Health Boards
This case has often been mentioned in discussions about Fumaderm (DMF) on Psoriasis Club and can sometimes end up in heated conversations which have taken some threads off topic. I personally don't have an opinion about it, but as it is back in the news again I thought I would post it here for future reference. And should it get brought up again in other threads we can move posts here.
Source: nejm.org
*The above conversation is taken from The New England Journal of Medicine.
Quote:
Balak and Hajdarbegovic (Aug. 6 issue) discuss an old case of Kaposi’s sarcoma2 in a patient with psoriasis who was treated with Fumaderm, a drug containing different fumaric acid esters (FAE). The authors claim that the patient had normal total lymphocyte counts before the diagnosis of Kaposi’s sarcoma, whereas the original publication shows counts of 500 to 800 per cubic millimeter for more than 18 months.
In the same issue of the Journal, van Kester et al. report a case of suspected generalized varicella–zoster virus (VZV) infection in a 23-year-old patient with psoriasis who was treated with a compounded Dutch FAE preparation for 2 months, without the development of lymphocytopenia. The authors conclude that FAE treatment may reactivate VZV infection in the absence of lymphocytopenia. However, from the clinical picture and in the absence of IgG antibodies to VZV, other interpretations need to be considered, including adult chickenpox and generalized zoster related to preexisting immune deficiencies or irrespective of immunosuppression.
Both letters reference a report previously published in the Journal of a case of progressive multifocal leukoencephalopathy (PML) in a patient with psoriasis who was treated with a compounded Dutch FAE preparation for approximately 2 years, which was reported to have occurred without severe lymphocytopenia. Such a conclusion is questionable, because lymphocytes were not monitored for 19 months before the diagnosis of PML, and the extent of lymphocytopenia during that period is unknown.
We conclude that PML and other opportunistic infections have not been observed during FAE therapy without lymphocytopenia and in the presence of appropriate monitoring and drug-discontinuation rules.
Drs. Balak and Hajdarbegovic reply: Reich et al. emphasize that the case of dimethyl fumarate (DMF)–related Kaposi’s sarcoma was linked to a moderate lymphocytopenia and that current drug-monitoring rules remain applicable. We conclude that the occurrence of immunosuppressive adverse events during DMF treatment is not restricted to lymphocytopenia in which the lymphocyte count is less than 500 per cubic millimeter. Illustratively, another case of treatment-related PML was reported in a patient with psoriasis who was treated with DMF and had lymphocyte counts of 500 to 1000 per cubic millimeter. In response, psoriasis guidelines have increased the threshold for dose adjustment or discontinuation of DMF in the event of a count of less than 700 lymphocytes per cubic millimeter. These drug-discontinuation rules remain to be validated. More important, absolute lymphocyte counts seem to be insensitive indicators of an increased risk of infections.1 DMF-associated moderate lymphocytopenia with selective reductions in lymphocyte subpopulations could confer a predisposition to PML, as is the case with idiopathic CD4+ lymphocytopenia.
In view of the increasing use of DMF, there is a need for more awareness and appropriate monitoring strategies to minimize risks of immunosuppression. Meanwhile, PML should be considered in patients receiving DMF who present with progressive neurologic symptoms, irrespective of the severity of lymphocytopenia.
Dr. van Kester and colleagues reply: We agree with Reich et al. that other interpretations of the clinical findings in our patient are possible, but these interpretations are not very likely. Varicella infection develops in 95% of the Dutch population during childhood, and our patient had reported having a previous varicella infection when he was a child, which makes the possibility of a primary varicella infection unlikely. Except for his psoriasis, our patient was healthy, and he had no history of repeated infections. We did not see an indication to exclude preexisting immunodeficiencies or human immunodeficiency virus infection, but we cannot completely rule out this unlikely explanation for the clinical findings in our patient. Therefore, we conclude that reactivation of VZV infection by FAE treatment is the most likely interpretation of the clinical findings in our patient.
Dr. Murk and colleagues reply: Reich et al. question our conclusion that DMF may induce PML without severe lymphocytopenia, because screening of lymphocytes in our patient contains a 19-month gap. However, none of three lymphocyte counts in the 6 months before symptom onset was below 792 cells per cubic millimeter. Moreover, three cases of FAE-associated PML without severe lymphocytopenia were published recently, corroborating our conclusion.
FAEs affect lymphocyte function, the number of lymphocytes, and the ratio of CD4 cells to CD8 cells.4 In our patient, the lymphocyte count was just below normal, with 880 cells per cubic millimeter; CD4 cells were reduced to 270 cells per cubic millimeter, and CD8 cells were reduced to 40 cells per cubic millimeter. Accordingly, a recent study showed CD4 and CD8 lymphocytopenia with a total lymphocyte count above 500 cells per cubic millimeter with DMF treatment, which is relevant because CD8 lymphocytopenia might confer a predisposition to JC-virus replication. These new insights should be taken into account when lymphocyte counts are monitored in patients receiving DMF.
Source: nejm.org
*The above conversation is taken from The New England Journal of Medicine.