To Investigate Genetic Factors Associated With the Response to Anti-TNF Therapy in Patients With Early AS

Ankylosing Spondylitis Clinical Trial

Official title:

To Investigate Genetic Factors Associated With the Response to Anti-TNF Therapy in Patients With Early Ankylosing Spondylitis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02311842
• Other study ID #: WA1627494
• Status: Completed
• Phase: N/A
• First received: December 4, 2014
• Last updated: December 4, 2014
• Start date: January 2012
• Est. completion date: December 2013

Study information

• Verified date: December 2014
• Source: Sun Yat-sen University
• Contact: n/a
• Is FDA regulated: No
• Health authority: China: Food and Drug Administration
• Study type: Observational

Clinical Trial Summary

Ankylosing spondylitits (AS) is a chronic, systemic rheumatic disease primarily affecting spine and sacroiliac joints, which belongs to the group of conditions known as spondyloarthopathies and causes eventual fusion of the spine. Twin study in AS estimated a heritability of over 90%. HLA-B27 is regarded as the earlist and most important gene associated with AS heritability, and over 90% of AS patients carry HLA-B27 gene. HLA-B27 was highly polymorphic, and more than 89 subtypes of B27 gene have been found. Subtypes of HLA-B27 vary between different regions, and so on as the relationship between HLA-B27 subtypes and disease development among different races. Anti-TNF- agents were regarded as one milestone in recent years development on treatment of ankylosing spondylitis, and most patients showed significant improvement after anti-TNF- therapy. Yet part of patients still showed insufficient response. Our previous study suggested AS patients carrying different genotype of SNP in TNF gene had different response to anti-TNF- therapies. But more studies should be carried out to identified more gene polymorphisms associated with treatment response. In this study we designed a prospective, open-label trial to investigate the genetic difference beween AS patients with different response to anti-TNF- therapy. We plan to enroll 50-100 early AS patients which fulfill the 2009 ASAS axial spondyloarthritis classification criteria and have axial symptom for no more than 2 years. The patients must have high disease activity defined as BASDAI 4, and HLA-B27 test must be positive. The patients should be able to receive 24 weeks of etanercept treatment. And patients who have previous other anti-TNF- therapy and any contraindication of anti-TNF- therapy must be excluded. Other medicines should be stable for at least 4 weeks before etanercept treatment begins. For the clinic assessment, patients should fill in the AS questionaires and receive physical examination at each visit. ASAS20 is thought as the primary endpoint. For the genetic polymorphysm detection, we select 10-20 SNP in MHC region associated with AS and 5-10 HLA-B27 subtypes which have been worked over and have definite association with AS. At the first visit 4ml of anticoagulated blood was collected and DNA was extracted. Target SNPs are detected by PCR then direct sequencing. HLA-B27 subtypes are identified using PCRSSP methods. And the relationship between SNPs/HLA-B27 subtypes and different response to anti TNF- therapy is accessed using chi-square statistic process in SPSS software. In this study we plan to investigate the relationship between genetic background and the clinical response to anti-TNF- therapy in AS patients, which has been seldom reported before. Our group have been studying the disease-associated gene of AS for years, and got plenty of data and experience about genetic study of AS.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 68
• Est. completion date: December 2013
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:1.Fulfilled ASAS2009 criterioncriteria; 2.The duration of axial syptoms less than 2 years and in active status before treatment(BASDAI=4);3.HLA-B27 positive;4.Completed the Etanercept treatment of 12-24 weeks;5. Completed the clinical data and questionnaire rbefore and after of the treatment; 6. Assigend the ICF. Exclusion Criteria:1. Received other anti-TNF-aagents treatment; 2.Patients with other rheumatic disease which may influent gene test and efficacy, including RA, PsA, OA, SLE, etc. 3.Other possible influence factors , including articular cavity local injections of glucocorticoid prior 4 weeks before TNF alpha antagonists treatment;4. Incomplete data.

Study Design

Observational Model: Case-Crossover, Time Perspective: Prospective

Related Conditions & MeSH terms

• Ankylosing Spondylitis
• Spondylitis
• Spondylitis, Ankylosing

Locations

Country	Name	City	State
China	Department of Rheumatology, the Third Affiliated Hospital of Sun Yat-sen University	Guangzhou	Guangdong

Sponsors (2)

Lead Sponsor	Collaborator
Sun Yat-sen University	Pfizer

Country where clinical trial is conducted

China, 

References & Publications (6)

Braun J, Bollow M, Neure L, Seipelt E, Seyrekbasan F, Herbst H, Eggens U, Distler A, Sieper J. Use of immunohistologic and in situ hybridization techniques in the examination of sacroiliac joint biopsy specimens from patients with ankylosing spondylitis. Arthritis Rheum. 1995 Apr;38(4):499-505. — View Citation

Brown MA, Kennedy LG, MacGregor AJ, Darke C, Duncan E, Shatford JL, Taylor A, Calin A, Wordsworth P. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum. 1997 Oct;40(10):1823-8. — View Citation

Carter KW, Pluzhnikov A, Timms AE, Miceli-Richard C, Bourgain C, Wordsworth BP, Jean-Pierre H, Cox NJ, Palmer LJ, Breban M, Reveille JD, Brown MA. Combined analysis of three whole genome linkage scans for Ankylosing Spondylitis. Rheumatology (Oxford). 2007 May;46(5):763-71. Epub 2007 Jan 27. — View Citation

Gratacós J, Collado A, Filella X, Sanmartí R, Cañete J, Llena J, Molina R, Ballesta A, Muñoz-Gómez J. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br J Rheumatol. 1994 Oct;33(10):927-31. — View Citation

Tam LS, Gu J, Yu D. Pathogenesis of ankylosing spondylitis. Nat Rev Rheumatol. 2010 Jul;6(7):399-405. doi: 10.1038/nrrheum.2010.79. Epub 2010 Jun 1. Review. — View Citation

van der Linden S, Valkenburg H, Cats A. The risk of developing ankylosing spondylitis in HLA-B27 positive individuals: a family and population study. Br J Rheumatol. 1983 Nov;22(4 Suppl 2):18-9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ASAS20 response		12 weeks	No
Secondary	ASAS40/70 response proportion		12 weeks	No
Secondary	ASAS5/6 response proportion		12 weeks	No
Secondary	BASDAI50 response proportion		12 weeks	No