Cyclosporine is used for the prevention of rejection of kidney, liver, or heart allografts. The manufacturers and some clinicians recommend that cyclosporine be used in conjunction with corticosteroid therapy, at least initially. Cyclosporine is also used for the treatment of chronic allograft rejection in patients previously treated with other immunosuppressive agents (e.g., azathioprine).
Cyclosporine is used to prolong graft survival of allogeneic renal transplants. Therapy with cyclosporine alone has achieved graft survival rates ranging from 71-91% 1 year after renal transplantation. In a retrospective study, patient and graft survival rates were 86 and 70%, respectively, 4 years after transplantation in cyclosporine-treated patients.
Concomitant administration of cyclosporine and corticosteroids in some studies has resulted in reduction of cyclosporine dosage and decreased frequency of cyclosporine's nephrotoxic effects while continuing to optimally prolong graft survival; however, some clinicians suggest that concomitant administration of cyclosporine and corticosteroids does not increase effectiveness and may increase the frequency of adverse systemic effects (e.g., lymphoma). In a study in renal allograft recipients receiving cyclosporine alone or in combination with corticosteroids, graft survival rates after 1 year were 88 vs 84%, respectively; infectious complications and hypertension occurred more frequently in patients receiving combined therapy with cyclosporine and a corticosteroid than in those receiving cyclosporine alone. Concomitant administration of cyclosporine and corticosteroids did not improve renal function and was associated with increased frequency of lymphoma, probably resulting from excessive immunosuppression. Although the manufacturers recommend that cyclosporine be used in conjunction with corticosteroid therapy, at least initially, further study is needed to determine the role of concomitant therapy in renal allograft recipients.
When immunosuppressive therapy with cyclosporine alone or combined with corticosteroids has been compared with combined azathioprine and corticosteroid therapy, graft survival rates generally were equivalent or higher in patients receiving cyclosporine with or without corticosteroids. In patients with renal allografts, the 1-year actuarial graft survival rates for cyclosporine vs combined azathioprine and corticosteroid therapy have been reported to be 72-77 vs 52-62%, respectively; the 1-year patient survival rates for cyclosporine vs combined azathioprine and corticosteroid therapy were 88-94 vs 76-92%, respectively. Some cyclosporine-treated patients also received periodic corticosteroid therapy for acute rejection episodes. The 4-year actuarial graft survival rates for these therapies have been reported to be 76 vs 62%, respectively, and the 4-year actuarial patient survival rates were 86 vs 70%, respectively. In one study, graft survival rate in cyclosporine-treated patients was higher in patients receiving first renal allografts than in those receiving second ones and in patients receiving HLA-A and/or B mismatched allografts than in those receiving allografts matched at HLA-A and B loci; there was no correlation in graft survival with warm or cold ischemia or with anti-HLA antibodies. Cyclosporine-treated patients generally have had higher serum creatinine concentrations than those receiving combined azathioprine and corticosteroid therapy. The relative effects of prophylactic immunosuppressive regimens containing cyclosporine and/or equine antithymocyte globulin (ATG) on graft survival rates remain to be determined. Results of several comparative studies indicate that the effects on graft survival rates of prophylactic immunosuppressive regimens containing cyclosporine or equine antilymphocyte globulin (ALG) are similar.
Although cyclosporine prolongs graft survival, the drug may not prevent acute episodes of renal allograft rejection. The number of patients experiencing acute episodes of renal allograft rejection and the median time to onset of these episodes (about 1 week) have been reported to be similar for cyclosporine- or combined azathioprine/corticosteroid-treated patients. However, in one study, first acute episodes of rejection were substantially less severe in patients receiving cyclosporine than in those receiving combined azathioprine and corticosteroid therapy. In some cyclosporine-treated patients, renal graft losses resulting from irreversible acute graft rejection may be associated with persistently low trough serum concentrations of the drug; however, optimum therapeutic trough concentrations have not been determined. The occurrence of graft rejection is difficult to differentiate from cyclosporine-induced nephrotoxicity.
(See Cautions: Renal Effects.)Rapid increases in serum creatinine concentration that occur simultaneously with low blood or plasma cyclosporine concentrations may indicate graft rejection.
