The purpose of this study is to investigate how RA affect the brain structures in RA-patients and if anti-inflammatory treatment that target TNF-α or JAK OR physical training of hands has positive impact on neuropsychiatric symptoms and morphological changes in the brain caused by the disease.

The goal of this research project is to improve the knowledge of morphological changes in brain developed in connection to RA and to identify clinical and serological markers to predict development of those changes and finally, to investigate if anti-rheumatic interventions counteract destructive processes in the central nervous system (CNS) and improve the patient's health with respect to functionality, pain experience and psychological well-being.

Based on the information gained in previous studies the investigators want to examine if;

A. anti-inflammatory treatment that target TNF-α or JAK signalling or

B. physical training of hands

has a positive impact on neuropsychiatric symptoms and morphological changes in the brain caused by RA.

To examine this the investigators will employ a prospective open-label study design with two parts, one observation part (1) and one intervention part (2). Patients will be assigned to either:

1. OBSERVATION PART

Aim: Mapping brain morphology in relation to functional impairment, inflammation and neuropsychiatric symptoms in patients with RA of various disease duration.

To study this 80 RA patients will be recruited from the outpatient clinic at Sahlgrenska university hospital for an observational prospective study.

RA-patients will be identified via the diagnosis registry within Reumatologi/Sahlgrenska Universitetssjukhuset.

Inclusion criteria: patients age 45-75 years; confirmed RA diagnosis, in the early stage of the disease (1-3 years after the diagnosis, n=20); in the established stage of the disease (5-8 years after the diagnosis, n=30) and in the late stage of the disease (>12 years after the diagnosis, n=30).

Exclusion criteria: any conditions precluding MRI imaging; e.g claustrophobia; pacemaker etc, medical history of ischemic stroke or cerebral hemorrhage; medical history of neurological disease; inability to read and communicate in Swedish, hence being able to give informed consent and fill out study questionnaires.

The patient will then undergo the study related activities; clinical examination by rheumatologist and occupational therapist, blood sampling, height and weight, waist circumference, blood pressure measurement, questionnaires (see below and attachment), plain radiological imaging of hands and MRI of the head.

1. * Clinical examination:

   • Documentation of number of tender and swollen joints according to the established Disease Activity Score 28-protocol (DAS28) (see attachment DAS28).
   • Documentation of number of Tender Points ie sensitive areas on the body that become painful when pressure is applied according to the established TP 18 protocol (see attachment TP18).
   • Documentation of the hand joint mobility,
   • pain (VAS), grip strength,
   • Functional arm-shoulder-hand status according to DASH protocol (see attachment Handstatus).
   • Questionnaires used in the study are:

   the Health Assessment Questionarie (HAQ), the Fibromyalgia Questionaire (FIQ), the Hospital Anxiety and Depression Scale (HADS) (HADS), the Short Form Health Survey (SF-36), the IPAQ (International Physical Activity Questionnaire), the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. Questions on the patients´ diagnosis and pharmacological treatment (and for women questions on hormonal status) and tobacco habits are also collected.

   • Radiological imaging of hands
   • Anatomical 3D MRI of the head will be performed using a standard protocol of T1-weighted 3D scan with approximately isotropic voxels and a resolution of approximately 1 mm^3 per voxel. The field of view (FOV) will include the head in full and extend caudally to include the cerebellum and medulla. Automatic anatomical segmentation using MAPER (multi-atlas propagation with enhanced registration) will be applied.

2. INTERVENTION PART

Aim: To study the effect of TNF-α inhibitors/JAK inhibitors and regular physical training of hands on RA-related intracranial changes. Based on the information gained in the cross-sectional and in the pilot part of the investigators previous studies (Erlandsson 2016; Andersson 2018), they want to investigate if anti-inflammatory treatment that target TNF-α or JAK OR physical training of hands has a positive impact on neuropsychiatric symptoms and morphological changes in the brain caused by RA.

To examine this a prospective open-labeled study with two groups with 66 patients in each group will be employed.

