Safety and Efficacy of Adalimumab in Patients With Active Ankylosing Spondylitis

ASAS 20 responders - improvement of >=20% and absolute improvement of >=10 units from Baseline in a visual analog scale (VAS) 0 [no disease activity]-100 [high disease activity]) for >=3 of 4 domains; Patient's Global Assessment of disease activity VAS; (0[none]-100 [severe]), Total Back Pain VAS; (0 [no pain]-100 [severe]), BAth Ankylosing Spondylitis Functional Index (BASFI) VAS (0 [easy ]-100[impossible]); and Inflammation VAS; (1 [no pain] to 10 [severe pain]) and absence of deterioration in the potential remaining domain. Applied to each scale and not to an overall global scale.

Radiographic progression was based on change in mSASSS scoring (comparison of the means) from double-blind Baseline visit to Week 104. The mSASSS is the sum of the lumbar and cervical spine score ( 0 [no change] to 72 [progression]), derived from scoring the anterior site of the lumbar spine (T12 to S1) and the cervical spine (C2 to T1) as either 0 (normal), 1 (erosion, sclerosis, or squaring), 2 (syndesmophyte), 3 (bridging syndesmophyte), or N (vertebral body not evaluable). Data from NCT00195819 was compared with data from AS patients in OASIS.

ASAS 20 responders - improvement of >=20% and absolute improvement of >=10 units from Baseline in a visual analog scale (VAS) 0 [no disease activity]-100 [high disease activity]) for >=3 of 4 domains; Patient's Global Assessment of disease activity VAS; (0[none]-100 [severe]), Total Back Pain VAS; (0 [no pain]-100 [severe]), BASFI VAS (0 [easy ]-100[impossible]); and Inflammation VAS; (1 [no pain] to 10 [severe pain]) and absence of deterioration in the potential remaining domain. Applied to each scale and not to an overall global scale

ASAS 50 responders - improvement of >=50% and absolute improvement of >=20 units (0-100) from Baseline in visual analog scale (VAS) for >=3 of the 4 domains; Patient's Global Assessment of disease activity; (0[none]-100[severe]) VAS scale; Total Back Pain VAS; (0 [no pain]-100 [severe]); BASFI VAS; (0 [easy ]-100[impossible]) and Inflammation VAS; (1 [no pain] to 10 [severe pain]). In addition, absence of deterioration in the potential remaining domain. Applied to each scale and not overall global scale.

ASAS 70 responders - improvement of >=70% and absolute improvement of >=30 units (0-100) from Baseline in visual analog scale (VAS) for >=3 of the 4 domains; Patient's Global Assessment of disease activity VAS; (0[none]-100[severe]) Total Back Pain VAS; (0 [no pain]-100 [severe]); BASFI VAS; (0 [easy ]-100[impossible]) and Inflammation VAS; 1 [no pain] to 10 [severe pain]). In addition, absence of deterioration in the potential remaining domain. Applied to each scale and not to an overall global scale.

Evaluation of the effect of adalimumab 40 mg every other week (eow) on patient's global assessment of disease activity. The patient was to assess his/her disease activity in the past week using a visual analog scale (VAS) on a scale of 0 to 100 mm with no activity being indicated by 0 and severe activity by 100.

The patient assesses his/her disease activity for the past week using a Patient Global Assessment of Disease on visual analog scale (VAS) with 0 being none and 100 being severe.

BASFI consist of a set of 10 questions designed to determine the degree of functional limitation in subjects with AS. The BASFI score was derived based on the average of questions 1 through 10. The first 8 questions considered activities related to functional anatomy and the final 2 questions assessed the subject's ability to cope with everyday life over the last week. A 10 cm visual analog scale (VAS) was used to answer the questions and the mean of the ten scales gave the BASFI score a value between 0 (easy) and 10 (impossible).

BASFI consisted of 10 Visual Analog Scale (VAS) questions with a response ranging from 0 (easy) to 100 (impossible). The BASFI score was derived based on the average of questions 1 through 10. A responder is a subject who demonstrates an absolute improvement of at least 10 units and a percentage improvement of at least 20% from Baseline.

Evaluation of the effect of 40 mg every other week (eow) adalimumab on Total Back Pain VAS. The subject was to assess his/her disease activity in the past week using a total spine VAS on a scale 0 (no pain) to 100 (severe pain).

