Abstract
Objective To report on 2 women with multiple sclerosis (MS) who developed severe neurologic deterioration and a drug reaction with eosinophilia and systemic symptoms (DRESS) after treatment with 2 and 4 subcutaneous injections of daclizumab, respectively.
Methods This report includes clinical, MRI, and histopathologic data.
Results Daclizumab is a humanized monoclonal antibody that binds the interleukin-2 receptor. It was approved for the treatment of relapsing MS. DRESS is an immunologic reaction to various medications that is characterized by eosinophilia as well as cutaneous and visceral manifestations. Following daclizumab treatment, both patients showed fulminant neurologic deterioration along with blood eosinophilia and skin changes, and both fulfilled the clinical criteria for the diagnosis of DRESS. They presented with multiple gadolinium-enhancing supra- and infratentorial lesions, with lesions in the basal ganglia, mesencephalon, and cerebellum. Brain biopsies revealed a pronounced inflammatory infiltrate including numerous eosinophils infiltrating demyelinating lesions, a feature that is atypical for MS but compatible with DRESS. In addition, numerous plasma cells and changes reminiscent of vasculitis were evident.
Conclusions Neurologic deterioration and DRESS occurred as severe adverse drug effects of daclizumab treatment. Early diagnosis and treatment of DRESS are essential because it is associated with complications such as new autoimmune diseases and liver failure, and may even be lethal. Because of its potential serious side effects, daclizumab was recently suspended for use in the European Union.
Glossary
- DRESS=
- drug reaction with eosinophilia and systemic symptoms;
- EDSS=
- Expanded Disability Status Scale;
- MS=
- multiple sclerosis;
- NK=
- natural killer;
- RegiSCAR=
- European Registry of Severe Cutaneous Adverse Reaction
We report on 2 women with multiple sclerosis (MS) who developed severe neurologic deterioration and a drug reaction with eosinophilia and systemic symptoms (DRESS) after daclizumab therapy.
Daclizumab is a monoclonal antibody that binds the high-affinity α subunit of the interleukin-2 receptor (CD25). It was approved for the treatment of relapsing MS,1 but has been suspended for use because of reports of severe inflammatory brain disorders (European Medicines Agency press release, July 3, 2018). Its mode of action includes a reduction in activated T lymphocytes and regulatory T cells, as well as an increase in natural killer (NK) cells.2
DRESS, also called drug-induced hypersensitivity syndrome, is a distinctive immunologic reaction induced by different medications including immunomodulators.3 It is characterized by eosinophilia as well as cutaneous and visceral manifestations weeks to months after initiation of drug treatment. DRESS may also involve the CNS. For clinical diagnosis of DRESS, the European Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) criteria are applied (table).3
RegiSCAR criteria (3 or more required) of DRESS
Case 1
A 30-year-old woman, diagnosed with MS in May 2016, was switched from peginterferon beta-1a to daclizumab in October 2016 because of ongoing disease activity shown on MRI (Expanded Disability Status Scale [EDSS] score = 1). In January 2017, 1 week after the fourth dosage of daclizumab, a relapse with fatigue and memory difficulties occurred that was treated with high-dose corticosteroids and oral tapering. CSF cell count was 6/µL. At the beginning of March, an exanthema and facial swelling were noted, both characteristic symptoms of DRESS. The patient experienced complete hair loss. Pronounced neurologic deterioration with mental changes and apathy led to hospitalization on March 20th (EDSS score = 4). MRI showed numerous new and enlarging preexisting brain lesions (figure 1, A.a and A.b). Blood analysis revealed eosinophilia (11.4% eosinophils, 1.06 × 103/μL) and elevation of liver enzymes (aspartate aminotransferase 217 U/L, alanine aminotransferase 511 U/L), indicating a visceral involvement. CSF and serum analysis showed NMDA receptor antibodies for the first time, but MRI changes were not considered typical for NMDA receptor encephalitis. Because herpes simplex virus encephalitis could not be excluded by MRI, antiviral treatment was administered. Fever (39°C) and leukocytosis were noted, and antibiotic treatment was started. A brain biopsy showed inflammatory demyelinating lesions with numerous eosinophils and changes reminiscent of vasculitis (figure 2, A–F). These changes, especially the presence of eosinophils, are atypical of MS lesions, but they are compatible with DRESS. The patient was treated with high-dose corticosteroids (2 g/6 d) followed by plasma exchange. Clinical symptoms improved (EDSS score = 3), but the generalized exanthema and leukocytosis with up to 33 × 103 leukocytes/µL remained until May/June 2017. The patient experienced an epileptic seizure. A skin biopsy was compatible with DRESS (figure 2, G–M). The patient finally stabilized and became self-reliant (EDSS score = 2).
