Efficacy And Safety of Wenbu Zhibi Granule In Patients With Ankylosing Spondylitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

doi:10.21203/rs.3.rs-695199/v1

Background: Ankylosing spondylitis (AS) is a chronic disease in which the column is the main lesion. It is caused by a combination of genetic and environmental factors, mainly involving the axial skeleton, resulting in column rigidity and difficulty in movement, and there may be different degrees of eye, lung, cardiovascular, kidney and other organ damage. Long term treatment lacks in ankylosing spondylitis. Wenbu Zhibi granule (WZG) is a prescription handed down from the history of Chinese medicine for thousands of years, which is used to treat the pain of patients with AS and to prevent the further development of the disease. However, there is no scientific evidence based on clinical trial to evaluate the efficacy and safety of WZG for ankylosing spondylitis.

Methods/design: We will conduct a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of WZG in the treatment of AS. We will randomly assign 100 patients with active AS to two groups, treated for 16 weeks. The primary efficacy endpoint is the proportion of subjects who reached ASAS40 at 16 weeks from baseline, the secondary efficacy endpoint includes ASAS20 response rate, ASAS partial remission response rate, ASAS5/6 response rate, and change in Spondyloarthritis Research Consortium of Canada (SPARCC) MRI spine score, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS), linear Bath Ankylosing Spondylitis Metrology Index (BASMI), ankylosing spondylitis quality of life (ASQoL). In addition, the time points will be set as baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 24 weeks and 48 weeks.

Discussion: The results of this study will elucidate the efficacy and safety of WZG and provide an appropriate treatment option for patients with AS.

Trial registration: ClinicalTrials.gov ID: ChiCTR2000041010. (Chinese Clinical Trail Registry, Registered 16 December 2020, http://www.chictr.org.cn)

Orthopedics

Surgery

ankylosing spondylitis

traditional chinese medicine

Wenbu Zhibi granule

multicenter

randomized controlled trial

Ankylosing spondylitis (AS) is a chronic progressive inflammatory rheumatism which is usually present in early adulthood and strongly associated with the HLA-B27 gene with a prevalence of about 1.4%.^[1] AS, otherwise known as radiographic axial spondyloarthritis, is a type of spondylitis, which also includes psoriatic arthritis, arthritis associated with inflammatory bowel disease, and reactive arthritis.^[2] Each of these spondylitis is progressive and can develop into a typical ankylosing spondylitis. AS, characterized by chronic back pain and stiffness of the pelvis and lower back, mainly affects the axial skeleton such as the column and sacroiliac joint.^[3] Extra-articular manifestations in AS include acute uveitis, peripheral arthritis, enthesitis (inflammation of where tendons insert on bones), psoriasis, aortic root, and gut inflammation.^[4] AS is a hidden onset and long course of disease. With the development of the disease, it eventually caused joint fibrosis, ankylosis, loss of joint function and a high rate of disability.^[5]

According to the existing international management recommendations,^[6,7] long-term drug and non-drug therapy is recommended to control the disease. The main drug treatment are non-steroidal anti-inflammatory drugs (NSAIDs), anti-rheumatic drugs (DMARDs) and biological DMARDs (TNF α blocker or IL-17 blocker). Some studies have shown that long-term use of NSAIDS does not lead to substantial improvement in the treatment of the disease, but also increases the risk of gastrointestinal and cardiovascular diseases.^[8] DMARDs such as methotrexate, sulfasalazine are just limited to the improvement of muscle stiffness and discomfort, but it can not avoid the occurrence and progression of AS.^[2] Poddubnyy et al found that long-term use of TNF α slowed the radiographic progress of patients with AS, but the effectiveness was limited to remission rather than radical cure.^[9] Whether IL-17 blockade might reduce the progression of new bone formation is unknown,^[10] and up to 40% of patients do not respond to them.^[11,12] Therefore, on the basis of reducing inflammation, it is important to look for alternative therapies to relieve symptoms and improve the quality of life of the patients with AS. As a complementary and alternative medicine, some traditional Chinese medicine such as WZG may have the potential to relieve AS symptoms and reduce disease activity.^[13]

Participants:

This study will enroll patients who are signed up by website, poster and telephone from 3 hospitals (Zhejiang Provincial Hospital of Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Zhongshan Hospital of Zhejiang Province and the Affiliated JiangNan Hospital of Zhejiang Chinese Medical University orthopedics). All the participants who sign the informed consent form will be divided into test group and control group according to random number method, and will be followed up for 48 weeks.

