Alemtuzumab-induced thyroid eye disease successfully treated with a single low dose of rituximab

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Abstract

Introduction

Secondary thyroid autoimmunity, especially Graves’ disease (GD), frequently develops in patients with multiple sclerosis (MS) following alemtuzumab treatment (ALTZ; anti-CD52). Thyroid eye disease (TED) can also develop, and rituximab (RTX; anti-CD20) is a suitable treatment.

Case presentation

A 37-year-old woman with MS developed steroid-resistant active moderate-to-severe TED 3 years after ALTZ, that successfully responded to a single 500 mg dose of i.v. RTX. Before RTX peripheral B-cells were low, and were totally depleted immediately after therapy. Follow-up analysis 4 years post ALTZ and 1 year post RTX showed persistent depletion of B cells, and reduction of T regulatory cells in both peripheral blood and thyroid tissue obtained at thyroidectomy.

Conclusion

RTX therapy successfully inactivated TED in a patient with low B-cell count derived from previous ALTZ treatment. B-cell depletion in both thyroid and peripheral blood was still present 1 year after RTX, indicating a likely cumulative effect of both treatments.

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Most cited references 48

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The 2016 European Thyroid Association/European Group on Graves' Orbitopathy Guidelines for the Management of Graves' Orbitopathy

Luigi Bartalena, Lelio Baldeschi, Kostas G. Boboridis … (2016)

Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.

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THE 2021 EUROPEAN GROUP ON GRAVES’ ORBITOPATHY (EUGOGO) CLINICAL PRACTICE GUIDELINES FOR THE MEDICAL MANAGEMENT OF GRAVES’ ORBITOPATHY

Luigi Bartalena, George J. Kahaly, Lelio Baldeschi … (2021)

Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). Choice of treatment should be based on assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight threatening GO, antithyroid drugs are preferred when managing Graves’ hyperthyroidism. In moderate-to-severe and active GO, intravenous (iv) glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness and patient choice after extensive counselling, a combination of iv methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 grams (g) of iv methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include: a) a second course of iv methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; c) orbital radiotherapy combined with oral or iv glucocorticoids, d) teprotumumab; e) rituximab and f) tocilizumab. Sight threatening GO is treated with several high single doses of iv methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint and eyelid surgery) is indicated for inactive residual GO manifestations.

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Alemtuzumab vs. interferon beta-1a in early multiple sclerosis.

Alasdair J Coles, D Alastair S Compston, Krzysztof W Selmaj … (2008)

Alemtuzumab, a humanized monoclonal antibody that targets CD52 on lymphocytes and monocytes, may be an effective treatment for early multiple sclerosis. In this phase 2, randomized, blinded trial involving previously untreated, early, relapsing-remitting multiple sclerosis, we assigned 334 patients with scores of 3.0 or less on the Expanded Disability Status Scale and a disease duration of 3 years or less to receive either subcutaneous interferon beta-1a (at a dose of 44 microg) three times per week or annual intravenous cycles of alemtuzumab (at a dose of either 12 mg or 24 mg per day) for 36 months. In September 2005, alemtuzumab therapy was suspended after immune thrombocytopenic purpura developed in three patients, one of whom died. Treatment with interferon beta-1a continued throughout the study. Alemtuzumab significantly reduced the rate of sustained accumulation of disability, as compared with interferon beta-1a (9.0% vs. 26.2%; hazard ratio, 0.29; 95% confidence interval [CI], 0.16 to 0.54; P<0.001) and the annualized rate of relapse (0.10 vs. 0.36; hazard ratio, 0.26; 95% CI, 0.16 to 0.41; P<0.001). The mean disability score on a 10-point scale improved by 0.39 point in the alemtuzumab group and worsened by 0.38 point in the interferon beta-1a group (P<0.001). In the alemtuzumab group, the lesion burden (as seen on T(2)-weighted magnetic resonance imaging) was reduced, as compared with that in the interferon beta-1a group (P=0.005). From month 12 to month 36, brain volume (as seen on T(1)-weighted magnetic resonance imaging) increased in the alemtuzumab group but decreased in the interferon beta-1a group (P=0.02). Adverse events in the alemtuzumab group, as compared with the interferon beta-1a group, included autoimmunity (thyroid disorders [23% vs. 3%] and immune thrombocytopenic purpura [3% vs. 1%]) and infections (66% vs. 47%). There were no significant differences in outcomes between the 12-mg dose and the 24-mg dose of alemtuzumab. In patients with early, relapsing-remitting multiple sclerosis, alemtuzumab was more effective than interferon beta-1a but was associated with autoimmunity, most seriously manifesting as immune thrombocytopenic purpura. The study was not powered to identify uncommon adverse events. (ClinicalTrials.gov number, NCT00050778.) 2008 Massachusetts Medical Society

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Author and article information

Journal

Journal ID (nlm-ta): Eur Thyroid J

Journal ID (iso-abbrev): Eur Thyroid J

Journal ID (publisher-id): ETJ

Title: European Thyroid Journal

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 2235-0640

ISSN (Electronic): 2235-0802

Publication date (Electronic): 11 April 2024

Publication date (Electronic preprint): 12 March 2024

Publication date Collection: 01 April 2024

Volume: 13

Issue: 2

Electronic Location Identifier: e230236

Affiliations

[1 ]Department of Clinical Sciences and Community Health , University of Milan, Italy

[2 ]Endocrinology Unit , Graves’ Orbitopathy Center, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

[3 ]Ophthalmology Unit , Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

[4 ]Department of Specialistic Surgical Sciences , Otolaryngology and Head and Neck Surgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

[5 ]Endocrinology Unit , Department of Medicine (DIMED), University of Padova, Padova, Italy

[6 ]National Institute of Molecular Genetics (INGM) “Romeo and Enrica Invernizzi” , Milan, Italy