Endocrine complications of high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in autoimmune diseases

Introduction

Autoimmune diseases (ADs) represent a heterogeneous group of inflammatory human diseases primarily caused by autoaggressive immune reaction of the body against own antigens. Globally, an estimated 5% of people suffer from various ADs. Every year we see a steady increase in both incidence and severity of ADs [1]. Approximately 25% of patients with one AD tend to develop other autoimmune comorbidities. For instance, type 1 diabetes (T1D) and autoimmune thyroid disease (AITD) can occur concomitantly – the close relationship between these two diseases is largely explained by sharing a common HLA haplotype which serves as a predisposing factor [2]. The combination of at least three ADs in the same patient is defined as multiple autoimmune syndrome [3] and underlies the development of autoimmune polyglandular syndromes [4].

Effective treatment of ADs, including autoimmune endocrinopathies, is limited, and finding new approaches to restore immune tolerance becomes extremely relevant [5]. Since the late ’90s high-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HSCT) has been used to treat severe cases of progressive ADs refractory to conventional therapy [6, 7]. The data from the EBMT Autoimmune Diseases Working Party (ADWP) suggests that over 4000 HSCT procedures for various ADs have been performed in Europe up to date [8, 9]. We see a steady rise in using HSCT for the treatment of autoimmune disorders.

The purpose of HSCT in ADs – is the immune reconstitution ("rebooting" the immune system), reduction or complete suppression of immune cell auto-aggression, and restoration of immune tolerance. HSCT is the only treatment method that helps to achieve durable remission with no need for lifelong immunosuppressive therapy [10, 11]. The procedure of HSCT consists of several steps. First, hematopoietic stem cells get mobilized out of the bone marrow into the peripheral bloodstream, collected (through apheresis) and cryopreserved. Next, the patient receives conditioning cytostatic treatment (in most cases 4-7 days of chemotherapy) to eliminate autoreactive T and B lymphocyte clones. Then the stem cells get thawed and infused into the patient. Here, immunotherapy (anti-thymocyte globulin/rituximab) may be considered after autologous transplantation for additional elimination of T-/B-lymphocytes. Lastly, there is a period of hematopoietic recovery, also known as the "exit from cytopenia", which serves the purpose for which the transplant is transfused [11].

It should be noted that the clinical effect of autotologous HSCT may correlate with the intensity of the conditioning regimen which strongly determines the risk of potential complications. The major indications for HDIT are autoimmune diseases such as multiple sclerosis, Crohn's disease, systemic scleroderma, rheumatoid arthritis, and T1D [12]. The similarity of AD HSCT protocols allows us to consolidate the data and analyze the most common complications associated with this treatment [10, 11].

HDIT may cause a range of adverse effects, including those related to the endocrine system [13]. Due to the limited research in this area, the frequency and severity of early and late endocrine-related complications of HSCT, the impact of endocrinopathies on the course and outcome of HSCT and the efficiency and safety of HSCT in autoimmune endocrinopathies (including T1D) is of particular interest.

The aim of this review was to conduct an evaluation of clinical research literature concerning endocrine complications following the HSCT in AD patients.

Materials and methods

For the purpose of this study, we conducted a systematic review of the PubMed and Scopus database to identify any relevant research publication from 1995 to 2023. Our search strategy included keywords "HDIT" "HSCT", "stem cells", "multiple sclerosis", "endocrine", "complications". We analyzed the data from scientific literature, summarized and classified it in the following sections depending on the type of impact of HSCT: 1) fertility; 2) thyroid function; 3) other complications associated with endocrine disorders.

Results

Impact of HDIT-HSCT on the reproductive system

Menstrual cycle

HDIT protocols use cytostatic drugs which help to eliminate autoreactive T and B lymphocyte clones, but have toxic effect on highly sensitive and rapidly dividing gonadal cells, potentially leading to primary hypergonadotropic hypogonadism. The degree of gonadotoxic effect varies depending on age, gender, pre-transplant therapy, type and dosage of cytostatic drug(s) [14].

Female patients in the post-transplant period are at risk of developing menstrual irregularity or complete menstrual suppression, leading to premature ovarian insufficiency. Postmenopausal transitioning is accompanied by typical estrogen deficiency symptoms [15]. Possible hormone replacement therapy for ovarian insufficiency remains questionable in such cases, because its impact on the risk of AD recurrence is yet to be determined [16].

