Session Information
Date: Monday, November 9, 2015
Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy Poster II
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Rapidity of onset of therapeutic
efficacy may be critically important in the management of early RA and may
reduce long-term impact of the disease. Traditional DMARDs have slow onset,
potentially losing an opportunity to mitigate damage. Information on the
trajectory of response to biologics relative to DMARDs in early RA could be
important in making treatment decisions and influencing payer decisions. We
therefore performed a network meta-analysis comparing biologics and tofacitinib to MTX in early RA, specifically evaluating
treatment responses at early time points.
Methods: Medline, EMBASE, Web of Science, and
Cochrane Database were searched from inception through June 1, 2015. We
included all randomized controlled trials involving early RA patients that
reported extractable data for disease activity score (DAS) remission, and
ACR50, and compared a biologic/tofacitinib
with/without MTX to MTX. Odds ratios were calculated for all DAS remission and
ACR 50 outcomes reported at the following time points: 2, 4, 8, 12, 16, and 24
weeks. Network meta-analysis was performed using a Bayesian hierarchical random
effects model for mixed multiple treatment comparisons.
Results: We included 18 studies involving 8658
patients with early RA. The mean age of the patients ranged from 48 to 55
years, and the mean disease duration ranged from 2 to 43 months. 83% were
biologic naïve and 78% were MTX naïve (Table 1). Biologic + MTX combination
therapy worked more quickly than MTX achieving better ACR50 and DAS remission
rates even at week 2 (Table 2). Although the therapeutic trajectories
converge over time, they remain significantly different for up to 6 months. Tofacitinib monotherapy emerged as the best treatment
option at almost all the time points with odds ratios for DAS remission
compared to MTX monotherapy ranging from 18.97 (95% Credible interval 1.68,
354.32) at 4 weeks to 3.42 (1.64, 8.26) at 24 weeks, and ACR50 ranging from
7.53 (1.35, 44.96) at 4 weeks to 3.54 (1.65, 7.85) at 24 weeks.
Conclusion: Biologics combined with MTX, or tofacitinib alone, both result in faster onset of efficacy
than MTX alone for early RA. Onset of efficacy is evident as early as 2 weeks,
with superiority over MTX that persists for as long as six months. Our findings
suggest that early introduction of biologics could produce rapid and sustained
suppression of inflammatory disease, preserving function and reducing joint
damage. Consideration should be given to whether the health economics favor
introduction of biologics/tofacitinib earlier in the
treatment pathway.
|
Table 1: Study and Patient Characteristics |
||||||||
|
Author, Year |
Comparison – Dose & N |
Treatment 1 – Dose & N |
Treatment 2 – Dose & N |
Mean age (years) |
Female (%) |
RA Duration (months) |
Treatment experience |
Baseline DAS28 score |
|
Westhovens, 2009 |
MTX+ iv Placebo 253 |
