Abstract
Graves' disease (GD) is a frequent complication of immune reconstitution after immunomodulatory treatment for multiple sclerosis (MS). Alemtuzumab and beta interferon (IFB) are the most frequent MS drugs associated with GD, with an overall incidence of 12–30%. 1,2
A recent case series showed that up to 24.4% of alemtuzumab-induced GD require total thyroidectomy due to difficult control. 3
We present three clinical cases of secondary GD, without extrathyroidal manifestations, induced by MS immunomodulatory treatments, in which thyroid remission was achieved after the introduction of ocrelizumab, an anti-CD20 monoclonal antibody.
All three patients provided written informed consent for the use of their data and the publication, and we received the authorization of the ethics committee of INCLIVA (2022/276).
Case 1
A 42-year-old male was diagnosed with relapsing-remitting multiple sclerosis (RRMS) in 2015, and started on alemtuzumab in September 2017.
Two years later, the patient developed alemtuzumab-induced vitiligo and simultaneously alemtuzumab-induced GD (Table 1). GD was confirmed by ultrasonography and scintigraphy.
Description of Methimazole Doses and Thyroid-Stimulating Immunoglobulin Antibodies Before and After Ocrelizumab
Belgian Case: Case published in reference 4.
First episode.
Relapsing episode.
In regimen block-replacement with levothyroxine.
TSI 3 months after switch to ocrelizumab.
TSI 6 months after switch to ocrelizumab.
aTPO, antithyroid peroxidase antibodies; fT4, free thyroxine; GD, Graves' disease; MD, methimazole dose; MS, multiple sclerosis; N, normal levels; OCREL, ocrelizumab; TSH, thyrotropin; TSI, thyroid-stimulating immunoglobulin-antibody; UK, unknown.
Treatment with methimazole was started and followed up every month, including thyroid function studies for dose adjustment. His thyroid autoimmunity responded poorly to antithyroid drugs (ATD), with thyroid-stimulating immunoglobulin (TSI) escalating to a peak level of 40 IU/L. Treatment with radioactive iodine was proposed.
He presented a new enhancing lesion on magnetic resonance imaging (MRI) in September 2021, and was switched to ocrelizumab in November 2021. Radioactive iodine was postponed, and ATD treatment continued. At this moment thyrotropin (TSH) was still suppressed.
Since the start of ocrelizumab, the patient has experienced an improvement in the course of his GD with a dramatic, uninterrupted, and continuous decrease of TSI levels (Table 1), which has enabled a reduction of the dose of methimazole from 15 to 2.5 mg/day.
Case 2
A 38-year-old female was diagnosed with RRMS in 2008. First alemtuzumab cycle was given in February 2017.
Two years later, the patient developed GD (Table 1), confirmed by ultrasonography. She was administered methimazole and followed up every month, but despite correct treatment, TSH remained suppressed.
She suffered a relapse of her MS in August 2019, and treatment was changed to ocrelizumab.
Since starting ocrelizumab, her GD has improved and the ATD was stopped in May of 2021 (Table 1).
Case 3
A 49-year-old female was diagnosed with RRMS in 2013. She started on IFB in June 2016. Eight months later the patient was diagnosed with IFB-induced GD and started on methimazole. Her methimazole dose was subsequently gradually decreased and stopped after 13 months.
Her GD relapsed in December 2020 (Table 1), under MS treatment with teriflunomide, and methimazole was reintroduced. In March 2021, MS treatment was changed to ocrelizumab due to a relapse demonstrated on MRI.
Three months after ocrelizumab, the TSI was negative and the methimazole was successfully withdrawn.
All three patients have remained neurologically stable without clinical and radiological evidence of MS after treatment with ocrelizumab.
Secondary GD is a frequent complication of MS immunomodulatory treatments. 1,2 Alemtuzumab-induced GD develops between 6 and 36 months after the first dose, and is in many cases difficult to control, requiring treatment with radioactive iodine or thyroidectomy. 3
In our series, among the patients who developed GD secondary to immunomodulatory treatment of MS, the three cases who switched to ocrelizumab due to worsening of their neurological disease, achieved control or remission of their hyperthyroidism. During the preparation of this article, a case of post-alemtuzumab GD that remitted 3 months after ocrelizumab has been published. 4 This last case is similar to our cases 1 and 2, with persistently high values of TSI despite ATD, and a fast decrease after switch to ocrelizumab (Table 1), achieving control of GD very quickly after the first dose. This temporal relationship makes it unlikely that control of the disease would be the result of spontaneous remission of GD, although these findings should be confirmed in controlled studies.
B cell depleting anti-CD20 monoclonal antibodies (rituximab, ocrelizumab, and ofatumumab) have demonstrated efficacy in MS. Rituximab have been tested for the treatment of sporadic GD, 5 and especially for active Graves' orbitopathy. We speculate that the humanized nature of ocrelizumab may have a broader immunomodulatory effect that may confer greater efficacy in controlling GD.
We hypothesize that ocrelizumab may have enabled control of hyperthyroidism due to GD in the patients described in this case series. This anti-CD20 monoclonal antibody may possibly be helpful in treatment of concomitant MS with active refractory GD. Further research is needed to prove this hypothesis.
Immunomodulatory treatments, particularly the new generation anti-CD20 drugs, may provide a potentially novel physiopathological approach to treatment of GD and warrant further study.
Footnotes
Acknowledgments
We are grateful to all patients who agreed to participate in this report.
Authors' Contributions
Conceptualization, methodology, investigation, resources, writing—original draft, writing—review and editing, visualization, supervision, and project administration by R.C.-F. Conceptualization, methodology, investigation, resources, writing—original draft, writing—review and editing, supervision, and project administration by F.G.-G. Conceptualization, investigation, resources, writing—original draft, writing—review and editing, and visualization by E.J.M.S. Conceptualization, investigation, writing—review and editing, and visualization by F.P.L. Writing—review and editing, visualization, and supervision by J.A.D.-M. Resources and writing—review and editing by J.F.C. Conceptualization, resources, writing—review and editing, supervision, and project administration by J.T.R.C.
Author Disclosure Statement
All authors have declared no conflict of interest.
Funding Information
All authors have no funding information to declare.