Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation, demyelination, and neurodegeneration within the central nervous system (CNS), characterized by demyelination, axonal damage, and progressive neurological disability. MS typically manifests between the ages of 20 and 40, with a higher prevalence in women, and is recognized as the leading cause of non-traumatic disability among young adults (Ghiasian et al. 2021). While the exact etiology of MS remains elusive, it is widely accepted that genetic and environmental factors contribute to disease susceptibility and progression. Among the environmental factors, vitamin D deficiency, viral infections, and smoking have been implicated in the pathogenesis of MS (Abdollahzadeh et al. 2016; Poorolajal et al. 2017).

The efficacy and safety of disease-modifying therapies (DMTs) have garnered significant attention in MS management. While DMTs have revolutionized the treatment landscape for MS, their use is not without risk. Moreover, the efficacy of DMTs varies among individuals, and a substantial proportion of patients continue to experience disease progression despite treatment (Ghiasian et al. 2022). Recent studies have reported new adverse effects associated with therapies, underscoring the importance of post-marketing pharmacovigilance in optimizing patient care (Sahraian et al. 2022; Simbrich et al. 2021).

Among the various biological therapies used in MS management, alemtuzumab has drawn attention to its efficacy in reducing disease activity. However, it is associated with a spectrum of thyroid-related adverse events, including Graves’ disease and orbitopathy, which can have significant clinical implications (Scappaticcio et al. 2020). Additionally, studies have identified risk factors and clinical characteristics associated with alemtuzumab-induced Graves’ disease, providing insights into personalized risk stratification and preventive measures (Ueland et al. 2023).

Given these challenges, there is an urgent need for more personalized therapeutic approaches and a deeper understanding of the disease mechanisms at the individual level. Although extensive research has been conducted on MS, critical gaps remain, particularly in identifying biomarkers for predicting treatment response and understanding the long-term effects of current therapies.

In light of the multifaceted nature of MS pathogenesis and management, this study aims to investigate the potential role of biological therapy in inducing autoimmune endocrine diseases in MS patients. By doing so, it seeks to contribute to developing of more tailored treatment strategies, ultimately improving outcomes for individuals living with MS.

Method

Data sources

This systematic review aimed to identify and analyze autoimmune endocrine disorders associated with DMTs used to manage MS attacks and progression. The review adhered to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist guidelines. Searches were conducted in Google Scholar, PubMed, and Scopus databases for studies published up to February 2024.

Search strategy

The search strategy included the following terms: “multiple sclerosis,” and (Natalizumab or Ocrelizumab or Rituximab or Alemtuzumab or Ofatumumab or Ublituximab), and (case report) and all MeSH terms in Pubmed Database. In Scopus, each monoclonal antibody AND “multiple sclerosis” was searched separately in Abstract/Title section and the total was added to the records. Google Scholar was searched for each monoclonal antibody AND “multiple sclerosis” separately; the total was then added. The selection of biologic drugs was based on therapies recommended by Wolters Kluwer’s UpToDate®.

Eligibility criteria

The inclusion criteria for this study were as follows: (a) case reports or case series, (b) addressed the autoimmune endocrine complications of MS immunotherapy, (c) had a full text available. Records were excluded if they were (a) non-English or (b) complications other than endocrine disorders, (c) the review and meta-analysis studies, and letters to editors, clinical trials, and qualitative studies.

The authors agreed to refer to the Global Autoimmune Institute’s Autoimmune Disease List (2024) to standardize disease categorization.

Data extraction

Endnote® 7 (Clarivate Analytics) facilitated screening and data extraction. Two researchers independently extracted data based on predefined criteria, with results reviewed by the remaining authors.

Quality assessment

The methodological quality of case report studies was assessed using the Joanna Briggs Institute (JBI) critical appraisal checklist, which includes eight Likert questions evaluating crucial aspects of case reports (Munn et al. 2020). These criteria assess the accuracy of patient demographic information, documentation of patient history, description of current clinical conditions, clarity of diagnostic and therapeutic measures, elucidation of post-therapeutic intervention outcomes, and identification and explanation of reported side effects. The overall utility of case reports was evaluated accordingly. See t 2 for detailed assessment criteria.

Results

A comprehensive search of the aforementioned databases up to February 21st, 2024, yielded 85 articles. After removing 58 duplicate articles, 27 unique articles underwent independent review by two researchers. Screening of titles and abstracts led to excluding additional six articles. Subsequently, the remaining articles underwent full-text assessment, resulting in the exclusion of no articles (see Fig. 1). Ultimately, 21 articles met the eligibility criteria.

