Intestinal Inflammation in Ankylosing Spondylitis and the Effects of Adalimumab on Mucosal Healing

Study Overview
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Brief Summary
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Studies with intestinally asymptomatic patients with spondyloarthritis showed that approximately 1/3 had visible ulcers in the colon by scopic examinations and 2/3 had changes detectable by microscopy. Only those patients who improved in arthritis symptoms showed improvement in colonic changes. In these studies only colon and the terminal ileum was examined. Inflammation of the small intestine was not examined. Newer studies have shown an immunological link between Crohns disease and spondyloarthritis but not ulcerative colitis. The investigators wish to examine the small intestine in these patients before and after treatment, since they expect to find ulcers there linking spondyloarthritis to Crohns disease and healing after treatment.

Detailed Description
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Patients with inflammatory axial spondyloarthritis according to the assessment group in ankylosing spondylitis (ASAS) criteria (8) and active disease assessed by a physician are recruited in the outpatient clinics of the rheumatology departments, provided that the patient under normal circumstances is expected to benefit from TNF-alpha inhibitor treatment and full fill the criteria for treatment. Screening with a view to participating in the study is carried out in accordance with the inclusion and exclusion criteria. Oral and written patient information about the study, the patient's signing of the informed consent form and the signing of the patient's power of attorney in accordance with the study protocol are also a condition for the inclusion. The including physician will ensure that a potential participant is informed about the right to at least 1 hour's reflection time and the right to have a friend/family member present at the information interview. If the patient meets the basis for the participation in the study the informed consent form and the power of attorney are signed. The screened patients are not coded but are identified using their Civil Registration Number (CPR) for several reasons. The study is open-label, which removes the need for blinding of patients as well as investigator. Blood samples are booked electronically and printed labels with CPR number are put on the test tubes for both immediate analysis and storage. This guarantees a more fail-safe method for handling of various analyses, since this procedure is similar to the routine procedure. We find this to be the safest system as the method, by which labels with CPR number follow the patient has been thoroughly tested. Source data will be kept in the Danish Biologics Online Registry (DANBIO registry) for clinical measures, the electronic patient file for lab data and the paper file for imaging data. Data validity and completeness is controlled by external good clinical practice monitoring. Adalimumab will be supplied as a sterile solution without preservatives for subcutaneous injection in 1 ml prefilled syringes containing adalimumab 40 mg/0.8 ml, to be self-injected by the patient every 2 weeks until week 20. After week 20 patients continue adalimumab treatment 40 mg every other week but may change to injections with pens containing the same drug and dosage. The drug is injected under the skin of the abdomen or the thigh. All patients will be instructed by the study personnel in correct sterile subcutaneous injection of the study drug.

Official Title
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Intestinal Inflammation in Ankylosing Spondylitis Assessed by Fecal Calprotectin, Capsular Endoscopy and Colonoscopy and the Effects of Adalimumab on Mucosal Healing

Conditions
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Spondyloarthritis, Enterocolitis

