Does cyclosporine (Cyclosporin) cause lymphadenopathy?

From the Guidelines

Cyclosporine is not directly associated with an increased risk of lymphadenopathy, as the available evidence suggests that the incidence of lymphoproliferative disease is more likely to arise indirectly as a result of immunosuppression inhibiting the host response to neoplasms, particularly in transplant patients 1. When considering the potential side effects of cyclosporine, it is essential to distinguish between the risks associated with immunosuppression in transplant patients and those in dermatological patients receiving cyclosporin as monotherapy.

• The British Association of Dermatologists guidelines for the safe and effective prescribing of oral ciclosporin in dermatology 2018, published in the British Journal of Dermatology, notes that apart from patients who have received a transplant, no increased risk of malignancy has been established in dermatological patients treated with ciclosporin, with the exception of nonmelanoma skin cancer in those who have previously received high doses of UV irradiation 1.
• A study of 272 patients who had received ciclosporin for treatment of inflammatory skin disease used the Finnish Cancer Registry to establish the incidence of malignancy, demonstrating no significant increase in the incidence rates for lymphoma or skin cancer relative to the general population 1.
• While there are case reports of dermatological patients treated with ciclosporin who have developed malignancies, including pseudolymphoma and lymphomas, these instances are not directly linked to cyclosporine-induced lymphadenopathy 1. In clinical practice, patients taking cyclosporine who develop lymphadenopathy should inform their healthcare provider, as it may require monitoring or evaluation to distinguish it from other potential causes of enlarged lymph nodes, such as infection or malignancy.
• Regular monitoring of cyclosporine blood levels is important to maintain therapeutic efficacy while minimizing side effects like lymphadenopathy. However, based on the available evidence, cyclosporine is not considered a primary cause of lymphadenopathy, and its use should be weighed against the potential benefits in treating certain autoimmune conditions, such as severe psoriasis, rheumatoid arthritis, and severe atopic dermatitis 1.

From the FDA Drug Label

As in patients receiving other immunosuppressants, those patients receiving cyclosporine are at increased risk for development of lymphomas and other malignancies, particularly those of the skin. Five cases of lymphoma were detected: four in a survey of approximately 2,300 patients treated with cyclosporine for rheumatoid arthritis, and another case of lymphoma was reported in a clinical trial There were two lymphoproliferative malignancies: one case of non-Hodgkin's lymphoma which required chemotherapy, and one case of mycosis fungoides which regressed spontaneously upon discontinuation of cyclosporine There were four cases of benign lymphocytic infiltration: 3 regressed spontaneously upon discontinuation of cyclosporine, while the fourth regressed despite continuation of the drug.

Lymphadenopathy is not directly mentioned in the provided drug labels as a side effect of cyclosporine. However, lymphomas and lymphoproliferative malignancies are mentioned, which may be associated with lymphadenopathy.

• Lymphomas are a type of cancer that can cause lymphadenopathy.
• Lymphoproliferative malignancies can also cause lymphadenopathy. However, without direct information on lymphadenopathy, no conclusion can be drawn about the relationship between cyclosporine and lymphadenopathy 2, 2, 2.

From the Research

Cyclosporine and Lymphadenopathy

• There is limited direct evidence linking cyclosporine to lymphadenopathy, but some studies suggest that cyclosporine can cause lymphoproliferative disorders, particularly in patients with immunosuppression following organ transplantation 3.
• A case study published in 2010 reported a patient who developed lymphoproliferative disease after long-standing cyclosporin therapy for psoriatic arthritis, which presented as a recurrent nasopharyngeal mass 3.
• Another study published in 1993 mentioned that cyclosporin can cause malignancies, but it did not specifically mention lymphadenopathy as a side effect 4.
• The other studies reviewed did not provide direct evidence of a link between cyclosporine and lymphadenopathy, but they did discuss the immunosuppressive properties of cyclosporine and its potential to cause various side effects, including nephrotoxicity, hepatotoxicity, and neurotoxicity 5, 6, 7.

Mechanism of Action

• Cyclosporine works by suppressing T-lymphocyte function, which can lead to immunosuppression and potentially increase the risk of lymphoproliferative disorders 5, 4.
• The exact mechanism of how cyclosporine causes lymphoproliferative disorders is not fully understood, but it is thought to be related to its immunosuppressive properties and its ability to inhibit the activation and/or maturation of various cell types, including those involved in cell-mediated immunity 4, 3.

Clinical Implications

• The available evidence suggests that cyclosporine can cause lymphoproliferative disorders, particularly in patients with immunosuppression following organ transplantation or those receiving long-standing cyclosporin therapy for other conditions 3.
• Clinicians should be aware of this potential side effect and monitor patients receiving cyclosporine for signs of lymphadenopathy or other lymphoproliferative disorders 3.