Evaluation of the efficacy of Tongdu Shujin Decoction combined with Adalimumab in the treatment of ankylosing spondylitis: A study protocol for a randomized controlled trial

doi:10.21203/rs.3.rs-3131455/v1

Download PDF

Study protocol

Evaluation of the efficacy of Tongdu Shujin Decoction combined with Adalimumab in the treatment of ankylosing spondylitis: A study protocol for a randomized controlled trial

https://doi.org/10.21203/rs.3.rs-3131455/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Introduction

Ankylosing spondylitis (AS) is a chronic inflammatory disease that typically affects the axial skeleton and entheses, and can lead to severe physical and psychological damage to patients. However, the current therapies have limitations.

Methods and analysis

Eighty-patients with AS will be recruited from the Rheumatology Department of the First Affiliated Hospital of the Henan University of Chinese Medicine. The participants will be randomly divided into the treatment and control groups at a 1:1 ratio. Subsequently, all subjects in the treatment group will receive 40 mg adalimumab administered subcutaneously every two weeks for 12 weeks, while patients in the control group will receive an extra dose of Tongdu Shujin Decoction (TDSJ) each day. The primary outcome will be determined by the change in the Ankylosing Spondylitis Disease Activity Score (ASDAS) from baseline to 12 weeks. The secondary outcomes include changes of serum inflammatory cytokines, interleukin-6 (IL-6), interleukin-17 (IL-17), Tumor necrosis factor alpha (TNF-α), changes of anxious depression-related scales, Hospital Anxiety and Depression Scale (HADS) and Patient Health Questionnaire-9 (PHQ-9) as well as changes of McGill Pain Questionnaire (MPQ) and Fatigue Severity Scale (FSS) in patients from baseline to 12 weeks.

Ethics and dissemination

The ethics committee of the First Affiliated Hospital of Henan University of Chinese Medicine has approved the study on April 27, 2023 (2023HL-116-02). The Chinese national authorities issued approval on 15 May 2023. The outcome of the study will be disseminated via peer-reviewed publications and at congresses.

Trial registration number

Chinese Clinical Trial Registry. ChiCTR2300071418. Registered on 15th May 2023. https://www.chictr.org.cn/showproj.html?proj=196506

Ankylosing spondylitis

Tongdu Shujin Decoction

Adalimumab

Anxious depression

Ankylosing Spondylitis Disease Activity Score

Ankylosing spondylitis (AS) is a common chronic inflammatory rheumatic disease that affects the axial skeleton, causing characteristic inflammatory back pain and stiffness, which can lead to structural and functional impairments, and decrease quality of life (1–4). Physical dysfunction in AS can potentiate serious health conditions and lead to fatigue, depression, anxiety, and decreased quality of life (5, 6). Epidemiological investigations showed that the prevalence of AS ranged from 9 to 30 per 10000 persons and varied widely by geographical region (7, 8). The mean prevalence of AS per 10,000 (from 36 eligible studies) was 23.8 in Europe, 16.7 in Asia, 31.9 in North America, 10.2 in Latin America and 7.4 in Africa (9). Besides, AS typically affects young people, presenting around 26 years of age. Men are more often affected than women (10–12). The pathogenesis of AS is poorly understood. However, the prevailing hypothesis is that immune-mediated mechanisms play a major role (13). Non-steroidal anti-inflammatory drugs (NSAIDs) effectively relieve inflammatory symptoms and are presently the first-line drug treatment for AS. However, NSAIDs only have a symptomatic effect and probably do not alter the disease course. For symptoms refractory to NSAIDs, second-line treatments, including corticosteroids and various disease-modifying anti-rheumatic drugs, are employed but offer limited benefit (3, 14). Therefore, it is necessary to search for alternative treatment methods for AS, such as a combination of Traditional Chinese Medicine (TCM).