Estrogens have a wide spectrum of impact on the immune system, mediating both pro- and anti-inflammatory responses. Notably, estrogens stimulate the proliferation of regulatory T-lymphocytes, which play a key role in maintaining immune system tolerance. However, the role of estrogens is ambiguous, as they may promote autoimmunity and increase clinical activity of systemic lupus erythematosus while exhibiting immune-protective effect in multiple sclerosis and rheumatoid arthritis [17-19]. Studies focused on T1D have shown that estradiol protects pancreatic β-cells from autoimmune and metabolic disturbances, prevents their apoptosis and slows down disease progression. Moreover, estrogens positively regulate carbohydrate metabolism [20, 21].

In a questionary study by M. Maciejewska, E. Snarski, et al., (2016) 35% of patients (median – 29 y.o.) spontaneously recovered their menstrual cycle four months after HSCT. 65% of patients (median – 45 y.o.), who developed amenorrhea during the procedure, subsequently reached postmenopausal status. The authors of this study concluded that at the time of treatment ovarian function was preserved in all patients under 32 y.o. [22].

A multicenter retrospective analysis of the EBMT database has demonstrated 80% of women (median – 28 y.o.) spontaneously recovered their menstrual cycles 3 to 4 months after HSCT [23].

In a Norwegian study of HSCT for multiple sclerosis, 10 patients out of 23 (median – 35 y.o.) developed amenorrhea lasting for >12 months and accompanied by symptoms typical of estrogen deficiency. Six patients with amenorrhea exhibited hypogonadism confirmed by laboratory tests, indicating low estradiol levels coupled with elevated levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) [24].

In a clinical trial of HSCT for multiple sclerosis (conditioning with cyclophosphamide/rituximab) performed at the Raisa Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation (Pavlov University, EBMT CIC 725), amenorrhea was detected in 2 out of 10 patients, aged 38 and 43 [25]. Subsequent analysis of treatment outcomes showed amenorrhea in 34% of 35 women of reproductive age (39±6 y.o.). Among these patients 23 women had their menstrual cycle recovered, with average recovery period of 3 months (1 to 12 months).

Considering the predictable cytopenia in the course of inpatient cytostatic treatment, preventive measures to regulate menstrual bleeding are taken. Induction of treatment-related amenorrhea with combined oral contraceptives, progestogens, gonadotropin-releasing hormone receptor agonists, and anti-androgens may be considered. Patients also undergo post-discharge follow-up combined with a selection of hormonal contraceptives [15].

Conflicting data is available on the efficiency of prescribed hormone therapy to protect ovarian function in patients who undergo HSCT [25]. It is presumed that suppression of reproductive system aimed to reduce oogenesis activity can protect germinal epithelium from the cytotoxic effects of chemotherapy. Small studies assessing the impact of gonadotropin-releasing hormone (GRH) receptor agonists have demonstrated some promising results; however, to confirm the positive effect of these drugs on gonadotoxicity further extensive clinical trials are required [26-28].

According to the literature, women 40 years and older have high risk of amenorrhea in the long-term post-transplantation period. Menstrual cycle disturbances in younger women are transient in nature. Hormone replacement therapy for premature ovarian insufficiency after HSCT is still poorly studied.

Pregnancy and childbirth

In addition to menstrual cycle recovery it is crucial to predict successful pregnancy outcomes and childbirth in young women who underwent HSCT, and to define potential effects on the health of newborns. In a 2015 retrospective study by E. Snarski and colleagues within the framework of the EBMT research in 324 adult women who underwent HSCT for various autoimmune diseases (multiple sclerosis, systemic sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, Takayasu's disease), 22 pregnancies were registered in 15 patients. It should be noted that not for all of the surveyed patients it was wanted or planned pregnancy. The median age of patients at the time of childbirth was 32 years, and the median period from HSCT to the childbirth was 4 years. Of 22 cases, 20 were spontaneous pregnancies, and two were IVF pregnancies [23].

Pregnancies with complications accounted for 32% of cases and included gestational diabetes, congestive heart failure, atrial fibrillation, hypertension and premature birth. In 10 cases pregnancy ended with physiologic birth, and in 5 cases with cesarean section. Ectopic pregnancies or spontaneous abortions were registered in 7 cases. The median gestational age at birth was 38 weeks. All the newborns were healthy, without detectable developmental abnormalities, and had median body weight of 3200 g. Of all the patients recurrence of the underlying AD during pregnancy after HSCT was observed in 2 cases (13%), where one patient died due to progression of pulmonary fibrosis associated with systemic sclerosis. For 5 patients (33%) underlying disease remained in remission, 4 patients (26%) showed improvement, and for 3 women (21%) underlying condition was stabilized. One patient (7%) developed secondary autoimmune hemolytic anemia [23].

The study group reported that at the time of auto-HSCT 75% of patients had one child, and for only 4 out of 28 patients it was a planned pregnancy, which succeeded in one single case [22].

