Efficacy and safety of thalidomide for recurrent aphthous stomatitis: a systematic review and meta-analysis of randomized controlled trials.

Introduction

Recurrent aphthous stomatitis is a common chronic disease of the oral mucosa with a prevalence of 5–25% and up to half of patients have a recurrence within three months [ 1 ]. The ulcers usually occur on the non-keratinized oral mucosa with a yellow or white, crater-shapes base surrounded by an erythematous halo, and usually heal spontaneously within 7–10 days [ 2 ]. Continuous and recurrent oral ulcers and severe pain influence the life quality of patients. RAS is classified as minor RAS, major RAS, and herpetiform RAS [ 3 ]. The aetiology of RAS remains unclear and it is thought to be multifactorial. The current research suggests that genetically mediated innate and acquired immune dysregulation play a key role in the disease development. Factors that modify the immune response include: trauma, drugs, nutritional deficiency, hormonal changes, food allergies, stress, tobacco, and oral micro-organisms [ 4 , 5 ]. Aphthous-like ulcerations may also occur in systemic diseases, including gastrointestinal disorders, Behçet disease, and immunodeficiencies [ 6 ]. The aim of treating RAS is to reduce the number and size of ulcers, relieve symptoms and prolong disease-free periods. For some mild patients, palliative treatment for pain relief and maintaining the good mouth hygiene is sufficient. For individuals who experience multiple episodes and/or severe pain and eating difficulties, medication treatment should be considered. The recommended treatment for RAS includes topical agents and systemic medications. The topical agents are the first option of the treatment of RAS. For systemic drugs, corticosteroids, thalidomide, levamisole, dapsone, colchicine, seem to exert certain effects through different mechanisms [ 7 ]. In addition, the Consensus of China also recommends Traditional Chinese Medicine (TCM) for RAS [ 8 ]. Thalidomide, a synthetic derivative of glutamic acid, was used to relieve morning sickness in pregnant women, and was eventually banned because of its teratogenic effects [ 9 ]. In recent years, thalidomide has attracted the attention of researchers as its immunomodulatory effects. Thalidomide has significant therapeutic effects in many diseases including cutaneous lesions of systemic lupus, β-thalassemia, ankylosing spondylitis and multiple myeloma [ 10 – 13 ]. Thalidomide has gradually been introduced into the treatment of oral mucosal diseases with certain therapeutic effects [ 14 – 16 ]. However, the clinical application of thalidomide is limited because the current evidence is not as strong as other therapies such as corticosteroids. Meanwhile, in addition to embryonic toxicity, thalidomide also has other significant side effects, such as peripheral neurotoxicity, venous thromboembolism and somnolence [ 17 – 19 ]. Thalidomide for RAS treatment has not been systematically evaluated, so to better balance the benefits and risks, we conducted a review of all RCTs, aiming to evaluate the efficacy and safety profile of thalidomide for treatment of RAS.

Methods

This systematic review and meta-analysis were performed according to the PRISMA guideline.

Search strategies

The following electronic databases were searched by two independent researchers (Jian and Zhao) for published studies from inception to December 2023: PubMed, Scopus, Embase, Web of Science, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), VIP information, Wanfang Data.

The main search strategy was as follows: (thalidomide OR sedoval) AND (recurrent aphthous stomatitis, stomatitis, aphthous, recurrent aphthous ulcers, aphthous stomatitis, recurrent oral ulcers).

Eligibility criteria

Inclusion criteria were set according to the PICOS component:

Participants (P): individuals diagnosed with RAS, including patients with RAS who also suffer from basic diseases such as AIDS, Behçet’s disease or acute leukaemia.

Intervention (I): treatment groups received oral thalidomide alone or thalidomide combined with other interventions.

Comparator (C): placebo or any form of medical intervention except thalidomide, whether topical or systemic.

Outcomes (O): The primary outcomes included complete response and overall response, and we defined overall response as complete response plus partial response. The secondary outcomes included: recurrence interval, number of ulcers, days to ulcer healing, VAS score, ulcer diameter, immunological data, adverse effects.