AS can aggravate patients’ fear and anxiety related to worsening of the disease, and subsequently lead to depression (15). This may be related to the patient's disease activity. It was found that the disease activity was the most powerful predictor of fatigue and pain (15, 16). Other studies have shown depressed mood and higher anxiety scores in AS patients compared to healthy controls, and significantly higher scores for depressed mood and anxiety in patients with high Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores (17–19).

However, there is evidence to suggest that although fatigue and pain frequently occur together with depression and anxiety, fatigue or pain is neither sensitive nor specific to the diagnosis of anxious depression (20–24). Therefore, it is necessary to find specific and sensitive markers for the diagnosis of patients with AS complicated with anxious depression.

This high-quality prospective cohort study embedded in a single-blind randomized controlled trial is designed through a practical protocol. The purpose of this study is to verify the feasibility of integrating traditional Chinese and western medicine in the treatment of AS, and to explore the correlation between anxious depression and disease activity in patients with AS. Moreover, specific and sensitive markers of AS patients complicated with anxious depression will be identified.

Design and objective

A 12-week, single-center, randomized controlled trial is planned. The treatment group (TDSJ in combination with adalimumab intervention) and the control group (adalimumab intervention) will be compared to verify the feasibility of TDSJ combined with adalimumab in the treatment of AS, in order to explore the correlation between anxious depression and disease activity in patients with AS, and in order to find specific and sensitive markers of AS patients complicated with anxious depression. The trial will be conducted in the Rheumatology Department of the First Affiliated Hospital of Henan University of Chinese Medicine. All the participants will be required to provide written informed consent prior to entry into the trial. The study flow chart is shown in Fig. 1 following.

Study setting and recruitment

After obtaining informed consent, this study will include 80 AS patients. In addition to hospital websites and social media, posters and advertisements will be used to announce recruitment information. All participants who meet the inclusion criteria will be invited to visit the Rheumatology and Immunology Department of the First Affiliated Hospital of Henan University of Chinese Medicine for a baseline assessment. All eligible participants will be randomly allocated in 1:1 ratio between the control and intervention groups. The treatment duration will be 12 weeks.

Eligibility criteria

The diagnostic criteria will be in accordance with the revised New York AS diagnostic criteria of 1984 (25).

Clinical criteria: (1) Low back pain for at least three months, and the pain increased with activity, but did not decrease with rest; (2) The movement of the lumbar spine is restricted in the anteroposterior and lateral flexion directions; (3) the thoracic extension range is less than the normal value of the same age and gender.

Radiological criteria: Bilateral sacroiliitis ≥ grade II, or unilateral sacroiliitis grade III to IV.

AS is confirmed, if the patient has radiological criteria and any one of the clinical criteria is appended. Diagnosis of probable AS is achieved in those who meet only three clinical criteria, or only those who meet radiological criteria.

Inclusion criteria: (1) Meet the AS diagnostic criteria of 1984; (2) 18–40 years of age, male or female; (3) Participation in the study is voluntary, and all patients must sign informed consent forms. (4) The patient had not taken any drugs to treat AS one month prior to receiving this clinical research protocol.

Exclusion criteria: (1) Pregnant women, children, prisoners, and other vulnerable groups; (2) Patients with other serious illnesses that require treatment (such as blood diseases, tumors, etc.); (3) Patients with other rheumatic immune system diseases; (4) Patients with allergies to the study drug; (5) Patients with mental disorders and those who are unable to communicate with others.

Sample size calculation

Sample size calculations were performed with version 15 of the PASS software, with α = 0.05 (2-tailed test). The sample size was N₁ in the treatment group and N₂ in the control group. According to the current clinical efficacy statistics of TCM in the treatment of AS, the effective rate of the treatment group was P₁ = 78%, while the control group P₂ = 43%. Using the Z test, H₀: P₁-P₂ = 0. H₁: P₁–P₂ = D₁ ≠ 0, calculated using the approximate normal method, N₁ = N₂ = 36. Based on a loss rate of 10%, we plan to enroll 80 subjects.

