1. A NEW LOOK AT RA Interactive Hot Topics Series
Evaluating Radiologic Progression in Our Patients: Understanding Scales and the Effectiveness of Therapies
Over the next 15 minutes, I’m going to discuss how we evaluate radiographic progression in our patients with RA and assess treatment efficacy.
MP-RA-0261

2. Progression of RA Immune response develops
Pathologic inflammatory response
Joint inflammation
Time
Rheumatoid arthritis is a systemic, inflammatory, autoimmune disorder. A combination of genetic and environmental factors contribute to the development of an immune response that leads to subclinical inflammation, symptoms, and then signs and symptoms that meet the criteria for a diagnosis of RA. The pathologic inflammatory response continues resulting in progressive joint destruction and the disability characteristic of RA.
Genetic and environmental factors
Symptoms
Joint destruction
Subclinical
inflammation
Criteria fulfilled for diagnosis of rheumatoid arthritis
Klareskog L, et al. Lancet. 2009;373:659–672.

3. Measuring Radiographic Progression
A number of methods have been developed for assessment of joint damage in patients in RA and I’d like to take just a few moments to review them.

4. How Do We Measure Progression?
Steinbrocker method: global damage score for hands and wrists on a 4-point scale from I (minimal damage) to IV (severe damage)1
Kellgren method: a global grade is given as the summation of abnormalities for all joints in both the hands and wrists2
Sharpe/van der Heijde method: continuous scale from 0 to 448 units; separate scores for erosions and joint space narrowing in the hands and feet3
Larsen method: continuous scale from 0 to 200 with a global score for each joint4
Several methods have been introduced for the scoring of plain radiographs in patients with RA.
The first methods characterized global damage in hands and wrists in a qualitative rather than quantitative approach. The Steinbrocker method assesses damage to the hands and wrists on a four-point scale from I (minimal damage) to IV (severe damage). The grade was determined by the worst change in any joint and is therefore biased toward the most severely affected joint. The Kellgren method is a similar global scale that summarizes abnormalities for all the joints in both the hands and wrists.
The two most widely used measures of radiographs are based on the work of Sharp and Larsen and they provide a continuous quantitative scale of more than 100 units, rather than a limited qualitative measure of radiographic damage.
Steinbrocker O, et al. JAMA. 1949;140:
Kellgren JH, Bier F. Ann Rheum Dis. 1956;15:55-60.
van der Heijde D. J Rheumatol. 1999;26:
Larsen A, et al. Acta Radiol Diagn (Stockh). 1977;18:

5. Sharp/van der Heijde Scoring
Joints Measured for Erosions
Joints Measured for Joint Space Narrowing
The Sharp method for scoring radiographs of hands and feet in RA is now the reference method used in the majority of clinical trials and longitudinal observational studies.
This method includes, in each hand, 16 areas for erosions and 15 areas for joint space narrowing, and, in each foot, 6 areas for erosions and 6 areas for joint space narrowing.
van der Heijde D. J Rheumatol. 1999;26:

6. Sharp/van der Heijde Scoring
EROSIONS:
Scoring of hands: 16 areas included (0-5 for each)
1: discrete erosions
2-3: larger erosions, depending on the surface area involved
4: erosion is large and extends over middle of the bone
5: complete collapse
Scoring of the feet: 10 MTP and 2 IP joints of big toes (0-5 for each side of the joint; total: 0-10)
JOINT NARROWING
Scoring of hands and feet: 15 areas for hands, 6 for feet (0-5 for each)
0: normal
1: focal narrowing
2: reduction of <50% of joint space
3: reduction of >50% of joint space
4: ankylosis
Total Scores
Maximum Possible
Erosions for hands
160
Erosions for feet
120
Joint space narrowing for hands
Joint space narrowing for feet 48
Overall Total
448
The erosion score per joint of the hands can range from 0 to 5. Erosions are scored as 1 if they are discrete but clearly present and a score of 5 is given if a complete collapse of the joint is present or if the full surface of the joint is affected. The maximal erosion score for each hand is thus 80, considering the 16 areas for erosions per hand.
Joint space narrowing and joint subluxation or luxation are combined in a single score with a range of 0 to 4. A normal joint space is scored 0. and a bony ankylosis or a complete luxation of the joint is scored 4. The maximal narrowing/(sub)luxation score for each hand is thus 60.
In the feet, the erosion score per joint can range from 0 to 10, with each side of the joint independently scored from 0 to 5. The maximal erosion score per foot is thus 60.
The joint space narrowing and joint (sub)luxation are combined in a single score with a range of 0 to 4. Criteria for scoring are identical to those of the hands. The maximal narrowing/(sub)luxation score per foot is thus 24.
IP, interphalangeal; MTP, metatarsophalangeal
van der Heijde D. J Rheumatol. 1999;26:

