ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2686

Impact of Methotrexate Dose Reduction Upon Initiation of Adalimumab On Clinical and Ultrasonographic Parameters in Patients With Moderate to Severe Rheumatoid Arthritis

Gurjit S. Kaeley1, Amy M. Evangelisto2, Midori Jane Nishio3, Shufang Liu4 and Hartmut Kupper5, 1College of Medicine, University of Florida, Jacksonville, FL, 2Arthritis, Rheumatic and Back Disease Associates, Voorhees, NJ, 3Diablo Clinical Research, Walnut Creek, CA, 4AbbVie Inc., North Chicago, IL, 5AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Title: Rheumatoid Arthritis Treatment - Small Molecules, Biologics and Gene Therapy: Novel Treatment Strategies in Rheumatoid Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Methotrexate (MTX) is the recommended first-line disease-modifying antirheumatic drug (DMARD) for the treatment of moderately to severely active rheumatoid arthritis (RA). Whether patients (pts) with inadequate response to MTX that begin combination therapy with adalimumab (ADA) can reduce MTX dose remains unclear. Clinical and ultrasonographic outcomes of MTX dose reduction when initiating ADA were examined.

Methods:

MUSICA was a double-blind, randomized, parallel-arm study to examine the impact of MTX dose on disease outcomes and ultrasonographic signs in moderately to severely active RA pts who have failed prior synthetic DMARDs. The study enrolled 309 pts taking MTX ≥ 15 mg/week (wk) for ≥ 12 wks prior to enrollment. Patients blindly received either high (20 mg/wk) or low dose (7.5 mg/wk) MTX; all pts received open-label 40 mg ADA every other wk for 24 wks. Non-inferiority was assessed using the 95% confidence interval of the difference between high and low dose wk-24 outcomes. A 15% margin (0.56) of the high dose mean 24-wk 28-joint disease activity score (DAS28) was used as the primary endpoint. Ultrasound images acquired every 4 wks were independently read and scored blindly by 4 ultrasound-experienced rheumatologists. A 10-joint semi-quantitative scoring system incorporating OMERACT definitions for pathology (1) measured synovial hypertrophy, vascularity, and bony erosions.

Results:

The study populations for both MTX dosages were well balanced for baseline demographics and disease characteristics and had overall age 54.8, 5.3 years RA disease duration, and a DAS28 of 5.8 (all means). Rapid improvement in clinical indices was seen in both groups after addition of ADA. After 24 wks of ADA combination therapy, pts receiving combination therapy with ADA displayed improvements consistent with other trials including low dose MTX. Differences in clinical and ultrasonographic outcomes comparing low vs high dose MTX were minimal. The primary endpoint, mean DAS28, did not meet non-inferiority criteria. Although outcomes favored maintaining 20 mg MTX, no statistically significant differences were detected for most clinical, functional, and ultrasound outcomes (Table). Statistically significant differences were only detected in wk-24 swollen joint count and physician’s global assessment of disease activity. The number of adverse events (AEs), serious AEs, and infectious AEs were fewer in the low dose MTX arm.

Table. Week 24 Clinical, Functional, and Ultrasonographic Outcomes

Non-Inferiority Parameter

ADA
+ 7.5 mg MTX
(N = 154)

ADA
+ 20 mg MTX
(N = 155)

Difference
(Low – High)

aDAS28(CRP)

4.11 (3.88, 4.34)

3.75 (3.52, 3.97)

0.37 (0.07, 0.66)

Clinical and Functional Outcomes*

 

 

p value

ACR20, n/N (%)

86/151 (57.0)

95/154 (61.7)

0.395

ACR50, n/N (%)

45/151 (29.8)

58/154 (37.7)

0.145

ACR70, n/N (%)

20/151 (13.2)

31/154 (20.1)

0.114

HAQ-DI

0.98 ± 0.75

0.95 ± 0.78

0.476

HAQ-DI improvement ≥ 0.22, n/N (%)

96/151 (63.6)

101/154 (65.6)

0.707

TJC (0 – 68)

15.1 ± 16.0

13.5 ± 15.3

0.264

SJC (0 – 66)

9.6 ± 12.8

7.7 ± 10.5

0.028

PGA disease activity (100 mm VAS)

23.7 ± 21.3

19.0 ± 17.4

0.035

PtGA pain (100 mm VAS)

40.0 ± 27.9

36.4 ± 27.7

0.141

PtGA disease activity (100 mm VAS)

38.2 ± 27.5

33.8 ± 26.8

0.094

Ultrasound Outcomes

Synovial hypertrophy

32.6 ± 7.2

32.9 ± 6.6

0.955

Synovial vascularity

4.43 ± 4.86

4.09 ± 4.53

0.779

Synovial vascularity improvement by 30%, n/N (%)

65/143 (45.5)

77/147 (52.4)

0.221

Synovial vascularity change from baseline

-1.52 ± 4.18

-1.46 ± 3.43

0.779

Bony erosions

1.36 ± 2.43

1.41 ± 2.01

0.598

aPrimary endpoint, mean (95% CI).
*Mean ± SD unless noted otherwise. Means were calculated using last observation carried forward (LOCF).
ADA, adalimumab; MTX, methotrexate; DAS28, 28-joint disease activity score; CRP, C-reactive protein; ACR, American College of Rheumatology; HAQ-DI, disability index of the health assessment questionnaire; TJC, tender joint count; SJC, swollen joint count; PGA, physician’s global assessment; VAS, visual analogue scale; PtGA, patient’s global assessment.

Conclusion:

Addition of ADA to MTX inadequate responders led to robust results consistent with prior studies. Compared to 20 mg MTX, lowering MTX weekly dose to 7.5 mg in combination with ADA resulted in small differences in clinical and ultrasonographic outcomes in RA pts. Statistically, non-inferiority was not met for mean DAS28. Based on the small differences in most outcomes, MTX dose reduction may be considered when initiating ADA therapy in MTX inadequate responders.

Disclosure:

G. S. Kaeley,

AbbVie Inc.,

5;

A. M. Evangelisto,

AbbVie Inc.,

2,

AbbVie Inc.,

8;

M. J. Nishio,
None;

S. Liu,

AbbVie Inc.,

3,

AbbVie Inc.,

1;

H. Kupper,

AbbVie,

3,

AbbVie,

1.

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