Background/Purpose: The Rituximab in Myositis (RIM) Study evaluated 200 refractory myositis patients treated with rituximab, 83% of whom met the definition of improvement (DOI). The aim of this study was to identify the clinical and laboratory predictors of response in this cohort.
Methods: All patients failed corticosteroids and at least 1 other immunosuppressive (IS) agent and received rituximab at weeks 0/1 (Early) or 8/9 (Late). The 1° endpoint in this 44-week trial was time to achieve DOI [³20% improvement in 3 of 6 core set measures (CSM) (includes manual muscle testing (MMT), muscle enzymes, HAQ, patient/parent global, physician global disease activity and extramuscular disease activity) with no >2 CSM worsening by ³25% (excluding MMT)] at 2 consecutive visits. We analyzed the effect of the following baseline variables on the time to DOI: myositis subtype, demographics, laboratory [IgM, IgG, myositis-associated autoantibodies (MAA), CBC, creatinine], damage measures (global, muscle damage and atrophy and organ-related), disease activity and other clinical parameters (skeletal/GI/pulmonary/muscle disease activity, Raynaud, calcinosis, mechanic hands), CSM, medication (early vs. late rituximab, IS agents and corticosteroids) and MAA subset [anti-synthetase (anti-Syn), Mi-2, SRP, TIF1-γ, MJ, other autoantibodies and those without an MAA]. The Wilcoxon test was used to univariately evaluate the association of baseline variables with the time to DOI. A multivariate time-dependent proportional hazard model was built using forward selection (α=0.05) based on univariate variables with p<0.1.
Results: 200 randomized patients (76 PM/76 DM/48 JDM) were analyzed (96 Early/104 Late).Table 1 lists the baseline variables which predicted time to DOI univariately. The multivariate model included autoantibodies (anti-Syn was the best DOI predictor followed by Mi-2 as compared to the ‘no MAA’ subset), and global damage (lower damage had a better response). The effects of global damage diminished by week 20. Myositis subtype (JDM had a better response than adult myositis) was not statistically significant univariately, however, final model was stratified by the subtypes due to their clinical relevance and post hoc had statistical significance in multivariate models.
Conclusion: Anti-Syn and Mi-2 autoAbs strongly predicted improvement in rituximab-treated refractory myositis patients. JDM and lower disease damage predicted more rapid improvement early in course of treatment. It is unclear whether this effect is due to a delayed beneficial effect of rituximab in patients with higher damage and adult PM/DM. These results suggest that early, more aggressive therapy could be considered in some clinical and serologic myositis subsets to achieve a better therapeutic response and to avoid disease-related damage.
Table 1. Univariate predictive factors and final multivariate model.
|
Univariate variable for predicting future DOI (0.1 level of significance)
|
||
|
Factor |
Associated with more rapid achievement of DOI (Hazard Ratio) |
p-value for Wilcoxon test for trend |
|
Gender |
males (1.28) |
p=0.10 |
|
Autoantibody |
Anti-Syn (2.83) Mi-2 (2.48), Other MAA (1.39) as compared with no MAA |
p=0.001 |
|
White blood count |
higher counts (1.44) |
p=0.04 |
|
Muscle damage |
lower damage (1.26) |
p=0.02 |
|
Muscle atrophy |
absence of atrophy (1.45) |
p=0.02 |
|
Global damage |
lower damage (1.30) |
p=0.004 |
|
Most abnormal muscle enzyme |
higher result (1.30) |
p=0.09 |
|
Extramuscular disease activity |
higher values (1.26) |
p=0.07 |
|
Disability index |
higher values (1.09) |
p=0.09 |
|
Multivariate model based on the variables identified in univariate analysis
|
||
|
Autoantibody |
Hazard ratio of DOI |
P-value (comments) |
|
no MAA |
– |
(Baseline) |
|
Jo-1/other antiSyn
|
3.03 |
<0.01 (for adult PM or DM) |
|
Mi-2 |
2.49 |
<0.01(for JDM or adult DM ) |
|
Other MAA (SRP, MJ, TIF1-γ, other) |
1.38 |
0.140 |
|
Global Damage (dichotomized at median <23 vs. >23) |
0.43 |
<0.01 for week 8, washes out by week 20
|
Disclosure:
R. Aggarwal,
None;
A. M. Reed,
None;
D. P. Ascherman,
None;
R. J. Barohn,
None;
B. M. Feldman,
baxter and Bayer,
2,
Novartis Pharmaceutical Corporation,
9,
Pfizer Inc,
9;
F. W. Miller,
None;
L. G. Rider,
None;
M. Harris-Love,
None;
M. C. Levesque,
Genentech and Biogen IDEC Inc.,
2;
C. V. Oddis,
Genentech and Biogen IDEC Inc.,
9;
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-and-serologic-predictors-of-response-in-rituximab-treated-refractory-adult-and-juvenile-dermatomyositis-dm-and-adult-polymyositis-pm-the-rim-study/