Study design (S): Randomized control trials and controlled clinical trials.

The exclusion criteria: uncontrolled trials, reviews, posters, secondary research, meeting abstracts, in vitro or animal studies, and papers without full text.

Paper screening and data extraction

First, two independent researchers screened the titles and abstracts against the eligibility criteria. Subsequently removing duplicate, they check the full text of all potential studies. EndNote X7.3 software was used for duplicates removal and paper screening. Two authors independently extracted the information from included research according to a designed data collection table. The following data were recorded: name of the first author, number of patients analyzed, publication year, study design, clinical intervention, outcomes, and treatment duration. Any discrepancies were resolved via discussion by a third researcher, if necessary.

Quality assessment

Two independent researchers evaluated the methodological quality of the included studies by the Cochrane Risk of Bias Assessment Tool, which considered following seven assessment criteria [ 20 ]: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. Any divergent assessment was resolved in open discussion or consultation with the corresponding author.

Statistical analysis

Meta-analysis was performed for each outcome using RevMan5.4 software. Dichotomous data, such as complete response, were assessed as risk ratio (RR) using the Mantel-Haenszal method. Continuous variables, including recurrence interval, number of ulcers, days to ulcer healing, VAS score, ulcer diameter, were assessed as the mean difference (MD). 95% confidence intervals (CIs) were used to evaluate the effect size. Statistical heterogeneity was evaluated using I 2 statistics. when I 2 50%, the trials were thought to be homogeneous and the data were pooled by fixed-effect model; otherwise, the trials were supposed to be heterogeneous, and random-effects model was chosen. For multiple intervention study, meta-analysis was performed between the comparison groups in interest according to subgroup analysis, if there were more than one control group in a trial for a subgroup analysis, the groups were combined into a single pair-wise comparison, as recommended by the Cochrane Handbook for Systematic Reviews of Interventions [ 21 ]. For cross-over trial, data from the first phase were analyzed.

Results

Search results and study characteristics

Figure 1 presented the study selection process. 1242 articles were found in nine databases following search strategy described above. After removing duplicates, screening the titles and abstracts, and reading entire articles, 21 studies with 1668 patients met the inclusion criteria and were included into our meta-analysis [ 22 – 42 ]. 15 publications were presented in Chinese language and 6 in English. The 17 included trials were conducted in China [ 22 – 24 , 26 , 28 , 31 – 42 ], while the other four were conducted in the United States, France, Mexico, and Brazil [ 25 , 27 , 29 , 30 ]. Of all the eligible studies, three compared [ 25 , 29 , 30 ] the efficacy of thalidomide with placebo, and seven [ 23 , 24 , 26 – 28 , 38 , 40 ] compared with other medical measures including prednisone, vitamin B1, montmorillonite powder, dapsone, colchicine, etc. Nine trials [ 31 – 34 , 36 , 37 , 39 , 41 , 42 ] evaluated the combination therapy of thalidomide and other drug compared to other drugs alone. And two triple-arms trials compared the efficacy and safety among the combination of thalidomide and TCM, thalidomide alone and TCM alone [ 22 , 35 ]. The duration of treatment ranged from 5 days to 6 months. The detailed information on the eligible trials is shown in Table 1 .

Risk of bias

Three independent raters assessed the methodological quality of the eligible RCTs using the Cochrane Risk of Bias tool. All selected studies were randomized controlled, but only two [ 25 , 38 ] reported allocation concealment and were evaluated as low risk. Only three [ 25 , 29 , 30 ] and four [ 25 , 29 , 30 , 38 ] studies were judged as low risk about detection bias and performance bias, respectively. All studies were classified as low-risk about selective reporting and incomplete outcome. There was insufficient information about other bias and the risk was assessed as unclear. The results of the quality evaluation are shown in Fig. 2 .

Meta-analysis results

We performed subgroup analysis under different outcomes.

Complete response.