In a group of 10 patients with multiple sclerosis who underwent HSCT within the EBMT CIC 725 from 2018 to 2020 (clinical trial of CR CyR), 3 pregnancies (33%) followed by successful deliveries were recorded 12-31 months posttransplant [25].

The analysis of relevant data has demonstrated that pregnancy after HSCT is possible. The course of pregnancy and childbirth did not exhibit specific features, and the rate of successful pregnancies was comparable to the general population of women.

Laboratory assessment of reproductive function

To monitor the status of reproductive health, some researchers limited themselves to assessing serum levels of sex hormone before and after transplantation. For example, the results of two studies addressing the outcomes of HSCT in patients with type 1 diabetes (T1D) have shown normal levels of FSH and LH for both genders, as well as normal testosterone values in all male participants and normal estradiol in all females [29]. In a Brazilian study of 15 patients there was only one case of hypergonadotropic hypogonadism in a woman after 1-year follow-up [30].

In 2011, data on the testicular function of 13 patients who underwent HSCT for type 1 diabetes were published [31]. All patients (median 16 y.o.) had type 1 diabetes for no more than 6 weeks before transplantation. All patients had normal pre-transplant levels of FSH and LH, though one patient had decreased testosterone. One year post-transplant, 10 patients had significantly elevated FSH and LH levels, but within 2 years of the follow-up it had returned to the reference range. Evaluation of sperm samples has shown that none of the patients exhibited normozoospermia before or after HSCT. Reduced sperm motility and morphological abnormalities were the most common changes. Moreover, the number of patients with post-HSCT severe sperm damage (oligoasthenoteratozoospermia) increased from 15.4% to 50%.

However, three years after transplantation two patients became fathers (the health status of the newborns is unknown). The authors concluded that testicular function is impaired in patients with type 1 diabetes at shorter terms of the disease and may worsen after HSCT, despite improved insulin secretion and metabolic control [32]. In a similar study by Couri et al. (2009), 9 of the 17 male patients had post-transplant oligozoospermia, but two years later 2 of these men became fathers. No information was provided regarding the health of the newborns [33].

Therefore, along with applying inclusion criteria and potential risk factors for HSCT, patients pre-transplant counseling regarding preservation of their reproductive function due to the post-treatment infertility risk is mandatory. Currently, no data is available to establish an upper age limit for fertility preservation in men and women who undergo HSCT. As the number of patients with autoimmune diseases treated by HSCT growth, the question of finding new methods to protect patients from iatrogenic infertility becomes increasingly topical. Cryopreservation of gametes is an obvious way to address post-HSCT fertility preservation [34, 35].

Impact of HDIT-HSCT on Thyroid Function

HSCT poses a risk of disrupting the balance between immunotolerance and autoimmunity, leading to the development of secondary autoimmune diseases within a period from 3 weeks to >4 years post-transplant. The presumed mechanisms of this complication suggest a significant decrease in the number of T-regulatory cells after chemotherapy, proliferation of autoreactive clones, lacking negative selection of T lymphocytes in thymus, and accumulation of mutations due to active cell proliferation after HSCT. Secondary autoimmune thyroid disease (AITD) is most commonly described condition. It may be related to a high prevalence of genetic predisposition to AITD in iodine sufficient populations. The HSCT procedure may trigger clinical manifestation of the disease [36].

A retrospective analysis of the EBMT Registry (1995-2009) has revealed that among 347 patients treated with HSCT for primary autoimmune diseases, 12 developed autoimmune thyroiditis, and 3 had Graves' disease, with one patient having blocking antibodies to the thyrotropin receptor. Autoimmune conditions developed on an average 22 months post-transplant (ranging from 6 to 49 months). Risk factors for emergence of secondary autoimmune diseases (e.g., thyroid disorders) include patient’s age <35 years, time from diagnosis to transplantation <61 months, primary autoimmune diseases, such as systemic lupus erythematosus, intensive T-cell depletion, and CD34+ cell selection in the graft [36]. The use of antithymocyte globulin was also identified as a risk factor, with a median onset of secondary autoimmune diseases 12 months [37].

In a prospective observational study by Burt et al. (2022) focused on evaluating HSCT in patients with multiple sclerosis, 16 cases (3.5%) of autoimmune thyroiditis and 15 cases (3.3%) of Graves' disease were documented. The average time to diagnosis of autoimmune thyroiditis after HSCT was 19 months, and for Graves' disease it was 42 months [38].