7. Natural History
The measure just discussed can be used to assess the natural history of joint damage in patients with RA.

8. Radiologic Progression in Untreated RA: Increase in Total Sharp Score Over 2 Years6 12 18 24
Time months 50 45 40 35 30 25 20 15 10 5
Total Score
Results from the control arm of a 2-year study of low-dose prednisone in patients with RA can be used to assess the progression of joint damage in individuals receiving no disease-modifying therapy. Results for untreated patients with a disease duration of <1 year at the beginning of the study indicated that Sharp scores increased by about 15 points per year and that progression was linearly related to time over this period.
Adapted from van Everdingen AA. Ann Intern Med. 2002;136:1-12.

9. Severity (arbitrary units)
Relationship Between Structural Damage and Disability in RA: Hypothetical 5 10 15 20 25 30
Years of Disease
Severity (arbitrary units)
Inflammation
Disability
Radiographs
An important issue in understand disease progression in patients with RA is elucidating the relationship between radiographic change and the long-term consequences of RA for the patient.
These idealized curves suggest approximately linear relationships between disease duration and both joint damage observed on plain film radiographs and disability.
The relationship between inflammation disability declines over long-term follow-up.
Kirwan JR. J Rheumatol. 1999;26:

10. Radiologic Progression and Disability: The Truro Cohort
In the early RA cohort the mean HAQ score fell from 1.08 initially (95% CI 0.79, 1.36) to 0.86 (95% CI 0.65, 1.08) by 6 months. Thereafter it increased gradually; by 5 years, the mean HAQ score was 1.26 (95% CI 0.99, 1.53)
By comparison, the mean Larsen score invariably increased. The initial mean Larsen score was 11 (95% CI 6, 15); by 5 years it had increased to 41 (95% CI 32, 49)
By 5 years, the correlations between HAQ and Larsen scores was significant (r=0.52) 6 12 18 24 30 42 60
Disease Duration (months) 50 40 20 10
Maximum Disability/Damage %
Correlation
HAQ
Larsen
0.6
0.5
0.4
0.3
0.2
0.1
Correlation Coefficient
Results from a 5-year study that actually assessed these relationships idealized in the preceding slide suggested that the relationships among disability, as measured by the Health Assessment Questionnaire, joint damage determined by Larsen scores, and disease duration are more complex.
Both HAQ and Larsen scores both rise with disease duration, but the correlation between these two measures only achieves significance after 5 years of follow-up.
CI, confidence interval; HAQ, Health Assessment Questionnaire.
Scott DL, et al. Rheumatology. 2000;39:

11. Effects of Treatment
All of us are very familiar with the large number of studies that have assessed the effects of both synthetic and biologic DMARDs on the progression of joint damage in patients with RA, but there are several aspects of these findings that are worth further consideration.