Inclusion and exclusion criteria:

Participants meeting the following requirement will be included and excluded, shown in Table 1.

Table 1: Screening Criteria of Participants

Inclusion criteria			Exclusion criteria
Diagnosed with AS according to the revised New York standards^[14];			Total spinal ankylosis;
Having active disease indicated by BASDAI score ≥4;			Other rheumatic diseases such as SLE, RA;
Older than 18 and the age of first onset was less than 45;			Other serious diseases of vital organs;
Consenting to the use of effective contraception during the trial period;			Pregnancy or lactation;
Voluntary participating in this study, adopting by the ethics committee,			Cancer, cognitive or mental disorders;
ensuring the test compliance and signing the informed consent.			Suspected or confirmed history of alcohol abuse;
			Infection and severe allergic reactions;
			Active systemic infection within 2 weeks before the baseline visit;
			Abnormal laboratory indexes of liver and kidney function.

AS: ankylosing spondylitis; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; SLE: systemic lupus erythematosus; RA: rheumatoid arthritis

Study design

This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled clinical trial (Fig. 1), which is being conducted at 3 centers in Zhejiang, China: Zhejiang Provincial Hospital of Traditional Chinese Medicine, Department of Obstetrics and Gynecology, Zhongshan Hospital of Zhejiang Province and Affiliated JiangNan Hospital of Zhejiang Chinese Medical University orthopedics to evaluate the efficacy and safety of WZG in the treatment of AS.

Sample size calculation

According to our primary study of WZG from January 2020 to August 2020, the response rate of ASAS40 was 84.5% in the WZG group and 54.4% in the WZG placebo group. We plan to provide at least 90% power and a (two-sided) 5% significance level for detecting treatment differences.^[15] When an assignment ratio of the groups of 1:1 are applied, according to the formula of sample size calculation:N₁ = N₂ = (N₁, N₂ are the size of each group; p₁ is the ASAS40 response rate of WZG group and p₂ is the rate of WZG placebo group, p ̅ is the mean of p₁ and p2; u_α/2=1.96 when type I error is 0.05; u_β=1.282 when type II error is 0.1 in two-sided tests), accounting for a dropout rate of 10%, at least 50 subjects per group are required, for total of 100 subjects.

Randomization and masking

The random assignment codes will be generated on the computer by the statistical professionals using SAS software, and the project team will assign a special person independent of this study to keep the group information confidential. According to the randomized sequence, a random distribution sheet with two copies shall be made and bound into a book in order to make a random distribution book with cover and instructions. One of the couplet on the top is to collect the enroll information and the other is to show the allocation information. The serial numbers of the couplet which around sealant are the same, and leave blank at the same areas of the couplet for signing the enter information. The content of the top couplet can be completely copied to the bottom one. In order to avoid exposing the allocation information in advance, the back of the bottom couplet should be black-printed. When the subjects are sure qualified, the researchers selected the corresponding couplet in a sequential order. Exposing the allocation information in the bottom couplet, and the subjects will be allocated to the group designated on the bottom couplet. This random allocation book will be printed by professional printing service. All the investigators except the special person will not know the corresponding relations between sequence numbers and different groups until the trials completed.

Blinding

None of the researchers will contact the special person or the pharmaceutical company or the printing service in this trial. The staff of the pharmaceutical factory and printing service will not be involved in other parts of the study. The special person will be separated from all researchers. Therefore, participants, doctors, nurses, researchers and statisticians (analyzing data) have no access to the study information and will not know the relationship between the numbers and groups until the end of this trial.

