Efficacy and safety of thalidomide in children with monogenic autoinflammatory diseases: a single-center, real-world-evidence study

Monogenic autoinflammatory diseases (AIDs) are a group of genetic disorders caused by defects or dysregulations of the innate immune system that lead to continuous or recurrent inflammation. Currently, there are three main subgroups: type 1 interferonopathies, defects affecting the inflammasome, and non-inflammasome-related conditions [1, 2]. Monogenic AIDs usually present with constitutional symptoms like fever and inflammation-related clinical manifestations of multiple organ systems, including but not limited to the skin, joints, eyes, ears, gastrointestinal tract, respiratory tract, central nervous system and cardiovascular system [2‐4]. While several medications have proven partially effective in some conditions, for example, colchicine for familial Mediterranean fever (FMF), interleukin 1 inhibitors for tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), JAK inhibitors for several type 1 interferonopathies, glucocorticoids and conventional immunosuppressive agents for Blau syndrome and pyoderma gangrenosum and acne syndrome [5‐7], there is no universal therapeutic agent for all kinds of AIDs, and these conditions are usually steroid-dependent and relapse once the dose is tapered. Another dilemma for monogenic AID patients in China is that some effective targeted biological agents such as canakinumab have not been marketed in China, and the drugs used in off label are also unaffordable. On this background, we turned our attention to a relatively old immunomodulatory drug, thalidomide. Previous studies have shown that thalidomide regulates signaling pathways through the NFκB-IRF4 pathway and AMPK/mTOR pathway, having anti-inflammatory, immunoregulatory and anti-angiogenic effects in cancer and autoimmune diseases [8], making it therapeutically useful in cancer, systemic lupus erythematosus, and Crohn's disease [9, 10]. Although short-term use of thalidomide has been seen in some isolated case reports of monogenic AIDs, data on long-term use in more pediatric monogenic AIDs patients are lacking. This study was dedicated to exploring the efficacy and safety of the long-term use of thalidomide in a pediatric monogenic AIDs series, in search of more options for the treatment of these diseases. We report the clinical and laboratory data of patients with monogenic AIDs who were treated with thalidomide and analyze its efficacy and adverse effects. The good outcomes provide another option for the treatment of AIDs.

In the latest 2022 inborn errors of immunity (IEI) classification, the monogenic AIDs were divided into 3 major groups of 56 diseases [2]. The pathogenesis of these rare diseases involves activation of the innate immune system causing repeated or persistent inflammation with cytokine overproduction, especially tumour necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-18, and interferon (IFN)-α [1]. Timely diagnosis and treatment are critical for a good prognosis. Unfortunately, most of these diseases are resistant to conventional immunosuppressive therapy. Previous studies have shown that thalidomide exerts anti-inflammatory, immunomodulatory, and angiostatic effects [11, 12]. Therefore, we attempted to add thalidomide to the current treatment in patients with monogenic AIDs. We report the largest cohort of monogenic AIDs treated with thalidomide in a pediatric population, who showed no intolerable side effects.

Thalidomide blocks the release of cytokines such as TNF-α, IFN-γ, IL-10, and IL-12, as well as cyclooxygenase 2 and the transcription factor nuclear factor NF-κB. Thalidomide has been considered to have potent broad-spectrum anti-inflammatory activity, which expands the possibilities for the treatment of inflammatory diseases [12], but evidence for the efficacy of thalidomide in AIDs is limited to sporadic case reports and series. Six of seven patients with DADA2 achieved persistent remission when the treatment of thalidomide [13]. Thalidomide can provide CINCA patients symptomatic relief of limited joint mobility, helping their weight gain and reducing pain associated with daily injections of biological agents [14]. Almost 10% of FMF patients are resistant or intolerant to colchicine treatment [15]. Thalidomide has persistently suppressed febrile attacks and acute phase responses in colchicine resistant FMF patients [16]. When two For HA20 patients were treated with thalidomide, both showed amelioration of gastrointestinal symptoms on a background of glucocorticoids or biological agents and eventually discontinued glucocorticoid therapy [17]. Our findings parallel the above data. Monogenic AIDs patients treated with thalidomide for 1 year in our study showed significant improvements in fever and rash, as well as control of inflammatory parameters, with decreased disease activity in most patients compared to baseline. Notably, some patients were even able to discontinue glucocorticoids and other immunosuppressive agents, suggesting the potential effectiveness of thalidomide in certain monogenic AIDs.