12. Continued treatment and evaluation
TEMPO: Design
Failure on 1 DMARD
No recent MTX
Baseline
Endpoints
Total Sharp Score
52 Weeks
ACR-N
24 Weeks
ETN + MTX (n=231)
Randomized
(N=686)
ITT Population
(N=682)
Continued treatment and evaluation
ETN (n=223)
An issue that has been addressed in many studies is the relative efficacy of conventional DMARDS, such as methotrexate, and biologic agents, such as etanercept.
TEMPO was a randomized, double-blind, parallel-group study with identical-appearing injectable and oral test articles and consisted of three treatment arms: etanercept, methotrexate, and the combination of the two medications.
A total of 686 patients were randomized and 682 were included in the intent-to-treat population.
An issue that has been addressed in many studies is the relative efficacy of conventional
DMARDS, such as methotrexate, and biologic agents, such as etanercept. TEMPO (Trial of Etanercept and MTX with radiographic Patient Outcomes) was a randomized, double-blind, parallel-group study with identical-appearing injectable and oral test articles and consisted of three treatment arms: etanercept, methotrexate, and the combination of the two medications. A total of 686 patients were randomized and 682 were included in the intent-to-treat population.
MTX (n=228)
Withdrawal rates: MTX, 30%; ETN, 24%; ETN + MTX, 16%
ACR, American College of Rheumatology; DMARD, disease-modifying antirheumatic drug; ETN, etanercept; ITT, intent-to-treat; MTX, methotrexate
Adapted from Klaresklog L, et al. Lancet. 2004;363:

13. TEMPO: Results at 3 Years
Mean change from baseline in total modified Sharp/van der Heijde scores 1 2 3 -2 6
Change From Baseline (mean ± SD)
Years
MTX
ETN
ETN + MTX * †‡ 4
Three-year results from the TEMPO study indicated that mean changes from baseline in the total Sharp score at year 1, year 2, and year 3 were significantly lower for patients receiving combination or etanercept therapy than for those receiving methotrexate.
In addition, the change in total Sharp score was lower for the combination group than for the etanercept group.
These results are typical of comparison of the type carried out in the TEMPO trial.
Three-year results from the TEMPO study indicated that mean changes from baseline in
the total Sharp score at year 1, year 2, and year 3 were significantly lower for patients
receiving combination or etanercept therapy than for those receiving methotrexate.
In addition, the change in total Sharp score was lower for the combination group than
for the etanercept group. These results are typical of comparison of the type carried out in the TEMPO trial.
P<0.05 *ETN vs MTX, †combo vs MTX ‡combo vs ETN
ETN, etanercept; MTX, methotrexate
van der Heijde D, et al. Arthritis Rheum. 2007;56: © 2007, American College of Rheumatology.

14. TEMPO: Results at 3 Years
Probability Plots of TSS Change Scores
220
200 90
Methotrexate
Etanercept
Combination 80 70 60 50 40
Change From Baseline 30
70% of patients 20 10
Results from TEMPO and other similar studies make another important point about the relative efficacies of methotrexate and biologic agents used to treat patients with RA.
The cumulative probability plot of the 3-year results from TEMPO shows that for about 70% of the patients included in the trial, radiographic progression was the same regardless of whether treatment was with methotrexate, etanercept, or the combination of these two agents.
The mean differences among the three groups result from differences in efficacy for about 20% of the total patient population.
-10
-20
-30
-40 10 20 30 40 50 60 70 80 90
100
Cumulative Probability
In probability plots, change from baseline = 0 for the majority of patients in all 3 arms, indicating that joint damage progression was undetectable for most patients
TSS, total Sharp score
van der Heijde D, et al. Arthritis Rheum. 2007;56: © 2007, American College of Rheumatology.

