Sarilumab

Adverse event (AE) was defined as any untoward medical occurrence in a participant who received IMP and did not necessary have to had a causal relationship with treatment. All AEs that occurred from the first dose of the IMP administration up to 6 weeks after last dose of treatment (up to Week 58) were considered as TEAEs. SAEs were AEs resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly or a medically important event. TEAEs included both SAEs and non-SAEs.

Criteria for potentially clinically significant vital sign abnormalities: * Systolic blood pressure (SBP) supine: \<=95 mmHg and decrease from baseline (DFB) \>=20 mmHg; \>=160 mmHg and increase from baseline (IFB) \>=20 mmHg * Diastolic blood pressure (DBP) supine: \<=45 mmHg and DFB \>=10 mmHg; \>=110 mmHg and IFB ≥10 mmHg * SBP (Orthostatic): \<=-20 mmHg * DBP (Orthostatic): \<=-10 mmHg * Heart rate (HR) supine: \<=50 beats per minute (bpm) and DFB \>=20 bpm; \>=120 bpm and IFB \>=20 bpm * Weight: \>=5% DFB; \>=5% IFB

Criteria for potentially clinically significant ECG abnormalities: * PR Interval: \>200 milliseconds (ms); \>200 ms and IFB \>=25%; \>220 ms; \>220 ms and IFB \>=25%; \>240 ms; \>240 ms and IFB \>=25% * QRS Interval: \>110 ms; \>110 ms and IFB \>=25%; \>120 ms; \>120 ms and IFB \>=25% * QT Interval: \>500 ms * QTc Bazett (QTc B): \>450 ms; \>480 ms; \>500 ms; IFB \>30 and \<=60 ms, IFB \>60 ms * QTc Fridericia (QTc F): \>450 ms; \>480 ms; \>500 ms; IFB \>30 and \<=60 ms; IFB \>60 ms

Criteria for potentially clinically significant abnormalities: * Hemoglobin: \<=115 g/L (Male\[M\]) or \<=95 g/L (Female\[F\]); \>=185 g/L (M) or \>=165 g/L (F); DFB \>=20 g/L * Hematocrit: \<=0.37 v/v (M) or \<=0.32 v/v (F); \>=0.55 v/v (M) or \>=0.5 v/v (F) * Red blood cells (RBC): \>=6 Tera/L * Platelets: \<50 Giga/L; \>=50 and \<100 Giga/L; \>=700 Giga/L * White blood cells (WBC): \<3.0 Giga/L (Non-Black \[NB\]) or \<2.0 Giga/L (Black \[B\]); \>=16.0 Giga/L * Neutrophils: \<1.5 Giga/L (NB) or \<1.0 Giga/L (B); \<1.0 Giga/L * Lymphocytes: \<0.5 Giga/L; \>=0.5 Giga/L and \<lower limit of normal (LLN); \>4.0 Giga/L * Monocytes: \>0.7 Giga/L * Basophils: \>0.1 Giga/L * Eosinophils: \>0.5 Giga/L or \>upper limit of normal (ULN) (if ULN \>=0.5 Giga/L)

Criteria for potentially clinically significant abnormalities: * Glucose: \<=3.9 mmol/L and \<LLN; \>=11.1 mmol/L (unfasted \[unfas\]) or \>=7 mmol/L (fasted \[fas\]) * Hemoglobin A1c (HbA1c): \>8% * Total cholesterol: \>=6.2 mmol/L; \>=7.74 mmol/L * LDL cholesterol: \>=4.1 mmol/L; \>=4.9 mmol/L * Triglycerides: \>=4.6 mmol/L; \>=5.6 mmol/L

Criteria for potentially clinically significant abnormalities: * Sodium: \<=129 mmol/L; \>=160 mmol/L * Potassium: \<3 mmol/L; \>=5.5 mmol/L * Chloride: \<80 mmol/L; \>115 mmol/L

Criteria for potentially clinically significant abnormalities: * Creatinine: \>=150 micromol/L (adults); \>=30% change from baseline, \>=100% change from baseline * Creatinine clearance: \<15 mL/min; \>=15 to \<30 mL/min; \>=30 to \<60 mL/min; \>=60 to \<90 mL/min * Blood urea nitrogen: \>=17 mmol/L * Uric acid: \<120 micromol/L; \>408 micromol/L

Criteria for potentially clinically significant abnormalities: * Alanine Aminotransferase (ALT): \>1 ULN and \<=1.5 ULN; \>1.5 ULN and \<=3 ULN; \>3 ULN and \<=5 ULN; \>5 ULN and \<=10 ULN; \>10 ULN and \<=20 ULN; \>20 ULN * Aspartate aminotransferase (AST): \>1 ULN and \<=1.5 ULN; \>1.5 ULN and \<=3 ULN; \>3 ULN and \<=5 ULN; \>5 ULN and \<=10 ULN; \>10 ULN and \<=20 ULN; \>20 ULN * Alkaline phosphatase: \>1.5 ULN * Total bilirubin (TBILI): \>1.5 ULN; \>2 ULN * Conjugated bilirubin(CBILI): \>1.5 ULN * Unconjugated bilirubin: \>1.5 ULN * ALT \>3 ULN and TBILI \>2 ULN * CBILI \>35% TBILI and TBILI \>1.5 ULN * Albumin: \<=25 g/L

DAS28-ESR is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); GH assessment by the participant assessed from the ACR and RA core set questionnaire (participant global assessment) in 100 mm VAS; Marker of inflammation assessed by ESR in mm/hr. The DAS28-ESR score provides a number indicating the current disease activity of the RA. DAS28-ESR total score ranges from 2-10. A DAS28-ESR score above 5.1 means high disease activity, DAS28-ESR score below 3.2 indicates low disease activity and DAS28-ESR score below 2.6 means disease remission. Least square (LS) mean and standard error (SE) at Week 24 were obtained using Mixed-effect model with repeated measures (MMRM) approach.

