# Presentation: 731387

## Radiographic Analyses of Disease Progression 

**Vibeke Strand, MD ****Biopharmaceutical Consultant**** ****Clinical Associate Professor****Division of Immunology****Stanford University School of Medicine**

## X-ray Analyses of Disease Progression

- DMARDs	– Leflunomide	– Methotrexate	– Sulfasalazine
- Biologic Agents	– Etanercept	– Infliximab	– Anakinra

## Phase III Trials: Analysis of X-ray Data

- 34 – 36 joints in the hands, 12 in feet	44 for erosions: 0 - 5; 48 for joint space narrowing: 0 - 4	Total score = sum of erosions + joint space narrowing
- X-rays at baseline and endpoint in all studies
- All films read by Dr. John Sharp; blinded, random sequence
- All films read by Dr. Arvi Larsen; erosion scores correlated
- 12 month ITT in 301US despite entry into alternate therapy or 	exit from protocol for active treatment
- Clinical data in patients with and without complete radiologic 	data were comparable
- Sensitivity analysis to account for early withdrawals

**Sharp Scoring Method**

## Phase III Trials: Design, Demographics

- Control	  Placebo	        Placebo	        –
- MTX 	   7.5–15 mg/wk 	       –	          7.5–15 mg/wk  [median dose]	15.0		        11.0 SSZ 	   –	       0.5–2 gm/d 	         – Duration (mo) 	   12	       6  12 	         12
- Disease duration (yr)	   6.7	    7.0	         3.7
-  2 Years 	      33–40%	       38–42%	           43–44%
- DMARDs  failed	   0.9	    1.0	         1.1
- No Prior DMARD 	   40–45%	       40–53%	             33–34%
- Mean HAQ DI	1.3	    1.7-1.9	        1.5

**	****   ****301US****	****      301MN****	****            302MN****  **

**Phase III Trials: Design, Demographics**

## Phase III Trials – Total Sharp Scores at Baseline

- Total Sharpscore              23.1   25.4    22.8      46.3    46.2   41.9        24.9   24.6
- Mean diseaseduration	           7.0	     6.9	      6.5	        7.6	      5.7	     7.4	          3.7     3.8
- Predictedyearlyprogression	     3.3  	   3.7	      3.5        6.1	      8.1     5.7          6.7     6.5

**	****LEF****	****PL****	****MTX****	****       LEF****	****      PL****	****    SSZ****	****             LEF     MTX****	****(131)****	****(83)****	****(138)****	****      (89)****	****      (62)****	****     (85)****	****               (304)****	****    (331)**

**                            ****	****301US****	****301MN **(6 mos)**	****302MN**

## Phase III Trials – Change in Total Sharp Scores

**        ****301US****	****       301MN   ****	****                  302MN**

**  ****LEF      PL       MTX    ****	****             LEF       PL       SSZ    ****	****           LEF      MTX**

**Phase III Trials – Change in Total Sharp Scores**

- Estimated Yearly Progression in back;Change at Endpoint in front

**‡**

**‡**

*******	****Active v PL   p ≤ 0.05**

*****

*****

**‡**** ****LEF v PL   p ≤ 0.01**

**Medians****	****0.0****	****0.0****	****0.0****	****0.0****	****3.0****	****0.5****	****0.0****	****0.0**

## Phase III Trials – Change in Total Sharp Scores

**	****301MN****	****	****	****	****301/3MN**
**	**** ****( 6 mos )****	****	****	****	****( 12 mos )**

**LEF****	**** PL****	****     SSZ****	****                   LEF****	****          SSZ**

**Phase III Trials – Change in Total Sharp Scores**

- Estimated Yearly Progression in back; Change at Endpoint in front

*****

** ********* LEF v PL    p ≤ 0.01**

- 

- ** ****SSZ v PL  p≤ 0.05**

## ULTRA Trial: US 301Mean Changes in Erosion + JSN Scores:1 year

**Mean Change**
**	**

**	****0.0****	****0.0****	****0.0****	****0.0****	****0.0****	****0.0****	**** Medians**

**Notes:**
This slide describes the baseline erosion, joint space narrowing, and total Sharp scores.  The estimated annual rate of progression prior to study entry was calculated by taking the baseline radiographic score and dividing that number by the estimated duration of disease prior to study entry.

