FormalPara Key Summary Points

Why carry out this study?

Racial disparities in disease severity, clinical outcomes, and treatment survival have been reported in patients with rheumatoid arthritis (RA); however, there remains a paucity of data on racial differences in response to advanced RA therapies, particularly Janus kinase inhibitors.

This post hoc analysis assessed the efficacy and safety of tofacitinib across racial groups using pooled data from the tofacitinib global clinical program.

What was learned from the study?

The efficacy and safety of tofacitinib across racial groups were consistent with previous findings from the tofacitinib RA clinical program.

Differences in clinical outcomes across racial groups may be attributable to differences in regional patient demography and clinical management of RA, or geographical differences in risk for safety outcomes.

These data provide insight into observed treatment response across patient backgrounds and reinforce the importance of the inclusion of patients with diverse racial/ethnic backgrounds into clinical trials of advanced therapies for RA.

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with progressive joint damage [1], diminished health-related quality of life, increased pain, and impaired physical function [2, 3]. While advancements in RA therapies and clinical management strategies have improved overall outcomes for patients [4], racial disparities in disease activity, clinical outcomes, and treatment survival persist. Data from North American registries have demonstrated significantly higher levels of disease activity, physical impairment [5], and pain [6] in African-American and Hispanic versus non-Hispanic White patients with RA. An analysis of real-world data in the UK showed that South Asian patients had significantly lower 12-month survival rates for disease-modifying antirheumatic drugs (DMARDs) versus patients of North European origin [7]. However, racial disparities are not restricted to RA, and have been observed in other diseases [8].

The exact mechanisms for these racial differences among patients with RA remain unknown but may partly be explained by genetic or biologic factors (e.g., racial variation in the frequency and types of RA-associated alleles [9]) and presence of comorbidities [6]. However, race is a social construct defined by cultural and geographical origins; therefore, healthcare inequalities and racial disparities in outcomes may also reflect broader differences in socioeconomic factors and access to care/treatment [10, 11]. Poorer clinical outcomes observed in minoritized patients with RA may be influenced by the greater preference for aggressive treatment [12] and use of advanced RA therapies [13] in White versus non-White patients. Delays in diagnosis and limited access to therapy are barriers in RA management in Latin America and Asia Pacific [14, 15]. Clinical trials provide the opportunity to investigate potential differences in outcomes across racial groups without the confounding effect of disparities in access to care. However, certain minoritized groups are largely under-represented in clinical trials, so evaluating differences in disease activity and treatment response in these groups is challenging and broadly uncharacterized. Consequently, data on racial differences in response to advanced RA therapies [7], particularly Janus kinase (JAK) inhibitors, are lacking [16].

Tofacitinib is an oral JAK inhibitor for the treatment of RA. In this post hoc analysis of pooled data from the tofacitinib global clinical program, we evaluate the impact of race on tofacitinib efficacy, including patient-reported outcomes, and safety in patients with RA.

Methods

Study Design and Patients

This post hoc analysis included pooled data from eight phase 2 and six phase 3 trials, and one phase 3b/4 randomized controlled trial, of patients with RA treated with tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks, or placebo. Full study details have been previously reported and are summarized in Table S1 (electronic supplementary material).

All efficacy and safety outcomes were summarized by treatment [tofacitinib 5 or 10 mg BID, all tofacitinib (i.e., tofacitinib 5 and 10 mg BID), adalimumab, or placebo] and stratified by self-reported patient race (White, Black, Asian, Other), captured via case report forms completed at the baseline visit. Some patients who selected the ‘Other’ category on the case report form used a free text option to specify their race/ethnicity.

Each study was conducted in accordance with the Declaration of Helsinki, International Council for Harmonisation Guidelines for Good Clinical Practice, and local country regulations, and approved by the Institutional Review Board and Independent Ethics Committee at each center. Patients provided written informed consent. No further ethical approval was required for this post hoc analysis in accordance with the policies of our institutions.

Clinical Efficacy and Patient-Reported Outcomes

Outcomes assessed at week 2 (tofacitinib and placebo groups only), months 1 and 3 (all treatment groups), and months 6 and 12 (tofacitinib and adalimumab only), included the proportions of patients achieving ≥ 20%/ ≥ 50%/ ≥ 70% improvement in American College of Rheumatology (ACR) response criteria (ACR20/50/70), and low disease activity (LDA) as defined by the Clinical Disease Activity Index (CDAI; ≤ 10) and Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR); ≤ 3.2], and least squares (LS) mean change from baseline in CDAI, DAS28-4(ESR), and Health Assessment Questionnaire-Disability Index (HAQ-DI), and Pain [Visual Analog Scale (VAS); scale: 0–10].

