American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 50% improvement in tender joint count;

• ≥ 50% improvement in swollen joint count; and

• ≥ 50% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI));
  • Acute phase reactant value (C-Reactive Protein).

Participants who withdrew early were considered non-responders.

The Full Analysis Set consisted of all patients who were randomized and who received at least one dose of double-blinded study medication. Participants with insufficient data to calculate ACR50 at Week 52 or who withdrew early were considered non-responders.

The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and Week 52 were scored in a blinded manner. Joints were scored for erosions on a scale from 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale from 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.

Full analysis set. For participants with missing data, mTSS was imputed by linear extrapolation.

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement.

Full analysis set with available data.

American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 50% improvement in tender joint count;

• ≥ 50% improvement in swollen joint count; and

• ≥ 50% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
  • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were considered non-responders.

Full analysis set. Participants with insufficient data to calculate ACR50 at Week 104 or who withdrew early were considered non-responders.

The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and Week 104 were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.

Full analysis set. For participants with missing data, mTSS was imputed by linear extrapolation.

The DAS28 is a validated index of rheumatoid arthritis disease activity. Twenty-eight tender joint counts, 28 swollen joint counts, C reactive protein, and general health were included in the DAS28 score. Scores on the DAS28 range from 0 to 10. A DAS28 score >5.1 indicates high disease activity, a DAS28 score <3.2 indicates low disease activity, and a DAS28 score <2.6 indicates clinical remission.

Full analysis set. Participants with insufficient data to calculate DAS28 at Week 52 or who withdrew early were considered non-responders.

The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 comprise the physical component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement.

Full analysis set with available data.

Major clinical response was defined as an American College of Rheumatology 70% (ACR70) response for any six continuous months, over 104 weeks of treatment. A participant was a responder if the following criteria for improvement from Baseline were met:

• ≥ 70% improvement in tender joint count;

• ≥ 70% improvement in swollen joint count; and

• ≥ 70% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
  • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were non-responders.

Full analysis set.

The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 5-8 comprise the mental component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement.

Full analysis set with available data.

American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 50% improvement in tender joint count;

• ≥ 50% improvement in swollen joint count; and

• ≥ 50% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
  • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were considered non-responders.

Full analysis set. Participants with insufficient data to calculate ACR50 or who withdrew early were considered non-responders.

American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 20% improvement in tender joint count;

• ≥ 20% improvement in swollen joint count; and

• ≥ 20% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
  • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were considered non-responders.

Full analysis set. Participants with insufficient data to calculate ACR20 or who withdrew early were considered non-responders.

American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 70% improvement in tender joint count;

• ≥ 70% improvement in swollen joint count; and

• ≥ 70% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire Disability Index [HAQ-DI]);
  • Acute phase reactant value (C-Reactive Protein).

Participants withdrawing early were considered non-responders.

Full analysis set. Participants with insufficient data to calculate ACR70 or who withdrew early were considered non-responders.

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement.

Full analysis set with available data.

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability.

Full analysis set. Missing values were considered to be < 0.3.

The HUI 2/3 is an assessment of various aspects of participants' health and ability to perform various tasks on a day-to-day basis, including reading, seeing, hearing, speaking, general outlook on life, pain/discomfort, ability to walk, use of hands, memory, ability to think/solve, and ability to perform basic activities such as eating, bathing, and dressing. The HUI 2/3 is a combined 15-item questionnaire based on a recall period of the previous 4 weeks. HUI-2 and HUI-3 scores are calculated independently. The HUI-2 score includes 6 attributes: Sensation, Mobility, Emotion, Cognition, Self-Care, and Pain. The HUI-3 score is comprised of 8 attributes: Vision, Hearing, Speech, Ambulation, Dexterity, Emotion, Cognition, and Pain.

The range of each score is from 0 (dead) to 1 (perfect health). An increase from Baseline indicates improvement.

Full analysis set with available data.

The SF-36 determined participants' overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 comprise the physical component and items 5-8 comprise the mental component of the SF-36. Scores on each item were summed and averaged (range = 0-100); increases from Baseline indicate improvement.