Medication

WZG will be produced, packaged and marked by the factory in Zhejiang Province. Table 2 lists the components of WZG.

Table 2

Components of Wenbu Zhibi granule.
Chinese name	Latin name	Proportion
Du Huo	radix angelicae pubescentis	9kg
Sang Jisheng	radix loranthi seu visci	6kg
Du Zhong	cortex eucommiae ulmoidis	6kg
Niu Xi	radix achyranthis bidentatae	6kg
Xi Xin	herba asari cum radice	3kg
Qin Jiao	radix gentianae macrophyllae	6kg
Fu Lin	sclerotium poriae cocos	6kg
Rou Guixin	radix cinnamomi cassiae	6kg
Fang Feng	radix ledebouriellae divaricatae	6kg
Chuan Xiong	radix ligustici wallichii	6kg
Ren Shen	radix panacis ginseng	6kg
Gan Cao	radix glycyrrhizae	6kg
Dang Gui	radix angelicae sinensis	6kg
Shao Yao	radix dioscoreae oppositae	6kg
Sheng Dihuang	radix rehmanniae	6kg
Ma Huang	herba ephedrae	9kg
Huang Qi	radix astragali	9kg
Chuan Wu	radix aconiti kusnezoffii	6kg

WZG is prepared as follows :

Extraction: The herbs are placed in a ceramic pot, then pour 1,000 litres of distilled water into the pot to soak the materials for 1 hour, then boil it at 100°C for 1 hour for the first extraction; Pour the liquid extract into another pot, and add 1000 litres of distilled water and boil it at 100°C for 1 hour to extract it again; And then repeat it for the third extraction.
Concentration: Mix the liquid we collected and concentrate it at 60°c (660 mmHg) with a 1:1.30 concentration ratio (80°C). Then spray-dry it into powders before crushed and sieved through a mesh size of 80.
Packing: Finally, the granules are packed (5g per bag) and stored in a clean and dry room. WZG placebo is consisted of WZG extract (10%) and bitters (90%). Some food additive will be added to make the taste, color, smell and shape of placebo similar to WZG.

Allocation and Intervention

All patients are randomly divided into WZG group (experimental group) and placebo group (control group). Patients either take oral WZG 5g (one pack, dissolved in 200mg of hot water) twice a day or matching placebo for a 16-week period;

Two groups of supportive therapy: One type of NSAIDs, DMARDs or biological DMARDs can be used during the observation period, such as methotrexate. In addition, patients should provide a detail list of medications usage during the trial.

Study visits occurred at baseline and at weeks 2, 4, 8, 12, 16, 24 and 48. The schedule of this trial is shown in Table 3.

Table 3

Schedule of the measures.
Measure Time point Study period	Per-treatment period		Treatment period					Follow-up period
Measure Time point Study period	−2 Week	Week 0	Week 2	Week 4	Week 8	Week 12	Week 16	Week 24	Week 48
ENROLLMENT:
Inclusion criteria	√
Exclusion criteria	√
Informed consent	√
Allocation		√
INTERVENTIONS:
WZG		√
WZG placebo		√
ASSESSMENTS:
ASAS40		√	√	√	√	√	√	√	√
BASDAI	√	√	√	√	√	√	√	√	√
ASAS20		√	√	√	√	√	√	√	√
ASAS5/6		√	√	√	√	√	√	√	√
ASAS partial remission		√	√	√	√	√	√	√	√
SPARCC MRI spine score		√	√	√	√	√	√	√	√
BASFI		√	√	√	√	√	√	√	√
BASMI		√	√	√	√	√	√	√	√
ASDAS		√	√	√	√	√	√	√	√
ASQoL		√	√	√	√	√	√	√	√
ESR, CRP		√	√	√	√	√	√	√	√
Vital signs	√	√	√	√	√	√	√	√	√
Blood, urine, feces routine		√					√
Liver and kidney function	√	√					√
Compliance assessments			√	√	√	√	√	√	√
AE		√
WZG: Wenbu Zhibi granule; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; SPARCC: Spondyloarthritis Research Consortium of Canada; BASFI: Bath Ankylosing Spondylitis Functional Index; BASMI: Bath Ankylosing Spondylitis Metrology Index; ASDAS: Ankylosing Spondylitis Disease Activity Score; ASQoL: ankylosing spondylitis quality of life; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; AE: adverse events.