MRIs of the patients (case 1, A; case 2, B) after severe neurologic deterioration showed numerous new and enlarging lesions. The biopsied lesion of the second patient is indicated with an arrow (B.a). Both patients presented with multiple supra- and infratentorial lesions at a periventricular and juxtacortical localization as well as with lesions in the basal ganglia, mesencephalon, and cerebellum. Nearly all lesions showed gadolinium (Gd) enhancement, indicating blood-brain barrier breakdown (A.b, B.b). FLAIR = fluid-attenuated inversion recovery.
Brain biopsies of the first (A–F) and second (N–S) patient are shown. Macrophage-rich lesions with vessels densely infiltrated by inflammatory cells, reminiscent of vasculitis, are found (A, N, vessels marked by arrows). Lesions show myelin loss (B, O, myelin in blue color, demyelinated areas in purple) and a preservation of axons (C, P, linear brown structures). Densely infiltrated vessels are also clearly visible in the axon staining (arrows in C, P). The inflammatory infiltrate includes numerous eosinophils (D, Q, bright red cells) not typically seen in multiple sclerosis lesions. In addition, T cells (E, R) and abundant plasma cells (F, S) are present. No evidence of progressive multifocal leukoencephalopathy or neuromyelitis optica could be found. The skin biopsy of the first patient (G–M) reveals a dominant mononuclear cell infiltrate (overview shown in G). An interface dermatitis, located in the basal layers of the epidermis, can also be seen (H–J indicated by arrows). T cells infiltrate the epidermis (I) including cytotoxic T cells (J). In addition, perivascular inflammatory infiltrates (not shown in detail) and a perifollicular inflammation are evident (K–M). Focal accumulations of eosinophils are demonstrated (K, arrows) next to dominant T cell infiltrates (L). Some natural killer cells are also present (M, arrows). CD = cluster of differentiation; HE = hematoxylin & eosin; LFB/PAS = Luxol fast blue/periodic acid-Schiff; NF = neurofilament. Scale bars: A–C, L, N–P: 200 µm; E, F, H–J, R, S: 100 µm; D, K, M, Q: 50 µm; G: 1 mm.
Case 2
This woman had relapsing-remitting MS diagnosed in 2004. She was treated with interferon beta-1b and fingolimod. Fingolimod was stopped because of lymphopenia and daclizumab was started at the age of 43 years (EDSS score = 3). The second dosage of daclizumab was given in November 2016. In December, a relapse occurred and high-dose steroids were given (1 g/5 d). In January 2017, the patient presented with another relapse, showing lack of energy and tetraparesis. CSF showed 17 cells/µL. She was treated with high-dose corticosteroids (2 g/4 d) and plasma exchange, leading to clinical improvement; however, her symptoms deteriorated again at the beginning of February (EDSS score = 8). MRI showed prominent lesion progression (figure 1, B.a and B.b). Apheresis therapy was repeated. A maculopapular exanthema occurred and blood eosinophilia developed, first noticed in February (up to 25% eosinophils, 1.95 × 103/μL). Leukocytosis up to 16.22 × 103/μL and an elevated body temperature up to 37.9°C were observed. Because of continuing neurologic deterioration, a brain biopsy was performed and showed pathologic changes virtually identical to those described for the first patient (figure 2, N–S). Cyclophosphamide was given 3 times. The exanthema resolved in April 2017. Finally, rituximab was given, leading to stabilization of the patient, but she was unfortunately left severely disabled (EDSS score = 9.5).
Both patients fulfilled the RegiSCAR criteria for diagnosis of DRESS (table). Before daclizumab treatment, no elevation of antinuclear antibodies or skin, liver, or immune-mediated diseases other than MS were evident.
Discussion
Both patients showed severe neurologic deterioration and clinical and pathologic characteristics of DRESS, which occurred after daclizumab treatment. Differential diagnoses include an allergic reaction due to plasma exchange, but this was excluded because, in our first patient, DRESS symptoms occurred before apheresis was started. We excluded other medications, such as antiepileptics or antibiotics, as the cause of DRESS. Histopathologically, neuromyelitis optica has to be considered as a differential diagnosis, as inflammatory demyelinating lesions with eosinophils are typical for this disease. However, further pathologic characteristics, clinical symptoms, and the absence of anti-aquaporin-4 antibodies did not favor this diagnosis. We therefore conclude that the most likely diagnosis is DRESS associated with daclizumab therapy.