Full analysis set with available data.

ACR-N is a composite, continuous variable which measures the percentage of improvement from Baseline in individual participants based on the 7 core set variables of the ACR. ACR-N is defined as the smallest percent change from Baseline of 3 measures: tender joint counts (TJC), swollen joint counts (SJC), and the median percent improvement in the 5 remaining measures (Patient's Assessment of Pain, Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, Health Assessment Questionnaire - Disability Index [HAQ-DI], and C-Reactive Protein). A positive ACR-N value indicates improvement; a negative ACR-N value indicates worsening; ACR-N of 0 indicates no change.

Full analysis set with available data.

The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables:

• 28 tender joint counts,
• 28 swollen joint counts,
• C-reactive protein, and
• Patient's global assessment of disease activity.

Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

Full analysis set with available data.

Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints on each hand/wrist (17 joints) and each forefoot (6 joints) were scored for erosions on a scale of 0 = no erosions; 1 = 1 discrete erosion or ≤20% joint involvement; 2 = 2 separate quadrants with erosion or 21-40% joint involvement; 3 = 3 separate quadrants with erosion or 41-60% joint involvement; 4 = all 4 quadrants with erosion or 61-80% joint involvement; and 5 = extensive destruction with >80% joint involvement. Scores were summed to calculate the total erosion score, which ranges from 0 (no erosion)to 230 (worst). A large increase in erosion score is indicative of worsening, whereas a small change or no change is indicative of inhibition of joint erosion.

Full analysis set. Missing values were imputed.

Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joint space narrowing (JSN) scores were recorded for each hand/wrist (16 joints) and each forefoot (5 joints) on a 5-point scale (0 = no narrowing; 1 = up to 25% narrowing; 2 = 26-65% narrowing; 3 = 66-99% narrowing; and 4 = complete narrowing). Scores were summed to calculate the total score ranging from 0 (no narrowing) to 168 (maximum narrowing). A large increase in joint narrowing score is indicative of worsening, whereas a small change or no change is indicative of inhibition of JSN.

Full analysis set. Missing values were imputed.

The number of participants with no worsening in the modified Total Sharp Score (mTSS) and in erosion and joint space narrowing (JSN) scores, where no worsening is defined as a change from Baseline of ≤ 0 in mTSS, erosion score and JSN score, at Weeks 52 and 104.

Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.

Full analysis set. Participants with missing data or who withdrew early were considered non-responders.

The number of participants with no erosions at Baseline and no erosions at Weeks 52 and 104, where no erosions and no new erosions are defined as an erosion score = 0.

Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints on each hand/wrist (17 joints) and each forefoot (6 joints) were scored for erosions on a scale of 0 = no erosions; 1 = 1 discrete erosion or ≤20% joint involvement; 2 = 2 separate quadrants with erosion or 21-40% joint involvement; 3 = 3 separate quadrants with erosion or 41-60% joint involvement; 4 = all 4 quadrants with erosion or 61-80% joint involvement; and 5 = extensive destruction with >80% joint involvement. Scores were summed to calculate the total erosion score, which ranges from 0 (no erosion) to 230 (worst).

Full analysis set participants with no erosions at Baseline and non-missing data.

Number of participants with non-involved joints at Baseline and no newly involved joints at Weeks 52 and 104, where involved joints or no newly involved joints are defined as modified Total Sharp Score (mTSS) = 0.

Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]).

Full analysis set participants with non-involved joints at Baseline and non-missing data.

American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 20% improvement in tender joint count;

• ≥ 20% improvement in swollen joint count; and

• ≥ 20% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
  • Acute phase reactant value (C-Reactive Protein).

Baseline is the last value prior to the first dose of adalimumab. For participants randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase.

Intent-to-treat (ITT) Analysis Set (all patients who received at least 1 dose of adalimumab during the study, including patients who received their first dose during the DB phase and those who received MTX during the DB phase and adalimumab in the OL phase) with available ACR data. "N" indicates patients with non-missing data at each time point.