Patient and Public Involvement

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

Outcome measures

Primary measurement

The main outcome measure is the Assessment in SpondyloArthritis international Society 40% (ASAS40) response in patients. The ASAS40 response has been used as a primary endpoint in clinical trials of patients with AS.^[16] The ASAS40 response criteria is at least 40% improvement and an absolute improvement of at least two units on a numerical rating scale of 0–10 from baseline in at least three of the following four domains, with no worsening in the remaining domain: Patient global assessment of disease activity;Patient assessment of back pain;Bath Ankylosing Spondylitis Functional Index (BASFI);Inflammation: the mean of the BASDAI questions on severity and duration of morning stiffness.

Similarly, ASAS20 response (at least 20% improvement and and at least 1 unit of absolute change, with no worsening of a similar amount in the fourth domain), ASAS5/6 (at least 20% improvement in 5 of 6 domains—the same 4 domains as the ASAS40 response criteria plus 2 extra domains, acute-phase reactants and spinal mobility) and ASAS partial remission (Assessment of low disease activity state and remission, a value of < 2 on a 0–10 scale in each of the 4 ASAS40 domains) are also validated measure to assess signs and symptoms, but the advantage of the ASAS40 response criteria set is simplicity: it is based on the same domains as those for the ASAS20 response criteria with no qualitative distinction.^[17]

Secondary measurements

The secondary endpoint includes the proportion of patients who achieve the ASAS20, ASAS5/6, ASAS partial remission and change from baseline to weeks 2, 4, 8, 12, 16, 24 and 48 in following outcomes: Spondyloarthritis Research Consortium of Canada (SPARCC) MRI spine score, Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath Ankylosing Spondylitis Metrology Index (BASMI) and Ankylosing Spondylitis Quality of Life (ASQoL). Unlike ASAS40, the secondary measurements may be used to monitor the actual level of disease activity, to define a state of remission or low disease activity and to measure response to treatment.^[18]

SPARCC MRI spine score: Within clinical trials, MRI is often repeated over short periods to test the efficacy of treatment. Spondyloarthritis Research Consortium of Canada (SPARCC) MRI spine score, the assessment of structural damage, is frequently used because it is a feasible, reproducible, and responsive method for measuring spinal inflammation on a continuous scale with good sensitivity to change.^[19–21]

BASFI: Bath Ankylosing Spondylitis Functional Index (BASFI) is used to define and monitor physical functioning in patients with AS. It is composed of 8 items concerning activities referring to the functional anatomy (bending, reaching, changing position, standing, turning, and climbing steps) and 2 items assessing the patients' ability to cope with everyday life with a response scale (0–10) or visual analog scale (0–10 cm) anchored by “easy” and “impossible.”^[22]

BASDAI: Historically, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) has been the most widely used and comprehensive self-administered measure of disease activity in AS. BASDAI is user friendly, reliability, sensitive to change and reflects the entire spectrum of disease.^[23] It is a combined disease activity score, ranging from 0 (no disease activity) to 10 (maximal disease activity), including patient-reported levels of back pain, fatigue, peripheral joint pain and swelling, localized tenderness, and the duration and severity of morning stiffness. A cut off of 4 is used to define active disease.^[24]

ASDAS: The Ankylosing Spondylitis Disease Activity Score (ASDAS) has been used to assess treatment outcomes in clinical trials and to monitor disease activity in patients with AS.^[25] Different to BASDAI, ASDAS is a composite disease activity instrument which incorporates both objective inflammatory markers such as C reactive protein (CRP), erythrocyte sedimentation rate (ESR) and patient-oriented measures (back pain, duration of morning stiffness, patient global assessment and peripheral joint pain).^[26] Its response option is continuous scale from zero with no defined upper end determined by the level of the CRP or ESR.