In smaller studies, the frequency of autoimmune thyroiditis in patients with various autoimmune diseases (multiple sclerosis, T1D, systemic sclerosis, rheumatoid arthritis, etc.) ranged after HSCT from 1 to 12.5%, whereas incidence of Graves' disease varied from 3.3 to 10% [39]. These differences are likely due to the heterogeneity of underlying autoimmune disorders in the study groups (for example, T1D is considered a predisposing factor for autoimmune thyroiditis being independent on transplantation outcomes), the number of patients included in the study, and variable duration of follow-up [39].

Therefore, some patients may develop thyroid disorders like autoimmune thyroiditis and Graves' disease after HSCT, with varying frequency observed by different authors. The issues of clinically significant predictors of thyroid disorders remain poorly understood.

Other complications of HDIT-HSCT potentially related to endocrine disorders

Some studies have shown that the patients undergoing HSCT for lymphoproliferative diseases have an increased risk of developing osteopenia and osteoporosis [40]. For instance, in a retrospective study assessing risk factors for reduced bone mineral density in patients with Hodgkin's lymphoma, more significant reduction in bone density was observed in an HSCT-group compared to a standard polychemotherapy group [41]. Phosphorus-calcium metabolism disturbances are thought to be associated with the use of glucocorticoids as well as deficiencies in sex hormones, growth hormone, physical inactivity, low calcium diet, and decreased body mass [42]. Moreover, high-dose chemotherapy itself can lead to loss of trabecular and cortical bone mineral density [43]. It should be noted that different chemotherapy regimens, cumulating doses of glucocorticoids, and the primary disorders contribute to the course of the post-transplantation period. Therefore, not all adverse events occurring after AHSCT can be conclusively linked to this therapeutic approach. To timely diagnose and treat osteoporosis and to prevent low-energy fractures, bone densitometry is recommended to patients one year after HSCT [44].

Below we present the results of a single-center (CIC725) study of early and delayed endocrine complications after HSCT in patients with multiple sclerosis. We have analyzed the questionnaires and case history of post-transplant visits at Pavlov University 6-60 months after HSCT. Only hypercholesterolemia may be attributed to early complications, which was detected in 54/130 patients (41.5%) when evaluated 2 weeks post-discharge from the hospital. This "complication" may be evaluated ambiguously: on the one hand, it may be a manifestation of the negative effect of alkylating drugs on the endothelium, and increased serum cholesterol can be considered a compensatory function [44-46]. On the other hand, hypercholesterolemia may induce incorrect differentiation of T-regulatory cells, which, theoretically, can lead to subsequent recurrence of the autoimmune process [47].

Table 1. Long-term (late) complications of HDIT-HSCT (5 years follow-up)

The endocrine complications after HSCT can mainly be considered as long-term adverse events. The results of a single-center analysis (CIC725; n=130; male/female 53/77) are presented in Table 1.

One should acknowledge that not all patients pay attention to certain manifestations associated with their main diagnosis, irrelevant of some personal life factors. Therefore, it is likely that the frequency of some specific gender-related complications is clearly underestimated, and it is impossible to specify the timing of its occurrence. The median terms of thyroid disease detection is 24.7±10.4 months (hypothyroidism, 36 mo.; hyperthyroidism, 15.2 mo.) The median age for amenorrhea in women is 38.5 y.o.

To the best of our knowledge, there is no information on the negative consequences of HSCT performed in severe ADs, concerning functions of the parathyroid glands, adrenal glands, somatotropic and lactotropic functions of the pituitary, as well as changes in antidiuretic hormone secretion. These areas of clinical research require further investigation.

The data on endocrinological complications reported in the literature are presented below (Table 2).

Table 2. Endocrine complications after HSCT in severe autoimmune disorders

Conclusion

HSCT is considered a promising approach for the treatment of several severe autoimmune disorders. However, its significant drawback is a relatively high risk of early and late adverse events of varying severity, due to aggressive nature of intensive cytostatic treatment. The spectrum of hematological complications in the early post-transplantation period during inpatient treatment is well-known due to regular screening and treated. The impact of HSCT on the endocrine system of patients with ADs is still poorly understood. However, it has been shown to negatively affect the reproductive function of both men and women, and to promote development of autoimmune thyroid diseases. Therefore, further research on possible endocrine-related complications following HSCT in ADs, including risk factors and preventive and treatment strategies remains highly relevant. The need for dynamic assessment of the patient's endocrine system status during early and late post-transplant period is evident, as well as the importance of informing the patient about risks of appropriate complications.

Conflict of interest

The study was not sponsored. The authors declare no conflict of interest. The authors are fully responsible for submitting the final version of the manuscript. All the authors took part in the development of the concept of the article and writing of the manuscript. The final version of the manuscript was approved by all authors.

Compliance with ethical principles

The authors confirm that they respect the rights of the people who participated in the study, including obtaining the required informed consent.

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