Safety

Safety was evaluated up to 24 months, encompassing the duration of the observation period across studies, though the duration of most studies was either 6 or 12 months. Safety outcomes included all adverse events (AEs), serious AEs (SAEs), discontinuations due to AEs, all-cause mortality, and AEs of special interest, including: serious infections, adjudicated opportunistic infections (excluding tuberculosis), tuberculosis, herpes zoster (serious and non-serious), malignancies [excluding non-melanoma skin cancer (NMSC)], NMSC, gastrointestinal perforations, major adverse cardiovascular events (MACE), venous thromboembolism [VTE; including deep vein thrombosis (DVT), and pulmonary embolism (PE)], and hepatic disorders. All opportunistic infections, malignancies, and gastrointestinal perforations were adjudicated by separate blinded independent adjudication committees. MACE after February 2009 were adjudicated by committees of independent external experts in the fields of cardiovascular and/or neurovascular disease.

Statistical Analyses

Efficacy analyses were based on the full analysis set of each study that included all patients who were randomized and received ≥ 1 dose of study medication and had non-missing race data.

Categorical outcomes were analyzed using a logistic regression model for each self-reported race that included treatment, disease duration, and baseline value for CDAI and DAS28-4(ESR) LDA. For ACR20/50/70 responses, only treatment and disease duration were included in the model. Adjusted proportions [95% confidence intervals (CIs)], and odds ratios (ORs; 95% CI) for all time points and p values for active treatment versus placebo up to month 3 were obtained from the model. Across treatment/racial groups, ACR20 response and CDAI and DAS28-4(ESR) LDA rates at month 3 were further analyzed for each geographic region [Central Asia, East Asia, South East Asia, East Europe, West Europe (includes Canada), Latin America, United States (US), and rest of world (South Africa, Australia, and New Zealand)].

Continuous outcomes were analyzed using a mixed-effect model of repeated measurements for each self-reported race, with treatment, geographical region, disease duration, visit, and treatment-by-visit interaction included with the baseline value as covariates, and patients as a random effect. Estimates of mean change [CDAI, DAS28-4(ESR), HAQ-DI, Pain (VAS)] from baseline (LS means) and placebo-adjusted (mean values of active treatment minus mean values of placebo) changes from baseline for all time points, with 95% CI and p values for active treatment versus placebo up to month 3, for each treatment/racial group were derived from the model.

Safety was assessed in the safety analysis set of each study that included all patients who received ≥ 1 dose of study medication. Incidence rates (IRs) for all safety endpoints were defined as the number of unique patients (per 100 patient-years of exposure) with events during the time between first and last dose plus 28 days, divided by the patient time accrued between first and last dose plus 28 days, or up to first event date, data cut-off, whichever occurred earlier. 95% CIs for IRs were based on the Exact Poisson method, adjusted for exposure time.

For the purposes of this post hoc analysis, across all efficacy and safety outcomes evaluated, comparisons between racial groups are described as higher or lower if 95% CIs do not overlap, and numerically higher or lower if 95% CIs do overlap, as appropriate. Nominal significance level was considered as p < 0.05. All statistical analyses were conducted using SAS version 9.4.

Results

Patients

Overall, 6355 patients were included in the analysis (White, 4145; Black, 213; Asian, 1348; Other, 649). Patient demographics and baseline disease characteristics are shown in Table 1 (all tofacitinib, adalimumab, and placebo treatment groups) and Table S2 (electronic supplementary material; tofacitinib 5 and 10 mg BID). Generally, baseline disease characteristics were comparable across racial groups though some differences were observed. Largely, across treatment groups, higher proportions of White and Black patients were aged ≥ 65 years, had prior biologic DMARD (bDMARD) exposure, had hypertension or cardiovascular or PE risk, and were current or ex-smokers versus Asian and Other patients. Exposure to conventional synthetic DMARDs (csDMARDs) excluding methotrexate was lower in Black versus White/Asian/Other patients. Mean disease duration was also generally higher in White versus Black/Asian/Other patients in all treatment groups, while median disease duration did not show clear trends between racial groups. Mean and median body mass index were highest in Black patients and lowest in Asian patients. Across treatment groups, White patients were most commonly enrolled from East Europe (40.7%) and the US (27.2%), Black patients from the US (67.1%), Asian patients from East Asia (Japan, Republic of Korea, and Taiwan; 50.7%) and Central Asia (China and India; 30.3%), and Other patients from Latin America (80.6%). Patient-reported race/ethnicity captured under the ‘Other’ category is shown in Table S3 in the electronic supplementary material; most Other patients self-reported as Hispanic and/or Latino (52.4%), followed by mixed race (36.8%).

Table 1 Demographics and baseline disease characteristics, stratified by self-reported race, for patients in the a all tofacitiniba, b adalimumab, and c placebo treatment groups (SAS)
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Due to low patient numbers, efficacy and safety outcomes related to Black patients should be interpreted with caution.

Clinical Efficacy and Patient-Reported Outcomes

ORs (active treatment vs. placebo) for achieving ACR20/50 across treatments tended to be numerically higher for White/Asian/Other versus Black patients at month 3 (Fig. 1 and Fig. S1a, b, electronic supplementary material). Similarly, numerically higher ORs for achieving ACR70 were observed with tofacitinib 5 mg BID, tofacitinib 10 mg BID, and all tofacitinib, for White/Asian versus Black patients (Fig. S1c, electronic supplementary material). For all tofacitinib, ORs were consistently numerically higher for Asian versus White patients across ACR20/50/70 outcomes (Fig. S1, electronic supplementary material).