BASMI: Bath Ankylosing Spondylitis Metrology Index (BASMI) can quantify the mobility of the axial skeleton in AS patients and allow objective assessment of clinically significant changes in spinal movement. It contains clinical measures of cervical rotation, tragus to wall distance, lumbar flexion, lumbar side flexion, and intermalleolar distance with a score from 0–10 based on individually defined cut points. Ranges are given as cervical rotation (> 85.0° to ≤ 8.5°), tragus to wall (< 10 cm to ≥ 38 cm), lumbar flexion (> 7.0 cm to ≤ 0.7 cm), lumbar side flexion (> 20.0 cm to < 1.2 cm), and intermalleolar distance (≥ 120 cm to < 30 cm).^[27]

ASQoL: Ankylosing Spondylitis Quality of Life Scale (ASQoL) is used to measure the impact of AS on health-related quality of life from the patient's perspective. The questionnaire includes items related to the impact of disease on sleep, mood, motivation, coping, activities of daily living, independence, relationships, and social life with 0 scored for a “no” and 1 scored for a “yes” for each item. Total score is the sum of the individual responses. Score range is 0–18, with higher scores reflecting greater impairment of health‐related quality of life.^[28]

Safety assessments

All patients receiving treatment will be evaluated for safety of the treatment. The vital signs (body temperature, pulse, respiration, heart rate and blood pressure) of the patients will be collected at each visit. Data for adverse events (AE) defined as began or worsened in severity after the first dose of treatment through 30 days after the last dose will be recorded during the research. Laboratory tests will be conducted at baseline and week-16, including blood routine, urine routine, feces routine, liver function and kidney function including the levels of HGB, PLT, AST, ALT, BUN and CRE.

Statistical analysis

SPSS22.0 statistical software will be used for statistical analysis. The continuous variables will be expressed as mean ± standard deviation and the categorical data will be presented as percentage using chi-square test or Fisher’s exact test. T test and non-parametric tests will be used to compare the differences between groups, and repeated measures analysis of variance will be used to analyse the data in different time points. All hypothesis tests will use two-sided test, and P < 0.05 is statistically significant.

Data collection and management

All the data will be collected and all sensitive information will be preserved in the Affiliated JiangNan Hospital of Zhejiang Chinese Medical University orthopedics. Two independent investigators will compare and double-check the data to rule out the difference based on the source documents of this trial.

Quality control

In order to maintain the quality of this trial, the Affiliated JiangNan Hospital of Zhejiang Chinese Medical University orthopedics will monitor the study documents and procedure and be responsible for quality control.

Ankylosing spondylitis (AS) otherwise known as radiographic axial spondyloarthritis as the lesions of the sacroiliac joint or column could observed in the radiographic image.^[2] AS is characterized by inflammation with an excess spinal bone formation on the axial skeleton which could results in progressive and irreversible structural damage of bones,^[29,30] and therefore cause stiffness, pain, and reduced functions among patients.^[5,31] The main objectives of AS treatment are maximizing long-term healthy quality of life by controlling symptoms and inflammation, preventing progressive structural damage, and maintaining or normalizing functional and social participation.^[32,33] Treatment with NSAIDs alone is often insufficient to control the disease. AS/EULAR does not recommend DMARDs for axial arthropathy because the evidence of its ability to alter the natural course and imaging progression of AS is insufficient.^[1,2,34] Due to the immune system suppressed, infection is a major complication in patients with AS using some current biological DMARDs.^[7,35−38] Facing the difficult problem of treating AS, it is a great clinical significance to find new drugs for treating AS, and it may bring good news to the patients with AS.