Three studies [ 25 , 29 , 30 ] evaluated the complete response of thalidomide versus placebo for RAS, the meta-analysis showed a significant improvement in those who received thalidomide versus placebo (RR = 6.95, 95% CI: 3.04–15.92, I 2 = 39%, p < 0.00001, fixed-effect model, Fig. 3 a). Pooled data from eight trials [ 22 – 24 , 26 – 28 , 35 , 40 ] showed that thalidomide had a better therapeutic effect than other drug on complete response (RR = 2.18, 95% CI: 1.38–3.45, I 2 = 68%, p = 0.008, random-effect model, Fig. 3 b). A meta-analysis of ten trials [ 22 , 31 – 37 , 39 , 41 ] revealed that the combination therapy of thalidomide and other medicine was better than other medicine alone in complete response (RR = 2.44, 95% CI: 1.55–3.84, I 2 = 59%, p = 0.0001, random-effect model, Fig. 3 c).

Overall response

In the only study [ 25 ] that reported overall response compared with placebo, the thalidomide group had the higher overall response rate (RR = 3.59, 95% CI: 1.87–6.89, Fig. 4 a). Seven studies [ 22 , 24 , 26 – 28 , 35 , 40 ] evaluated the overall response between the thalidomide and other medicine, and although this did not reach statistical significance, it implies that the thalidomide group might be more effective than the control group in terms of overall response (RR = 1.18, 95% CI: 0.99–1.41, I 2 = 80%, p = 0.07, random-effect model, Fig. 4 b). Ten studies [ 22 , 31 – 37 , 39 , 41 ] evaluated that the overall response of the combination of thalidomide and other drug, the meta-analysis indicated that the combination of thalidomide and other drug was superior to other drug alone in overall response (RR = 1.32, 95% CI: 1.23–1.42, I 2 = 0%, p < 0.00001, fixed-effect model, Fig. 4 c).

Recurrence interval

Three studies [ 23 , 38 , 42 ] reported on RI, pooled data indicated thalidomide can significantly prolong the RI compared to other interventions (MD = 26.91, 95% CI: 2.29–51.54, p = 0.03, I 2 = 99%, random-effect model, Fig. 5 ).

Healing time

Four studies [ 31 , 32 , 35 , 38 ] provided data on the healing time of the ulcers, the analysis results suggested that thalidomide group was better able to accelerate the healing process compared to the control group (MD = -1.31, 95% CI: -2.06 to -0.56, I 2 = 70%, p = 0.0006, random-effect model, Fig. 6 ).

Number of ulcers

Number of ulcers was reported in four studies [ 23 , 26 , 35 , 38 ], a statistically significant reduction was seen in the thalidomide treatment group compared to placebo or other medicine on ulcers number (MD = -0.98, 95% CI: -1.87 to -0.08, p = 0.03, I 2 = 91%, random-effect model, Fig. 7 ).

Ulcer size

Ulcer size was assessed in two RCTs [ 37 , 42 ] which were measured by mean diameter of the ulcers, and the results showed that the thalidomide group significantly reduced the mean diameter of the ulcers compared to other drugs group (MD = -0.85, 95% CI: -1.02 to -0.68, I 2 = 4%, p < 0.00001, fixed-effect model, Fig. 8 ).

VAS score

Three of the included studies [ 35 , 37 , 42 ] used the VAS score as an outcome indicator, the pooled result showed that there were no significant differences between the thalidomide group and the control group (MD = -0.64, 95% CI: -1.75 to 0.47, I 2 = 91%, p = 0.26, random-effect model, Fig. 9 ).

Immunological data

Five trials [ 22 , 25 , 28 , 35 , 37 ] reported immunological indicators, including TNF-α, IgA, IgG, IgM. Four studies assessed TNF-α, three of which reported a reduction in TNF-α by thalidomide, and one reported an unexpected increase. The substantial heterogeneity among the four studies and the abnormity of numerical data precluded us from performing the meta-analysis on TNF-α. Xu Q et al. [ 37 ] found that the combination of thalidomide and cimetidine could significantly reduce levels of IgA, IgG and IgM compared with cimetidine alone.

