Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction, and affects approximately 0.5–1.0% of the adult population in industrialized countries.1 In Latin American (LA) countries, the overall prevalence of RA is estimated to range from 0.4 to 1.6%,2 with regional variation apparent throughout LA. LA patients with RA differ from patients from the Rest of the World (RoW) in terms of genetic and epidemiologic factors, and in prognosis.2,3
Common clinical practice for treatment of patients with RA in LA involves prescription of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) as first-line therapy, followed by biologic DMARDs (bDMARDs) in the case of inadequate response.3 Despite the relative effectiveness of csDMARD treatment, not all patients with RA respond to treatment, and response may diminish over time.4 Many patients experience an inadequate clinical response to methotrexate,4 and although most patients treated aggressively with csDMARDs show rapid improvements, these effects are often not maintained following 1 year of treatment.4 Several bDMARDs are approved for use in LA, including abatacept, rituximab, tocilizumab, and the tumor necrosis factor inhibitors (TNFi) adalimumab, etanercept, infliximab, certolizumab pegol, and golimumab.5,6 However, given that not all patients respond to or tolerate treatment with DMARDs,4 and that the administration of injectable therapies represents a significant burden on LA health systems,2 new therapies that demonstrate clinical effectiveness and acceptable safety over time are required for the treatment of RA in LA. Additionally, for patients with RA, the route of drug administration may influence their everyday lives. In certain regions, patients may have to travel long distances to access medical centers, which may preclude treatment compliance. In this sense, the majority of patients with RA would prefer oral treatment rather than an injection or intravenous infusion.7
Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The efficacy and safety of tofacitinib in the treatment of RA, as monotherapy or in combination with csDMARDs, has been demonstrated in several Phase 2,8–13 Phase 314–19 and long-term extension (LTE) studies.20,21 In LA, based on these results, tofacitinib has been included as second- or third-line treatment for RA in clinical practice guidelines from Argentina,22 Chile,23 Colombia,24 Mexico5 and Brazil.25 American College of Rheumatology (ACR) 2015 guidelines for RA treatment recommend tofacitinib therapy for patients with inadequate response to, or failed treatment with, traditional DMARD therapy.26
The management of RA in LA faces a number of challenges that can influence treatment response, including delays in specialist referral, limited resources, limited access to affordable medication, lack of informed decision making regarding public policies, and lack of education surrounding RA.2,3,27 Moreover, tuberculosis, visceral leishmaniasis, paracoccidioidomycosis, histoplasmosis, Chagas disease and malaria, among other infectious diseases, are endemic in some LA countries and also need to be taken into account when considering treatments for patients with RA due to an increased risk of infections with immunosuppressive therapies.28
In this post hoc analysis of pooled data from Phase 2, Phase 3 and LTE studies of tofacitinib, the safety of tofacitinib in LA patients with RA was assessed in comparison with the RoW population.
MATERIALS AND METHODS
Patients and Study Treatments
Data from 14 studies of tofacitinib in patients with RA (six Phase 2, six Phase 3 and two LTE studies) were pooled for this analysis (Table 1). Eligible patients were ≥18 years of age with active RA. Active RA was defined as ≥6 tender or painful joints (68-joint count) and ≥6 swollen joints (66-joint count) and by an erythrocyte sedimentation rate of >28 mm/hr or C-reactive protein level of >7 mg/l.
Phase 2 Studies
In two studies (NCT0041366010; NCT0060351212), patients were required to have a previous inadequate response to methotrexate; in three studies (NCT001474989; NCT005504468; NCT0068719313), patients had previous inadequate response to csDMARDs or bDMARDs; one study had no criteria for prior DMARD exposure (NCT0105986411). Patients received tofacitinib 1–30 mg twice daily (BID) or placebo (tofacitinib 20 mg once-daily dose was included in one study [NCT00413660]10) as monotherapy (NCT00147498; NCT00550446; NCT00687193; NCT01059864) or in combination with background csDMARDs (mainly methotrexate; NCT00413660; NCT00603512). One study (NCT005504468) included an active control arm of adalimumab 40 mg administered subcutaneously once every 2 weeks.