Fig. 1
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Study selection process

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These 20 articles provided data on 38 patients, with records primarily originating from Italy, Germany, and the UK, in descending order of prevalence. Additional records were sourced from Canada, Greece, Australia, Ireland, the USA, and Portugal. The summarized findings of these studies are presented in Table 1.

Table 1 Case report studies of endocrine autoimmune disease induced by MS monoclonal antibodies
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Of the eligible studies, 17 investigated autoimmune dermatologic complications associated with Alemtuzumab in MS patients, while two studies focused on Natalizumab and one on Ocrelizumab. Consequently, 38 patients across 20 studies examining three different biological therapies for MS were identified.

Alemtuzumab

Alemtuzumab, a monoclonal antibody that targets CD52, a protein on surface of B, T lymphocytes, monocytes and dendritic cells, has been utilized for chronic lymphocytic leukemia (CLL) and other lymphoid neoplasms (Katsavos and Coles 2018). Research has confirmed its effectiveness in decreasing relapse rates of multiple sclerosis (MS) and disability progression, as well as its beneficial effects on radiological disease outcomes (Willis and Robertson 2016). However, its complications such as secondary autoimmune disease, necessitate careful monitoring and management (Cossburn et al. 2011).

Autoimmune complications

Alemtuzumab has been associated with many autoimmune complications, e.g., immune thrombocytopenia, hemolytic anemia, hepatitis, encephalitis, myasthenia gravis, Lambert–Eaton myasthenia, sarcoidosis, vitiligo, alopecia, myositis, and type 1 diabetes, but most prevalent reported is autoimmune thyroiditis by 33%, of which 63% were GD and 15% Hashimoto’s. (Yue et al. 2023).

Research indicates that alemtuzumab can lead to prolonged lymphopenia and trigger secondary autoimmunity during the reconstitution of the lymphocyte repertoire. Cytokine signaling, e.g., increased Interleukin 21 and decreased IFN, also has been proposed to play a role (Conway 2022). Patients with high baseline levels of Interleukin21 are at a higher risk of developing autoimmune conditions post-treatment with alemtuzumab (Ruck et al. 2022; Costelloe et al. 2012). The incidence of thyroid dysfunction in the first 3 years rises each year (Alamo et al. 2019). This typically tends to resolve on its own in approximately 30% of cases, possibly attributed to a higher frequency of neutralizing or blocking TRAb. (Moli et al. 2021).

Natalizumab

Natalizumab is a monoclonal antibody used to treat RRMS (Hutchinson 2007). Natalizumab inhibits the interaction between the integrin alpha subunit of VLA-4 on leukocytes and VCAM-1, which is vital in regulating immune and inflammatory responses. Research indicates that the VLA-4 and VCAM-1 pathways may be significant in the autoimmune response seen in autoimmune thyroid disorders (Marazuela et al. 1994; Nakashima et al. 1994).

Autoimmune complications

Natalizumab has been associated with the development of autoimmune hepatitis, immune thrombocytopenic purpura, and rheumatoid arthritis (Lisotti et al. 2012; Stosic et al. 2011; Su et al. 2020). Some theories suggest that Immune Reconstitution Syndrome (IRS) plays a role (Carcelén-Gadea et al. 2013; Metz et al. 2012) and also inducing a shift towards a Th17-mediated inflammatory response while blocking Th1 cell entry can be an explanation (Su et al. 2020). However, additional research is necessary to fully understand the mechanisms and potential risk factors for these complications.

Ocrelizumab

Ocrelizumab, a second-generation humanized antibody that targets the CD20 antigen expressed by a vast range of B cells and about 5% of T cells, has been approved for the treatment of RRMS and primary progressive MS (Duarte et al. 2021; Lünemann et al. 2020). Main complications of ocrelizumab-therapy have been infusion-related reactions and infections (Montalban et al. 2017).

Autoimmune complications

Increased risk of developing psoriasis and inflammatory bowel disease has been reported by ocrelizumab administration (Lamb 2022). Also, glomerulosclerosis and Graves’ disease have been reported in some case reports (Duarte et al. 2021; Greve et al. 2023). Some hypotheses state there may be an association with B cell depletion immune system dysregulation (Lee et al. 2020) (Table 2).

