PHASE 4, MULTICENTER RANDOMISED STUDY, AIMED AT EVALUATING THE MAINTENANCE OF REMISSION AFTER 6, 12, 18 AND 24 MONTHS FROM SUSPENSION OF TNF-ALPHA THERAPIES (ADALIMUMAB, ETANERCEPT, INFLIXIMAB, CERTOLIZUMAB PEGOL, GOLIMUMAB) IN RHEUMATOID ARTHRITIS (RA) PATIENTS

INTERVENTION: Trade Name: HUMIRA ‐ 40 MG SOLUZIONE INIETTABILE USO SOTTOCUTANEO 2 SIRINGHE PRERIEMPITE 0.8 ML + 2 TAMPONI IMBEVUTI DI ALCOL IN 1 BLISTER Product Name: HUMIRA (ADALIMUMAB) Product Code: [NA] Pharmaceutical Form: Solution for injection INN or Proposed INN: ADALIMUMAB Current Sponsor code: NA Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 50‐ Trade Name: CIMZIA ‐ 200MG‐SOLUZIONE INIETTABILE‐USO SOTTOCUTANEO‐SIRINGA PRERIEMPITA(VETRO) 1ML 6(3X2) SIRINGHE PRERIEMPITE+6(3X2) SALVIETTINE IMBEVUTE DI ALCOOL Product Name: CIMZIA (Certolizumab Pegol) Product Code: [NA] Pharmaceutical Form: Solution for injection INN or Proposed INN: CERTOLIZUMAB PEGOL Current Sponsor code: NA Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 200‐ Trade Name: ENBREL ‐ 50 MG POLV SOLUZ INIET SOTTOC. POLV. FLAC VETRO SOLV. SIRI. VET. SOLV 1 ML (50 MG/ML) 12 FLAC+12 SIRI. PRE+12 AGHI+12 ADAT PER FLAC+24 TAMP. PRE INIEZ Product Name: ENBREL (Etanercept) Product Code: [‐] Pharmaceutical Form: Powder and solvent for solution for injection INN or Proposed INN: ETANERCEPT Current Sponsor code: NA Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 25‐ Trade Name: REMICADE ‐ 100 MG POLVERE PER CONCENTRATO PER INFUSIONE ENDOVENOSA 1 FLACONE VETRO 20 ML USO EV Product Name: REMICADE (INFLIXIMAB) Product Code: [‐] Pharmaceutical Form: Powder for solution for injection INN or Proposed INN: INFLIXIMAB Current Sponsor code: NA Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 10‐ Trade Name: SIMPONI ‐ 50 MG‐SOLUZIONE PER INIEZIONE IN PENNA PRERIEMPITA‐USO SOTTOCUTANEO‐PENNA PRERIEMPITA(VETRO) ‐0.5 ML 3 (3X1) PENNE PRERIEMPITE P CONDITION: RHEUMATOID ARTHRITIS (RA) PATIENTS ; MedDRA version: 23.1 Level: LLT Classification code 10003268 Term: Arthritis rheumatoid System Organ Class: 100000004859 Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: The primary objective is the evaluation of sustained remission of disease activity after 6, 12,18 and 24 months from anti‐TNF suspension in AR patients. Primary end point(s): Evaluation of number of RA patients that maintain clinical remission after 6, 12, 18 and 24 months from suspension of anti TNF‐alpha therapy (i.e. infliximab, adalimumab, etanercept, certolizumab pegol, golimumab) Secondary Objective: • to evaluate the differences between the group of patients that suspending the anti TNF by the tapering and the patients without tapering. ; • to evaluate the maximum latency of administration efficacy, only in the arm A ; • to evaluate the correlation between sustained remission after anti‐TNF suspension and combined therapy with classical DMARDs ; • to evaluate the ultrasound echography at baseline and after 3, 6, 12 18 and 24 months from anti‐TNF suspension ; • radiographic articular evaluation at baseline and after 12 and 24 months from anti‐TNF suspension ; • to evaluate correlation between clinical and instrumental evaluation and disease activity; Timepoint(s) of evaluation of this end point: 24 months SECONDARY OUTCOME: Secondary end point(s): ‐ Number of patients that maintain remission after suspension of TNF‐alpha therapy (i.e. infliximab, adalimumab, etanercept, certolizumab pegol, golimumab) either with a tapering schedule and without any tapering schedule ; ‐ clinical remission (DAS 28, CDAI, SDAI, ACR remission criteria) at baseline and 6, 12, 18 and 24 months) ; ‐ ultrasound evaluation (score 0‐4) at 3, 6, 12, 18 and 24 months. ; ‐ radiographic articular evaluation (at baseline and after 12 and 24 months) ; ‐ Quality‐of‐life measured by the SF‐36 and HAQ questionnaires (Italian version) at baseline and after , 6, 12, 18 and 24 months ; ; ‐ Number of patients that maintain remission after suspension of TNF‐alpha therapy (i.e. infliximab, adalimumab, etanercept, certolizumab pegol, golimumab) either with a tapering schedule and without any tapering schedule ; ‐ clinical remission (DAS 28, CDAI, SDAI, ACR remission criteria) at baseline and 6, 12, 18 and 24 months) ; ‐ ultrasound evaluation (score 0‐4) at 3, 6, 12, 18 and 24 months. ; ‐ radiographic articular evaluation (at baseline and after 12 and 24 months) ; ‐ Quality‐of‐life measured by the SF‐36 and HAQ questionnaires (Italian version) at baseline and after , 6, 12, 18 and 24 months ; Timepoint(s) of evaluation of this end point: 24 months ; 24 months INCLUSION CRITERIA: 1. Able to comply and give informed consent; 2. Age > 18 and < 70 years; 3. diagnosis of RA according to ACR Criteria 4. clinical remission since at least 12 months (DAS 28 = 2.6, ACR remission criteria) 5. current therapy with anti TNF‐alpha (adalimumab, etanercept o infliximab, certolizumab pegol, golimumab) from at least 15 months 6. = 6 mg/die of 6‐methylprednisolone at stable dose for at least 3 months. 7. if the patient takes stable DMARDs (Methotrexate or Leflunomide or Hydroxicloroquine) therapy they must be at a stable dose for at least 3 months. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 50 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 10