Randomization and blinding

Random assignment concealment will be used in this study. Participants who meet the eligibility criteria and consent to participate will be randomly divided into the intervention and control groups at a 1:1 allocation ratio. We will use a computer-generated random number table to assign the numbers, and these numbers will be concealed in opaque envelopes. Zihua Wang and Wen Fu will perform the tasks such as assigning sequences, recruiting subjects, and intervening. Because of the nature of the study design, blinding of participants and physicians to the group assignment is not possible.

Interventions

In order to ensure the study quality, all personnel in this study have a rigorous work style and professional knowledge of rheumatology and clinical psychology and all participating staff will receive the same training before the study begins. The lead investigator will oversee the entire trial. Anti-rheumatic treatments and care beyond interventions will be prohibited during the trial.

Treatment group: Patients in this group will take oral TDSJ and subcutaneous injection of adalimumab. The composition of TDSJ is as follows (26): eucommia 20 g, rehmannia glutinosa 15 g, pyrola 15 g, paeoniae alba 15 g, achyranthes bidentata 20 g, ground beetle 10 g, ligusticum chuanxiong 20 g, angelica sinensis 15 g, safflower 10 g, clematis chinensis 20 g, angelicae pubescentis radix 10 g, corydalis yanhusuo 20 g, and licorice 6 g. The drug will be uniformly provided by the Chinese Pharmacy of the First Affiliated Hospital of Henan University of Chinese Medicine, decocted in water, 400 ml per dose, one dose per day, oral, for 12 weeks in the evening. At the same time, each patient will receive consecutive subcutaneous injections of 40 mg adalimumab every two weeks for 12 weeks. Adalimumab will be provided by Suzhou UNION Biopharm Biosciences Co., Ltd., SFDA approval number is S20220008, 40 mg per dose.

Control group: Patients in this group will receive subcutaneous injection of adalimumab. Each patient will receive consecutive subcutaneous injections of 40 mg adalimumab every two weeks for 12 weeks. Adalimumab will be provided by Suzhou UNION Biopharm Biosciences Co., Ltd., SFDA approval number is S20220008, 40 mg per dose.

Adherence and participant retention

To control the adherence of the participants to their drugs, drug record will be taken from the participants every 2 weeks. To accurately complete the questionnaires, all individuals will be given information on how to complete the questionnaire, units of measurement and a selection of appropriate days to complete the forms. Researchers will make phone calls to patients every 2 weeks to encourage them to continue what they are doing.

Criteria to stop or change assigned treatments based on certain standards

(1) Patients with aggravated ankylosing spondylitis; (2) Participants who experience intense emotional tension within the trial; (3) Pregnancy within the trial.

Data management and protection

The study will only involve a limited number of participants, so the data monitoring committee is not necessary. Moreover, data will be retained in local and cloud storage as well as SPSS programme (version 21). There will be no personal information about the participants in the information. Results will be presented as an overall total. Although efforts will be made to keep participants’ information confidential, sometimes patient information may be reviewed by the Ethics Committee of the First Affiliated Hospital of Henan University of Chinese Medicine for purposes such as safety or quality control.

Harms

Researchers will monitor and assess any adverse events that may be connected to the study intervention. The patients will receive ongoing observation. The Ethics Committee of the First Affiliated Hospital of Henan University of Chinese Medicine will be notified if any negative occurrences arise throughout the course of the study. The attending physician will oversee any such event, and the trial fund will pay for the expense.

Frequency and plans for auditing trial conduct

The sponsor may carry out a functional trial audit of the participating centres to verify that the provisions described in the study procedures are fully adhered to.

Study outcomes

Primary outcomes

The primary outcome will be Ankylosing Spondylitis Disease Activity Score (ASDAS), which will be tested at 0 and 12 weeks of treatment. Disease activity will be assessed by pain, swelling, morning stiffness, and erythrocyte sedimentation (ES) or C-reactive protein (CRP).

Secondary outcomes

IL-6, IL-17, TNF-α, HADS, PHQ-9, MPQ, and FSS will be secondary indicators, which will be tested at 0 and 12 weeks of treatment.

