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There has recently been three letters published in The New England Journal Of Medicine about the use of fumarates which is used to treat psoriasis. Letters 1 & 2 by GPs are reports on 2 patients diagnosed with progressive multifocal leukoencephalopathy (PML) as a result of using fumarates, letter 3 is a Manufacturer's Response to these letters.
*PML (progressive multifocal leukoencephalopathy) is a rare and usually fatal viral disease characterized by progressive damage or inflammation of the white matter of the brain.
All these letters were found in The New England Journal Of Medicine [web]https://www.nejm.org[/web]
*PML (progressive multifocal leukoencephalopathy) is a rare and usually fatal viral disease characterized by progressive damage or inflammation of the white matter of the brain.
Quote:
Letter #1 by Ummehan Ermis, Joachim Weis, M.D. Jörg B. Schulz, M.D. Rheinisch–Westfälische Technische Hochschule Aachen, Aachen, Germany.
Fumaric acid is considered effective and safe in the treatment of psoriasis vulgaris and is licensed for this use in Germany. We diagnosed progressive multifocal leukoencephalopathy (PML) in a 74-year-old man who had received monotherapy for psoriasis with oral fumaric acid for 3 years (2007 through 2010) in doses of up to 120 mg of dimethyl fumarate and 95 mg of monoethyl fumarate, each taken two times a day. The patient had had psoriasis for more than 5 years and had been treated topically with glucocorticoids (January through May 2005) and orally with acitretin (maximum dose of 50 mg once daily, May 2005 through June 2006) and methotrexate (maximum dose of 22.5 mg once weekly, July 2006 through July 2007). In July 2010, progressive sensory aphasia developed. Magnetic resonance imaging (MRI) of the brain and positive results on polymerase-chain reaction (PCR) assays for the JC virus in the cerebrospinal fluid (CSF) (90 copies per milliliter) and brain tissue (88,800,000 copies per microgram of DNA) led to the diagnosis of PML.
A differential blood count revealed grade 3 lymphocytopenia, retrospective analysis revealed that the lymphocytopenia had reached grade 3 status within 1 year after the initiation of treatment with fumaric acid. Although it was the manufacturer's recommendation to discontinue treatment with fumaric acid in patients with severe lymphocytopenia, treatment was continued in this patient until the diagnosis of PML was made 2 years later.
Before implicating fumaric acid–associated lymphocytopenia as the probable cause of immunodeficiency, we ruled out other causes of immunodeficiency and cancer. Flow-cytometric immunophenotyping of peripheral blood and bone marrow aspirate did not reveal any myelodysplastic syndrome. Tests for markers of paraneoplastic tumors were negative, and computed tomographic scans of the chest, abdomen, and pelvis were normal. PCR assays of the CSF for neurotropic viruses were negative, as were the results of HIV testing. At the time of diagnosis, the only other medication the patient was taking was tamsulosin, for the treatment of prostate hyperplasia.
When PML was diagnosed in August 2010, fumaric acid was discontinued and treatment with mefloquine and mirtazapine was started. Within 5 weeks, an immune reconstitution inflammatory syndrome (IRIS) developed, manifested by clinical worsening and detected in areas of enhancement on MRI of the brain after the administration of gadolinium Methylprednisolone was administered at a dose of 500 mg per day for 5 days.
In January 2011, MRI studies revealed regression of T2-weighted hyperintensities, with almost complete absence of gadolinium enhancement. The patient's condition had improved despite the persistence of a marked sensory aphasia syndrome. PCR assays for the JC virus in the CSF and plasma were now negative.
Fumarate, unlike other immune-based therapies that may cause PML (e.g., rituximab, natalizumab, efalizumab, and infliximab), does not belong to the monoclonal antibody family. Although this patient may have been at higher risk for PML for other reasons, long-term treatment with fumarate was probably an important factor in its development, given the unrevealing evaluation for other causes of immune deficiency, the induction of an IRIS with 5 weeks after the withdrawal of fumarate, and the patient's clinical improvement and survival after a follow-up of more than 2 years. Similar to treatment with natalizumab,3 long-term treatment with fumaric acid and prior treatment with other immunosuppressants may have increased this patient's risk of PML.
Letter #2 by Bob W. van Oosten, M.D., Ph.D, Joep Killestein, M.D., Ph.D, Frederik Barkhof, M.D., Ph.D, Chris H. Polman, M.D., Ph.D, Mike P. Wattjes, M.D. VU University Medical Center, Amsterdam, the Netherlands.
Preparations containing various mixtures of fumaric acid esters are prescribed for psoriasis in several countries, in many cases for off-label use, and are regarded as safe. One such preparation is enteric-coated, slow-release Psorinovo (compounding pharmacy, Mierlo-Hout), in which the active agent is dimethyl fumarate and in which copper gluconate was used as an additive until 2010.
On November 5, 2012, a 42-year-old woman who reported having progressive right-sided hemiparesis since May consulted us for a second opinion. She had been given a diagnosis of possible multiple sclerosis in September and at that time received 3000 mg of intravenous methylprednisolone over 3 days, without effect. Her medical history was notable for psoriasis, for which she had been taking 420 mg of Psorinovo per day since 2007, supplemented by 1000 mg of calcium ascorbate per day and EPA-1000 fish oil capsules (EPA denotes the omega-3 fatty acid eicosapentaenoic acid).