Adverse events

Due to the severity of symptoms in patients with severe underlying diseases such as AIDS, Behçet’s disease or acute leukemia, these patients are not included in the analysis of adverse effects. Four trials reported the patients who withdrew from treatment due to adverse reactions, with 12 patients in the thalidomide group in total and only one patient in the control group. Eight studies did not report adverse events or did not provide detailed information. The remaining nine studies [ 22 , 27 , 32 , 34 , 35 , 38 , 40 – 42 ] evaluated the adverse event such as constipation, somnolence, dizziness, rash, peripheral neurotoxicity, etc. The result of the meta-analysis indicated that thalidomide-containing regimens significantly increased adverse events (RR = 1.87, 95% CI: 1.17–2.99, p = 0.009, I 2 = 36%, fixed-effect model, Fig. 10 ).

Discussion

Aphthous lesions are painful, and affect the quality of life and psychological condition by interfering with swallowing, chewing, and speaking [ 43 , 44 ]. Unfortunately, despite the high incidence and extensive research on RAS, its management remains quite challenging with no definitive treatment methods [ 45 ]. Topical agent, including glucocorticoids, corticosteroids, anesthetics, antibiotics, seem to be the first option of the treatment of RAS, but there are no evidence-based guidelines available to indicate which systemic treatment should be considered as first-line treatment for RAS cases that do not respond to topical agents. So far, the etiopathogenesis of RAS remains unclear; the results of current research indicate that multiple factors contribute, of which innate and acquired immune disturbance may play an essential role [ 7 ]. Th1 type cytokines, including TNF-a, IL-2, and IL-12, determine the propensity of autoimmunity and induce cellular responses. Some studies have indicated that Th1 type immune response plays a key role in the development of RAS, with significantly higher secretion of Th1 cytokines in RAS patients compared to the healthy [ 46 – 48 ]. The TNF-α cytokine, a major inflammatory mediator, induces initiation of the inflammatory process. It has been found that RAS individuals showed significantly higher level of TNF-α than healthy individuals in both peripheral blood and saliva [ 49 – 51 ]. This event stimulates cytotoxic T lymphocytes and increases endothelial cell expression, leading to the migration of inflammatory cells to the site of inflammation, resulting in the development of ulcers [ 45 ]. Thalidomide can block expression of TNF-α by different possible mechanisms. One such mechanism is by blocking the expression of NF-kB which works as a transcription factor for TNF-α [ 52 ]. Another study by Noman, A.S. et al. found that thalidomide inhibits lipopolysaccharide-induced TNF-α production by downregulating MyD88 protein and mRNA [ 53 ]. It has also been described that thalidomide reducing the expression level of TNF-α by enhancing mRNA degradation [ 54 ]. A Cochrane review evaluating the systemic intervention for RAS did not explicitly recommend thalidomide as a treatment [ 55 ]. We first performed a systematic evaluation of the efficacy and safety of thalidomide for RAS treatment as more trials were conducted. The results of the meta-analysis indicated that, compared to control group, thalidomide significantly improved the complete response and overall response rate, prolonged the recurrence interval, accelerated the healing process, reduced the number and size of ulcers, and lowered levels of TNF-α. However, thalidomide did not provide an advantage over the control group in pain alleviation. Notably, compared to non-thalidomide therapy, thalidomide-containing therapy significantly increased adverse events such as peripheral neuropathy, thrombosis/embolism events, constipation, somnolence. Systemic corticosteroids such as prednisone are often the common choice of RAS treatments [ 56 ]. Zeng QX et al. [ 38 ] concluded that thalidomide had a long-term effect of prolong the RAS recurrence interval than prednisone. It is important to note that the outstanding efficacy of thalidomide must be balanced against its adverse events. Treatment for RAS should follow a stepwise approach, starting with topical medication and progressing to systemic medication [ 43 ]. Considering the self-healing nature of RAS and the potential side effects of thalidomide, it may be a promising option for major RAS patients or cases that do not respond to topical agents. Although thalidomide is an absolute contraindication in pregnant women or women planning to conceive, its other adverse reactions can be minimized by a stepwise reduction of dosage. In early studies, thalidomide was often administered at higher doses. Jacobson [ 25 ] and David [ 14 ] opted for a daily dose of 200 mg with high incidence of adverse reactions. High doses and long-term use of thalidomide significantly increased the incidence of thromboembolism and peripheral neuropathy, which are the most common major adverse reactions [ 19 ]. In more recent research, Zeng [ 38 ] designed a dosage of 100 mg/d for 10 days, followed by 50 mg/d for 10 days, and finally 25 mg/d for 10 days with mild to moderate adverse reaction. Deng [ 23 ] compared the safety and efficacy between 25 mg/d and 50 mg/d thalidomide doses, and found that 25 mg/d thalidomide had a long-term effect on prolong the recurrence interval of RAS with better safety. In Wei’s study, RAS patients were treated with maintenance thalidomide at doses of 25 mg/d or 50 mg/d after initial treatment with prednisone, and it was found that the effect of 50 mg/d thalidomide was not superior to that of the 25 mg/d drug [ 57 ]. In the light of recent research findings, we believe that thalidomide at a dose of 25 mg/d is a good choice. Therefore, during thalidomide treatment, peripheral neuropathy symptoms such as poor sensation, distal limb numbness, muscle weakness and hypotonia should be carefully monitored. Thalidomide treatment should be stopped immediately if any of the above symptoms occur to avoid irreversible damage to the peripheral nerve [ 17 ]. In the future, a RCT could perhaps be designed to administer thalidomide every other day or even twice a week, to explore lower doses that can achieve better safety while ensuring effectiveness.

