Does Immunogenicity Have an Influence on the Efficacy of Anti-TNF Therapy in Patients With AS: An Inception Cohort Study

Study Overview
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Brief Summary
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The purpose of this prospective cohort study is to evaluate the influence of serum drug levels and development of anti-drug antibodies on clinical response to anti-TNF agents in ankylosing spondylitis(AS) treatment. Secondary aims are to assess the demographic, clinical and laboratory variables associated with the development of anti-TNF drug antibodies at baseline or disease course and to reveal the impact of anti-drug antibodies on long-term efficacy or safety in particular drug survival in AS patients treated in daily clinical practice.

Detailed Description
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Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that predominantly affects sacroiliac joints and spine. It is the prototype of spondyloarthritides (SpA) and one of the most common rheumatic diseases. Sacroiliitis is the earliest manifestation of disease and accompanying with spinal involvement cause inflammatory back pain (IBP). IBP usually starts insidiously in the early adulthood and typically it is felt deep in the buttock and/or lower lumbar regions. It improves with activity and returns with the rest and is usually accompanied by morning stiffness lasting at least 30 minutes. Involvement of the spine in patients with AS is usually not limited to the sacroiliac joints and lumbar region and usually it extends up to the thoracic and cervical segment. Currently the only sign that is diagnostic for AS is radiographic sacroiliitis. However radiography detects structural changes and take up to ten years to appear unequivocally. In some patients bone tenderness due to enthesitis may be the primary complaint. Arthritis in the hips and shoulders occur in some patients and is associated with worse prognosis. Typical arthritis pattern in AS patients is asymmetric and usually involves the lower extremity joints. There are several extra-articular features of AS and the most common is acute anterior uveitis. Until recently treatment options for AS were limited and based on non-steroidal anti-inflammatory drugs (NSAIDs), traditional disease modifying anti-rheumatic drugs (DMARDs) for the rheumatoid arthritis and physical therapy. The last decade witnessed a major advance in AS therapy with the use of anti-tumor necrosis factor (anti-TNF) agents. Anti-TNF agents have a substantial effect not only the axial disease but also in peripheral arthritis, enthesitis and extra-articular features (like psoriasis and inflammatory bowel disease). Currently there are four anti-TNF agents approved for AS: (1) infliximab which is a monoclonal chimeric antibody and given at a dose of 5 mg/kg every 6-8 weeks; (2) etanercept which is human TNF receptor fusion protein and administered subcutaneously at a dose of 50 mg/once a week; (3) adalimumab which is a humanized monoclonal antibody and administered as subcutaneous injection at a dose of 40 mg fortnightly; and (4) golimumab which is a fully human monoclonal antibody and administered subcutaneously at a dose of 50 mg once a month. Since there is no head-to-head studies comparing the anti-TNF agents in the treatment of AS patients there is no ranking for the prescription of anti-TNF agents. Mixed treatment comparisons (that is statistical model allowing the simultaneous multiple meta-analysis of different pair-wise comparisons) between infliximab, adalimumab and etanercept did not show a statistically significant difference. Indeed similar improvements in Bath ankylosing spondylitis activity index (BASDAI 50) scores and ASAS partial remission (between 45.2% to 51.0% BASDAI 50 and 22.1% to 22.4% for partial remission) have been reported in randomized controlled clinical trials. Although many AS patients respond very well to anti-TNF therapy, a considerable amount of them do not and additionally a significant proportion of patients have to stop their treatment. In clinical practice the reported 1-year and 2-year drug survival rates for anti-TNF agents are 70-85% and 60-75%, respectively.Moreover in a substantial proportion of patients either increase in the administered dosage or dosing frequency have become necessary. Therefore factors, which can predict the response or related with the primary or secondary non-response for anti-TNF treatment have a growing attention among treating specialists. In a study providing an overview of clinical trials and observational studies showed that increased acute phase reactants, higher disease activity, functional status, younger age, and HLA-B27 positivity were independent baseline predictors of response to anti-TNF treatment and increased acute phase reactants, presence of peripheral arthritis, and male sex were the predictors of long-term drug survival. Immunogenicity refers to development of antibodies by the adaptive immune system in response to foreign substances. The development of anti-drug antibodies were extensively studied in rheumatoid arthritis and it was shown that anti-drug antibodies has a varying impact on the clinical efficacy depending on whether these antibodies are neutralizing or non-neutralizing. Recent review demonstrated that neutralizing antibodies are associated with a reduced chance of achieving a minimal disease activity or clinical remission, decreased drug survival, increased dose escalation and adverse drug reactions in RA patients. However data regarding the immunogenicity in patients treated with AS is scarce and somewhat controversial. In a small study including 38 AS patients treated with infliximab de Vries et al showed that anti-infliximab antibodies was found significantly more often (59% vs 5%) and mean serum through infliximab levels were significantly lower in ASAS20 non-responders. In the above-mentioned study infusion reactions were also seemed to be associated with the development of anti-drug antibodies. In another study de Vries et al (26) were found no antibodies to etanercept and similar serum etanercept levels in responder and non-responder AS patients (n=53). Same group also observed that anti-adalimumab antibodies were become detectable in 31% of AS (n=35) patients in 6 months period and this corresponded with diminished serum drug levels. Arends et al reported that 0 to 30% of AS patients (n=60) developed anti-drug antibodies during one year of follow-up of anti-TNF treatment and patients with anti-IFN or anti-ADA antibodies had significantly lower drug serum levels. The objective of this prospective cohort study is to evaluate the influence of serum drug levels and development of anti-drug antibodies on clinical response to anti-TNF agents. The assessment of demographic, clinical and laboratory variables associated with the development of anti-TNF drug antibodies at baseline or disease course will be also evaluated. Via this study, it might also be possible to reveal the impact of anti-drug antibodies on long-term efficacy or safety in particular drug survival in AS patients treated in daily clinical practice.

