-term outcome series have been published [118, 119, 134–136]. Cohen et al. found that none of the 42 patients followed for up to 5.5 years had renal toxicity [134]. Arts et al. reported that only 6 % of the 86 patients treated with CsA and followed for a mean of 2.1 years developed renal insufficiency, defined as an increase in serum creatinine of at least 20 %, most of which occurred during the IV phase [119]. In a study by Campbell et al., of the 76 patients followed for a median of 2.9 years, only one had to discontinue the use of CsA due to renal toxicity [135]. Moskovitz et al. retrospectively followed 142 patients for up to 7 years and observed that only 3.5 % developed renal toxicity [136]. Finally, Sternthal et al. found that of the 111 patients treated with CsA for a mean of 9.3 months, 5.4 % had to discontinue CsA due to major nephrotoxicity, defined as serum creatinine of ≥1.4 mg/dL or an increase of at least 33 % from baseline not responding to dose adjustment, while 19 % developed minor nephrotoxicity, defined as above but with return to normal serum creatinine after dose adjustment [118]. Thus, overall the available data in the IV inpatient and oral outpatient setting indicate that the risk of major nephrotoxicity with CsA use is low and that minor nephrotoxicity, which may occur more frequently in the IV inpatient phase, is often reversible with dose adjustment. It is likely that the higher incidence of CsA-induced nephrotoxicity in the transplantation population compared to the IBD population is due to the long-term use of CsA in transplant recipients who remain on CsA for years, in contrast to the 3–9 months of CsA therapy for IBD patients.

Risk factors for CsA-induced nephrotoxicity in IBD patients are unknown. However, in renal transplantation patients, risk factors for the development of CsA-induced CKD include: the number of CsA-induced episodes of AKI, the number of unexplained episodes of AKI, CsA trough level, primary renal function, and the number of nephrotoxic drugs [137]. With respect to monitoring of serum creatinine in UC patients treated with CsA, no specific guidelines exist. During inpatient IV therapy, serum creatinine is generally measured at least every other day, while during outpatient long-term oral therapy, serum creatinine is often checked weekly for 1 month and at least monthly thereafter and also rechecked 1 week after each dose adjustment of CsA [118]. With respect to monitoring of CsA levels, these levels are generally checked at least every other day during the IV phase with a target level of 250–450 ng/ml, whereas they are usually checked weekly for 1 month and at least monthly thereafter and also rechecked 1 week after each dose adjustment of CsA during the oral phase with a target level of 150–300 ng/mL [117, 118, 133–135].