Limitations should be taken into account for our research. The most critical limitation is the low quality of most the analyzed studies. Specifically, most of studies did not provide detailed information on blinding methods and allocation concealment, which we consider to be high risk. Another important limitation is the considerable heterogeneity among the included trials. This heterogeneity is evident in the type of RAS, type of underlying disease, difference in doses, comparison groups, outcome measures, treatment duration, follow-up period and participant characteristics. Additionally, most the eligible trials were performed in China, which limits the generalizability of these findings to other populations.

Conclusions

Currently, there are no guidelines indicating which systemic treatment to choose as the first treatment for RAS cases that do not respond to topical medicine. Our research firstly systematically demonstrated that thalidomide has a significant effect in improving the response rate, prolonging the recurrence interval, accelerating the healing process, reducing levels of TNF-α, the number and size of ulcers in treatment of RAS. However, thalidomide therapy was associated with a significant increase in adverse events. However, our results provide clinicians with an optimal treatment option for the RAS patient who do not respond to topical medication. Nevertheless, due to the low quality and heterogeneity of the trials we included, large-sample randomized, controlled, multicenter, clinical trials are warranted.

Acknowledgements

Not applicable.

Abbreviations

Recurrent aphthous stomatitis

Randomized controlled trial

Recurrence interval

Visual analogue scale

Traditional Chinese medicine

Risk ratio

Confidence interval

Complete response

Overall response

Mean difference

Author contributions

Conceptualization: XY Wang, Y Jian; Data curation: Y Jian, MR Zhao, and XR Han; Methodology: FQ Wang, XR Han; Formal analysis: XY Wang, MR Zhao; Investigation: Y Jian, MR Zhao; Writing—original draft preparation: Y Jian, MR Zhao; Writing—review and editing: XY Wang, FQ Wang; Supervision: XY Wang, Y Jian; Project administration: XY Wang, Y Jian. All authors have read and agreed to the published version of the manuscript.

Funding

No funding was received to conduct this research.

Data availability

Data is provided within the manuscript or supplementary information files.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

1. Jonathan AS, Arbor DMD, Mich A. Recurrent aphthous stomatitis: an update. Oral Surg Oral Med Oral Pathol Oral Radiol. 1996;81(2):141–7.

2. Barrons RW. Treatment strategies for recurrent oral aphthous ulcers. Am J Health-Syst Pharm. 2001;58(1):41–50.

3. Altenburg A, El-Haj N, Micheli C, Puttkammer M, Abdel-Naser MB, Zouboulis CC. The treatment of chronic recurrent oral aphthous ulcers. Dtsch Arztebl Int. 2014;111(40):665–73.