Official Title
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Does Immunogenicity Have an Influence on the Efficacy of Anti-tumor Necrosis Factor (Anti-TNF) Therapy in Patients With Ankylosing Spondylitis (AS): An Inception Cohort Study

Conditions
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Ankylosing Spondylitis, Axial Spondyloarthritis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients whom are receiving their first anti-TNF treatment(not switch) Ankylosing spondylitis diagnosis according to modified New York Criteria Patients whom were older than 18 years old on anti-TNF initiation Exclusion Criteria: Spondyloarthritis other than AS HIV positive or malignancy Being treated with another biological drug prior to study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| AS patients receiving Anti-TNF treatment<br>Three hundred and fifty consecutive AS patients fulfilling the modified New York criteria for the classification of AS (5), and with a new anti-TNF agent prescription (either for the first time or switched) in the last two weeks period will be included. Treatment with anti-TNF agents will be in accordance with the regulations of Turkish Social Security Agency (SGK) on the initiation and continuation of anti-TNF agents in AS, as well as ASAS/EULAR recommendations for the management of AS (29, 30). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum drug levels | It will be measured in mg/L or other measurement levels by using ELISA | 0, 3, 6 12 and 24 months of the study | 
| Anti-drug antibody levels | It will be measured in AU/mL or other measurement levels by using ELISA | 0, 3, 6 12 and 24 months of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) | In order to evaluate function BASDAI will be evaluated in numeric rating scale (0-10) | every third months up to 104 weeks | 
| Bath Ankylosing Spondylitis Functional Index (BASFI) | In order to evaluate function BASFI will be evaluated in numeric rating scale (0-10) | every third months up to 104 weeks | 
| Ankylosing Spondylitis Disease Activity Index (ASDAS) | ASDAS-CRP (the preferred version) will be calculated by using the following formula: 0.12 X Back pain + 0.06 X Duration of morning stiffness + 0.11 X Patient global + 0.07 X Peripheral pain / swelling + 0.58 X Ln (CRP + 1) | every third months (if available) up to 104 weeks |