Phase 3 Studies
Patients had a previous inadequate response to methotrexate (ORAL Scan18 and ORAL Standard16), DMARDs (ORAL Solo14 and ORAL Sync19), or TNFi (ORAL Step17). ORAL Start15 enrolled patients who were methotrexate-naïve or had received ≤3 doses of methotrexate. At the time of this analysis, ORAL Start was an ongoing study; therefore, the study database had not yet been locked; some values may change for the final, locked study database; data presented here include up to Month 12 of the study. Patients were randomized to receive tofacitinib 5 mg BID, tofacitinib 10 mg BID, methotrexate (ORAL Start only15), adalimumab (ORAL Standard only16) or placebo as monotherapy (ORAL Start and ORAL Solo) or in combination with csDMARDs (ORAL Sync, ORAL Standard, ORAL Scan and ORAL Step). In ORAL Solo14 and ORAL Step17 patients randomized to receive placebo were automatically advanced to receive tofacitinib 5 mg BID or tofacitinib 10 mg BID in a blinded manner after 3 months. In ORAL Standard,16 ORAL Scan18 and ORAL Sync,19 patients receiving placebo and not achieving ≥20% reduction from baseline in swollen and tender joint counts were advanced to receive tofacitinib 5 mg BID or tofacitinib 10 mg BID in a blinded manner after 3 months; all patients continuing to receive placebo were advanced in a blinded manner to tofacitinib after 6 months. In ORAL Start,15 patients randomized to receive methotrexate initiated treatment at a dose of 10 mg per week, with increments of 5 mg per week every 4 weeks to 20 mg per week by Week 8.
Patients participating in qualifying Phase 1, Phase 2 or Phase 3 index studies were eligible for inclusion in one of two open-label LTE studies (ORAL Sequel20 and NCT0066166129; studies were ongoing at the time of analysis; therefore, the study databases had not yet been locked; some values may change for the final, locked study databases; data cut-off date: April 2013).
Patients from qualifying index studies initiated treatment in the LTE studies with tofacitinib 5 or 10 mg BID as monotherapy or in combination with background csDMARDs. For patients enrolling in the LTE within 14 days of participation in the index study, baseline values were those of the index study; for all other patients baseline was the start of the LTE study. Adjustments to tofacitinib dose and concomitant RA medications were permitted at the discretion of the investigator.
All studies were conducted in accordance with the Declaration of Helsinki, Good Clinical Practice Guidelines established by the International Conference on Harmonization, and local country regulations. The studies were approved by a central or local institutional review board or an independent ethics committee. All patients provided written informed consent.
Safety data were pooled across all patients who received at least one dose of tofacitinib in any study included in the analysis. Data from patients in the placebo, adalimumab and methotrexate comparator treatment groups were not included due to small sample size in the LA population. LA countries that enrolled patients were Argentina, Brazil, Chile, Colombia, Costa Rica, the Dominican Republic, Mexico, Peru and Venezuela. The RoW population included all patients from the global population in the tofacitinib RA clinical program (all studies outlined in Table 1), excluding those patients from LA countries.
Safety data were calculated as incidence rates (IR; patients with events per 100 patient-years of treatment exposure) for safety events of special interest combined across tofacitinib doses. Safety events of special interest included in this analysis were discontinuations due to adverse events (AEs), serious infection events (SIEs), tuberculosis, opportunistic infections (excluding tuberculosis), all herpes zoster (HZ), serious HZ, malignancies (excluding non-melanoma skin cancer [NMSC]), lymphoma, major adverse cardiovascular events (MACE), and all-cause mortality. 95% confidence intervals (CI) for IRs were calculated using the maximum likelihood method. Descriptive comparisons were made between the LA and RoW populations of patients with RA; statistical comparisons were not performed.
Data from patients recruited in LA countries (n = 984) and the RoW (n = 4687) in the 14 Phase 2, Phase 3 and LTE tofacitinib clinical studies were included in the analysis. Baseline demographic characteristics were generally similar between LA and the RoW patient populations (Table 2). Total tofacitinib exposure was 2148.33 patient-years in the LA population and 10515.68 patient-years in the RoW population; mean exposure was 2.18 years and 2.24 years, respectively.
The IRs for safety events of special interest in patients receiving tofacitinib were generally similar between the LA and RoW populations, with 95% CIs that were generally overlapping (Table 3). IRs for opportunistic infections were similar for LA patients and RoW patients. Opportunistic infections that occurred in LA patients were esophageal candidiasis (n = 4; one patient had 2 separate events), sepsis (n = 1), pneumonia (n = 1), and separate events of HZ (n = 1) and cytomegalovirus hepatitis (n = 1) in the same patient.
IRs for discontinuation due to AEs, SIEs, tuberculosis, all HZ, serious HZ, malignancies (excluding NMSC) and MACE were numerically lower for LA patients compared with RoW patients. No cases of lymphoma were reported in the LA population; the IR for the RoW population was 0.08 (95% CI: 0.04–0.15; Table 3).