Safety outcomes

The safety outcomes will be determined by vital signs (respiration, heart rate, body temperature, blood pressure, electrocardiogram), blood routine, urine routine, stool routine, liver function, and renal function, which will be tested at 0, 4, 8 and 12 weeks of treatment. A patient who experiences an adverse event during the study will inform the study investigator immediately and receive prompt treatment. If there are serious adverse effects, the Ethics Committee of the First Affiliated Hospital of Henan University of Chinese Medicine will be notified and the protocol will be revised.

Participant timeline

Table 1 is used to demonstrate the schedule of enrolment, interventions, assessments, and visits for participants.

Table 1

Participant timeline.
Study period
	Enrolment	Allocation	Post-allocation
Timepoint	Before allocation	0	Week 2	Week 4	Week 6	Week 8	Week 10	Week 12
Enrolment:
Eligibility screen	×
Informed consent	×
Allocation		×
Interventions:
Treatment group: TDSJ combined with Adalimumab		×	×	×	×	×	×	×
Control group: Adalimumab		×	×	×	×	×	×	×
Assessments:
Primary outcomes: ASDAS, ES, and CRP		×						×
Secondary outcomes: IL-6, IL-17, TNF-α, HADS, PHQ-9, MPQ, and FSS		×						×
Safety outcomes: vital signs		×		×		×		×

Statistical assessment

In this study, SPSS 21.0 will be used to process and analyze the relevant information and data. Statistical data meeting normal distribution will be expressed as mean ± standard deviation (x ± s), and non-normal distribution measurement data will be expressed as P50 (P25-P75). When variances are equal and the data are normally distributed, Tukey's multiple comparison test will be used for multiple comparisons across groups. A nonparametric test will be used if the data are not normal. The counting data by rate will be analyzed with the χ2 test. The correlation will be determined through univariate linear regression analysis. A 2-tailed test will be used, and P < 0.05 will denote a statistically significant difference.

The major causative factors of AS are genetic, and the gene encoding HLA-B27 is the most important genetic factor (27, 28). Current treatment recommendations for the management of AS recommend non-pharmacological management along with non-steroidal anti-inflammatory drugs (NSAIDs) as the first-line treatment (3, 29, 30). However, NSAIDs treatment is not always well tolerated and can be insufficient to control symptoms. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), such as methotrexate and sulfasalazine, are typically ineffective for the treatment of axial symptoms (31), although they might have a limited role for the treatment of peripheral symptoms that coexist with axial disease. Treatment with tumor necrosis factor (TNF) inhibitors is recommended for patients who have persistent disease activity despite conventional treatment. However, approximately 40% of patients do not achieve adequate disease control and some patients might be intolerant to TNF inhibitors (32). Hence, effective treatments for AS are being explored, and traditional Chinese medicine combined with Western medicine may be a good treatment.

Previous studies have indicated that anxious depression in patients with AS may be related to the disease activity (15, 16). This provides a new thinking for the subsequent treatment of depression and anxiety in patients with AS.

Previous studies have shown that although fatigue and pain frequently occur together with anxiety and depression (20–24), fatigue or pain is neither sensitive nor specific to the diagnosis of patients who suffer from AS with anxious depression. Therefore, it is necessary to find specific and sensitive markers for the diagnosis of patients with AS complicated with anxious depression.

The purpose of this study is to verify the feasibility of integrating traditional Chinese and western medicine in the treatment of AS in order to provide a better plan for the treatment of AS, and to explore the correlation between anxious depression and disease activity in patients with AS, in order to provide new ideas for further treatment. Moreover, specific and sensitive markers of AS patients complicated with anxious depression will be identified to provide a new basis for the diagnosis of these patients.