Table 2 JBI critical appraisal checklist for case reports
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Discussion

This study aims to explore the mechanisms underlying biological therapy-induced autoimmune endocrine diseases in MS patients as is summarized in Table 3. By elucidating the underlying pathophysiology, pictured in Fig. 2 and identifying at-risk patient populations, this research seeks to inform personalized treatment strategies and enhance the safety and efficacy of MS management.

Table 3 Different proposed mechanisms behind endocrine complications of MS monoclonal antibodies
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Fig. 2
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Different pathophyisiology behind developing Graves’ disease in alemtuzumab-treated patients

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To our knowledge, this is the first systematic review of case reports on secondary autoimmune endocrine disorders induced by multiple sclerosis immunotherapy monoclonal antibodies.

We reviewed 20 articles that met the inclusion criteria (3 America, 16 Europe, and 1 Australia). Seventeen studies involved Alemtuzumab with a total of 34 patients who developed autoimmune endocrine complications; two studies included Natalizumab with 3 patients suffering from its endocrine adverse effects. One study contributed to Ocrelizumab endocrine complications, with one patient experiencing the side effects of this drug. A total of 38 patients had experienced induced autoimmune endocrine side effects.

A systematic review and meta-analysis highlight the prevalence and clinical characteristics of alemtuzumab-induced thyroid events in MS patients, emphasizing the importance of vigilant monitoring and early intervention (Scappaticcio et al. 2020). This aligns with findings by other studies, which have consistently demonstrated the necessity for proactive management of thyroid dysfunction in this patient population due to the autoimmune risks associated with immune reconstitution therapies (IRT). Additionally, it was hypothesized in the same article that there is an antigen preference of TRAb in MS patients treated with alemtuzumab, suggesting a specific immunological shift linked to the therapy.

Interferons, which have been used as a pharmacotherapy for MS, have long been associated with thyroid complications and one of the stated theories proposes their indirect immune-mediated action, pro-inflammatory cytokines increase, inhibition of regulator T cells and switching to immunological Th1 pattern (Tomer and Menconi 2009). This mechanistic insight is crucial for understanding the broader context of immune responses in MS therapies. Development of immune reconstitution therapies, including antibody-based cell depletion therapies, targeting CD52 + (alemtuzumab) or CD20 + (ocrelizumab) leukocytes (Kazakou et al. 2023), through short-term intense immunosuppression or immune cell depletion, rebuilds an immune system with freshly built immune tolerance (Lünemann et al. 2020).

The majority of immune reconstitution autoimmune diseases post-alemtuzumab treatment of MS have been theorized to be antibody-dependent; however, type 1 diabetes is the result of pancreas cell destruction by self-reactive T cells. Therefore, Malmetrom et al. suggest that post-alemtuzumab secondary autoimmune conditions are not confined to be mediated by autoantibody (Malmeström et al. 2014).

A study on cardiac transplantation indicated that induction therapy with alemtuzumab may result in a lower incidence of new onset diabetes, suggesting a complex relationship between alemtuzumab and diabetes across different medical contexts. However, it was suggested that lower need of corticosteroid post transplantation can be the possible etiology (Jones et al. 2010). This finding contrasts with the higher incidence of autoimmune conditions in MS patients, highlighting the need for disease-specific investigations into the drug's effects.

The associated thyroid dysfunction related to IRT has been characterized as delayed onset with transient dysfunction and spontaneously resolved. Also, although conventional GD is thought to be induced by humoral immunity, T cells are at function in this case (Muller et al. 2018). During immune reconstitution autoimmunity, Th2 profile cytokines are replenished to greater extent, making Th1 mediated disorders like Hashimoto’s thyroiditis less common (Weetman 2009). Interestingly, MS progression is also derived by Th1 phenotype (Conway 2022).

Although alemtuzumab causes depletion of B and T lymphocytes (including CD8 + and CD4 +); recovery of B cell counts occurs earlier (by 3 to 6 months) while T cell counts, especially CD4 + , remain low even after 12 months. Overpopulation of B cells (127% of their base level at 27th months (Roos et al. 2019)), in the absence of regulatory T cells, and overpopulation of naive B cells with prolonged depletion of memory B cells is the possible cause for the secondary autoimmunity of B cells that may occur with alemtuzumab treatment.