In the LA cohort, 10 patients died during the studies (IR for all-cause mortality 0.47 [95% CI: 0.25–0.87]), accounting for 30 days after the last dose of tofacitinib, compared with 25 patients (IR 0.24 [95% CI: 0.16–0.35]) from the RoW population (Table 3). Cause of death in LA patients was determined by the investigator to be related to tofacitinib treatment in 5 of the 10 cases—three cases of pneumonia, one case of appendicitis, and one case of cardio-respiratory arrest (investigator assessment). Causes of death for patients in the LA and RoW cohorts are listed in Table 4.
The safety profile of tofacitinib across the global clinical trial program in patients with RA has been well characterized and previously reported.20,30–32 This pooled, post hoc analysis of tofacitinib was conducted to compare the safety of tofacitinib in LA versus RoW, and includes one of the largest cohorts of DMARD-treated patients with RA from LA countries to be evaluated.
Our findings suggest that the safety profile of tofacitinib in patients with RA is generally similar between patients from LA and patients from RoW. The IRs for discontinuation due to AEs, SIEs, tuberculosis, malignancies (excluding NMSC) and MACE reported for patients receiving tofacitinib in the LA and RoW populations are generally consistent with those reported for biologic DMARDs in the global population of patients with RA.32–35 The rate of opportunistic infections in LA tofacitinib-treated patients was similar compared with the RoW population and consistent with the global analysis of tofacitinib-treated patients.36
Although the LA region is associated with increased risk of tuberculosis,37 and the risk of tuberculosis when using immunomodulatory therapies is proportional to the background rate of tuberculosis,38 the rate of tuberculosis observed in LA tofacitinib-treated patients in this analysis was low, and similar to that observed for RoW patients (which included patients from countries in Asia and Eastern Europe that also have high rates of tuberculosis and other opportunistic infections). Given the increased risk of tuberculosis in LA countries, it may be possible that physicians in LA are inherently more aware of the relevant risks of immunosuppressant therapy for patients with RA. This may contribute to the similar observed rate of tuberculosis compared to the RoW population, despite the high background tuberculosis prevalence in LA. It should also be noted that patients who had tuberculosis at the screening visit were excluded from Phase 2 tofacitinib studies; however, in tofacitinib Phase 3 studies, patients with tuberculosis at screening were permitted entry after they received preventative isoniazid therapy. No patients in this group developed tuberculosis. These observations also support the recent ACR recommendation that patients with RA initiating tofacitinib therapy should undergo screening for tuberculosis (and treatment, if necessary) as is recommended for patients undergoing therapy with bDMARDs.26
The all-cause mortality rate for patients with RA from LA countries was numerically higher than that for patients with RA in the RoW population. This observed difference may be a consequence of differences between the two populations in terms of comorbidities or socioeconomic factors including increased mortality rates due to infection which are observed in many LA countries.39 The IR for all-cause mortality (death within 30 days post-last dose) for tofacitinib in the LA population was similar to rates reported with TNFi and other bDMARDs.32–34,40
It is known that patients with RA have an increased risk of HZ compared with the general population, and that certain RA therapies can exacerbate this risk.30,41 In this analysis, the IRs of all HZ events with tofacitinib in both the LA and RoW populations were higher than those reported for bDMARDs.42 Rates of HZ reported in this analysis are consistent with crude incidence rates for HZ reported with baricitinib in patients with RA,43 suggesting that the increased rate of HZ may be a class effect of JAK inhibitors and not specific to tofacitinib. The IRs for all HZ events and serious HZ events were numerically lower in the LA population versus RoW population. Data presented here are also consistent with a pooled analysis of tofacitinib Phase 2 and Phase 3 studies comparing US versus RoW populations,44 where the IRs for all HZ and serious HZ were numerically lower in the US population versus the RoW (non-US) population. In the tofacitinib RA development program, the overall risk of HZ was increased and particularly in patients from Japan and Korea.30 Additionally, genetic analysis of ~5300 tofacitinib-treated patients identified that interleukin-17RB polymorphism associated with increased risk of HZ was more prevalent in East Asian patients.45 In patients with RA initiating therapy with tofacitinib, zoster vaccination has been shown to be effective in boosting immunity against varicella zoster virus.46
A pooled analysis of data from tofacitinib Phase 1, 2, 3, and LTE studies (cut-off date was April 2014 and included up to 72 months of follow-up) identified geographic region (Asia—specifically Japan/Korea), baseline glucocorticoid use, higher doses of tofacitinib, age, and background DMARD use as risk factors for HZ in tofacitinib-treated patients (after adjusting for other covariates). This analysis suggested that patients using tofacitinib monotherapy without glucocorticoids have a lower risk of developing HZ.42 Additionally, a post hoc analysis showed that the following baseline risk factors were associated with the development of HZ in tofacitinib-treated LA patients: increased age; age category (≥50 vs. <50 years) and baseline corticosteroid use.41 Therefore, physicians should consider these risk factors when deciding treatment regimens for patients with RA.