Despite the measures taken to ensure a well-controlled trial, there are several methodological limitations to this prospective cohort study. The treatment intervention duration of three months might make it difficult to ensure patient compliance. In some self-evaluation forms and other evaluation forms, the subjective feelings of patients and doctors may bias the results. In spite of these limitations, we hope that the trial will provide new insights into the value of integrating traditional Chinese and western medicine in the treatment of AS, explore the correlation between anxious depression and disease activity in patients with AS, and find specific and sensitive markers for the diagnosis of patients with AS complicated with anxious depression.

AS	Ankylosing spondylitis
TDSJ	Tongdu Shujin Decoction
ASDAS	Ankylosing Spondylitis Disease Activity Score
BASDAI	Bath Ankylosing Spondylitis Disease Activity Index
IL-6	Interleukin-6
IL-17	Interleukin-17
TNF	Tumor necrosis factor
HADS	Hospital Anxiety and Depression Scale
PHQ-9	Patient Health Questionnaire-9
MPQ	McGill Pain Questionnaire
FSS	Fatigue Severity Scale
NSAIDs	Non-steroidal anti-inflammatory drugs
TCM	Traditional Chinese Medicine
csDMARDs	Conventional synthetic disease-modifying anti-rheumatic drugs
ES	Erythrocyte sedimentation
CRP	C-reactive protein

TRIAL STATUS

Recruiting will start in June 2023. The current protocol is version 1 of 26-04-2023. Patient recruitment will be estimated to be completed around December 2023.

Ethics approval and consent to participate

The investigation has been registered in the Chinese Clinical Trial Registry (ChiCTR2300071418). Before participants give written, informed consent, they will receive the necessary information about the trial. Participants will be informed that they can withdraw from the research at any time. All collected information will be coded and kept in separate, secure locations. There is no psychological or physical harm associated with the trial. The findings of this study will be published in national and international conferences and scientific journals. The ethics committee of the First Affiliated Hospital of Henan University of Chinese Medicine has approved the experiment on April 27, 2023 (2023HL-116-02). Informed consent will be obtained from all participants involved in the study. All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable

Availability of data and materials

A trained rheumatologists will keep the information in external storage and cloud storage. A statistician will analyse the data. Throughout the trial, data will not be accessible to researchers. There is no arrangement to restrict access for researchers.

Competing interests

None declared.

Funding

This work is funded by Special Project of Scientific Research on Traditional Chinese Medicine in Henan Province (grant number 2022 JDZX047, 2022JDZX105, and 2019JDZX2091).

Authors’ contributions

Guanghua Liu conceived the trial, contributed to acquiring ethical approval for the trial and wrote the final manuscript. Zihua Wang and Wen Fu significantly contributed to development of the study protocol. Dongliang Shi and Zihua Wang contributed to collection, analysis and interpretation of data. Wen Fu and Bowen Ren contributed to the statistical analysis. All authors reviewed and contributed to the final manuscript.

Acknowledgements

We would like to thank all staff involved for their support and cooperation.

Authors’ affiliations

Guanghua Liu, Henan University of Traditional Chinese Medicine, Zhengzhou, China.

Zihua Wang, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.

Wen Fu, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.

Bowen Ren, Henan Provincial Hospital of Traditional Chinese Medicine, No.6 Dong-feng Road, Zhengzhou, China.

Dongliang Shi, Henan Provincial Hospital of Traditional Chinese Medicine, Zhengzhou, China.

Corresponding author

Dongliang Shi, Henan Provincial Hospital of Traditional Chinese Medicine, No.6 Dong-feng Road, Zhengzhou, China (email: [email protected]).

Name and contact information for the trial sponsor

Dongliang Shi, Henan Provincial Hospital of Traditional Chinese Medicine, No.6 Dong-feng Road, Zhengzhou, China (email: [email protected]).

Role of sponsor

Dongliang Shi contributed to collection, analysis and interpretation of data.