iv Abatacept, 10 mg/kg once every other week for 4 weeks, then every month+ MTX 256 |
NA |
50 |
78 |
6.5 |
MTX and biologic naïve. 2.7-4% of patients were taking DMARDs at baseline. |
MTX/Pbo: 6.2 ABT/MTX: 6.3 |
|
Schiff, 2014 |
sc Adalimumab, 40 mg every other wk+ MTX 328
|
sc Abatacept, 125 mg once/wk+ MTX 318 |
NA |
51 |
82 |
21.6 |
Biologic naïve DMARD-IR |
ADA/MTX: 5.5 ABT/MTX: 5.5
|
|
Soubrier, 2009 |
MTX 32 |
sc Adalimumab, 40 mg every other wk+ MTX 33 |
NA |
48 |
80 |
4.4 (median) |
MTX and biologic naïve. Other treatment not described. |
MTX: 6.15 ADA/MTX: 6.31 |
|
Detert, 2013 |
sc MTX+ sc Placebo 85 |
sc Adalimumab, 40 mg every other wk+ SC MTX 87 |
NA |
50 |
69 |
1.7 |
DMARD and biologic naïve |
MTX/Pbo: 6.3 ADA/MTX: 6.2 |
|
Heimans, 2013 |
MTX+HCQ+ SSZ 83 |
sc Adalimumab, 40 mg every other wk+ MTX 78 |
NA |
50 |
76 |
3.1 |
DMARD and biologic naïve. Pretreated with MTX and GCs before randomization. |
MTX/HCQ/ SSZ: 3.6 ADA/MTX: 3.6
|
|
Hørslev-Petersen, 2014 |
MTX+ sc Placebo 91 |
sc Adalimumab, 40 mg every other wk+ MTX 89
|
NA |
55 |
66 |
3.1 |
DMARD and biologic naïve |
MTX/Pbo: 5.6 (median) ADA/MTX: 5.5 (median) |
|
Keystone, 2014 |
MTX+ sc Placebo 257 |
sc Adalimumab, 40 mg every other wk+ MTX 268 |
sc Adalimumab, 40 mg every other wk+ oral Placebo 274 |
52 |
74 |
8.8 |
MTX and biologic naïve. Other DMARDs: 30% |
MTX/Pbo: 6.3 ADA/MTX: 6.3 ADA/Pbo: 6.4 |
|
Smolen, 2014 |
MTX+ sc Placebo 112 |
sc Adalimumab, 40 mg every other wk+ MTX 207 |
NA |
49 |
71 |
3.9 |
MTX and biologic naïve. One or more DMARDs: 8.8-12.7%
|
MTX/Pbo: 5.5 ADA/MTX: 5.8 |
|
Takeuchi, 2014 |
MTX+ sc Placebo 163 |
sc Adalimumab, 40 mg every other wk+ MTX 170 |
NA |
54 |
81 |
3.6 |
MTX and biologic naïve. 1 DMARD: 34-43% 2 DMARDs: 10-11% |
MTX/Pbo: 6.6 ADA/MTX: 6.6 |
|
Bathon, 2000 |
MTX+ sc Placebo 217 |
sc Etanercept, 25 mg twice/wk+ oral Placebo 207 |
NA |
50 |
75 |
12 |
MTX and biologic naïve. One or more DMARDs: 39-46% |
ND |
|
Emery, 2008 |
MTX+ sc Placebo 263 |
sc Etanercept, 50 mg once/wk+ MTX 265 |
NA |
51 |
73 |
9.0 |
MTX and biologic naïve. One or more DMARDs: 18-24%
|
MTX/Pbo: 6.5 ETN/MTX: 6.5 |
|
Nam, 2014 |
MTX+ sc Placebo 55 |
sc Etanercept, 50 mg once/wk+ MTX 55 |
NA |
48 |
76 |
8 (median) |
DMARD and biologic naïve |
MTX/Pbo: 4.17 ETN/MTX: 4.1 |
|
Emery, 2009 |
MTX+ sc Placebo 160 |
sc Golimumab, 50 or 100 mg once/mo+ MTX 318 |
sc Golimumab 100 mg once/mo+ oral Placebo 159 |
50 |
83 |
42.6 |
Biologic naïve One or more DMARDs: 50.3-58.5% |
MTX/Pbo: 6.2 GOL/MTX: 6.3 GOL/Pbo: 6.3 |
|
Smolen, 2009 |
MTX+ iv Placebo 298 |
iv Infliximab, 3 mg/kg or 6 mg/kg once at baseline, then wk 2 and 6, then at 8 wk intervals for 46 wks+ MTX 751 |
NA |
50 |
71 |
10.4 |
MTX and biologic naïve; 68-71% of patients were naïve to all DMARDs at baseline. |
MTX/Pbo: 6.69 IFX/MTX: 6.67 |
|
Tak, 2011 |
MTX+ iv Placebo 250 |
iv Rituximab, 2 infusions 500 mg or 1000 mg on day 1 and day 15+ MTX
|
NA |
48 |
81 |
4.8 (median) |
MTX and biologic naïve; 69-72% of patients were naïve to all DMARDs at baseline |
MTX/Pbo: 7.1 RTX/Pbo: 7 |