American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 50% improvement in tender joint count;

• ≥ 50% improvement in swollen joint count; and

• ≥ 50% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
  • Acute phase reactant value (C-Reactive Protein).

Baseline is the last value prior to the first dose of adalimumab. For patients randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase.

ITT Analysis Set with available ACR data. "N" indicates patients with non-missing data at each time point.

American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met:

• ≥ 70% improvement in tender joint count;

• ≥ 70% improvement in swollen joint count; and

• ≥ 70% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
  • Acute phase reactant value (C-Reactive Protein).

Baseline is the last value prior to the first dose of adalimumab. For patients randomized to the methotrexate (MTX) arm in the double-blind (DB) phase, Baseline was the last visit prior to the first adalimumab dose at Week 106 of the open-label (OL) phase.

ITT Analysis Set with available data. "N" indicates patients with non-missing data at each time point.

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement.

ITT Analysis Set, with available data. "N" indicates patients with non-missing data at each time point.

The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables:

• 28 tender joint counts,
• 28 swollen joint counts,
• C-reactive protein, and
• Patient's global assessment of disease activity.

Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

ITT Analysis Set, with available data. "N" indicates patients with non-missing data at Baseline and the specified time point.

The DAS28 is a composite score of rheumatoid arthritis disease activity derived from the following variables:

• 28 tender joint counts,
• 28 swollen joint counts,
• C-reactive protein, and
• Patient's global assessment of disease activity.

Scores on the DAS28 range from 0 to 10. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

ITT Analysis Set, with available data. The Number of Participants Analyzed indicates patients with non-missing DAS28 scores at any post-baseline time point; "N" indicates patients with non-missing data at each specified time point.

The modified TSS (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement.

ITT Analysis Set, with available data. "N" indicates patients with non-missing radiographic data at each time point.

The modified Total Sharp Score (mTSS) is a measure of change in joint health. Digitized images of radiographs of hands and feet obtained at screening and during the study were scored in a blinded manner. Joints were scored for erosions on a scale of 0 (no damage) to 5 (complete collapse) and joint space narrowing on a scale of 0 (no damage) to 4 (ankylosis or complete dislocation). Erosion scores and narrowing scores were added to obtain the mTSS (range = 0 [normal] to 398 [maximal disease]). An increase in mTSS from Baseline represents disease progression and/or joint worsening, no change represents halting of disease progression, and a decrease represents improvement. The number of participants with change from Baseline ≤ 0.5 and ≤ 0 is reported as a measure of no disease progression.

ITT Analysis Set, with available data. "N" indicates patients with non-missing radiographic data at each time point.

This outcome measure was not analyzed due to a protocol amendment.

A major clinical response was defined as maintenance of an ACR70 response for at least a 6-month continuous period at any time during the study following the first dose of adalimumab. A participant was a responder if the following criteria for improvement from Baseline were met:

• ≥ 70% improvement in tender joint count;

• ≥ 70% improvement in swollen joint count; and

• ≥ 70% improvement in at least 3 of the 5 following parameters:

  • Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]);
  • Patient's global assessment of disease activity (measured on a 100 mm VAS);
  • Physician's global assessment of disease activity (measured on a 100 mm VAS);
  • Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index [HAQ-DI]);
  • Acute phase reactant value (C-Reactive Protein).

ITT Analysis Set for participants with non-missing ACR data.

The Health Assessment Questionnaire - Disability Index (HAQ-DI) is a patient-reported questionnaire specific for rheumatoid arthritis. It consists of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and daily activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task were summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. A decrease in the HAQ-DI score represents an improvement in physical function; a clinically significant improvement is defined as a decrease of least 0.22 from Baseline in the HAQ-DI score. The number of participants with improvement in HAQ-DI of at least 0.22 and 0.5 units from Baseline is reported.

ITT Analysis Set, with available data. The Number of Participants Analyzed indicates patients with non-missing HAQ-DI scores at any post-baseline time point; "N" indicates patients with non-missing data at each specified time point.