Treatment of traditional Chinese medicine in AS has accumulated rich experience in clinical. WZG is a granule-shaped herbal medicine combined with two classical prescriptions: Duhuo Jisheng granule and Wutou granule. Duhuo Jisheng granule could nourish Xiajiao to prevent the further development of the disease and Wutou granule could nourish Zhongjiao to alleviate the pain of patients with AS. Both of those two granules are used as conventional prescriptions for thousands of years to treat patients with AS. Its effectiveness has already been experienced, but there is no clear and convincing evidence to be scientifically confirmed. Therefore, we design this randomized, double-blind, placebo-controlled clinical study, on the basis of our initial trial, to scientifically prove the traditional prescription’s effectiveness and safety. In addition, the results of this study will elucidate the efficacy and safety of WZG and provide an appropriate treatment option for patients with AS.

Trial status

The trial is expected to begin in 1st May 2021, and we will complete the recruitment in 1st May 2022.

AS: ankylosing spondylitis; WZG: Wenbu Zhibi granule; ASAS: Assessment of SpondyloArthritis International Society; SPARCC: Spondyloarthritis Research Consortium of Canada; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; ASDAS: Ankylosing Spondylitis Disease Activity Score; BASMI: Bath Ankylosing Spondylitis Metrology Index; Asqol: ankylosing spondylitis quality of life; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; NSAIDs: Non-steroidal anti-inflammatory drugs; DMARDs: Disease-modifying anti-rheumatic drugs; TNF: tumor necrosis factor; IL-17: interleukin-17; SLE: systemic lupus erythematosus; RA: rheumatoid arthritis; HGB: hemoglobin; PLT: platelet; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BUN: blood urea nitrogen; CRE: serum creatinine.

Author contributions

All authors have read and approved the final manuscript. All authors will participate in performing the trial. Helou Zhang designed this protocol and drafted the manuscript. Helou Zhang, Weibin Du, Yang Yu, Yijiang Wu, Yang Gao, Huateng Zhou, Fengqing Wu, Yang Zheng, Lincong Ren, Weifan Ren, Renfu Quan proposed the methodology. Renfu Quan revised the manuscript for important content critically and will supervise the clinical trial. YJW, YG, HTZ, FQW, YZ, LCR, WFR are responsible for recruiting the participants.

Footnotes

Funding: This work was supported by the National Natural Science Foundation (81904053 to WBD), Medical and Health Science and Technology Project of Zhejiang Province (2020KY797 to WBD), Science and Technology Project of Traditional Chinese Medicine of Zhejiang Province (2020ZA094 to RFQ).

Ethical issues: The trial, which will be conducted in accordance with the Declaration of Helsinki and Ethical Guidelines for Clinical Research, has been approved by the Research Ethical Committee of Zhejiang Provincial Hospital of Traditional Chinese Medicine (approval Number: 2020LCSY038), Zhongshan Hospital of Zhejiang Province (approval Number: 2020ZZ1115) and the Affiliated JiangNan Hospital of Zhejiang Chinese Medical University orthopedics (approval Number: 2020-D-10). Every participant in this study will provide a written informed consent before participating.

The authors declare that they have no conflicts of interest to disclose.