4. Wang ZH, Cao HB, Xiong JQ, Lu YL, Deng YX, Nan H, et al. Recent advances in the aetiology of recurrent aphthous stomatitis (RAS). Postgrad Med J. 2022;98(1155):57–66.

5. Slebioda Z, Szponar E, Kowalska A. Etiopathogenesis of recurrent aphthous stomatitis and the role of immunologic aspects: literature review. Arch Immunol Ther Exp. 2014;62:205–15.

6. Manfredini M, Guida S, Giovani M, Lippolis N, Spinas E, Farnetani F, et al. Recurrent aphthous stomatitis: treatment and management. Dermatol Pract Concept. 2021;11(4):e2021099.

7. Tarakji B, Gazal G, Al-Maweri SA, Azzeghaiby SN, Alaizari N. Guideline for the diagnosis and treatment of recurrent Aphthous Stomatitis for Dental Practitioners. J Int Oral Health. 2015;7(5):74–80.

8. Shi LJ, Zhou ZT. Diagnosis and management of recurrent aphthous ulcer. Chin J Stomatol. 2022;57(3):314–8.

9. Vargesson N. Thalidomide-induced teratogenesis: history and mechanisms. Birth Defects Res C Embryo Today. 2015;105(2):140–56.

10. Wang DD, Chen HF, Wang SY, Zou YH, Li J, Pan JP, et al. Thalidomide treatment in cutaneous lesions of systemic lupus erythematosus: a multicenter study in China. Clin Rheumatol. 2016;35(6):1521–7.

11. Lu YF, Wei ZB, Yang GH, Lai YR, Liu RR. Investigating the efficacy and safety of Thalidomide for treating patients with β-Thalassemia: a Meta-analysis. Front Pharmacol. 2022;12:814302.

12. Huang F, Gu JR, Zhao W, Zhu J, Zhang JL, Yu DT. One-year open-label trial of thalidomide in ankylosing spondylitis. Arthritis Rheum. 2002;47(3):249–54.

13. Aguiar PM, de Mendonça Lima T, Colleoni GWB, Storpirtis S. Efficacy and safety of bortezomib, thalidomide, and lenalidomide in multiple myeloma: an overview of systematic reviews with meta-analyses. Crit Rev Oncol Hematol. 2017;113:195–212.

14. Paterson DL, Georghiou PR, Allworth AM, Kemp RJ. Thalidomide as treatment of refractory aphthous ulceration related to human immunodeficiency virus infection. Clin Infect Dis. 1995;20(2):250–4.

15. Harte MC, Saunsbury TA, Hodgson TA. Thalidomide use in the management of oromucosal disease: a 10-year review of safety and efficacy in 12 patients. Oral Surg Oral Med Oral Pathol Oral Radiol. 2020;130(4):398–401.

16. Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, et al. Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 1998;128(6):443–50.

17. Xue HX, Fu WY, Cui HD, Yang LL, Zhang N, Zhao LJ. High-dose thalidomide increases the risk of peripheral neuropathy in the treatment of ankylosing spondylitis. Neural Regen Res. 2015;10(5):814–8.

18. Moore TJ, Bennett CL. Underreporting of hemorrhagic and thrombotic complications of pharmaceuticals to the U.S. Food and Drug Administration: empirical findings for warfarin, clopidogrel, ticlopidine, and thalidomide from the Southern Network on adverse reactions (SONAR). Semin Thromb Hemost. 2012;38(8):905–7.

19. Hello M, Barbarot S, Bastuji-Garin S, Revuz J, Chosidow O. Use of thalidomide for severe recurrent aphthous stomatitis: a multicenter cohort analysis. Med (Baltim). 2010;89(3):176–82.

20. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.

21. Higgins J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA. Cochrane Handbook for Systematic Reviews of Interventions. 2nd Edition. Chichester (UK): John Wiley & Sons; 2019.

22. Chen H, He J, Zhou SL, Zhang EP. Comparison of effect on major recurrent aphtha with different methods of treatment. J Dent Prevent Treat. 2014;22(1):18–21.

