Effectiveness of RA drugs
If you have RA, you will want to become familiar with the basic language used to discuss the efficacy and safety of drugs and other treatments. This language can seem difficult at first. But once you have learned some common terms and read through several articles reporting results from clinical trials, you will start to build a vocabulary and gain an understanding that will pay dividends in the long run. Remember, knowledge is power. A little knowledge about how we measure the efficacy and safety of treatments will give you insights into the relative strengths and weaknesses of treatments and allow you to ask the right questions as you work with your doctor to plan your RA management strategy.
Determining the efficacy of a treatment
There are a variety of symptom and laboratory measures that tell us about RA disease activity. There are also systems for scoring these symptoms and measures that are used by doctors to evaluate RA disease activity and the effectiveness of the treatments for controlling disease activity.
Individual symptom measures include counts of swollen and tender joints, pain, and laboratory measurements such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Individual measures have been brought together into core sets of criteria for disease activity and composite indices of disease activity. Questionnaires have also been developed to measure the impact of RA on the patient’s functional ability and level of disability. Additionally, systems have been developed to evaluate radiographic and other imaging information to determine the extent of damage to joints and related structures.1
Individual measures of disease activity. Individual measures recognized as indicators of RA disease activity include:
- Swollen and tender joint counts (typically based on assessment of swelling and tenderness in 28 specific joints)
- Pain (patient reported using a visual analog scale [VAS])
- Global assessments of disease activity (patient and physician assessments)
- Acute phase reactants (eg. erythrocyte sedimentation rate [ESR] and CRP)
- Duration of morning stiffness
- Individual symptoms, such as fatigue and weakness
Core criteria for disease activity
Different groups of doctors specializing in RA, such as the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR), have developed core sets of measures for assessing disease activity (including remission) and responses to treatment.
For instance, the ACR core set includes a total of seven measures: (1) swollen joint count, (2) tender joint count, (3) global assessment of disease activity (by physician), (4) patient self-report of functional status, (5) patient self-report of pain, (6) global assessment of disease activity (by patient), and (7) a laboratory measure (ESR or CRP).1
Composite indices of disease activity
Composite indices (indices is the plural of index, which is a list or record, such as the index at the end of a book) are combined core sets of measures, where each measure in a core set is assigned a score and all the individual scores are totaled up to give a combined total score of disease activity.
Examples of composite indices often used in clinical trials include the Disease Activity Score (DAS) and a concise version of DAS covering 28 items called the DAS28, the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI).
The DAS includes a count of swollen joints covering 44 joints and a complicated system of evaluating joint tenderness. The DAS28 is a modification of the DAS that made this composite index more practical, reducing the number of joints evaluated to 28. The DAS28 places emphasis on counts of swollen and tender joints, as well as measurement of acute phase reactants (ESR and CRP).1
The SDAI is a composite index that combines five core set measures:
- Tender joint count (28 joints)
- Swollen joint count (28 joints)
- Global assessment by patient (0 to 10 scale)
- Global assessment by physician (0 to 10 scale)
- CRP level
CDAI is a simplified version of SDAI that does not require measurement of CRP.
Patient-reported outcome measures. Patient-reported outcome measures commonly used in clinical trials include the Patient Activity Scale (PAS or PAS-II), the Rheumatoid Arthritis Disease Activity Index (RADAI), the Rapid Assessment of Disease Activity in Rheumatology (RADAR), and the Routine Assessment of Patient Index Data (RAPID3).1
PAS or PAS-II are generic patient-reported measures of disease activity across different rheumatic disorders.1
RADAI is a 5-item instrument that includes joint counts based on patient assessments. RADAR is 2-page questionnaire that includes 6 items covering RA symptoms, physical functioning, impact on work, psychological status, social health status, and patient satisfaction with health status.1
The RAPID3 (an expansion of the original RAPID) score is based on patient-reported outcomes covering areas including functional capacity and disability, physical function, pain, and patient global estimate.1
Functional capacity and disability indices. Various indices are used to measure disability related to RA and functional capacity. The Medical Outcomes Study Short Form 36 (SF-36) is a commonly used questionnaire used to measure general health status. Functional capacity is often measured using the Health Assessment Questionnaire (HAQ).