## MN 301Mean Changes in Erosion + JSN Scores: 6 mos.

**Mean Change**

**	****0.0****	****0.0****	****0.0****	****0.0****	****3.0****	****0.5****	**** Medians**

**Notes:**
This slide describes the baseline erosion, joint space narrowing, and total Sharp scores.  The estimated annual rate of progression prior to study entry was calculated by taking the baseline radiographic score and dividing that number by the estimated duration of disease prior to study entry.

## MN302Mean Changes in Erosion + JSN Scores: 1 year

**Mean Change**

**	****0.0****	****0.0****	****0.0****	****0.0****	**** Medians**

**Notes:**
This slide describes the baseline erosion, joint space narrowing, and total Sharp scores.  The estimated annual rate of progression prior to study entry was calculated by taking the baseline radiographic score and dividing that number by the estimated duration of disease prior to study entry.

## Total Sharp Scores for ACR Responders vs Non-Responders

- 11/02/98

- 038

**                                       ****	****	****301US****	****	****                          301MN****	****                     302MN**
**                                       ****LEF     PL****	****   MTX             LEF****	****      PL     SSZ           LEF     MTX**

**Total Sharp Scores for ACR Responders vs Non-Responders**

-         Responders  N		       71	       27	        66             50	        18	        50	           181      232	Baseline:	25.5	     22.6     27.4      	    44.2    49.3    40.9       	      21.8	     24.7	 at endpoint:	**0.2****	****       1.0****	****       0.4            1.3      4.7      2.7         ****	****      1.7       0.1**
-    Non-responders N	        58	      56	       72             39	        44	        35            123	        99	Baseline:	20.2	26.7	     18.5          48.9     44.9    43.3      	      29.6	     24.4	 at Endpoint:	**1.0****	**** 2.7****	****       1.4           -1.7       6.0     -0.4         ****	****     3.0****	****       3.8**

## Phase III Trials% of Patients with No Newly Eroded Joints

**Notes:**
The key points of the Sharp scoring method are shown in this slide.  Two modifications of the method originally described by Sharp were used to include feet, and to estimate the percent of the affected joint that was eroded. Joints were scored for narrowing and for erosions, and the Sharp score is the sum of both of these.

Erosion score range: 0-230Joint space narrowing score range: 0-168Total Sharp score range: 0-398

## ERA Trial:  Analysis of X-ray DataModified Sharp Scoring Method

- 36 joints for erosions (grades 0-5); 42 for joint space narrowing (grades 0-4);summed for total score
- X-rays at baseline, 6 months and 1 year
- Modifications:
- Included feet (van der Heijde)
- Added percentage joints eroded or narrowed to grading method (Rau)
- Each case read by 2 of 6 physicians trained in the same                                method (inter-reader variability: r = 0.85)
- Sequence of films blinded to readers

**Notes:**
The key points of the Sharp scoring method are shown in this slide.  Two modifications of the method originally described by Sharp were used to include feet, and to estimate the percent of the affected joint that was eroded. Joints were scored for narrowing and for erosions, and the Sharp score is the sum of both of these.

Erosion score range: 0-230Joint space narrowing score range: 0-168Total Sharp score range: 0-398

## ERA Trial: Demographics

- Mean age	49	51	51
- Female (%)	74	74	74
- RA duration (mean months)	11.9	10.9	11.9
- RF positive (%)	89	87	87
- Baseline HAQ DI	1.4	1.5	1.5
- Mean prior DMARDs	0.6	0.5	0.5
- Conc NSAIDs (%)	80	76	86
-           Steroids (%)	41	42	39

**Methotrexate**
**(n = 217)**

**25 mg**
**(n = 207)**

**Etanercept**

**10 mg**
**(n = 208)**

**ERA Trial: Demographics**

**Notes:**
This slide describes the demographics of the 632 patients who were randomized to receive the study drug.

## ERA Trial1 Year change in Total Sharp Scores

- 8.3

- 1.4

**Predicted**

**/Actual**

- Etanercept 10 mg

- Etanercept 25 mg

**Mean Change**

- 9.5

- 1.3

- 8.7

- 0.8

**0**

**2**

**4**

**6**

**8**

**10**

**Predicted**

**/Actual**

**Predicted**

**/Actua**l

- Methotrexate

**ERA Trial****1 Year change**** in Total Sharp Scores**

**Notes:**
Based on total Sharp score divided by duration of disease at enrollment, the patients in this study were progressing at an approximate rate of 9 total Sharp units per year, 5 erosion units per year and 4 units per year joint space narrowing  prior to beginning treatment.  Both methotrexate and etanercept treatments decreased the rate of joint damage from baseline approximately 6 to 11 fold.  