23. Deng YW, Wei W, Wang YF, Pan L, Du GH, Yao H, et al. A randomized controlled clinical trial on dose optimization of thalidomide in maintenance treatment for recurrent aphthous stomatitis. J Oral Pathol Med. 2022;51(1):106–12.

24. Gao Q, Chen HZ, Li HB, Jia ZY. The clinical effects of thalidomide in the treatment of Major Aphthous Ulcer. J Mod Stomatol. 2007;21(3):326.

25. Jacobson JM, Greenspan JS, Spritzler J, Ketter N, Fahey JL, Jackson JB. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection. N Engl J Med. 1997;336:1487–93.

26. Revuz J, Guillaume J-C, Janier M, Hans P, Marchand C, Souteyrand P. Crossover study of Thalidomide vs placebo in severe recurrent aphthous stomatitis. Arch Dermatol. 1990;126:923–7.

27. Lin YH. Clinical study of thalidomide in the treatment of recurrent oral ulcer. J Med Aesthet Cosmetol. 2020;29(16):83.

28. Mimura MAM, Hirota SK, Sugaya NN, Sanches JA Jr., Migliari DA. Systemic treatment in severe cases of recurrent aphthous stomatitis: an open trial. Clinics. 2009;64(3):193–8.

29. Peng Y. Montmorillonite dispersed and Sally amine curative effect analysis for the treatment of recurrent oral ulcer. J Gen Stomatol. 2015;2(4):88–90.

30. Ramirez-Amador VA, Lilly EP, Sergio PDL, Gustavo RT, Martha GG, Samuel PDL, et al. Thalidomide as therapy for human immunodeficiency virus-related oral ulcers: a double-blind placebo-controlled clinical trial. Clin Infect Dis. 1999;28:892–4.

31. Tian FQ, Tang MQ, Li JH, Huang YC, Li HQ, Zhong QZ, et al. Clinical study of thalidomide treating oral ulcers secondary to acute leukemia. J Clin Hematol. 2016;29(5):404–5.

32. Wang PH, Zhong SS, Su RB. The clinical efficacy and safety of thalidomide combined with vitamin B1 and vitamin AD in the treatment of recurrent aphthous ulcer. Chin J Clin Ration Drug Use. 2022;15(30):152–4.

33. Xu HX, Qiu P. The clinical effects of thalidomide combined with total glucosides of Paeony Capsules in the treatment of RAU. Clin Res Pract. 2016;1(02):34.

34. Xu HY, Jiao HM, Guo YL, Li F. The clinical effects of low dose thalidomide combined with multivitamin and minerals tablet for treating recurrent aphthous ulcer. Shaanxi Med J. 2018;47(2):238–40.

35. Xu JC, Chen ZL. Clinical observation of thalidomide combined with total glucosides of Paeony Capsules in the treatment of recurrent aphthous ulcer. Strait Pharm J. 2017;29(06):108–10.

36. Xu Q. Clinical observation of thalidomide in the treatment of recurrent aphthous ulcer. Strait Pharm J. 2019;31(12):127–9.

37. Xu Q, Zhou L. Effect of Thalidomide combined with cimetidine on the treatment of recurrent oral Ulcer. Shenzhen Vintegr Tradit Chin West Med. 2021;31(20):153–5.

38. Zeng QX, Shi XK, Yang J, Yang M, Zhao W, Zhao XY, et al. The efficacy and safety of thalidomide on the recurrence interval of continuous recurrent aphthous ulceration: a randomized controlled clinical trial. J Oral Pathol Med. 2019;00:1–8.

39. Zhang J, Ma M, Zhu LH. Short-term effects of thalidomide in the treatment of recurrent aphthous ulcer. J Ningxia Med Univ. 2010;32(09):997–9.

40. Zong JJ, Lin L, Su S. Effect of thalidomide in the treatment of intractable recurrent aphthous ulcer. J Nanchang Univ(Med Sci). 2014;54(10):71–2.

41. Zhou H, Huang FY. The clinical efficacy of thalidomide for recurrent oral aphthous ulcers. Med J West China. 2011;23(8):1534–7.