A PTF was defined as any product technical complaint (PTC) related to the use of the AID that had a validated technical cause. Each participant was given a diary having questions related to participant's ability to remove the cap, to start the injection, to complete the injection and regarding confirmation of completing the injection. Participants were asked to answer the questions each time they self-inject the sarilumab. If the response was "no" to any of the first 3 questions, this was considered as a PTC. The used AID, for which PTC was reported, was sent to sponsor, examined and evaluated for the occurrence of a PTF.

ACR responses are assessed with a composite rating scale of the American College of Rheumatology that includes 7 variables: tender joint count (TJC); swollen joint count (SJC); levels of an acute phase reactant (C-reactive Protein levels \[CRP\]); participant's assessment of pain; participant's global assessment of disease activity; physician's global assessment of disease activity; participant's assessment of physical function by (health assessment questionnaire disability index \[HAQ-DI\]). ACR20 is defined as achieving at least 20% improvement in both TJC and SJC, and at least 20% improvement in at least 3 of the 5 other assessments of the ACR.

Physical function was assessed by HAQ-DI. It consisted of at least 2 questions per category, participant reported assessment of ability to perform tasks in 8 categories of daily living activities: dress/groom; arise; eat; walk; reach; grip; hygiene; and common activities over past week rated on a 4-point scale where 0 = no difficulty; 1 = some difficulty; 2 = much difficulty; 3 = unable to do. Overall score was computed as the sum of category scores and divided by the number of categories answered, ranging from 0 to 3, where 0 = no disability and 3 = unable to do, high-dependency disability. Least-squares (LS) means and standard errors (SE) at Week 12 were obtained from a mixed-effect model with repeated measures (MMRM) with treatment, region, number of previous anti-TNFs, visit, and treatment-by-visit interaction as fixed effects and baseline HAQ-DI as a covariate.

The Cmax was defined as maximum serum concentration. The values reported are mean and standard deviation.

The AUC0-t was defined as area under the concentration in serum versus time curve calculated using the trapezoidal method during a dose interval (tau). The values reported are mean and standard deviation.

The Ctrough was defined as concentration observed before treatment administration during repeated dosing from baseline to Week 12. The values reported are mean and standard deviation.

At least 2-step reduction in VH per central review from baseline was evaluated on Miami 9-step scale. VH is the obscuration of fundus by vitreous cells and protein exudation. Each of the 9-step scale (from grade 0 \[low opacity\] to 8 \[more opacity\]) images (in increasing order of opacity) are equivalent to approximately 0.3 log units of degradation in visual acuity based on the Bangerter calibration. Participants with prednisone dose \<10 mg/day (or equivalent oral corticosteroid) were also evaluated.

ACR20 response was defined, based on guidelines set forth by the American College of Rheumatology (ACR), as ≥20 % improvement in tender joint count and swollen joint count as well as ≥20% improvement in at least 3 of 5 following measures: C-Reactive Protein (CRP), Participant assessment of pain; Participant's global assessment of disease activity; Physician global assessment of disease activity; and Health Assessment Question-Disability Index (HAQ-DI). Missing data imputed by Last Observation Carried Forward (LOCF).

ACR20 improvement responses were determined without imputation of missing post-baseline values. In addition data collected after treatment discontinuation or rescue was set to missing. Responder status was determined if possible. With these rules, participants automatically became non-responders for all time points beyond the time point they started rescue treatment or discontinued study treatment.

HAQ-DI was a participant-reported questionnaire that assesses the difficulty of performing daily activities: dress/groom, arise, eat, walk, reach, grip, hygiene and common activities. Overall score range from 0=least difficulty to 3=extreme difficulty. An increase in the score indicates a worsening of physical function while a decrease in the score represents improvement. Data collected after treatment discontinuation was set to missing.

The Sharp method modified by D. van der Heijde involves separate scores for erosions and joint space narrowing based on radiographs to assess the degree of structural damage. Total score range from 0 (normal) to 448 (worst possible total score). An increase in total score represents progression of structural damage. Missing data were imputed by the linear extrapolation method.

Clinical response to treatment for ASAS20 was assessed according to ASAS20 criteria. Treatment response for ASAS20 was defined as an improvement by a decrease of ≥20% and ≥1unit on a 0 (no pain) - 10 (most severe pain) numerical rating scale (NRS) in at least 3 of the 4 ASAS improvement criteria (ASAS-IC) domains: assessment of physical function (measured by Bath Ankylosing Spondylitis Functional Index \[BASFI\]), back pain (0-10 NRS), participant global assessment (0-10 NRS) and inflammation (measured as the mean of the last 2 Bath Ankylosing Spondylitis Disease Activity Index \[BASDAI\] questions) and no worsening (increase in score) of ≥20% and ≥1 unit on a 0-10 NRS in the remaining 4th domain.

Area under the concentration versus time curve from time zero to time corresponding to the last measurable concentration, tlast.

Maximum concentration observed.

Concentration observed before treatment administration during repeated dosing at steady state.