Patient and public involvement

Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

van der Heijde D, Braun J, Deodhar A, et al. Modified stoke ankylosing spondylitis spinal score as an outcome measure to assess the impact of treatment on structural progression in ankylosing spondylitis. Rheumatology (Oxford). 2019;58(3):388–400. https://doi.org/10.1093/rheumatology/key128.
Taurog JD, Chhabra A, Colbert RA. Ankylosing Spondylitis and Axial Spondyloarthritis. N Engl J Med. 2016;374(26):2563–74. .https://doi.org/10.1056/NEJMra1406182.
Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis: an overview. Ann Rheum Dis. 2002;61(Suppl 3):iii8–18. https://doi.org/10.1136/ard.61.suppl_3.iii8.
Braun J, Sieper J. Ankylosing spondylitis. Lancet. 2007;369(9570):1379–90. .https://doi.org/10.1016/s0140-6736(07)60635-7.
Kwan YH, Fong W, How P, et al. The impact of axial spondyloarthritis on quality of life (QoL): a comparison with the impact of moderate to end-stage chronic kidney disease on QoL. Qual Life Res. 2018;27(9):2321–7. .https://doi.org/10.1007/s11136-018-1900-x.
Ramonda R, Marchesoni A, Carletto A, et al. Patient-reported impact of spondyloarthritis on work disability and working life: the ATLANTIS survey. Arthritis Res Ther. 2016;18:78. https://doi.org/10.1186/s13075-016-0977-2.
Wang R, Ward MM. Epidemiology of axial spondyloarthritis: an update. Curr Opin Rheumatol. 2018;30(2):137–43. https://doi.org/10.1097/bor.0000000000000475.
Ward MM, Deodhar A, Gensler LS, et al. 2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis Care Res (Hoboken). 2019;71(10):1285–99. .https://doi.org/10.1002/acr.24025.
Davis CM, Beck DC. Axial Spondyloarthritis: Recognition, Diagnosis, and Classification. JBJS J Orthop Physician Assistants. 2021;9(4):e21.
Rosenbaum JT, Pisenti L, Park Y, et al. Insight into the quality of life of patients with ankylosing spondylitis: real-world data from a US-based life impact survey. Rheumatol therapy. 2019;6(3):353–67.
Elolemy G, Aboughanima A, Ganeb S, et al. Health-Related Quality of Life in Patients with Ankylosing Spondylitis: Relationship with Disease-Related Variables. Curr Rheumatol Rev. 2020;16(4):311–8. .https://doi.org/10.2174/1573397115666191018162606.
Bittar M, Yong WC, Magrey M, et al. Worldwide Differences in Clinical Phenotype of Axial Spondyloarthritis. Curr Rheumatol Rep. 2021;23(10):76. https://doi.org/10.1007/s11926-021-01043-5.
Visha M, Brundha MP. A review on ankylosing spondylitis. Int J Clinicopathological Correlation. 2019;3:44–9.
Schett G, Landewé R, van der Heijde D. Tumour necrosis factor blockers and structural remodelling in ankylosing spondylitis: what is reality and what is fiction? Ann Rheum Dis. 2007;66(6):709–11. https://doi.org/10.1136/ard.2007.071159.
Lim JM, Cho OH. Effects of Home-and-Workplace Combined Exercise for Patients with Ankylosing Spondylitis. Asian Nurs Res (Korean Soc Nurs Sci). 2021;15(3):181–8. .https://doi.org/10.1016/j.anr.2021.03.001.
Tönük ŞB, Arısoy Ö, Öztürk EA, et al. Temperament and Character Profiles of Ankylosing Spondylitis Patients Compared With Major Depression Patients and Healthy Controls. J Clin Rheumatol. 2021;27(8):e425–e31. https://doi.org/10.1097/rhu.0000000000001510.
Harth M, Nielson WR. Pain and affective distress in arthritis: relationship to immunity and inflammation. Expert Rev Clin Immunol. 2019;15(5):541–52. https://doi.org/10.1080/1744666x.2019.1573675.
Ulus Y, Akyol Y, Bilgici A, et al. Association of work instability with fatigue and emotional status in patients with ankylosing spondylitis: comparison with healthy controls. Clin Rheumatol. 2019;38(4):1017–24. .https://doi.org/10.1007/s10067-018-4366-x.