Single case reports described CNS involvement in DRESS with (limbic) encephalitis, meningitis, or possible vasculitis.3,–,5 We are not aware of any histopathologic descriptions with CNS affection to date. The pathogenesis of DRESS is still not completely understood. The causative drug may trigger an immunologic reaction, for example via haptenation or direct stimulation of the T cell receptor.3 Allergic reactions have been described after challenging mice that had experimental autoimmune encephalomyelitis, an animal model of MS, with myelin peptides.6 Similarly, daclizumab may trigger an exaggerated immune response by preexisting autoreactive T and B cells. The disease may be exacerbated by immune dysregulation, e.g., due to a reduction in regulatory T cells.2 The resulting strong immune response may affect the CNS, as was observed in our patients by demyelinating brain lesions with pronounced inflammation.
A subsequent herpes virus reactivation could be responsible for symptom flares.4 Human herpes virus 6 reactivation is most often associated with DRESS.4 We thus analyzed human herpes virus 6 reactivation by PCR analysis in our patients, but the results were negative: either reactivation did not occur or the timing of sampling was inappropriate.
Early recognition of DRESS is considered the most important step for successful treatment.4 DRESS is treated with drug discontinuation and high-dose, prolonged cycles of steroids, as symptom flare may occur with steroid taper.3,4 Antiviral therapy may be helpful.3 An increased risk of autoimmunity after DRESS has been described.3 Our first patient also developed NMDA antibodies and had memory deficits and epileptic seizures, compatible with limbic encephalitis. Most important, DRESS can be life-threatening; the mortality is estimated as high as 10%.3 Unpredictable and potentially fatal immune-mediated liver injury can occur during treatment with daclizumab (European Medicines Agency press release, November 11, 2017).
Further side effects of daclizumab include an increased number of infections (65%) and cutaneous events such as rash (7%) or eczema (4%).1 Reports of skin biopsies after daclizumab therapy described inflammatory changes with numerous NK cells. The skin biopsy of our first patient showed a moderate number of NK cells (figure 2M).
DRESS in association with daclizumab was suggested in 2 patients, but finally considered consistent with delayed-type hypersensitivity reaction instead.7 A lethal DRESS was diagnosed in a child with small bowel transplantation who had received basiliximab, another interleukin-2 receptor antibody, but this was assumed to be secondary to vancomycin treatment.8 CNS vasculitis after daclizumab therapy has been described.9 Moreover, one daclizumab-treated patient with an erythematous macular rash accompanied by fever and followed by alopecia universalis was reported, clinically resembling our first patient.10 Since DRESS is not well known, it may be overlooked.
We suggest that severe neurologic deterioration accompanied with DRESS may occur after daclizumab therapy. These 2 cases and others finally led to the current suspension for use of daclizumab in the European Union.
Author contributions
Conception and design of the brief communication were performed by I.M., W.B., and S.R. S.R., A.S., A.M., and I.M. reviewed patient records. W.B., I.M., P.S., and M.P. performed histologic analysis. H.U. analyzed MRIs. Drafting of the manuscript was done by I.M., and drafting of the figures by I.M. and L.S. All authors were involved in proofreading the manuscript.
Study funding
This work was supported by the German Ministry of Education and Research (BMBF) German Competence Network Multiple Sclerosis (KKNMS) (to W.B. and M.P.).
Disclosure
S. Rauer reports personal fees from Biogen, Merck Serono, Genzyme, Bayer, Novartis, Teva, and Sanofi-Aventis, other from ravo Diagnostika, outside the submitted work. L. Stork, H. Urbach, A. Stathi, A. Marx, and P. Süß report no disclosures relevant to the manuscript. M. Prinz was supported by the German Ministry of Education and Research (BMBF German Competence Network Multiple Sclerosis [KKNMS]). W. Brück was supported by the German Ministry of Education and Research (BMBF German Competence Network Multiple Sclerosis [KKNMS]). Dr. Brück has received, outside the submitted work, honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis, and Novartis and is a member of scientific advisory boards for Teva Pharma, Biogen, Novartis, and Genzyme. He received funding for research projects by Teva Pharma, Biogen, Novartis, and Genzyme. Dr. Brück serves on the editorial boards of Neuropathology and Applied Neurobiology, Multiple Sclerosis International, and Therapeutic Advances in Neurologic Disorders. I. Metz reports personal fees from Biogen Idec, Bayer Healthcare, Teva, Serono, Novartis, Genzyme, and Roche, and grants from Biogen Idec, outside the submitted work. Go to Neurology.org/N for full disclosures.
Acknowledgment
The authors acknowledge Sven Müller, Cynthia Bunker, and Gisela Schluh for their outstanding administrative support.
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received November 28, 2017.
- Accepted in final form April 17, 2018.
- © 2018 American Academy of Neurology
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