Patients will be assigned to either:

Group A. Pharmacological treatment with TNF-α inhibitor or JAK inhibitor

Group B. Physical hand training 10 min twice daily while on stable treatment with TNF-α inhibitor or JAK inhibitor

Inclusion criteria: patients age 45-75 years; confirmed and established RA. Naïve to treatment with TNF-α inhibitors or JAK inhibitors to be eligible for Group A and to be on a stable treatment of TNF-α inhibitors or JAK inhibitors for the last 3 months to be eligible for Group B.

Exclusion criteria: other serious conditions precluding MRI imaging, claustrophobia; medical history of ischemic stroke or cerebral hemorrhage; medical history of neurological disease; inability to read and communicate in Swedish, hence being able to give informed consent and fill out study questionnaires.

For Group A, RA patients attending the outpatient clinic at Sahlgrenska university hospital set to start treatment with TNF-α inhibitors or JAK inhibitors for the first time will be included. Both TNF-α inhibitors and JAK inhibitors are well tolerated, efficient anti-rheumatic drugs administered to RA patients with moderate to severe disease in accordance with the current recommendations for pharmacological treatment of RA (www.svenskreumatologi.se/srfs-riktlinjer/#).

For Group B, RA patients who already receive stable treatment with TNF-α or JAK inhibitors since 3 months will be included. These patients will be instructed to carry out hand exercises designed by an occupational therapist for 10 min twice daily for the entire study period of 6 months (training program attached).

Patients fulfilling the inclusion criteria are informed of the study by their responsible rheumatologist. Before approaching the patient, the doctor will have made sure he/she fulfils the study criteria and that he/she is susceptible and open for information about a clinical study. The decision to start treatment with TNF-α or JAK inhibitors will be made by a rheumatologist on the intention to treat basis, completely outside the scope of this study. We will not in any way affect this decision, but simply recruit patients from those that are starting TNF-α or JAK inhibitors. Once the patient has received information about the study, both orally and in text, and has been given time to think and ask questions, they are asked to participate and if so sign the informed consent. After consent is signed by both patient and personnel a copy is given to the patient.

The patient will then undergo the study related activities; clinical examination by rheumatologist and occupational therapist, blood sampling, height, weight, waist circumference and blood pressure measurement, completion of study questionnaires (see below and attachment), plain radiological imaging of hands and MRI of the head. Information regarding RA duration, clinical activity and medication will be retrieved from medical records.

1. Clinical examination:

   • Documentation of number of tender and swollen joints according to the established Disease Activity Score 28-protocol (DAS28) (see attachment DAS28).
   • Documentation of number of Tender Points, ie sensitive areas on the body that become painful when pressure is applied according to the established TP 18 protocol (see attachment TP18).
   • Documentation of the hand joint mobility,
   • pain (VAS),
   • Grip strength,
   • Functional status in shoulder, arm and hand according to DASH (see attachment Handstatus).

2. Anatomical 3D MRI of the head will be performed using a standard protocol of T1-weighted 3D scan with approximately isotropic voxels and a resolution of approximately 1 mm^3 per voxel. The field of view (FOV) will include the head in full and extend caudally to include the cerebellum and medulla.

3. Radiological imaging of hands

4. The study participants of both groups will write a pain diary to register pain (by visual analogue scale) on daily basis (attached).

For all patients participating in the interventional part of study, both group A and B, follow-up visits 3 and 6 months after first visit will be booked. At these visit they will meet with occupational therapist for assessment of hand function, leave blood, complete study questionnaires and hand over their completed pain diary. At the 6 month-visit an anatomic 3D MRI of the head will also be performed.

Inclusion Criteria:

• confirmed RA diagnosis, in the early stage of the disease (1-3 years after the diagnosis, n=20); in the established stage of the disease (5-8 years after the diagnosis, n=30) and in the late stage of the disease (>12 years after the diagnosis, n=30)

Exclusion Criteria:

• any conditions precluding MRI imaging; e.g claustrophobia; pacemaker etc, medical history of ischemic stroke or cerebral hemorrhage; medical history of neurological disease; inability to read and communicate in Swedish, hence being able to give informed consent and fill out study questionnaires