Strand V, Rao SA, Shillington AC, Cifaldi MA, McGuire M, Ruderman EM. Prevalence of axial spondyloarthritis in United States rheumatology practices: Assessment of SpondyloArthritis International Society criteria versus rheumatology expert clinical diagnosis. Arthritis Care Res (Hoboken). 2013 Aug;65(8):1299-306.
Rudwaleit M, van der Heijde D, Landewé R, Listing J, Akkoc N, Brandt J, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009 Jun;68(6):777-83.
Sieper J, Braun J, Dougados M, Baeten D. Axial spondyloarthritis. Nat Rev Dis Primers. 2015 Jul 9;1:15013.
Stolwijk C, Essers I, van Tubergen A, Boonen A, Bazelier MT, De Bruin ML, et al. The epidemiology of extra-articular manifestations in ankylosing spondylitis: a population-based matched cohort study. Ann Rheum Dis. 2015 Jul;74(7):1373-8.
Tan S, Dasgupta A, Yao J, Flynn JA, Yao L, Ward MM. Spatial distribution of syndesmophytes along the vertebral rim in ankylosing spondylitis: preferential involvement of the posterolateral rim. Ann Rheum Dis. 2016 Nov;75(11):1951-1957.
Ward MM, Deodhar A, Gensler LS, Dubreuil M, Yu D, Khan MA, 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 Oct;71(10):1285-1299.
van der Heijde D, Ramiro S, Landewé R, Baraliakos X, Van den Bosch F, Sepriano A, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017 Jun;76(6):978-991.
Braun J, van den Berg R, Baraliakos X, Boehm H, Burgos-Vargas R, Collantes-Estevez E, et al. 2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis. 2011 Jun;70(6):896-904.
Poddubnyy D, Sieper J. Radiographic progression in ankylosing spondylitis/axial spondyloarthritis: how fast and how clinically meaningful? Curr Opin Rheumatol. 2012 Jul;24(4):363-9.
Braun J, Baraliakos X, Deodhar A, Baeten D, Sieper J, Emery P, et al. MEASURE 1 study group. Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study. Ann Rheum Dis. 2017 Jun;76(6):1070-1077.
van der Heijde D, Schiff MH, Sieper J, Kivitz AJ, Wong RL, Kupper H, et al. Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: long-term results from the ATLAS trial. Ann Rheum Dis. 2009 Jun;68(6):922-9.
Braun J, Kiltz U, Heldmann F, Baraliakos X. Emerging drugs for the treatment of axial and peripheral spondyloarthritis. Expert Opin Emerg Drugs. 2015 Mar;20(1):1-14.
Zhang D, Liu W, Yang H, Wu Y. [Clinical review of ankylosing spondylitis treated with acupuncture and medicine]. Zhongguo Zhen Jiu. 2016 Aug 12;36(8):893-896. Chinese.
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 Apr;27(4):361-8.
van der Heijde D, Deodhar A, Wei JC, Drescher E, Fleishaker D, Hendrikx T, et al. Tofacitinib in patients with ankylosing spondylitis: a phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis. 2017 Aug;76(8):1340-1347.
van der Heijde D, Joshi A, Pangan AL, Chen N, Betts K, Mittal M, et al. ASAS40 and ASDAS clinical responses in the ABILITY-1 clinical trial translate to meaningful improvements in physical function, health-related quality of life and work productivity in patients with non-radiographic axial spondyloarthritis. Rheumatology (Oxford). 2016 Jan;55(1):80-8.
van der Heijde D, Dougados M, Davis J, Weisman MH, Maksymowych W, Braun J, et al. ASsessment in Ankylosing Spondylitis International Working Group. ASsessment in Ankylosing Spondylitis International Working Group/Spondylitis Association of America recommendations for conducting clinical trials in ankylosing spondylitis. Arthritis Rheum. 2005 Feb;52(2):386-94.
Zochling J. Measures of symptoms and disease status in ankylosing spondylitis: Ankylosing Spondylitis Disease Activity Score (ASDAS), Ankylosing Spondylitis Quality of Life Scale (ASQoL), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Global Score (BAS-G), Bath Ankylosing Spondylitis Metrology Index (BASMI), Dougados Functional Index (DFI), and Health Assessment Questionnaire for the Spondylarthropathies (HAQ-S). Arthritis Care Res (Hoboken). 2011 Nov;63 Suppl 11:S47-58.