Sequential magnetic resonance imaging (MRI) scans of the brain showed small, deep white-matter lesions and one large progressive lesion, which was suggestive of progressive multifocal encephalopathy (PML), as described in a study of imaging findings in relation to PML resulting from treatment with monoclonal antibodies. Hematologic studies revealed lymphopenia, with a count of 200 lymphocytes per cubic millimeter (normal range, 600 to 2900). We realized in retrospect that the lymphopenia had developed after the initiation of treatment with Psorinovo. The patient was seronegative for HIV, but a semiquantitative, real-time polymerase-chain-reaction (PCR) assay of a specimen of the cerebrospinal fluid was positive for the JC virus.
We made a diagnosis of PML, stopped treatment with Psorinovo on November 7, and then started treatment for PML with mefloquine and mirtazapine.
Initially, the hemiparesis remained progressive, even though the lymphopenia began to abate. On December 7, we noticed signs of an immune reconstitution inflammatory syndrome (IRIS) on MRI, with indications becoming more evident on December 13. We initiated treatment with intravenous methylprednisolone. Her clinical condition stabilized in early January 2013, and we observed the first signs of recovery on January 31.
We believe that treatment with Psorinovo contributed to the development of PML in our patient. First, lymphopenia developed during treatment with Psorinovo and is a well known side effect. Second, our patient had used no immunosuppressive medication before the onset of PML, and she was seronegative for HIV. Finally, the occurrence of IRIS after the discontinuation of Psorinovo argues in favour of a causal link.
We think this case report is of special relevance since preparations of fumaric acid esters, including dimethyl fumarate, are emerging drugs that may have a broader range of therapeutic indications in the near future.
Letter #3 by Marianne T. Sweetser, M.D., Ph.D, Katherine T. Dawson, M.D, Carmen Bozic, M.D. Biogen Idec, Cambridge, MA
In the letters from Ermis et al. and van Oosten et al. published in this issue of the Journal, progressive multifocal leukoencephalopathy (PML) is reported in two patients with psoriasis who were being treated with Fumaderm (Biogen Idec) or a compounded version of fumaric acid esters (FAEs) referred to as Psorinovo (compounding pharmacy, Mierlo-Hout). Compounded FAEs and other compounded products are not approved by regulatory authorities and may be associated with risks. Fumaderm, an approved, fixed-combination product, contains four active ingredients: dimethyl fumarate and three monoethyl hydrogen fumarates (calcium, magnesium, and zinc salts). The compounded product Psorinovo contains dimethyl fumarate and may also contain other ingredients, such as copper monoethyl fumaric acid. In the two case reports, both patients had severe lymphopenia for prolonged periods — 2 and 5 years, respectively — before receiving a diagnosis of PML.
There are two additional reports of PML in patients with psoriasis who were treated with Fumaderm and had significant confounding factors for PML. In one patient with a history of sarcoidosis that was treated with methotrexate and steroids, PML was diagnosed after 1 month of exposure to Fumaderm. The other patient had been treated with efalizumab and received a diagnosis of cancer. Efalizumab was stopped, and the patient subsequently began treatment with Fumaderm for psoriasis. Sarcoidosis, cancer, and efalizumab are known risk factors for PML. Overall, there have been a total of four reports of PML in patients with psoriasis who were treated with fumarates — three with Fumaderm and one with compounded FAEs.
Fumaderm is an oral medication that is widely prescribed for the systemic treatment of moderate-to-severe plaque psoriasis. Its safety profile has been assessed in 19 years of postmarketing surveillance and physician experience, since its approval in Germany. Its efficacy and safety have been comprehensively reviewed, and the results of a large retrospective study of long-term therapy with Fumaderm have been published. Although decreased levels of lymphocytes are commonly observed in patients receiving Fumaderm, severe lymphopenia occurs in 3% of patients, and it is likely that prolonged and severe lymphopenia occurs even less frequently. Compounded FAEs have been used for psoriasis, but they are unregulated, and the exact composition, quality, and safety of these compounds, and the number of patients who have been exposed to them, are unknown.
On the basis of more than 180,000 patient-years of experience with Fumaderm, reports of PML are rare. In the two patients reported by Ermis et al. and van Oosten et al., Fumaderm or compounded FAEs may have contributed to the development of severe and prolonged lymphopenia. Severe lymphopenia is a risk factor for PML6 and can be mitigated through the periodic monitoring of lymphocytes.
In BG-12 (Biogen Idec), a product recently approved in the United States for the treatment of relapsing forms of multiple sclerosis, the only active ingredient is dimethyl fumarate. In the clinical program for BG-12, more than 2600 patients with multiple sclerosis have been treated for periods of up to 4 years or more, with a median follow-up of approximately 2 years. BG-12 is associated with a reduction in mean lymphocyte counts of approximately 30% from baseline. Among patients treated with BG-12 to date, there has been no evidence of an increased risk of serious or opportunistic infections, and no reports of PML.
Overall, fumarates are distinct products with different active ingredients, metabolites, and formulations, and they are used in different populations with varying coexisting conditions. These factors may lead to important differences in the safety profiles among the various products.
All these letters were found in The New England Journal Of Medicine [web]https://www.nejm.org[/web]