This pathophysiology requires the involvement of T cells. It is therefore less likely to occur until CD4 + T cell numbers reach a sufficient level, leading to a delay between hyperreactivity of B-lymphocytes and the development of autoimmunity. Furthermore, T cell reconstitution is primarily due to peripheral expansion (rather than thymic reconstitution), promoting self-reactive immune cell populations (Sellner and Rommer 2020).

Ocrelizumab, on the other hand, B cell and CD20 + T cell are depleted while CD4 + and CD8 + T cells levels do not change (Sellner and Rommer 2020). Repopulation of B cells is preferentially achieved by immature or transitional B cells and myeloid cells following anti-CD20 + treatment have an enhanced activation state and proinflammatory differentiation (Häusler et al. 2018). These differences in immune reconstitution mechanisms between alemtuzumab and ocrelizumab highlight the necessity of drug-specific monitoring protocols to mitigate the risk of secondary autoimmunity.

Secondary autoimmunity following treatment with alemtuzumab has been noted in individuals with MS, but it has not been observed in cancer or rheumatoid arthritis patients. It has been suggested that cytokine signaling or lymphocyte function specific to MS patients might enhance the development of autoimmunity after immune reconstitution. However, no such enhancing factors have been identified thus far (Conway 2022). The balance between Th1 and Th2 and the derivation from the original phenotype in each individual might be the main factor.

It has been suggested in another article (Carcelén-Gadea et al. 2013) that after discontinuation of natalizumab, a self-limited autoimmune thyroid disorder may emerge as a presentation of IRS in predisposed individuals who have a positive family history of thyroid disease or have had interferon therapy, as use of natalizumab appears to control the immune response against the thyroid, with implications for post-therapy monitoring strategies.

Homeostatic proliferation commonly refers to the expansion of peripheral T cells in situations of lymphopenia. In lymphoreplete settings, low-affinity interactions between the major histocompatibility (MHC)/peptide complex and T cell receptor (TCR) in the periphery provide continuous “survival signals” to naïve T cells without triggering proliferation. Conversely, in cases of lymphopenia, these signals prompt T cell proliferation, to the level of homeostatic proliferation is directly linked to the extent and duration of lymphopenia. Consequently, homeostatic proliferation selectively amplifies T cells with a heightened specificity and stronger avidity for self-antigens. This process may contribute to the development of autoimmunity triggered by lymphopenia, as observed with alemtuzumab and other depleting agents (Aranha et al. 2013).

Rituximab is an old generation of CD20 + targeting monoclonal antibodies which have been used in treatment of Graves’ orbitopathy but thyroid function levels have not been affected when using this drug (Salvi et al. 2015). The remaining non-CD20 + expressing plasma cells releasing autoantibodies can be the explanation (Duarte et al. 2021). Also, this agent, based on its mechanism of action, has been proposed to be administered as a protective agent, lowering the population of naïve B cell in reconstitution phase to lower the incidence of post-alemtuzumab GD autoimmunity (Conway 2022).

Smoking is one of the risk factors for developing thyroid complications post-alemtuzumab and sex distribution unlike dominant female prevalence in MS and GD is equal in this case (Nirmalan et al. 2023). Alemtuzumab dose, frequency, and interval have not appeared to be a risk factor (Trinh et al. 2016). In autoimmune thyroid disease, androgen-mediated reduction in thyroid cells expression of HLA-I and -II antigens have been suggested as a potential mechanism. Additionally, females are known to have an immune response with dominance of Th2, leading to enhanced B cell activation and production of autoantibodies (Tsourdi et al. 2015). Also it has been suggested that TSHRAb production by increased counts of memory-like T lymphocytes is more outstanding and more sustained in alemtuzumab induced thyroid disease than conventional cases (Tsourdi et al. 2015).

Also findings of Rolla et al. emphasize that alemtuzumab leads to a long-lasting reduction in CD4 + T cell counts, with Treg cell playing a crucial role in maintain long-term immune regulation and potentially mitigating some autoimmune responses (Rolla et al. 2022).

Conclusion

Multiple sclerosis (MS) presents significant management challenges due to its complex nature and the evolving landscape of treatment options. To optimize patient care, clinicians should consider enhancing clinical education, adopting a multidisciplinary approach, implementing routine monitoring, and developing personalized care plans.

For future research directions, we suggest conducting longitudinal studies to explore the long-term impact of novel MS treatments, risk factors and prognosis, and prioritizing patient-centered outcomes.

Declaration of Generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the authors used ChatGPT 3.5 in order to enhance the grammar and presentation of this article. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the publication’s content.