|
Maini, 2006 |
MTX+ iv Placebo 49 |
iv Tocilizumab, 4 mg/kg or 8 mg/kg once every 4 wk+ MTX 101 |
iv Tocilizumab, 4 mg/kg or 8 mg/kg once every 4 wk+ oral Placebo 99 |
50 |
79 |
9.8 |
MTX-IR. Other treatment not described. |
MTX/Pbo: 6.75 TCZ/MTX: 6.41 TCZ/Pbo: 6.49 |
|
Burmester, 2013 |
MTX+ iv Placebo 287 |
iv Tocilizumab, 4 mg/kg or 8 mg/kg once every 4 wk+ MTX 578 |
Iv Tocilizumab, 8 mg/kg once every 4 wk+ oral Placebo 292 |
ND |
ND |
4.8 – 6 |
MTX naïve. Other treatment not described. |
6.6 – 6.7 |
|
Lee, 2014 |
MTX+ oral Placebo 186 |
Oral Tofacitinib, 10 mg twice/day+ oral Placebo 397 |
NA |
50 |
79 |
36.8 |
MTX naïve. One or more DMARDs: 39%. Biologic experience not described. |
MTX/Pbo: 6.6 TOF/Pbo: 6.5 |
|
N= Number of Patients; ND= No data available; NA= Not applicable; RA= Rheumatoid Arthritis; sc= Subcutaneous; iv= Intravenous; wk= weeks; mo=months; DMARD-IR= Incomplete response to one or more disease modifying anti-rheumatic drug; Pbo= Placebo; MTX/HCQ/SSZ= Triple DMARD therapy with Methotrexate, Hydroxychloroquine, and Sulphasalazine; GC= Glucocorticoid |
||||||||
|
Table 2: Estimates of Odds Ratios for comparative efficacy of biologic and Methotrexate therapy in early RA patients within six months of treatment initiation |
|||||||
|
ACR50 |
|||||||
|
Treatment |
|
Week 2 |
Week 4 |
Week 8 |
Week 12 |
Week 16 |
Week 24 |
|
MTX |
N |
745 |
1091 |
1091 |
1380 |
793 |
1720 |
|
OR |
REF |
REF |
REF |
REF |
REF |
REF |
|
|
Abatacept +MTX |
N |
574 |
574 |
574 |
574 |
574 |
574 |
|
OR |
3.62 (0.49, 20.09) |
2.44 (0.63, 9.17) |
2.75 (1.11, 7.00) |
2.26 (1.35, 4.36) |
1.97 (0.66, 6.14) |
2.06 (1.09, 3.56) |
|
|
Adalimumab +MTX |
N |
705 |
705 |
705 |
1006 |
498 |
1060 |
|
OR |
7.21 (1.62, 29.59) |
3.99 (1.41, 11.95) |
3.28 (1.60, 7.25) |
2.61 (1.86, 4.13) |
2.45 (0.86, 7.52) |
2.17 (1.43, 3.12) |
|
|
Adalimumab |
N |
0 |
0 |
0 |
274 |
0 |
274 |
|
OR |
——————– |
——————– |
——————– |
1.23 (0.63, 2.61) |
——————– |
0.82 (0.41, 1.64) |
|
|
Etanercept |
N |
207 |
207 |
207 |
207 |
207 |
207 |
|
OR |
21.59 (1.59, 766.48) |
9.14 (1.57, 61.17) |
2.36 (0.71, 8.05) |
1.21 (0.58, 2.98) |
1.50 (0.38, 5.68) |
1.46 (0.68, 3.33) |
|
|
Golimumab +MTX |
N |
0 |
318 |
318 |
318 |
318 |
318 |
|
OR |
——————– |
2.45 (0.44, 14.08) |
1.63 (0.47, 5.34) |
1.80 (0.85, 4.47) |
1.19 (0.29, 4.81) |
1.48 (0.66, 3.31) |
|
|
Golimumab |
N |
0 |
159 |
159 |
159 |
159 |
159 |
|
OR |
——————– |
3.53 (0.62, 20.91) |
1.38 (0.40, 4.48) |
1.77 (0.74, 3.72) |
0.89 (0.22, 3.46) |
1.15 (0.51, 2.68) |
|
|
Rituximab +MTX |
N |
0 |
499 |
499 |
499 |
499 |
499 |
|
OR |
——————– |
1.24 (0.21, 6.83) |
1.70 (0.54, 5.68) |
1.54 (0.77, 3.43) |
1.85 (0.48, 7.11) |
1.69 (0.75, 3.59) |
|
|
Tocilizumab +MTX |
N |
0 |
0 |
0 |
0 |
99 |
578 |
|
OR |
——————– |
——————– |
——————– |
——————– |
1.98 (0.46, 8.83) |
1.57 (0.73, 3.31) |
|
|
Tocilizumab |
N |
0 |
0 |
0 |
0 |
106 |
292 |
|
OR |
——————– |
——————– |
——————– |
——————– |
1.28 (0.30, 5.36) |
1.21 (0.55, 2.57) |
|
|
Tofacitinib |
N |
0 |
397 |
397 |
397 |
0 |
397 |
|
OR |
——————– |