A number of limitations of the current analysis should be considered. This was a retrospective, post hoc analysis of clinical studies that were not designed for the purpose of comparing LA and RoW data. Data were pooled across Phase 2, Phase 3, and LTE studies; therefore, safety data in LA patients included in this analysis are subject to different patient populations, including differences in previous treatment and failed treatments, different concomitant therapies and different study durations. The LA patient population in this analysis was substantially smaller than the RoW population and had less extent and duration of exposure. These factors should be considered when interpreting the findings; in particular, any comparison of long-latency AEs should be made with caution. Safety data for the LA subpopulation receiving tofacitinib were not compared with data from the placebo, adalimumab and methotrexate arms included in the original studies due to the small sample sizes. Furthermore, no formal statistical comparisons of safety data in LA patients versus RoW patients were conducted due to the relatively low number of patients in the LA patient population compared with the RoW population.
This analysis represents one of the largest datasets comparing the safety of DMARD therapy for RA in the LA population versus the RoW population. Data such as these are important in assessing the long-term safety and tolerability of novel therapies, including tofacitinib, for the treatment of patients with RA in LA. In summary, these data provide evidence that tofacitinib has a consistent safety profile across LA and RoW patient populations.
The authors thank Elaine Hoffman for statistical guidance during drafting of the manuscript. Medical writing support under the guidance of the authors was provided by Daniel Binks, PhD, of Complete Medical Communications and funded by Pfizer Inc.
1. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet
2. Burgos-Vargas R, Catoggio LJ, Galarza-Maldonado C, et al. Current therapies in rheumatoid arthritis: a Latin American perspective. Reumatol Clin
3. Cardiel MH. Treating rheumatoid arthritis in Latin America: current challenges and future treatment strategies. Int J Clin Rheumatol
4. van Vollenhoven RF. Treatment of rheumatoid arthritis: state of the art 2009. Nat Rev Rheumatol
5. Cardiel MH, Díaz-Borjón A, Vázquez Del Mercado Espinosa M, et al. Update of the Mexican College of Rheumatology guidelines for the pharmacologic treatment of rheumatoid arthritis. Reumatol Clin
6. da Mota LM, Cruz BA, Brenol CV, et al. 2012 Brazilian Society of Rheumatology Consensus for the treatment of rheumatoid arthritis. Rev Bras Reumatol
7. Augustovski F, Beratarrechea A, Irazola V, et al. Patient preferences for biologic agents in rheumatoid arthritis: a discrete-choice experiment. Value Health
8. Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib
(CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum
9. Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum
10. Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib
(CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum
11. McInnes IB, Kim HY, Lee SH, et al. Open-label tofacitinib
and double-blind atorvastatin in rheumatoid arthritis patients: a randomised study. Ann Rheum Dis
12. Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib
(CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken)
13. Tanaka Y, Takeuchi T, Yamanaka H, et al. Efficacy and safety of tofacitinib
as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod Rheumatol
14. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib
monotherapy in rheumatoid arthritis. N Engl J Med
15. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib
versus methotrexate in rheumatoid arthritis. N Engl J Med
16. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib
or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med
17. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib
(CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet
18. van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib
(CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum
19. Kremer J, Li ZG, Hall S, et al. Tofacitinib
in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med
20. Wollenhaupt J, Silverfield J, Lee EB, et al. Safety and efficacy of tofacitinib
, an oral janus kinase inhibitor, for the treatment of rheumatoid arthritis in open-label, longterm extension studies. J Rheumatol
21. Wollenhaupt J, Silverfield J, Lee EB, et al. Tofacitinib
, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: safety and clinical and radiographic efficacy in open-label, long-term extension studies over 7 years [abstract]. Arthritis Rheumatol
. 2015;67(Suppl 10):1645.
22. Citera G, Schneeberger EE. Updated Clinical Practice Guidelines for the Treatment of Rheumatoid Arthritis: Tofacitinib
. Available at: http://www.reumatologia.org.ar/docs/Tofacitinib_2014.pdf
. Accessed August 20, 2014.
23. Minesterio de Salud Gobierno de Chile. Guía Clínica AUGE: Artritis Reumatoide, Serie Guías Clínicas MINSAL 2014. Available at: http://www.hazteelexamen.cl/sites/default/files/files/GPC%20Artritis.pdf
. Accessed October 19, 2015.