## ERA TrialMean changes in Erosion + JSN Scores: 1 Year

- * *P* < 0.05 vs methotrexate

- 0

- 2

**JSN**

**Erosions**

- 1

- Mean Change

- 0.9

- 0.4*

- 0.4

- 0.4

- 1.0

- Etanercept 25 mg

- Etanercept 10 mg

- Methotrexate

- 0.4

**ERA Trial****Mean changes in Erosion + JSN Scores: 1 Year**

**Notes:**

During the first year of treatment, the rate of  joint space narrowing was the same for the three treatment groups.  It has been reported that erosions precede joint space narrowing in early disease.  The rate of erosions in the 25mg etanercept group was less than half that for the methotrexate group.  This difference was statistically significant.  This result could be explained by the patient study of patients early in their disease. 

## ERA Trial: Patients With No Newly Eroded Joints at 1 Year

- All patients
- 	With erosions at BL
- 	With NO erosions at BL

- 57%
- 52%
- (n=188)
- 	 86%
- (n=29)

- 75%
- 72%
- (n=181)
- 96%
- (n=25)

**Methotrexate**
**(n = 217)**

**25 mg**
**(n = 206)**

**Etanercept**

**Notes:**
This slide describes the baseline erosion, joint space narrowing, and total Sharp scores.  The estimated annual rate of progression prior to study entry was calculated by taking the baseline radiographic score and dividing that number by the estimated duration of disease prior to study entry.

## ATTRACT: Analysis of X-ray Datavan der Heijde Modification of Sharp Scoring Method	

- 44 joints for erosions: scored 0–5 in hands; 0–10 in feet;40 joints for joint space narrowing; summed for total score
- Two experienced readers scored every film
- blinded to patient identity, treatment, sequence of film
- Baseline, 30 and 54week films presented in random order
- 348 of 428 (81%) patients included in primary analysis
- Clinical data in patients with and without complete radiologic 	data were comparable
- Sensitivity analyses to account for missing data

## ATTRACT: Infliximab (ch TNFmAb)+ MTXTrial design; Demographics

- 428 patients; 34 centers in EU and US
- Active RA despite MTX  12.5mg/week for mean 3 yrsMedian dose: 15 mg/weekConcomitant steroids: 61%; NSAIDs: 76%
- Mean disease duration:  10.4 yearsMedian number DMARDs failed: 381% RF+; 37% with previous joint surgeryBaseline mean HAQ DI scores: 1.7-1.8
- Placebo vs	3.0 mg mAb IV 	q 4 weeks	3.0 mg 		q 8 weeks	10.0 mg 		q 4 weeks	10.0 mg 	 	q 8 weeks

## ATTRACT: Mean Changes in Total Sharp Scores at Week 54

**ATTRACT: Mean Changes in Total Sharp Scores at Week 54**

- PL +MTX
- (n = 63)

- 3mg/kg
- q8w
- (n = 71)

- 3mg/kg
- q4w
- (n = 71)

- 10mg/kg
- q8w
- (n = 77)

- 10mg/kg
- q4w
- (n = 66)

- All infliximal
- (n = 285)

- p-value vs. PL

- < 0.001

- < 0.001

- < 0.001

- < 0.001

- < 0.001

**Mean Change from Baseline**

**7.0**

**1.2**

**1.1**

**0.4**

**0.55**

**-0.5**

## Mean age (yr)		52	53	53	54
Mean ds duration (yr) 	3.7	4.3	4.2	3.9
% RF+		69	71	69	69
% with erosions	74	77	74	69
% No Prior DMARD 	19	21	25	34
% Conc steroids	41	49	41	41
% Conc NSAIDs 	89	82	88	85
Baseline Sharp scores	27.39	29.55	29.06	24.66

- Mean ds duration (yr) 	3.7	4.3	4.2	3.9
- % RF+		69	71	69	69
- % with erosions	74	77	74	69
- % No Prior DMARD 	19	21	25	34
- % Conc steroids	41	49	41	41
- % Conc NSAIDs 	89	82	88	85
- Baseline Sharp scores	27.39	29.55	29.06	24.66

**	****	**IL-1ra	IL-1ra	IL-1ra
- Total patients 	 Placebo 	30 mg	75 mg	150 mg
-     (n = 472) 	(n = 121)	(n = 119)	(n = 116)	(n = 116)