7.53 (1.35, 44.96) |
4.75 (1.46, 15.62) |
4.14 (1.76, 8.83) |
——————– |
3.54 (1.65, 7.85) |
|
|
DAS Remission |
|||||||
|
Treatment |
|
Week 2 |
Week 4 |
Week 8 |
Week 12 |
Week 16 |
Week 24 |
|
MTX |
N |
683 |
1209 |
1239 |
1466 |
1319 |
2161 |
|
OR |
REF |
REF |
REF |
REF |
REF |
REF |
|
|
Abatacept +MTX |
N |
256 |
256 |
256 |
256 |
256 |
256 |
|
OR |
1.10 (0.01, 119.06) |
6.23 (0.72, 71.30) |
3.15 (0.25, 39.76) |
2.15 (0.54, 9.16) |
1.79 (0.22, 14.74) |
2.25 (1.10, 4.61) |
|
|
Adalimumab +MTX |
N |
207 |
296 |
383 |
564 |
87 |
821 |
|
OR |
3.67 (0.23, 64.54) |
2.42 (0.64, 9.23) |
3.10 (0.76, 13.96) |
2.31 (1.06, 5.12) |
2.17 (0.27, 17.65) |
2.21 (1.55, 3.06) |
|
|
Adalimumab |
N |
0 |
0 |
0 |
274 |
0 |
274 |
|
OR |
——————– |
——————– |
——————– |
1.01 (0.28, 3.58) |
——————– |
0.71 (0.37, 1.32) |
|
|
Etanercept +MTX |
N |
320 |
320 |
265 |
320 |
320 |
320 |
|
OR |
8.24 (1.28, 83.38) |
8.58 (2.21, 36.43) |
7.67 (0.65, 104.32) |
3.13 (1.08, 8.38) |
3.19 (0.39, 26.16) |
2.28 (1.33, 3.88) |
|
|
Golimumab +MTX |
N |
0 |
0 |
0 |
0 |
0 |
318 |
|
OR |
——————– |
——————– |
——————– |
——————– |
——————– |
1.54 (0.78, 3.13) |
|
|
Golimumab |
N |
0 |
0 |
0 |
0 |
0 |
159 |
|
OR |
——————– |
——————– |
——————– |
——————– |
——————– |
0.85 (0.39, 1.78) |
|
|
Infliximab +MTX |
N |
0 |
0 |
0 |
0 |
751 |
0 |
|
OR |
——————– |
——————– |
——————– |
——————– |
2.07 (0.25, 16.82) |
——————– |
|
|
MTX/HCQ/SSZ |
N |
0 |
0 |
0 |
0 |
83 |
0 |
|
OR |
——————– |
——————– |
——————– |
——————– |
2.31 (0.13, 47.63) |
——————– |
|
|
Rituximab +MTX |
N |
0 |
499 |
499 |
499 |
499 |
499 |
|
OR |
——————– |
9.61 (0.97, 346.41) |
2.86 (0.23, 40.10) |
2.73 (0.66, 12.10) |
2.31 (0.26, 19.10) |
1.36 (0.68, 2.84) |
|
|
Tocilizumab +MTX |
N |
0 |
0 |
0 |
0 |
99 |
578 |
|
OR |
——————– |
——————– |
——————– |
——————– |
6.17 (0.64, 64.34) |
3.62 (1.84, 7.06) |
|
|
Tocilizumab |
N |
0 |
0 |
0 |
0 |
106 |
292 |
|
OR |
——————– |
——————– |
——————– |
——————– |
2.45 (0.25, 27.93) |
3.67 (1.82, 7.09) |
|
|
Tofactinib |
N |
0 |
397 |
397 |
397 |
0 |
397 |
|
OR |
——————– |
18.97 (1.68, 354.32) |
5.08 (0.39, 67.21) |
4.06 (1.02, 17.79) |
——————– |
3.42 (1.64, 8.26) |
|
|
Statistically significant odds ratios are presented in bold text. “REF”: MTX is the reference group. OR=odds ratio, ORs >1 favor the treatments over the reference group; N=number of patients randomized to a treatment group at that specific time point; DAS= Disease activity score |
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To cite this abstract in AMA style:
Bannuru RR, Osani M, Dharmarajan A, Vaysbrot E, McAlindon TE. Rapidity of Therapeutic Response of Biologics Compared to Methotrexate Monotherapy in Early RA: A Network Meta-Analysis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/rapidity-of-therapeutic-response-of-biologics-compared-to-methotrexate-monotherapy-in-early-ra-a-network-meta-analysis/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/rapidity-of-therapeutic-response-of-biologics-compared-to-methotrexate-monotherapy-in-early-ra-a-network-meta-analysis/