Session Information
Date: Sunday, November 8, 2015
Title: Rheumatoid Arthritis - Small Molecules, Biologics and Gene Therapy Poster I
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: Patients
with RA are at increased risk for herpes zoster (HZ). Tofacitinib is an oral
Janus kinase inhibitor for the treatment of RA. Treatment with tofacitinib
appears to increase the risk of HZ.1 However, it is unclear whether
the use of concomitant nonbiologic DMARDs or glucocorticoids (GCs) further
increases HZ risk in patients with RA using tofacitinib.
Methods: We
identified reports of serious and non-serious HZ from Phase (P)1/P2/P3 and
long-term extension (LTE) studies of tofacitinib in RA patients (data cut April
3, 2014; one LTE study still ongoing; database unlocked), and calculated crude
incidence rates (IRs) for all HZ (serious and non-serious; unique patients with
events per 100 patient-years [py]) with 95% confidence intervals (CIs).
Patients were censored at study withdrawal, first HZ event, or death. Within P3
studies we described HZ rates in stratified fashion according to concomitant
nonbiologic DMARDs and baseline GC use. To evaluate risk factors for HZ, we used
pooled P1/P2/P3/LTE data and performed univariate and multivariable analyses
using logistic regression. Stepwise selection with an entry and stay criterion
of α=0.1 was used to form the final multivariable model.
Results: In
19 pooled P1/P2/P3 and LTE studies (total: 6192 patients; 16,839 py of exposure)
HZ was reported in 636 tofacitinib-treated patients: IR 4.0 (3.7, 4.4). IRs for
HZ varied widely across regions of enrollment, being lowest in Eastern and
Western Europe (2.4 [2.0, 2.9] and 3.3 [2.4, 4.4], respectively) and highest in
Japan/Korea: IR 8.1 (7.0, 9.4). The IR for United States/Canada/Australia was
4.3 (3.7, 5.1). Within P3 studies, IRs varied according to tofacitinib dose,
background nonbiologic DMARDs (92% of patients using DMARDs were using MTX),
and baseline GCs: IRs per 100 py were lowest for tofacitinib 5 mg twice daily (BID)
monotherapy without GCs (IR 0.6 [0.1, 2.0]) and highest for tofacitinib 10 mg
BID with DMARDs and GCs (IR 5.4 [3.7,7.7]) (Figure). Multivariable analysis
showed that age, baseline GC use, concomitant DMARD use, tofacitinib dose (10
mg BID vs 5 mg BID), smoking history and region were likely predictors of HZ
(Table).
Conclusion:
Among patients with RA using tofacitinib, concomitant use of nonbiologic DMARDs
or GCs appears to increase the risk and overall IR per 100 py of HZ from 0.56
to 4.82 with 5 mg BID. Limiting the use of GCs or MTX could potentially
mitigate HZ risk.
References: 1.
Winthrop KL, et al. Arthritis Rheumatol 2014; 66: 2675-84.
|
Table. Multivariable analysis of HZ risk factors with tofacitinib |
||||
|
Factors |
Comparisons |
Odds Ratio |
95% CI |
P-value |
|
Age* |
|
|
|
<0.001 |
|
|
Units = 23.724* |
2.101 |
1.750, 2.523 |
|
|
Average tofacitinib dose group** |
|
|
|
0.019 |
|
|
Tofacitinib 10 mg vs 5 mg BID |
1.237 |
1.035, 1.479 |
|
|
Background therapy |
|
|
|
0.052 |
|
|
DMARDs vs monotherapy |
1.189 |
0.998, 1.417 |
|
|
Baseline GC dose group |
|
|
|
<0.001 |
|
|
>0 mg – ≤5 mg vs 0 mg (no use) |
1.677 |
1.352, 2.081 |
|
|
|
>5 mg vs 0 mg (no use) |
1.533 |
1.203, 1.954 |
|
|
Region |
|
|
|
<0.001 |
|
|
Asia vs Western Europe |
2.788 |
1.951, 3.986 |
|
|
|
Eastern Europe vs Western Europe |
1.078 |
0.739, 1.574 |
|
|
|
Latin America vs Western Europe |
1.632 |
1.107, 2.406 |
|
|
|
US/Canada/Australia vs Western Europe |
1.411 |
0.983, 2.025 |
|
|
Smoking status |
|
|
|
0.023 |
|
|
Ex/non-smoker vs current smoker |
1.379 |
1.070, 1.778 |
|
|
For the multivariable analysis, a stepwise procedure was used to screen the factors: age, gender, disease duration, average tofacitinib dose, baseline DAS28-4(CRP), baseline ALC, diabetes, BMI, baseline COPD, smoking status, baseline glucocorticoid use, and region to analyze the occurrence of HZ events. *Odds Ratios calculated for continuous variables are the factor by which the odds of HZ being present increased in response to an increase of 2 standard deviations in a given variable. **Tofacitinib dose was grouped based on the averaged TDD: if 0<TDD<15 mg, then the dose group of tofacitinib is 5 mg; if TDD ≥15 mg, the dose group of tofacitinib is 10 mg. ALC, absolute lymphocyte count; BID, twice daily; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; DAS28-4, disease activity score in 28 joints (4-variable); DMARD, disease-modifying antirheumatic drug; GC, glucocorticoid; HZ, herpes zoster; TDD, total daily dose; US, United States |
||||
To cite this abstract in AMA style:
Winthrop KL, Curtis JR, Lindsey S, Valdez H, Fan H, Wang L, Mendelsohn AM, Bananis E. Herpes Zoster and Tofacitinib: The Risk of Concomitant Nonbiologic Therapy [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/herpes-zoster-and-tofacitinib-the-risk-of-concomitant-nonbiologic-therapy/. Accessed .« Back to 2015 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/herpes-zoster-and-tofacitinib-the-risk-of-concomitant-nonbiologic-therapy/