A responder is a subject who demonstrates an absolute improvement of at least 10 units and a percentage improvement of at least 20% from Baseline.

The inflammation score is the mean of the two morning stiffness-related BASDAI visual analog scale (VAS) scores (items 5 and 6 of the BASDAI) of 0 (none) to 10 (very severe). A decrease in inflammation represents improvement.

A responder is a subject who demonstrates an absolute improvement of at least 10 units and a percentage improvement of at least 20% from Baseline in inflammation (mean of the BASDAI questions 5 and 6 on scale of 0 [none] to 10 [very severe].

The BASDAI is a questionnaire with 6 questions that subject completes by marking answers on a 10-cm Visual Analog Scale (VAS) during the last week with responses that range from 0 (none) to 100(very severe) and measures severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness. The final BASDAI score ranges from 0 (none) to 10 (very severe). Improvement in BASDAI by 20% was assessed. BASDAI Scoring:

• Measure each item of the BASDAI in centimeters (out of a total of 10)
• BASDAI Score = 0.2 (Item 1 + Item 2 + Item 3 + Item 4 + Item 5/2 + Item 6/2).

The BASDAI is a questionnaire with 6 questions that subject completes by marking answers on a 10-cm Visual Analog Scale (VAS) during the last week with responses that range from 0 (none) to 100 (very severe) and measures severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness. The final BASDAI score ranges from 0 to 10. Improvement in BASDAI by 50% was assessed. BASDAI Scoring:

• Measure each item of the BASDAI in centimeters (out of a total of 10)
• BASDAI Score = 0.2 (Item 1 + Item 2 + Item 3 + Item 4 + Item 5/2 + Item 6/2).

The BASDAI is a questionnaire with 6 questions that subject completes by marking answers on a 10-cm Visual Analog Scale (VAS) during the last week with responses that range from 0 (none) to 100 (very severe) and measures severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness. The final BASDAI score ranges from 0 to 10. Improvement in BASDAI by 70% was assessed. BASDAI Scoring:

• Measure each item of the BASDAI in centimeters (out of a total of 10)
• BASDAI Score = 0.2 (Item 1 + Item 2 + Item 3 + Item 4 + Item 5/2 + Item 6/2).

The BASDAI is a questionnaire with 6 questions that subject completes by marking answers on a 10-cm Visual Analog Scale (VAS) during the last week with responses that range from 0 (none) to 100 (very severe) and measures severity of fatigue, spinal and peripheral joint pain, localized tenderness and morning stiffness. The final BASDAI score ranges from 0 (none) to 10 (severe). A decrease in BASDAI represents improvement. BASDAI Scoring: 1) Measure each item of the BASDAI in centimeters (out of a total of 10) 2) BASDAI Score = 0.2 (Item 1 + Item 2 + Item 3 + Item 4 + Item 5/2 + Item 6/2).

Evaluation of the mean changes in CRP in subjects with adalimumab exposure from Baseline through 5 years. The test for CRP is a laboratory measurement for evaluation of an acute phase reactant of inflammation via the use of an ultrasensitive assay. A decrease in the level of CRP indicate reduction in inflammation. A decrease in CRP indicates improvement.

ASAS 40 responder: improvement of >= 40% and absolute improvement of >= 20 units (on a scale of 0 to 100) in >= 3 of the 4 domains: Patient global assessment (VAS score [0-100 scale]); Pain (Total Back Pain VAS score 0-100 scale); Function (BASFI score 0-100 scale); Inflammation (the mean of the two morning stiffness-related BASDAI VAS scores (i.e. the average of items 5 and 6 of the BASDAI. Applied to each scale. In addition, absence of deterioration in the potential remaining domain, where deterioration is defined as a net worsening of > 0 units (on a scale of 0 to 100).

The change in ASAS 5/6 was evaluated for the effect of adalimumab on structural damage.

ASAS 5/6 criteria is the 20% improvement in 5 out of 6 domains (physical function [BASFI], Total Back Pain, Patient's Global Assessment of Disease Activity, Inflammation [mean of Questions 5 and 6 of the BASDAI], spinal mobility [BASMI], and acute phase reactants [CRP]).