24. Minesterio de Salud y Proteccíon Social. Guía de Práctica Clínica artritis reumatoide. Available at: http://gpc.minsalud.gov/guias/Documents/Artritis%20Reumatoidea/GPC%20AR%20COMPLETA.pdf
. Accessed January 24, 2017.
25. da Mota LM, Cruz BA, de Albuquerque CP, et al. Update on the 2012 Brazilian Society of Rheumatology Guidelines for the treatment of rheumatoid arthritis: position on the use of Tofacitinib
. Rev Bras Reumatol
26. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol
27. Cardiel MH, Pons-Estel BA, Sacnun MP, et al. Treatment of early rheumatoid arthritis in a multinational inception cohort of Latin American patients: the GLADAR experience. J Clin Rheumatol
28. Barreto ML, Teixeira MG, Bastos FI, et al. Successes and failures in the control of infectious diseases in Brazil: social and environmental context, policies, interventions, and research needs. Lancet
29. Yamanaka H, Tanaka Y, Takeuchi T, et al. Tofacitinib
, an oral Janus kinase inhibitor, as monotherapy or with background methotrexate, in Japanese patients with rheumatoid arthritis: an open-label, long-term extension study. Arthritis Res Ther
30. Winthrop KL, Yamanaka H, Valdez H, et al. Herpes zoster and tofacitinib
therapy in patients with rheumatoid arthritis. Arthritis Rheumatol
31. Kremer JM, Kivitz AJ, Simon-Campos JA, et al. Evaluation of the effect of tofacitinib
on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial. Arthritis Res Ther
32. Cohen S, Radominski SC, Gomez-Reino JJ, et al. Analysis of infections and all-cause mortality in Phase II, Phase III, and long-term extension studies of tofacitinib
in patients with rheumatoid arthritis. Arthritis Rheumatol
33. Schiff MH, Kremer JM, Jahreis A, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther
34. van Vollenhoven RF, Emery P, Bingham CO 3rd, et al. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients. Ann Rheum Dis
35. Ahadieh S, Checchio T, Tensfeldt T, et al. Meta-analysis of malignancies, serious infections, and serious adverse events with tofacitinib
and biologic treatment in rheumatoid arthritis clinical trials. Arthritis Rheum
36. Winthrop KL, Park SH, Gul A, et al. Tuberculosis and other opportunistic infections in tofacitinib
-treated patients with rheumatoid arthritis. Ann Rheum Dis
37. World Health Organization. Global Tuberculosis Report 2013. Available at: http://www.who.int/tb/publications/global_report/en/
. Accessed July 11, 2014.
38. Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum
39. Bliss KE. Health in Latin America and the Caribbean: a report of the CSIS Global Health Policy Center. Available at: http://csis.org/files/media/csis/pubs/090422_bliss_healthlatinamer_web.pdf
. Accessed December 14, 2015.
40. Simard JF, Neovius M, Askling J. Mortality rates in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: drug-specific comparisons in the Swedish Biologics Register. Arthritis Rheum
41. Zerbini CAF, Radominski SC, Cardiel MH, et al. Herpes zoster in patients with rheumatoid arthritis: pooled analyses of tofacitinib
phase 2, 3 and long-term extension studies in a Latin American subpopulation. Abstract presented at the Sociedade Brasileira de Reumatologia—XXXII Congresso Brasileiro de Reumatologia, 2015.
42. Winthrop K, Lindsey S, Fan H, et al. Herpes zoster and tofacitinib
: the risk of concomitant nonbiologic therapy. Ann Rheum Dis
43. Fleischmann R, Takeuchi T, Schlichting DE, et al. Baricitinib, methotrexate, or baricitinib plus methotrexate in patients with early rheumatoid arthritis who had received limited or no treatment with disease-modifying anti-rheumatic drugs (DMARDs): phase 3 trial results. Arthritis Rheumatol
. 2015;67:Abstract 1045.
44. Cohen SB, Koenig A, Wang L, et al. Efficacy and safety of tofacitinib
in US and non-US rheumatoid arthritis patients: pooled analyses of phase II and III. Clin Exp Rheumatol
45. Bing N, Zhou H, Zhang B, et al. Genome-wide trans-ancestry meta-analysis of herpes zoster in RA and Pso patients treated with tofacitinib
. Arthritis Rheumatol
. 2015;67:Abstract 566.
46. Winthrop KL, Wouters A, Choy EH, et al. The effectiveness of Zoster vaccine in RA patients subsequently treated up to 19 months with tofacitinib
. Arthritis Rheumatol
. 2016;68:Abstract 2609.