Previously, it was reported that during thalidomide treatment of patients with PLAID, glucocorticoids and MTX have been used concomitantly, which improved only some of the symptoms improved and decreased CRP transiently, and immunosuppressive agents were discontinued because of abnormal liver function [18]. Another patient with granulomatous disease did not see improvement of his skin lesions with the addition of thalidomide [19]. The clinical manifestations of the 1 PLAID patient in this study were milder than those reported in the literature (Additional file 2), and thalidomide was effective in combination with glucocorticoids, after which the glucocorticoids were tapered to a low dosage. Therefore, thalidomide treatment may be trialled in PLAID patients with relatively mild clinical symptoms. Thalidomide can inhibit the inflammatory response and improve clinical symptoms in patients with Blau syndrome, with few adverse reactions [20, 21]. The efficacy of thalidomide in Blau syndrome was 50% in this study (Fig. 2D), suggesting that more extensive inflammatory pathways or cytokines may be involved in the mechanism of Blau syndrome [22]. In addition, our cohort reported the efficacy of thalidomide after 1 year treatment of AGS, SAVI and TRAPS in clinical practice firstly [23]. Thalidomide was partially effective against AGS and ineffective against SAVI and TRAPS in this study, but at present, studies about the treatment of these disorders are few, and more research is needed to evaluate the efficacy and side effects of thalidomide.

As for other diseases with autoinflammatory features, thalidomide is efficacious at controlling inflammation in patients suffering from sideroblastic anemia, immunodeficiency, periodic fevers, and developmental delay [24]. Pyoderma gangrenosum, acne, and hidradenitis suppurativa syndrome have been seen in a patient who initially failed to respond to immunosuppressive treatment but responded to a combination of colchicine and thalidomide [25]. It has been reported that the clinical symptoms and inflammatory indicators of a Muckle-Wells syndrome patient improved after treatment with thalidomide [26]. All of the above suggest that thalidomide has a broad anti-inflammatory effect and may be worth trying for a variety of autoinflammatory diseases.

One major concern about the widespread use of thalidomide is its side effects. One adult patient with colchicine resistant FMF developed a lower extremity numbness during treatment with thalidomide, which disappeared despite continuing the drug [16]. In our study, the treatment with thalidomide was well tolerated overall, and no patient developed severe side effects during the treatment. Only 2 patients had drug-related side effects, which included nausea, fatigue, and anorexia. We took detailed medical history and physical examination with special attention to identify potential peripheral neuropathies, and none of the patients had the symptoms such as numbness, tingling, pain or tremor. Generally, the preference of one treatment over the other can therefore be based on the price and/or the country’s payment conditions of the drugs [27]. Despite the possible toxic effects on the peripheral nervous system, this drug has the advantage of a low cost and could be considered in developing countries where the use of biologic agents is limited for economic reasons [14].

Our study further confirmed that thalidomide could be considered a promising therapeutic option for monogenic AIDs not only for reducing disease flare-ups but also for reducing the inflammation index. Furthermore, thalidomide can help taper or discontinue glucocorticoids and immunosuppressive agents that have relatively strong adverse reactions. Thalidomide is cheaper than biologics such as anakinra and easier to purchase for Chinese patients. The successful application of thalidomide in monogenic AIDs paves the way for further study of this treatment option.

The first and main limitation of this study is its small sample size and retrospective design. Because the monogenic AIDs are rare, only patients treated with thalidomide were included. Further studies with larger patient cohorts are required to validate recent findings with thalidomide.

This study evaluated the efficacy and safety of thalidomide in monogenic AIDs and is the largest study of thalidomide for the treatment of monogenic AIDs patients. Thalidomide can help alleviate clinical symptoms or disease activity in some patients, achieve remission of inflammatory indicators, and help the patient discontinue glucocorticoids or other immunosuppressive agents. The most common adverse reactions were gastrointestinal symptoms. During treatment, the dosage can start low and gradually increase to achieve therapeutic effects with the smallest dosage possible. Overall, data on the use of thalidomide in monogenic AIDs are scarce, so further studies are needed to evaluate its long-term efficacy and side effects.