**IL-1ra EU Monotherapy Trial:**** ****Demographics**

***European Monotherapy Study***

***European Monotherapy Study***

## IL-1ra EU Monotherapy: Analysis of X-ray DataGenant Modification of Sharp Scoring Method

- 28 joints for erosions (grades 0-3.5);26 for joint space (JSN) narrowing (grades 0-4); summed for total score
- X-rays at baseline, 24 weeks and 48 weeks continuing Rx
- Genant modification of Sharp method
- Did not include feet
- Maximum score 202
- Scored in pairs or triplicates by Genant
- Sequence of films blinded

***European Monotherapy Study***

***European Monotherapy Study***

**Notes:**
The key points of the Sharp scoring method are shown in this slide.  Two modifications of the method originally described by Sharp were used to include feet, and to estimate the percent of the affected joint that was eroded. Joints were scored for narrowing and for erosions, and the Sharp score is the sum of both of these.

Erosion score range: 0-230Joint space narrowing score range: 0-168Total Sharp score range: 0-398

## IL-1ra EU Monotherapy Trial: Mean Changes Total Sharp/Genant Scores: 24 wks

**Mean Change**

**	**

***European Monotherapy Study***

*****

*****

*****

**p <.01**

**Notes:**
This slide describes the baseline erosion, joint space narrowing, and total Sharp scores.  The estimated annual rate of progression prior to study entry was calculated by taking the baseline radiographic score and dividing that number by the estimated duration of disease prior to study entry.

## IL-1ra EU Monotherapy Trial: Mean Changes Total Sharp Scores: 0-24; 24-48 wks

**Mean Change**

******   ****IL-1ra**

***European Monotherapy Study***

********p***** < .01**

********p***** <.01**

***p<.01**

***European Monotherapy Study***

**Notes:**
This slide describes the baseline erosion, joint space narrowing, and total Sharp scores.  The estimated annual rate of progression prior to study entry was calculated by taking the baseline radiographic score and dividing that number by the estimated duration of disease prior to study entry.

## IL-1ra EU Monotherapy Trial: Change in Genant/Sharp Scores at 24; 48 Wks

**	****Placebo****	****30 mg****	****75 mg****	****150 mg**

**Weeks 0-24**

**Weeks 24-48**

**Change from Baseline**

**Erosion**

**Joint Space Narrowing**

**Treatment  Group**

***European Monotherapy Study***

**1.5**

**0.8**

**0.5**

**0.6**

**1.0**

**1.4**

**1.1**

**2.0**

**0.7**

**0.9**

**0.5**

**0.5**

**0.5**

**0.4**

******

*******

******

***      ****p< .05**
****     ****p< .01**
*****    ****p= .001**

*****

*****

## IL-1ra EU Monotherapy Trial: All active dosesMean Changes in Erosion + JSN Scores: 24; 48 wks

**Mean Change**

**	**

***European Monotherapy Study***

**Notes:**
This slide describes the baseline erosion, joint space narrowing, and total Sharp scores.  The estimated annual rate of progression prior to study entry was calculated by taking the baseline radiographic score and dividing that number by the estimated duration of disease prior to study entry.

## IL-1ra EU Monotherapy Trial Patients without Radiographic Progression at 24 Wks

**No change in erosion score**
**	**
**No change in JSN score****	**
**	**
**No change in TOTAL score**
**	**

**42%**
**44%**
**33%**

**53%**
**59%**
**43%**

**Placebo**
**(n = 78)**

**All doses**
**(n = 248)**

**IL-1ra**

***European Monotherapy Study***

**Notes:**
This slide describes the baseline erosion, joint space narrowing, and total Sharp scores.  The estimated annual rate of progression prior to study entry was calculated by taking the baseline radiographic score and dividing that number by the estimated duration of disease prior to study entry.

## Modified Sharp AnalysesBlinded, Sequence Randomized

**ULTRA,****MN301****MN302**
**ATTRACT**
**ERA**
**EU IL-1ra**

- 46 jts for erosions: 0 - 548 jts for JSN: 0 - 41 reader; Sensitivity analysis
- 44 jts for erosions: 0 - 5, 0 -1040 jts for JSN: 0 - 42 readers; Sensitivity analysis
- 36 jts for erosions: 0 - 542 jts for JSN: 0 - 42 of 6 readers
- 28 jts for erosions: 0 - 3.526 jts for JSN: 0 - 41 reader; Sensitivity analysis