Jiang Y, Yang M, Lv Q, et al. Prevalence of psychological disorders, sleep disturbance and stressful life events and their relationships with disease parameters in Chinese patients with ankylosing spondylitis. Clin Rheumatol. 2018;37(2):407–14. https://doi.org/10.1007/s10067-017-3907-z.
Bair MJ, Krebs EE, Fibromyalgia. Ann Intern Med. 2020;172(5):Itc33. -itc48.https://doi.org/10.7326/aitc202003030.
Sturgeon JA, Finan PH, Zautra AJ. Affective disturbance in rheumatoid arthritis: psychological and disease-related pathways. Nat Rev Rheumatol. 2016;12(9):532–42. https://doi.org/10.1038/nrrheum.2016.112.
Sarzi-Puttini P, Giorgi V, Marotto D, et al. Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment. Nat Rev Rheumatol. 2020;16(11):645–60. https://doi.org/10.1038/s41584-020-00506-w.
Newland P, Bettencourt BA. Effectiveness of mindfulness-based art therapy for symptoms of anxiety, depression, and fatigue: A systematic review and meta-analysis. Complement Ther Clin Pract. 2020;41:101246. https://doi.org/10.1016/j.ctcp.2020.101246.
Renna ME, Shrout MR, Madison AA, et al. Depression and anxiety in colorectal cancer patients: Ties to pain, fatigue, and inflammation. Psychooncology. 2022;31(9):1536–44. .https://doi.org/10.1002/pon.5986.
van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum. 1984;27(4):361–8. .https://doi.org/10.1002/art.1780270401.
Wang Z, Du M, Li J, et al. Clinical study of Tongdu Shujin decoction in the treatment of ankylosing spondylitis with cold-dampness obstruction type: Study protocol for a randomized controlled trial. Med (Baltim). 2023;102(6):e32852. https://doi.org/10.1097/md.0000000000032852.
Fiorillo MT, Haroon N, Ciccia F, et al. Editorial: Ankylosing Spondylitis and Related Immune-Mediated Disorders. Front Immunol. 2019;10:1232. https://doi.org/10.3389/fimmu.2019.01232.
Liu CH, Raj S, Chen CH, et al. HLA-B27-mediated activation of TNAP phosphatase promotes pathogenic syndesmophyte formation in ankylosing spondylitis. J Clin Invest. 2019;129(12):5357–73. https://doi.org/10.1172/jci125212.
Ramiro S, Nikiphorou E, Sepriano A, et al. ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update. Ann Rheum Dis. 2023;82(1):19–34. https://doi.org/10.1136/ard-2022-223296.
Tam LS, Wei JC, Aggarwal A, et al. 2018 APLAR axial spondyloarthritis treatment recommendations. Int J Rheum Dis. 2019;22(3):340–56. https://doi.org/10.1111/1756-185x.13510.
Pinto AS, Farisogullari B, Machado PM. Predictors of remission in people with axial spondyloarthritis: A systematic literature review. Semin Arthritis Rheum. 2022;56:152078. https://doi.org/10.1016/j.semarthrit.2022.152078.
Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis: Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol. 2019;71(4):599–611. https://doi.org/10.1002/art.40753.

No competing interests reported.

SPIRITFillablechecklist15Aug2013.doc

Download PDF

Version 1

posted

You are reading this latest preprint version

Evaluation of the efficacy of Tongdu Shujin Decoction combined with Adalimumab in the treatment of ankylosing spondylitis: A study protocol for a randomized controlled trial

Status:

Version 1

Abstract

Figures

Introduction

Methods and analysis

Design and objective

Study setting and recruitment

Eligibility criteria

Sample size calculation

Randomization and blinding

Interventions

Adherence and participant retention

Criteria to stop or change assigned treatments based on certain standards

Data management and protection

Harms

Frequency and plans for auditing trial conduct

Study outcomes

Participant timeline

Statistical assessment

Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1