Some clinicians recommend that cyclosporine generally be discontinued and combined therapy with azathioprine and corticosteroids be initiated in patients who do not tolerate cyclosporine (e.g., nephrotoxicity) or in whom intractable rejection occurs. In one study, the 1-year actuarial graft survival rate in patients switched from cyclosporine to combined azathioprine and corticosteroid therapy was 60%. Conversion to immunosuppressive therapy with azathioprine and corticosteroids usually results in decreased serum creatinine concentrations; however, complications, including acute rejection episodes, serious infections, or azathioprine-induced leukopenia, may occur. In one study, the need to switch from cyclosporine to combined azathioprine and corticosteroid therapy because of cyclosporine-induced nephrotoxicity or intractable rejection was eliminated when routine (3 times weekly) monitoring of trough serum cyclosporine concentrations was initiated; however, optimum trough concentrations have not been determined.
Cyclosporine is used to prolong graft and patient survival in hepatic allograft recipients. Administration of cyclosporine and low-dose prednisone has resulted in 1-year actuarial patient survival rates of 60-80% in a limited number of hepatic allograft recipients. However, response rates may be variable and may depend on the underlying condition of the patient or the immunosuppressive regimen used. Cyclosporine's effectiveness in hepatic allotransplantation has been shown in children and adults. Decreased frequency of postoperative infectious complications may be observed in hepatic allograft recipients who have received cyclosporine compared with those treated with other immunosuppressive therapy.
Cyclosporine is used to prolong graft and patient survival in cardiac allograft recipients. The drug has been used concomitantly with low-dose corticosteroid therapy to decrease the frequency and clinical severity of rejection episodes, reduce infectious complications compared with other immunosuppressive agents, and facilitate early patient rehabilitation following cardiac transplantation. Two-year actuarial patient survival rates for cardiac allograft recipients receiving cyclosporine vs combined azathioprine and corticosteroid therapy have been reported to be 77 vs 58%, respectively, in a limited number of patients.
Cyclosporine has also been used in a limited number of patients with combined heart-lung transplantation.
Bone Marrow Allotransplantation
The value of cyclosporine in the prevention of acute graft-vs-host disease following bone marrow transplantation remains to be clearly established. Results of studies to date suggest that prophylaxis with cyclosporine is comparable to, but not more effective than, prophylaxis with methotrexate for the prevention or amelioration of acute graft-vs-host disease or improving survival in patients undergoing bone marrow transplantation for leukemias. Limited data suggest that prophylactic combination therapy with cyclosporine and methotrexate is more effective for the prevention or amelioration of acute graft-vs-host disease and possibly improves survival compared with cyclosporine alone. Cyclosporine has also been used with some success for the treatment of moderate to severe, acute graft-vs-host disease following bone marrow transplantation. Limited data suggest that cyclosporine may be as effective as corticosteroid therapy. Corticosteroids are generally considered the initial therapy of choice for the treatment of acute graft-vs-host disease.
Oral cyclosporine is used in the management of the active stage of severe rheumatoid arthritis in selected adults who have an inadequate therapeutic response to methotrexate; the drug may be used in combination with methotrexate in those who do not respond adequately to methotrexate monotherapy. Oral cyclosporine also has been useful in the treatment of rheumatoid arthritis in adults who had an insufficient therapeutic response to, or who did not tolerate nonsteroidal anti-inflammatory agents (NSAIAs) and other disease-modifying antirheumatic drugs (DMARDs) (e.g., gold compounds, penicillamine). Cyclosporine is one of several DMARDs that can be used when DMARD therapy is appropriate. (For further information on the treatment of rheumatoid arthritis, .)
In a placebo-controlled study, cyclosporine administered for 6 months was more effective than placebo in decreasing the number of painful and tender or swollen joints. Results of an uncontrolled clinical study of patients treated with cyclosporine for a median of 29 months showed in comparison to baseline articular index that at 18 months pain (as rated on a visual analog scale) and the duration of morning stiffness were decreased, while functional capacity (as rated on a visual analog scale) was improved. After 24 months of therapy, articular index, pain, and duration of morning stiffness remained decreased. Although few comparative studies with other DMARDs have been published, cyclosporine appears to be as effective as azathioprine, chloroquine, or methotrexate in the management of rheumatoid arthritis. Cyclosporine, azathioprine, and methotrexate did not differ in global assessment of efficacy based on the number of clinical and laboratory variables that improved after 1 year of therapy. The decrease in the number of swollen joints did not differ between cyclosporine and chloroquine after 24 weeks of therapy with either drug as the initial DMARD. The difference between groups in radiologic evidence of progression of disease, as indicated by the increase in the number of target joints with juxtaarticular erosions at 12 months compared with baseline, favored patients who were receiving cyclosporine over the controls who were receiving another DMARD (e.g., chloroquine, hydroxychloroquine, sulfasalazine, auranofin, parenteral gold compounds, penicillamine).