Intervention / Treatment
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* Drug: Adalimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients (18 years and ≤45 years) with axial SpA according to the ASAS criteria Active SpA assessed by physician. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4. Faecal calprotectin ≥ 100mg/kg. Negative pregnancy test (serum-HCG) for women of childbearing age before the start of the study. (Women not of childbearing age are defined as postmenopausal for at least 1 year or surgically sterilised (bilateral tubal ligation, bilateral oophorectomy or hysterectomy)). Women of childbearing age included in the study will be required to use contraception during the entire study period (i.e. one of the following: contraceptive pills, intrauterine device, depot injection of gestagen, subdermal implant, hormonal vaginal ring or transdermal patch). In addition, contraception must be used following any discontinuation of the study drug for a period of 150 days. Ability and willingness to self-administer the subcutaneous injections or have a person available to administer the injections. Ability and willingness to give written informed consent and meet the requirements of the study protocol. Exclusion Criteria: Diagnosed inflammatory bowel disease or high risk of intestinal stricture (previous abdominal stricture, radiation of abdomen, major abdominal surgery). Non steroid anti inflammatory Drugs (NSAID) ingestion less than 4 weeks before inclusion. Psoriasis Persons with latent Tuberculosis (TB)(positive Mantoux skin test (>10 mm), positive cultivation for mycobacteria in tissue samples and/or chest X-ray indicating TB) or other risk factors for activation of untreated latent TB. Current or recurrent infections or serious infections requiring hospitalisation or treatment with intravenous antibiotics within the last 30 days or oral antibiotics within the last 14 days before inclusion. Positive serology for Hepatitis B or C indicating active infection. Medical history of positive HIV status (in case of suspicion control of HIV test). Medical history of histoplasmosis or listeriosis. Previous cancer or lymphoid proliferative disease except completely well-treated cutaneous squamous cell carcinoma, basal cell carcinoma or cervical dysplasia. Previous diagnosis or signs of demyelinising diseases of the central nervous system (e.g. optic neuritis, disturbance of vision, disturbed gait/ataxia, facial paresis, apraxia). Severe renal insufficiency (creatinine clearance < 35 ml/min - normogram).Affected hepatic function: Liver enzymes > 3 x above the normal limit. Clinically significant drug or alcohol abuse in the last year or daily current alcohol consumption. Diabetes, unstable ischemic heart disease, heart failure (NYHA III-IV), recent apoplexia cerebri (within 3 months), chronic leg ulcer and any other condition (e.g. indwelling catheter) which at the discretion of the investigator means that participation in the protocol would entail a risk for the person in question. Anticoagulant treatment. Pregnancy or breast-feeding. Other clinically significant inflammatory rheumatologic diseases that cannot be related to spondyloarthritis Current parvovirus B 19 infection. Glucocorticosteroid treatment within the last 4 weeks (except nasal and inhalation steroids). Contraindication to study drug.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Spondyloarthritis and calprotectin elevated<br>Spondylitis patients with elevated levels of fecal calprotectin. Patients are treated with adalimumab | Drug: Adalimumab<br>* Tumor Necrosis Factor (TNF) alpha inhibitor given 40 mg subcutaneously every other week except the first time where 80 mg is given<br>* Other names: Humira;|
| Active Comparator: Spondyloarthritis and calprotectin normal<br>Spondylitis patients with normal levels of fecal calprotectin. Patients are treated with adalimumab. | Drug: Adalimumab<br>* Tumor Necrosis Factor (TNF) alpha inhibitor given 40 mg subcutaneously every other week except the first time where 80 mg is given<br>* Other names: Humira;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change Lewis Score Index | Lewis' score describes the amount of inflammation seen optically by capsular endoscopy. Gralnek et al. devised and validated the Lewis score index, based on three endoscopic parameters: villous edema, ulcer and stenosis/stricture. Using these parameters, the authors established a score range of 8-4,800 points where: LS < 135 reflects normal mucosal appearances, LS 135-790 mild mucosal inflammatory change and an LS value ≥790 moderate to severe mucosal inflammatory changes. The patients had endoscopy performed at baseline and again after 20 weeks. The number of patients improving was compared to number of patients deteriorating | 20 weeks | 
| Change in Intestinal Inflammation Measured by Faecal Calprotectin | Feacal calprotectin is a protein and a marker of the degree of inflammation in the intestine, but not the site of inflammation. We measured the level calprotectin continuously in each of the patients. Difference was inferred by repeated measurement ANOVA | Baseline to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spondyloarthritis Consortium of Canada Score | Inflammation on MRI assessed by the Spondyloarthritis Consortium of Canada score and a Danish scoring method | one year | 
| Assessment Group in Ankylosing Spondylitis (ASAS) Core Set for Clinical Practice | clinical measurements of inflammation in spondyloarthritis patients as described by the Assessment Group in Ankylosing Spondylitis (ASAS) | one year |