42. Zhong ZQ, Cai ZX. Clinical study of thalidomide combined with prednisone in the treatment of major aphthous ulcer. Stomatol. 2011;31(06):376–8.

43. Edgar NR, Saleh D, Miller RA. Recurrent aphthous stomatitis: a review. J Clin Aesthet Dermatol. 2017;10(3):26–36.

44. Dhopte A, Naidu G, Singh-Makkad R, Nagi R, Bagde H, Jain S. Psychometric analysis of stress, anxiety and depression in patients with recurrent aphthous Stomatitis-A cross-sectional survey based study. J Clin Exp Dent. 2018;10(11):e1109–14.

45. Saikaly SK, Saikaly TS, Saikaly LE. Recurrent aphthous ulceration: a review of potential causes and novel treatments. J Dermatolog Treat. 2018;29(6):542–52.

46. Lewkowicz N, Lewkowicz P, Banasik M, Kurnatowska A, Tchórzewski H. Predominance of type cytokines and decreased number of CD4(+)CD25(+ high) T regulatory cells in peripheral blood of patients with recurrent aphthous ulcerations. Immunol Lett. 2005;99(1):57–62.

47. Borra RC, Andrade PM, Silva ID, Morgun A, Weckx LL, Smirnova AS, et al. The Th1/Th2 immune-type response of the recurrent aphthous ulceration analyzed by cDNA microarray. J Oral Pathol Med. 2004;33(3):140–6.

48. Lewkowicz N, Kur B, Kurnatowska A, Tchorzewski H, Lewkowicz P. Expression of Th1/Th2/Th3/Th17-Related genes in recurrent aphthous ulcers. Arch Immunol Ther Exp. 2011;59(5):399–406.

49. Chaudhuri K, Nair KK, Ashok L. Salivary levels of TNF-α in patients with recurrent aphthous stomatitis: a cross-sectional study. J Dent Res Dent Clin Dent Prospects. 2018;12(1):45–8.

50. Surboyo MDC, Boedi RM, Hariyani N, Santosh ABR, Manuaba IBPP, Cecilia PH, et al. The expression of TNF-α in recurrent aphthous stomatitis: a systematic review and meta-analysis. Cytokine. 2022 sep;157:155946.

51. Lewkowicza N, Lewkowiczb P, Banasikb M, Kurnatowska A, Tchorzewski H. Predominance of type 1 cytokines and decreased number of CD4 + CD25 + high T regulatory cells in peripheral blood of patients with recurrent aphthous ulcerations. Immunol Lett. 2005;99(1):57–62.

52. Kim YS, Kim JS, Jung HC, Song IS. The effects of thalidomide on NF-kB activity and TNF-α production stimulated with lipopolysaccharide in a human colonic epithelial cell line. Mol Cells. 2004;17(2):210–6.

53. Noman AS, Koide N, Hassan F, I-E-Khuda I, Dagvadorj J, Tumurkhuu G, et al. Thalidomide inhibits lipopolysaccharide-induced tumor necrosis factor-α production via down-regulation of MyD88 expression. Innate Immun. 2009;15(1):33–41.

54. Moreira AL, Sampaio EP, Zmuidzinas A, Frindt P, Smith KA, Kaplan G. Thalidomide exerts its inhibitory action on tumor necrosis factor α by enhancing mRNA degradation. J Exp Med. 1993 jun;177(6):1675–80.

55. Brocklehurst P, Tickle M, Glenny AM, Lewis MA, Pemberton MN, Taylor J, et al. Systemic interventions for recurrent aphthous stomatitis (mouth ulcers). Cochrane Database Syst Rev. 2012 Sep;12(9):CD005411.

56. Lau CB, Smith GP. Recurrent aphthous stomatitis: a comprehensive review and recommendations on therapeutic options. Dermatol Ther. 2022;35(6):e15500.

57. Wei W, Deng YW, Wang YF, Yao H, Du GH, Tang GY. Dynamic salivary cytokine profile of recurrent aphthous stomatitis patients in thalidomide maintenance treatment. Clin Oral Investig. 2024;28(2):140.

Associated Data

Data Availability Statement

Data is provided within the manuscript or supplementary information files.