Maksymowych WP, Inman RD, Salonen D, Dhillon SS, Krishnananthan R, Stone M, et al. Spondyloarthritis Research Consortium of Canada magnetic resonance imaging index for assessment of spinal inflammation in ankylosing spondylitis. Arthritis Rheum. 2005 Aug 15;53(4):502-9.
Hededal P, Østergaard M, Sørensen IJ, Loft AG, Hindrup JS, Thamsborg G, et al. Development and Validation of MRI Sacroiliac Joint Scoring Methods for the Semiaxial Scan Plane Corresponding to the Berlin and SPARCC MRI Scoring Methods, and of a New Global MRI Sacroiliac Joint Method. J Rheumatol. 2018 Jan;45(1):70-77.
van den Berg R, de Hooge M, Bakker PA, van Gaalen F, Navarro-Compán V, Fagerli KM, et al. Metric Properties of the SPARCC Score of the Sacroiliac Joints - Data from Baseline, 3-month, and 12-month Followup in the SPACE Cohort. J Rheumatol. 2015 Jul;42(7):1186-93.
Calin A, Garrett S, Whitelock H, Kennedy LG, O'Hea J, Mallorie P, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol. 1994 Dec;21(12):2281-5.
Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol. 1994 Dec;21(12):2286-91.
Cohen JD, Cunin P, Farrenq V, Oniankitan O, Carton L, Chevalier X, et al. Estimation of the Bath Ankylosing Spondylitis Disease Activity Index cutoff for perceived symptom relief in patients with spondyloarthropathies. J Rheumatol. 2006 Jan;33(1):79-81.
Machado P, Landewé R, Lie E, Kvien TK, Braun J, Baker D, et al. Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis. 2011 Jan;70(1):47-53.
Lukas C, Landewé R, Sieper J, Dougados M, Davis J, Braun J, et al. Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis. 2009 Jan;68(1):18-24.
Jenkinson TR, Mallorie PA, Whitelock HC, Kennedy LG, Garrett SL, Calin A. Defining spinal mobility in ankylosing spondylitis (AS). The Bath AS Metrology Index. J Rheumatol. 1994 Sep;21(9):1694-8.
Doward LC, Spoorenberg A, Cook SA, Whalley D, Helliwell PS, Kay LJ, et al. Development of the ASQoL: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis. 2003 Jan;62(1):20-6.
Cohen CJ, Karaderi T, Pointon JJ, Wordsworth BP. A CCR6 variant strongly associated with rheumatoid arthritis in two populations is not associated with ankylosing spondylitis. Rheumatol Int. 2013 Sep;33(9):2443-4.
Lee WY, Chang YH, Lo MK, Chang CP, Yang SC, Yang TP, et al. Polymorphisms of cytotoxic T lymphocyte-associated antigen-4 and cytokine genes in Taiwanese patients with ankylosing spondylitis. Tissue Antigens. 2010 Feb;75(2):119-26.
Ward MM, Deodhar A, Gensler LS, Dubreuil M, Yu D, Khan MA, 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 Oct;71(10):1285-1299.
Cho H, Kim T, Kim TH, Lee S, Lee KH. Spinal mobility, vertebral squaring, pulmonary function, pain, fatigue, and quality of life in patients with ankylosing spondylitis. Ann Rehabil Med. 2013 Oct;37(5):675-82.
López-Larrea C, Gonzalez-Roces S, Alvarez V. HLA-B27 structure, function, and disease association. Curr Opin Rheumatol. 1996 Jul;8(4):296-308.
Huang CH, Wong RH, Wei JC, Tsay MD, Chen WC, Chen HY, et al. Effects of genetic polymorphisms of programmed cell death 1 and its ligands on the development of ankylosing spondylitis. Rheumatology (Oxford). 2011 Oct;50(10):1809-13.
Chan AT, Kollnberger SD, Wedderburn LR, Bowness P. Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis. Arthritis Rheum. 2005 Nov;52(11):3586-95.
Allen RL, Trowsdale J. Recognition of classical and heavy chain forms of HLA-B27 by leukocyte receptors. Curr Mol Med. 2004 Feb;4(1):59-65.
Mear JP, Schreiber KL, Münz C, Zhu X, Stevanović S, Rammensee HG, et al. Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol. 1999 Dec 15;163(12):6665-70.
Fragoulis GE, Liava C, Daoussis D, Akriviadis E, Garyfallos A, Dimitroulas T. Inflammatory bowel diseases and spondyloarthropathies: From pathogenesis to treatment. World J Gastroenterol. 2019 May 14;25(18):2162-2176.

Efficacy And Safety of Wenbu Zhibi Granule In Patients With Ankylosing Spondylitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

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Journal Publication

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Introduction

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