REU-stop - Effect of Intensive Smoking Cessation Intervention on Smoking Cessation and Disease Activity in Patients With Rheumatoid Arthritis.

This study aims to test the effect of an intensive smoking cessation intervention (motivational counseling combined with nicotine replacement) on smoking cessation and disease activity in patients with Rheumatoid Arthritis (RA). Half of the patients will participate in a smoking cessation intervention; the other half will receive usual treatment.

Tobacco smoking is a well-known environmental risk factor for developing rheumatoid arthritis (RA). The onset of RA can occur in all age groups, with the majority being women aged 50-60 years. RA is a chronic inflammatory disease and cannot be cured. However, the activity of the disease can be reduced by medication. During periods with high disease activity, patients experience increased pain and fatigue and subsequent restrictions in social life, psychical activity and activities of daily life. Furthermore, the inflammatory process underlying RA can cause pain, fatigue, reduced health-related quality of life and reduced physical function. Patients with RA are at increased risk of cardiovascular diseases similar to the risk demonstrated in patients with diabetes. Furthermore, several studies indicate that smokers with inflammatory arthritis tend to experience more pain and fatigue, and a reduced quality of life compared to non-smokers.

Aim: This randomized controlled trial (RCT) in patients with RA aims to examine the effect of intensive smoking cessation intervention (motivational counselling combined with tailored nicotine replacement therapy) versus standard care on smoking cessation, and consequently on disease activity. Secondary objectives are to explore the effect on flare, risk factors for CVD, lung function, physical function, HR-QoL, pain and fatigue in patients with RA.

Material and Methods Trial design: The trial is an international, multicentre, randomized RCT in which daily smokers with RA in remission or with low-moderate disease activity ≤ 5.1 DAS28 (Disease Activity Score - based on 28 joints assessment, serum-C-reactive protein (CRP) and patient's Global assessment of a visual analogue scale (VAS)) will be randomized 1:1 to either an intervention group or to a control group. Patients will be followed for 58 weeks, including the 6-week intervention period and 3 months, 6 months and 12 months into the post-intervention follow-up period.

Study setting: We will recruit patients from the Center for Rheumatology and Spine Diseases, Rigshospitalet, Denmark and from the Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Randomization and blinding: Immediately after collecting baseline data using stratified block randomization (block size 6-10) participants will be randomized to either 1) the intervention group or 2) the control group. The stratification variables are trial site and Anti-cyclic citrullinated peptide (Anti-CCP status). The allocation sequence is generated using computer-generated random numbers. Participants will be informed about their group allocation directly after randomization. For participants randomized to the smoking cessation intervention group, the first intervention meeting will be scheduled as soon as possible, preferably immediately after randomization. It is not possible either to blind participants to their allocated intervention or to blind the project nurses performing the intervention. The primary outcomes will be assessed by blinded assessors and smoking cessation will be self-reported by participants and validated biochemically.

Data collection:All outcomes are assessed at three months (18 weeks post-intervention), 6 months (30 weeks post-intervention) and 12 months follow-up (58 weeks post-intervention).

We will retrieve data from the DANBIO database regarding the participants' pharmacological treatment, duration of RA, CRP levels, IgM rheumatoid factor and Anti-CCP status. Additional descriptive data include participants' demography, socio economic situation, lifestyle (smoking and alcohol) and consumption of pain killers obtained via a questionnaire. Co-morbidities are assessed using the Charlson's Co-morbidity Scale obtained from the electronic patient journal.

All participant-reported questionnaires will be completed electronically on a tablet connected to DANBIO, which will be used only for participants in the trial. Blood samples will be destroyed immediately after the analyses are done.

All outcomes excluding patient-reported outcomes will be assessed by project nurses blinded to the patients' group allocation.

Ethics, confidentiality and dissemination: The trial will be carried out in accordance with the Helsinki Declaration. The project has been approved by The Regional Committee on Health Research Ethics (H-16022001) and the Danish Data Protection Agency (I-suite number 04849). The trial has been reported to Clinicaltrials.gov (NCT02901886). All data and information collected during the trial will be kept confidential and in accordance with the requirements of the Danish and Norwegian Data Protection Agencies and Good Clinical Practice.

Eligibility Criteria:
Inclusion criteria Patients will be included in the study if they have RA as defined by the American College of Rheumatology (ACR) 1987 criteria and/or European League Against Rheumatism (EULAR) 2010 criteria (32, 33), \>18 years of age, smoking tobacco daily, are able to understand and speak Danish or Norwegian, respectively. Furthermore, patients need to for the past three months to have been in clinical remission or low-moderate disease activity (DAS28 ≤ 5.1) and in stable anti-rheumatic medical treatment as documented in 1) the DANBIO registry in Denmark, or 2) the electronic patient journal, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway.

Exclusion criteria Patients will be excluded from the study if they have had a change of dose or preparation in anti-rheumatic medical treatment within the previous 3 months, or a scheduled change in anti-rheumatic medical treatment, including glucocorticoid injection during the previous month, are cognitively or otherwise unable to give informed consent, are pregnant or breastfeeding.

Excluded patients, and eligible patients who do not want to participate, will be registered in one of the following three categories 1) not meeting the inclusion criteria 2) refused to participate 3) other reasons.