Combined use of cyclosporine and methotrexate appears to improve therapeutic response in patients with rheumatoid arthritis that had improved partially with methotrexate alone. After 6 months of therapy, improvement in the tender-joint count was greater with combined cyclosporine (mean dosage: 3 mg/kg daily) and methotrexate than with methotrexate alone. In addition, more patients treated with cyclosporine and methotrexate had improvement in rheumatoid arthritis, based on criteria of the American College of Rheumatology (i.e., improvement by at least 20% in the number of tender joints, number of swollen joints, and in 3 of 5 other clinical measures including pain, physician's global assessment, patient's global assessment, degree of disability, erythrocyte sedimentation rate). Complete blood cell count and liver function should be monitored at least monthly in patients receiving cyclosporine and methotrexate therapy concomitantly.
Oral cyclosporine is used in immunocompetent adults with severe (i.e., extensive and/or disabling), recalcitrant plaque psoriasis that is not adequately responsive to at least one systemic therapy (e.g., retinoids, methotrexate, psoralen and UVA light [PUVA therapy]) or in patients for whom other systemic therapy is contraindicated or cannot be tolerated. Discontinuance of therapy with cyclosporine, as with other therapies, will result in relapse of psoriasis in most patients, while rebound occurs rarely.
Cyclosporine has been used in the management of refractory inflammatory, fistulizing, and chronically active Crohn's disease.
Efficacy of cyclosporine has been evaluated in several uncontrolled studies in patients with refractory (e.g., to corticosteroids, anti-infective agents, mercaptopurine, azathioprine, surgery) inflammatory or fistulizing Crohn's disease. In these studies, a limited number of patients with inflammatory or fistulizing disease (who continued to receive anti-infective agents, corticosteroids, azathioprine, mercaptopurine, and/or mesalamine) initially received a continuous IV infusion of cyclosporine over 24 hours (4 mg/kg daily for about 2-10 days) until clinical response (complete response in inflammatory disease usually was defined as resolution of diarrhea and abdominal pain, while partial response was defined as a decrease in stool frequency and/or abdominal pain; complete response in fistulizing disease was defined as closure of the fistulas and cessation of drainage, while partial response was defined as reduction in the size, drainage, and discomfort associated with fistulas) was achieved. About 78-88% of patients responded while receiving IV cyclosporine and most of those who responded were switched to oral cyclosporine (5-8 mg/kg daily) for a mean duration of about 2.5-12.2 (range: 0.5-37 months) months. However, only about 29-71% of the patients who responded to IV cyclosporine, continued to respond while receiving oral cyclosporine and in 1 study (patients receiving oral cyclosporine for a median of 10.5 weeks), 71% of patients who responded to IV cyclosporine, relapsed after discontinuance of cyclosporine therapy. Some clinicians suggest, however, that a short course (about 4-6 months) of therapy with cyclosporine (administered as an IV infusion initially and followed by an oral course of the drug) given concomitantly with mercaptopurine or azathioprine (drugs associated with long-term improvement in fistulizing Crohn's disease) may be effective in some patients with refractory inflammatory or fistulizing Crohn's disease. Because both mercaptopurine and azathioprine have a slow onset of action (17 weeks or more) and cyclosporine has a faster onset, such an overlap of therapies (for about 4 months) may be beneficial in the fistulizing disease; however, additional well-controlled studies are needed to evaluate the clinical efficacy of these combinations. It also should be considered, that IV administration of cyclosporine may be associated with severe adverse effects and many clinicians state that the drug should be reserved for the management of severe refractory disease.
Results of several uncontrolled and some placebo-controlled trials indicate that oral cyclosporine (5-15 mg/kg daily) has not been consistently effective for inducing or maintaining remission in refractory chronically active Crohn's disease. In a placebo-controlled, double-blind, randomized trial in patients with refractory, chronically active Crohn's disease, clinical improvement has been reported in more patients receiving oral cyclosporine (5-7.5 mg/kg daily) than in those receiving placebo (59% for cyclosporine versus 32% for placebo) at the end of a 3-month treatment period. However, during a subsequent 3-month tapering period, 36 or 55% of patients receiving cyclosporine or placebo, respectively, whose disease improved during the initial 3-month therapy, have relapsed; no substantial difference in disease improvement between cyclosporine therapy and placebo has been observed during the 6-month follow-up period.
For further information about the management of Crohn's disease, .
For ophthalmic uses of cyclosporine, .
Cyclosporine potentially may be useful for the treatment of various other conditions that have an immunologic basis.
Cyclosporine also has been used to decrease the frequency of pancreatic or corneal allograft rejection.