Evaluation of the mean changes in BASDAI in subjects with adalimumab exposure from Baseline through 5 years for the effect of adalimumab on structural damage. Partial remission was calculated as follows: A value below 20 on a 0 - 100-point scale in each of the four domains of the ASAS (Patient's Global Assessment of Disease Activity, Pain, Function and Inflammation). Partial remission is also regarded as a low disease activity state.

BASMI measures the range of motion based on five clinical measurements: 1) cervical rotation, 2) tragus to wall distance, 3) lumbar side flexion, 4) lumbar flexion (modified Schober's) and 5) intermalleolar distance. BASMI 0 = indicates mild disease involvement, 1 = moderate disease, and 2 = severe disease involvement. The results for cervical rotation and lumbar side flexion are the means of the left and right measurements. Scoring range 0-10. The higher the BASMI score, the more severe was the subject's limitation of movement due to their AS.

The EDASMI is a composite spinal mobility index comprised of 4 measures: 1) cervical rotation, 2) lumbar side flexion, 3) chest expansion, and 4) hip internal rotation spread. A grade of 0-4 scoring system was developed for each of the measures. The sum of 4 items (range 0 to 16) provide the EDASMI score. Decrease in EDASMI represents improvement. All EDASMI measures were done with a simple tape measure and recorded in centimeters (cm) by a rheumatologist and a clinician nurse.

The patient is in a sitting position on the examination table with the hands on the hips. A pen mark is made at the xiphisternum and a tape measure placed around the circumference of the patient's chest at this level. The patient is asked to take a deep breath and to exhale as completely as possible while looking directly ahead. The measurement (in cm) is noted. The patient is asked to inhale as deeply as possible and the measurement (in cm) is noted. The difference in the 2 measurement points (in cm) constitutes the value for CE.

An increase in chest expansion represents improvement

MASES is measured by scoring of entheses of 0 (no tenderness) to 3 (severe tenderness) at 13 sites on the body. The score was derived as the sum of the 13 scores divided by 3 and the total range is 0 (no tenderness) to 13 (severe tenderness).

BAS-G consisted of two questions that asked the subject to indicate, on a 10 cm VAS, the effect the disease had on their well being over 1) last week, and 2) last 6 months. BAS-G was measured by two VAS scores (0 to 100 mm) to reflect the effect of Ankylosing Spondylitis on subject's well-being over the past week and over the last 6 months, respectively. The average of these two scores was reported. The mean of the two scores give a BAS-G score of 0-10.

Change from Baseline in the swollen joint index. An assessment of 44 joints for SJC done by physical examination. Joint swelling was classified as present ("1"), absent ("0") or injected/replaced ("9"). The joints assessed were: Sternoclavicular, Acromioclavicular, Shoulder, Elbow, Wrist, Metacarpophalangeal (1-5), Thumb interphalangeal, Proximal interphalangeal (2-5, Knee, Ankle, and Metatarsophalangeal (1-5).

Assessment of 46 joints for TJC was done by physical examination. Joint tenderness was classified as present ("1"), absent ("0") or injected/replaced ("9"). The joints assessed were: Sternoclavicular, Acromioclavicular, Shoulder, Elbow, Wrist, Metacarpophalangeal (1-5), Thumb interphalangeal, Proximal interphalangeal (2-5, Knee, Ankle, and Metatarsophalangeal (1-5).

The physician will globally assess the subject's current disease state using a VAS scale with 0 being very good and 100 being very bad.

The subject was to assess his/her nocturnal pain intensity for the past week using a Nocturnal Pain Visual Analog Scale (Nocturnal Pain VAS). The range was 0 to 100 mm with no pain being indicated by 0 and worse possible pain by 100.

The FACIT-Fatigue scale: overall score of 13 general questions divided into four primary Quality of Life (QoL) domains: 1) Physical Well-Being, 2) Social/Family Well-Being, 3) Emotional Well-Being, and 4) Functional Well-Being. For each question subject rates his/her condition for the past week on a 5-point scale ranging from 0 (not at all) to 4 (very much). The score ranges from 0 (highest level of fatigue) to 52 with 52 being the lowest level of fatigue.

Change from Baseline in the SF-36 Health Survey Index completed by Subject to help subject keep track of how he/she was feeling and how well he/she was able to do usual activities. Components of the SF-36 included the PCS and MCS, respectively. An increase in SF-36 PCS or MCS indicate improvement.