**TOTAL SCORE**
**	****422**
**	****440**
**	****348**
**	****202**

## Modified Sharp AnalysesEstimated v Observed Yearly Progression

**ULTRA**
**MN301**
**ATTRACT**
**EU IL-1ra**

- Disease Duration: 6.9 yrsBaseline score:	25Est. yearly progression: **3.7**
- Disease Duration: 5.7 yrsBaseline score:	46.2Est. 6 mos progression: **4.1**
- Disease Duration: 10.7 yrsBaseline score:	79-82Est. yearly progression: **7.6**
- Disease Duration: 3.7 yrsBaseline score:	27Est. 6 mos progression: **3.6**

**Placebo progression**
**	****2.2   **[formal ITT]
**	****5.9**
**	****7.0**
**	****3.5**

## Decreasing Radiographic ProgressionConclusions

_**Leflunomide effective**_**: **
**2 placebo controlled RCTs positive**
**Statistically equivalent to MTX; SSZ**
_**Methotrexate effective**_**:****  **
**Previous active controlled trials positive**
**Placebo controlled RCT positive**
**Active controlled trial: statistically equivalent to LEF**
_**Infliximab effective**_**:**** **
**All doses / dose schedules**
**v placebo in patients failing MTX**
_**Etanercept effective:**_
**Statistically equivalent to MTX in early RA**
_**Anikinra effective:**_
**v placebo at 24 wks; continued effect over 48 wks**

## Decreasing Radiographic ProgressionMethodologic Questions

**Each protocol population unique:**
**BL demographics, Sharp scores, rates of progression **
**Estimated yearly progression reasonable benchmark**
**Modified Sharp Analyses:**
**How many joints?**** Total scores: 422; 380; 348; 202**
**Include feet?**** Score 0-5 or 0-10? **
**In view of heterogeneity; increased or decreased ****	****	****      ****	****    sensitivity with less number of joint assessed?**
**Analyses of change:**
**Marked variability****; majority of patients, even with placebo ****	****    treatment, do NOT progress; **
**Expressed as mean or median changes?**
**Expressed as Total score**** v erosion and/or JSN subscores**

## Delaying Radiographic ProgressionMethodologic Questions

**Can we define “healing”?**
**v “No progression” or “No newly eroded joints”**
**Some erosions healed, others enlarged......**
**Measured when sequence of films blinded?**
**“****Disconnect” between clinical responses and x ray benefit**
**Correlations between ACR responses, AUC weak**
** ****What is ****clinically meaningful v statistically significant****?**
**Value of “sensitivity analyses” for missing data**
**Importance of “formal 12 month intent to treat analyses”**
**Applicability of group changes to individual definitions ****	****of improvement / lack of progression**
**Effect of variability assessment due to multiple readers**

## BACK UP SLIDES; WILL NOT SHOW 

## X-ray Results Inter-Reader Variability*

- 11/02/98

- 038

**X-ray Results Inter-Reader Variability***

**Reader****	****Correlation****(# subjects) ****	****Coefficient**
- 1,3 (122)	0.953
- 1,2 (230)	0.948
- 1,4 (72)	0.961
- 1,5 (71)	0.993

*******	****Sharp, Wolfe, Corbett, et al.  Radiological Progression in Rheumatoid Arthritis: How Many****Patients Are Required in a Treatment Trial to Rest Disease Modification? *****Ann Rheum Dis*****,****1993;52:332-337.**

## Repeated Scoring of X-Rays

- 11/02/98

- 038

**Repeated Scoring of X-Rays**

**	****	****	****      ****Correlation**** Reader****	****# Films****	****Interval ****	****        Coefficient**

**	****1****	****40****	****9 mos****	****.975**
**	****1****	****41****	****15 mos****	****.975**
**	****2****	****39****	****11 mos****	****.951**
**	****3****	****41****	****12 mos****	****.968**
**	****4****	****41****	****12 mos****	****.945**
**	****5****	****112****	****1 mo****	****.966****	**

**Sharp JT, Bluhm GB, Gofton JP, Mitchell DM, Weinstein AS (unpublished)**

## ULTRA US 301: Repeated Scoring of X-rays

- 11/02/98

- 038

**ULTRA US 301:**** ****Repeated Scoring of X-rays**

**	****	****Correlation**** Reader (JS) ****	****	****Coefficient**
- 159 subjects	Baseline	0.972
- 	Week 52	0.971

## Changes in Total Sharp ScoresUS 301 : Year 2 Cohort

- 						**LEF****	****	****MTX****	****	****	****	****	****(n=71)****	****	****(n=66)**
**Baseline Total Sharp Score****	****23.8****	****	****25.1**
**Change at 24 months****	****	****  ****	****  1.6****	****	****  1.2**
**Change during year 1****	****	**** ****	****  0.4****	****	****  0.6**
**Change during year 2****	****	****  ****	****  1.1****	****	****  0.7**
**Change year 2  v  year 1****	****	****  NS****	****	****  NS**
**% Pts w/ no newly eroded jts        89%****	****  ****	****  80%**