15. Camera II: Design and Results
MTX and placebo
MTX and prednisone
100 80 60 40 20
Cumulative Proportion of Patients 50 10
67%
78%
Erosion Score at 2 y
Adalimumab (if needed)
30 mg/wk
If ≥ 3 months remission: step-down: ↓ 2.5 mg/visit
25 mg/wk
MTX step-up (last step:SC)
20 mg/wk
15 mg/wk
start: 10 mg/wk MTX
random: prednisone 10 mg/day or placebo
at end of study: stop
time
The CAMERA-II tight control step-up strategy:1,2
If >20% improvement or remission was not achieved, treatment was intensified
If patients had remission for ≥3 months, MTX was reduced stepwise by 2.5 mg/week as long as patients met remission criteria
Otherwise, the dose of MTX was continued or increased according to protocol
Prednisone was tapered at the end of the study and stopped, if possible
Results similar to those from TEMPO were reported in the CAMERA (Computer- Assisted Management in Early Rheumatoid Arthritis) II trial in which patients were treated with a tight control step-up strategy. In this approach, if a >20% improvement or remission was not achieved with a starting 10 mg oral dose of methotrexate, treatment was intensified. If patients had remission for ≥3 months, methotrexate was reduced stepwise by 2.5 mg per week as long as patients met remission criteria; otherwise, the dose of methotrexate was continued or increased according to protocol shown on the slide. If oral methotrexate was not effective, patients were stepped up to subcutaneous administration of this drug and if this was not effective, patients received adalimumab. Prednisone was tapered at the end of the study and stopped, if possible.
Results for patients who remain on oral or subcutaneous methotrexate without prednisone indicated that 68% had no increase in joint erosion scores over 2 years of follow-up.
112 and 110 patients were analyzed for the MTX + prednisone group (22% on SC MTX) + the MTX and placebo group (50% on SC MTX), respectively2
Arrows with percentages show the proportion of patients in each treatment arm with no erosions at 2 years2
SC, subcutaneous; MTX, methotrexate;
1. Jacobs JWG, et al. Clin Exp Rheumatol. 2012;30(Suppl 72):S39-S43.
2. From Annals of Internal Medicine, Bakker MF, et al. 2012;156: Copyright © 2012 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.

16. COMET: Patient Disposition at 2 Years
Etanercept + Methotrexate (EM)
Methotrexate
(M)
Year 1
274 randomized in period 1
268 randomized in period 1
221 (81%) completed 52 weeks*
189 (71%) completed 52 weeks
EM/EM
EM/E
M/EM
M/M
111 entered period 2*
111 entered period 2
90 entered period 2
99 entered period 2
7 total withdrawals (6%)†
3 adverse event (3%)
0 lack of efficacy†
1 protocol violation (1%)
1 patient request (1%)
2 other (2%)
18 total withdrawals (16%)
5 adverse event (5%)
7 lack of efficacy (6%)
0 protocol violation
4 patient request (4%)
2 other (2%)
16 total withdrawals (18%)
7 adverse event (8%)
1 lack of efficacy (1%)
0 protocol violation
5 patient request (6%)
3 other (3%)
23 total withdrawals (23%)
9 adverse event (9%)
7 lack of efficacy (7%)
2 protocol violation (2%)
3 patient request (3%)
2 other (2%)
The COMET trial included 542 outpatients who were methotrexate-naive and had early moderate-to-severe RA for 3-24 months.
These patients were randomly assigned to receive either methotrexate alone titrated up from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate plus etanercept 50 mg a week
After 1 year of treatment, patients in the combination arm were randomized to continued methotrexate or combination therapy and those in the methotrexate arm were randomized to continued methotrexate or combination therapy.
A total of 411 subjects completed 1 year of either combination therapy or MTX monotherapy and continued into year 2 of this trial as originally randomized. Of these, 398 subjects were valid for evaluation of clinical efficacy.
The COMET (Combination Of Methotrexate and ETanercept in active early rheumatoid
arthritis) trial included 542 outpatients who were methotrexate-naive and had early
moderate-to-severe RA for 3-24 months.
These patients were randomly assigned to receive either methotrexate alone titrated up
from 7.5 mg a week to a maximum of 20 mg a week by week 8 or methotrexate plus
etanercept 50 mg a week. After 1 year of treatment, patients in the combination arm were randomized to continued methotrexate or combination therapy and those in the methotrexate arm
were randomized to continued methotrexate or combination therapy.
A total of 411 subjects completed 1 year of either combination therapy or MTX monotherapy and continued into year 2 of this trial as originally randomized. Of these, 398 subjects were valid for evaluation of clinical efficacy.
Year 2
104 completed
104 weeks
(94%)
93 completed
104 weeks
(84%)
74 completed
104 weeks
(82%)
76 completed
104 weeks
(77%)
EM/EM = etanercept+ methotrexate treatment in year 1 followed by continued combination treatment in year 2. EM/E = combination treatment in year 1 followed by etanercept alone in year 2. M/EM = methotrexate monotherapy in year 1 followed by combination treatment in year 2.
M/M = methotrexate monotherapy in year 1 followed by continued methotrexate monotherapy in year 2; †overall P=0.003
* 1 subject discontinued at final visit of year 1 but received 1 dose of study drug in period 2 (included in period 2 population)
Emery P, Arthritis Rheum. 2010;62:

17. COMET: No Evidence of Radiographic at 2 Years
Assessment of radiograph progression at 2 years in COMET (Combination Of Methotrexate and ETanercept in active early rheumatoid arthritis) provided results similar to those for TEMPO and CAMERA II.
This slide shows proportions of patients achieving radiographic non-progression (a change in the modified Sharp/van der Heijde score ≤0.5) at week 104, based on last observation carried forward analysis.
At the end of year 2, radiographic non-progression was demonstrated in a significantly higher proportion of subjects who received combination therapy for 2 years vs any of the other treatment groups. Nevertheless, 67% of the subjects who received methotrexate only for the entire 2-year study period had no progression.
Assessment of radiograph progression at 2 years in COMET provided results similar to those for TEMPO and CAMERA II.
This slide shows proportions of patients achieving radiographic non-progression (a change in the modified Sharp/van der Heijde score ≤0.5) at week 104, based on last observation carried forward analysis.
At the end of year 2, radiographic non-progression was demonstrated in a significantly higher proportion of subjects who received combination therapy for 2 years vs any of the other treatment groups. Nevertheless, 67% of the subjects who received methotrexate only for the entire 2-year study period had no progression.
EM/EM = etanercept + methotrexate treatment in year 1 followed by continued combination treatment in year 2, EM/E = combination treatment in year 1 followed by etanercept alone in year 2; M/EM = methotrexate monotherapy in year 1 followed by combination treatment in year 2.
M/M = methotrexate monotherapy in year 1 followed by continued methotrexate monotherapy in year 2
Emery P, Arthritis Rheum. 2010;62:

18. Mean change in x-ray Score
MTX vs Biologics
Baseline x-ray Score
Mean change in x-ray Score
P-value
MTX
Biologic
Etanercept1
Etanercept2
Adalimumab3
Tocilizumab4
Golimumab5
12.9
26.8
21.9
30.6
19.7
36.7
2.4
21.8
18.8
28.3
20.4
37.4
1.59
2.8
5.7
6.1
1.37
1.10
1.00
0.52
3.0
2.3
1.25
0.89
0.11
0.0469
<0.001
<0.01
0.266
0.967
A summary of trials that have compared monotherapy with biologics vs methotrexate indicates a pattern of results similar to those described in the previously slides. Progression of joint damage in greater with methotrexate than biologic agents, but these differences are generally small and, in some cases, fail to achieve statistical significance.
MTX, methotrexate
Jones G, et al. Biologics. 2012;6:
Bathon JM, et al. N Engl J Med. 2000;343:
van der Heijde D, et al. Arthritis Rheum. 2006;54:
Keystone EC, et al. Arthritis Rheum. 2004;50:
Nishimoto N, et al. Ann Rheum Dis. 2007;66:
Emery P, et al. Arthritis Rheum. 2011;63:

19. Summary
RA is characterized by progressive joint damage that can be demonstrated by plain film radiographs and quantified by any of several scoring methods
Biologics have been demonstrated to be the most effective agents for slowing radiographic progression in RA, however:
Differences between results for MTX and biologic agents in treatment-naïve patients are small and vary among studies
Approximately 70% of RA patients can obtain the same benefit from MTX and biologics
In summary, RA is characterized by progressive joint damage that can be demonstrated by plain film radiographs and quantified by any of several scoring methods.
Biologics have been demonstrated to be the most effective agents for slowing radiographic progression in RA. However, differences between results for methotrexate and biologic agents in treatment-naïve patients are small and vary among studies.
Approximately 70% of RA patients can obtain the same benefit from methotrexate and biologics.
Thanks very much for your attention.