SF-36 is a standardized survey evaluating 8 aspects of functional health and well being; physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for a section is an average of the individual question scores, which are scaled 0(no functioning)to 100 (highest level of functioning).

Responders were subjects with MCID > 3 points. Minimal clinically important difference (MCID) for PCS was determined by a >= 3.0 point increase during exposure to adalimumab.

SF-36 is a standardized survey evaluating 8 aspects of functional health and well being; physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for a section is an average of the individual question scores, which are scaled 0 (no functioning) to 100 (highest level of functioning). Change from Baseline in the SF-36 Health Survey Index was completed by Subject. Components of the SF-36 included the PCS and MCS, respectively. An increase in SF-36 PCS or MCS indicated improvement.

SF-36 is a standardized survey completed by Subject, evaluating 8 aspects of functional health and well being; physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The score for a section is an average of the individual question scores, which are scaled 0 (no functioning) to 100 (highest level of functioning). Responders are subjects with MCID > 3 points. Minimal clinically important difference (MCID) for PCS was determined by a >= 3.0 point increase during exposure to adalimumab.

Change from baseline in Health Utility Index Mark 3 (HUI-3) was reported. The HUI-3 is a generic approach to the measurement of health status and assessment of HRQL. The HUI-3 was comprised of two complementary components. The first component was a multi-attribute health status classification system that was used to describe health status. The second component was a multi-attribute utility function that was used to value health status as measured within the corresponding multi-attribute health status classification system. An increase in the HUI-3 score represents improvement.

ASQoL determined subject's quality of life and is comprised of 18 questions (yes or no) to be completed by the subject. Each statement on the ASQoL is given a score of "1" or "0." All item scores were summed to give a total score or index. Total scores ranged from 0 (good quality of life) to 18 (poor quality of life) related to ability to cope, relationships, mood, sleep, motivation, activities of everyday living, independence, and social life. Decrease in ASQoL score represents improvement.

ASQoL determined subject's quality of life comprised of 18 questions to be completed by the subject. Each statement on the ASQoL is given a score of "1" or "0." All item scores were summed to give a total score. Total scores ranged from 0 (good quality of life) to 18 (poor quality of life) related to ability to cope, relationships, mood, sleep, motivation, activities of everyday living, independence, and social life. Decrease in ASQoL score represents improvement. Responders are subjects with MCID <= -1.8 points. MCID was determined by a >= 1.8 score decrease during exposure to adalimumab.

Completed by subject at each visit. The MCIS was a patient reported outcome where the subjects were expected to respond (yes/no) to the following question:

Considering all the different ways your disease is affecting you, if you would stay in this state for the next months, do you consider that your current state is satisfactory? An increase in PASS indicates improvement.

During earlier weeks of the study PASS was measured/reported as minimal clinically important state (MCIS).

Cartilage and bone degradation were assessed by evaluating changes in MMP-3. A decrease in MMP-3 represents improvement.

Cartilage and bone degradation were assessed by evaluating changes in CTX-II. A decrease in CTX-II represents improvement.

Cartilage degradation and bone resorption were assessed by evaluating changes in NTx. A decrease in NTx represents improvement.

The S.P.A.R.C.C. MRI index is a tool for scoring inflammation and structural damage in both the spine and sacroiliac (SI) joints. The spinal SPARCC index score consists of 3 subscales (edema, intense edema, and deep edema). Edema was defined as the presence of increased STIR signal in each of 4 Discovertebral unit (DVU) quadrants and was assigned a score (0 = normal signal, 1 = increased signal). The scoring of edema was repeated for each of 3 consecutive sagittal slices with a maximum score of 12 per DVU (range for edema, 0-72). The total spinal SPARCC index score is 0 to 108.

The S.P.A.R.C.C. MRI index is a tool for scoring inflammation and structural damage in both the spine and sacroiliac (SI) joints. The spinal SPARCC index score consists of 3 subscales (edema, intense edema, and deep edema). Edema was defined as the presence of increased STIR signal in each of 4 Discovertebral unit (DVU) quadrants and was assigned a score (0 = normal signal, 1 = increased signal). The scoring of edema was repeated for each of 3 consecutive sagittal slices with a maximum score of 12 per DVU (range for edema, 0-72). The total spinal SPARCC index score is 0 to 108.