## ATTRACT: Median Changes in Total Sharp Scores at Week 54

- PL +MTX
- (n = 63)

- 3mg/kg
- q8w
- (n = 71)

- 3mg/kg
- q4w
- (n = 71)

- 10mg/kg
- q8w
- (n = 77)

- 10mg/kg
- q4w
- (n = 66)

- All infliximal
- (n = 285)

- p-value vs. PL

- < 0.001

- < 0.001

- < 0.001

- < 0.001

- < 0.001

**Mean Change from Baseline**

**4.0**

**ATTRACT: Median Changes in Total Sharp Scores at Week 54**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**0.5**

**0.0**

**0.5**

**-0.5**

**0.0**

## ATTRACT: Clinical Responders vs. Nonresponders at Week 54

**MTX+PL**

**3q8**

**3q4**

**10q8**

**10q4**

- p-value vs. PL

- 0.013

- 0.005

- 0.006

- < 0.001

**ACR20 responders**

**Median Changes from Baseline**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**2.0**

**-0.5**

**-0.05**

**0.65**

**-1.0**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**MTX+PL**

**3q8**

**3q4**

**10q8**

**10q4**

- p-value vs. PL

- < 0.001

- < 0.001

- < 0.001

- 0.003

**4.04**

**0.54**

**0.5**

**0.0**

**0.31**

**ACR20 nonresponders**

## ATTRACT: Comparison of Readers 1 and 2 at Week 54

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**ATTRACT:**** ****Comparison of Readers 1 and 2 ****at Week 54**

**	**

**-2**

**-1**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**PL**

**3q8**

**3q4**

**10q8**

**10q4**

**PL**

**3q8**

**3q4**

**10q8**

**10q4**

**Reader 1**

**Reader 2**

**Median Change from Baseline**

- p-value vs. PL

- <0.0001

- <0.0001

- <0.0001

- <0.0001

- <0.0001

- <0.0001

- <0.0001

- <0.0001

**5**

**.85**

**-1**

**0**

**0**

**2.5**

**1**

**0**

**0**

**0**

** **

** **

- 0 = normal
- 1 = slight abnormality, including 1 or more: periarticular soft 		tissue swelling, periarticular osteoporosis, and       	slight joint space narrowing
- 2 = definite early abnormality, including definite erosion, with or
-        	without joint space narrowing
- 3 = medium destructive abnormality
- 4 = severe destructive abnormality
- 5 = mutilating abnormality (the original articular surfaces have
-       	disappeared)

**  **

** **

**Larsen Scoring Method**

- * Fifteen areas are examined: interphalangeal of digit 1, distal and proximal interphalangeal of digits 2–5, metacarpophalangeal of digits 1–5, and the wrist. Dislocation and bony ankylosis are considered; if they are present, the scoring is based on the concomitant bone destruction. Maximum score (total for both hands) is 150.

## IL-1ra EU Monotherapy Trial Change in Larsen Scores at 24 weeks

**Change in Score at Week 24 (±SEM)**

**	****Placebo****	****30 mg****	**** 75 mg****	**** 150 mg**
**	****(n = 83)****	****(n = 89)****	****(n = 89)****	****(n = 86)**

**Larsen Score**

**Erosive Joint Count**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**IL-1ra EU Monotherapy Trial**** ****Change in Larsen Scores at 24 weeks**

**Treatment  Group**

**3.6**

**3.8**

**3.9**

**6.3**

**1.5**

**1.0**

**1.7**

**2.6**

***European Monotherapy Study***

## US301 and MN302 MTX PopulationsMedication Differences

**US301 and MN302 MTX Populations****Medication Differences**

**Folate Administration****	****98%****	****11%****	****                                             ****Mean MTX dose year 1****	****12.3 ****	****10.9****     Range****	****(7.5 - 15)****	****(7.5 - 15)****Mean MTX dose year 2****	****12.8****	****12.2****     Range****	****(7.5 - 20)****	****(7.5 - 15)**
**Median MTX dose year 1****	****15.0****	****11.0**
**Median MTX dose year 2****	****15.0****	****11.0**
**Conc steroids ****	****53%****	****45%**
**Conc NSAIDs****	****70%****	****87%****     ****	****	****	****	****	**