The SF-36 is a questionnaire designed to evaluate overall health status and quality of life. It is completed by the patient and consists of 36 questions that fall into 8 categories (called domains) that cover the range of health areas that contribute to well-being. These include: (1) physical function, (2) physical role, (3) general health, (4) bodily pain, (5) mental health, (6) social function, (7) vitality/fatigue, and (8) emotional role.1
The HAQ is another questionnaire designed to evaluate disability, discomfort, side effects from medication and other factors that contribute to patient well-being. The HAQ-Disability Index (HAQ-DI), the part of the HAQ that focuses on disability, is most often seen in clinical trials of treatments for RA and is a component in the ACR set of core measures. The HAQ-DI uses a series of questions (20 in total) to evaluate the patient’s ability to take part in activities of daily living, including dressing, rising, eating, walking, hygiene, reach, and grip. The HAQ asks the patient to rate their ability to perform each activity on 4-point scale, where 0 signifies no difficulty and 3 signifies total inability.1
Measuring response (efficacy) in clinical trials of treatment
There are certain common efficacy endpoints that you will encounter as you read results from clinical trials of RA treatments. Perhaps the most common is the ACR response criteria (these include ACR20, 50, and 70). The ACR response criteria are based on the ACR set of core measures. In the context of a clinical trial, an ACR20 response means a 20% improvement from the beginning of the trial (or baseline measurement). Similarly, ACR50 and 70 mean a 50% and 70% improvement, respectively, in ACR core measures from baseline.1
American College of Rheumatology 20 percent improvement (ACR20)
At least 20 percent improvement in:
1. Swollen joint count
2. Tender joint count
and 3 of the following 5 variables
3. Patient assessed global disease activity
4. Physician assessed global disease activity
5. Patient pain assessment
6. Functional disability (by HAQ)
7. Acute phase response (ESR or CRP)
Adapted from Smolen JS, Aletaha D. Assessment of rheumatoid arthritis activity in clinical trials and clinical practice. In: Maini RN, Romain PL, eds. UptoDate. Wolters Kluwer Health. Accessed at: www.uptodate.com. 2013.
Radiographic progression is another common efficacy endpoint used in clinical trials of RA drugs. X-rays (plain or using a contrast agent to enhance the appearance of structures and tissues) are taken and analyzed using one of several scoring methods. Joints are typically scored for erosions, joint space narrowing, misalignment, and other features indicative of the RA disease process. Common radiographic scoring methods that you may encounter as you read results from clinical trials include2:
A method for measuring joint erosions and joint space narrowing in the hands. This method is also now used for the feet, as well. It considers 17 joint areas for erosion, with erosions scored on a 0 to 5 scale. It considers 18 joints for narrowing on a 0 to 4 scale. There are several modified versions of Sharp’s Method.
A method for measuring joint erosions and joint space narrowing in small and large joints, using a 0 to 5 scoring scale. There are modified versions of the Larsen Score.
Simple Erosion Narrowing Score (SENS)
This method is used for measuring joint erosion in the hands and feet. Instead of scoring individual joints, it simply counts numbers of eroded and narrowed joints. Because it is simpler to apply than Sharp’s Method and the Larsen Score, SENS is more appropriate for assessment in clinical practice.
How is disease remission measured?
Various definitions for disease remission have been proposed based on scoring RA measures for disease activity discussed above. All of these definitions in theory reflect the clinical finding of no active disease. However, with RA, where there may be existing damage to joints and related structures, the criteria for remission can be difficult to determine precisely.
Common to both ACR and EULAR definitions of disease remission are swollen and tender joint counts (28 joints assessed) each totaling less than 1 and global assessment by patient (on a 0 to 10 scale) totaling less than 1. Other measures used in DAS28, SDAI, and CDAI composite scores may also be used to determine remission.1
Efficacy claims and FDA requirements for evidence
- ACR response criteria or other well-accepted composite endpoints or sign/symptoms measures
- ACR70 for 6 consecutive months
- Remission by ACR criteria and no radiographic progression for 6 consecutive months
- Remission by ACR criteria and no radiographic progression for 6 consecutive months while off all anti-rheumatic therapy
- HAQ or AIMS and SF-36
- Modified Sharp score or other validated radiographic index
AIMS, Arthritis Impact Measure Scales; HAQ, Health Assessment Questionnaire.Reproduced from Okada S, Siegel J. Regulatory veiw: US Food and Drug Administration. In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatoid Arthritis. Philadelphia, Penn: Mosby Elsevier; 2009:403-412.