By using functional MRI the investigators have recently shown that TNFi elicit rapid changes in brain function linked to the perception of RA [5]. Functional MRI represents a method allowing detecting tiny changes in neuronal activity by measuring alterations of blood flow in the context of neuronal activation. TNFi rapidly reversed the widespread activation of brain centers involved in pain such as the thalamus and the somatosensoric cortex, as well as those involved in the control, of mood and emotions such as the limbic system. Moreover, as small phase I study with 10 patients with RA showed that high brain activity detected in the functional MRI predicts clinical response to Certolizumab Pegol after 1 month, suggesting the central nervous system activity may be used as a tool to predict response to TNFi [8]. The rationale of this study is to test whether response to TNFi can be predicted by using functional MRI.

Randomized double-blinded controlled multi-centre, study over 12 weeks, followed by a 12 weeks single blinded multicenter trial in 156 patients with RA with inadequate response to DMARD therapy. The study is composed of 3 arms with a 1:1:1 randomization at baseline: High functional MRI/400mg Certolizumab Pegol on week 0,2 and 4 followed by Certolizumab Pegol 200mg every two weeks for a total of 24 weeks; low functional MRI/400mg Certolizumab Pegol on week 0,2 and 4 followed by Certolizumab Pegol 200mg every two weeks for a total of 24 weeks with the possibility of early escape at week 12.

Patients who did not respond sufficiently according to EULAR response criteria (DAS28 reduction ≥ 1.2) to Certolizumab-Pegol (Treatment Arm A and Arm B) after 12 weeks will be off-Study and treated according to local guidelines.

Patients in the Placebo group with an EULAR response ≥ 1.2 reaching remission (DAS28 ≤ 2.6) will also be off study and treated according to the local guidelines or will be followed while they are in clinical remission. Patients with an EULAR response (DAS28 reduction ≥ 1.2) but not fulfilling the clinical remission criteria (DAS28 ≤ 2.6) will receive Certolizumab Pegol in week 12,14 and 16 with Certolizumab Pegol 400mg s.c. followed by s.c.injection of 200mg Certolizumab Pegol every two weeks till week 24.

In the situation that in one group sufficient patients will be randomized, fMRI done at screening, needs to be analyzed first to ensure that no further patient will be randomized with the randomization to the closed group. A blinded person, not involved either in the analysation of the fMRI nor in the treatment of the patients or the clinical assessments, will be responsible for the randomization list. If the next number on the randomization list represent the number of the closed group, the patient is not eligible for the study and will be treated according to local guidelines.

Inclusion Criteria:

• Understands and voluntarily signs an informed consent form

• Male or female, aged ≥ 18 years at time of consent

• Must be able to adhere to the study visit schedule and other protocol requirements

• Must satisfy the 2010 ACR/EULAR classification criteria for rheumatoid arthritis plus a disease duration of at least 6 months.

• Must have active RA with a DAS28 ≥3.2

• Must be RF and/or ACPA positive

• ≥ 3 swollen and/or tender joints of the hands

• At screening- visit patients should have been treated without alterations of therapy for at least three months with DMARDS (i.e. Methotrexate) with or without concomitant use of steroids).

• Glucocorticoids treatment up to 10mg prednisolone per day will be allowed at study entry.

  . Exclusion Criteria:

• Individuals not able to understand and follow study protocol and not able to voluntarily sign informed consent

• Individuals not willing to follow study protocol and sign informed consent

• Individuals with claustrophobia, tattoos containing metal, magnetic endoprostheses, surgery on bone in between a time interval < 3 months.

• Patients treated before with any biological or small molecule or medication under investigation for the treatment of RA.

• Patients with serious or chronic infections within the previous 3 months

• Opportunistic infections within the 6 months before screening

• Cancer within the 5 years before screening (with the exception of treated and cured squamous or basal cell carcinoma of the skin)

• History of severe congestive heart failure

• Current signs or symptoms of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal (a.e.diverticulitis), endocrine, pulmonary, cardiac, neurologic or cerebral disease

• Transplanted organ (with the exception of corneal transplantation done more than 3 months before screening)

• Evidence of active tuberculosis