Fig. 1
figure 1

ORsa and response ratesa for patients achieving ACR20 at month 3 in the tofacitinib 5 mg BID, tofacitinib 10 mg BID, and adalimumab treatment groups, stratified by self-reported race (FAS). aOR (95% CI) for active treatment versus placebo and adjusted response rates [% (95% CI)] are obtained from a logistic regression model that included treatment and disease duration; only visit data from patients with response rates > 0 were included in the analysis. ORs (95% CI) are shown on a logarithmic scale. Response rates for the placebo group are shown for comparison. *p < 0.05, **p < 0.01, ***p < 0.001 for comparison versus placebo, based on ORs. ACR20 American College of Rheumatology > 20% response criteria, BID twice daily, CI confidence interval, FAS full analysis set, OR odds ratio

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ACR20/50/70 response rates were mostly higher at month 3 with tofacitinib or adalimumab versus placebo in White/Asian/Other patients (Fig. 1 and Fig. S1, electronic supplementary material), with comparable trends largely observed at other time points (Fig. S1 and Table S4, electronic supplementary material). ACR20/50 response rates with tofacitinib 5 mg BID, tofacitinib 10 mg BID, and all tofacitinib were generally numerically higher in Asian/Other patients versus White/Black patients (Fig. 1; Fig. S1a, b and Table S4, electronic supplementary material). ACR20/50 responses with adalimumab were generally similar across racial groups (Fig. 1; Fig. S1a, b and Table S4, electronic supplementary material). In placebo-treated patients, ACR20/50/70 responses were largely numerically higher in Black versus White/Asian/Other patients at month 3 (Fig. 1 and Fig. S1, electronic supplementary material); this trend was generally observed at earlier time points for ACR20/50 responses but not for ACR70 responses (Fig. S1 and Table S4, electronic supplementary material).

Across treatments, ORs (active treatment vs. placebo) for CDAI- and DAS28-4(ESR)-defined LDA rates tended to be numerically higher for White/Asian/Other versus Black patients at month 3 (Fig. 2). For all tofacitinib, ORs for CDAI-defined LDA were numerically higher in Asian/Other versus White patients (Fig. S2a, electronic supplementary material).

Fig. 2
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ORsa and ratesa for patients achieving a CDAI- and b DAS28-4(ESR)-defined LDA at month 3 in the tofacitinib 5 mg BID, tofacitinib 10 mg BID, and adalimumab treatment groups, stratified by self-reported race (FAS). aOR (95% CI) for active treatment versus placebo and adjusted rates [% (95% CI)] are obtained from a logistic regression model that included baseline value, treatment, and disease duration; only visit data of all treatment groups with rates > 0 are included in the analysis. ORs (95% CI) are shown on a logarithmic scale. Response rates for the placebo group are shown for comparison. *p < 0.05, **p < 0.01, ***p < 0.001 for comparison versus placebo, based on ORs. BID twice daily, CDAI Clinical Disease Activity Index, CI confidence interval, DAS28-4(ESR) Disease Activity Score in 28 joints, erythrocyte sedimentation rate, FAS full analysis set, LDA low disease activity [defined as CDAI score ≤ 10 or DAS28-4(ESR) ≤ 3.2], OR odds ratio

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CDAI- and DAS28-4(ESR)-defined LDA rates were higher with tofacitinib or adalimumab versus placebo at month 3 in White/Asian/Other patients (Fig. 2), consistent with observations at month 1 (Fig. S2 and Table S5, electronic supplementary material). CDAI-defined LDA rates from month 3 were generally comparable between racial groups with tofacitinib and adalimumab, although higher rates in the Other group were observed at month 3 for tofacitinib 5 mg BID and all tofacitinib (Fig. 2a; Fig. S2a and Table S5, electronic supplementary material). From month 3, DAS28-4(ESR)-defined LDA rates were also largely comparable between racial groups with tofacitinib and adalimumab (Fig. 2b; Fig. S2b and Table S5, electronic supplementary material). In placebo-treated patients, numerically higher CDAI- and DAS28-4(ESR)-defined LDA rates were observed in Black versus White/Asian/Other patients at month 3 (Fig. 2).

At month 3, numerically greater placebo-adjusted improvements from baseline in CDAI, DAS28-4(ESR), and Pain (VAS) were generally observed in White/Asian/Other versus Black patients across active treatments (Figs. 3 and 4). Placebo-adjusted improvements in DAS28-4(ESR) and HAQ-DI were greater in Asian versus White patients receiving tofacitinib at month 3, as were placebo-adjusted improvements in Pain (VAS) for tofacitinib 10 mg BID and all tofacitinib (Figs. 3 and 4).

Fig. 3
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Placebo-adjusted LS mean changes from baseline, and LS mean changes from baselinea in a CDAI and b DAS28-4(ESR) at month 3 in the tofacitinib 5 mg BID, tofacitinib 10 mg BID, and adalimumab treatment groups, stratified by self-reported race (FAS). aPlacebo-adjusted LS mean and LS mean change from baseline (95% CI) were obtained from a mixed-effect model of repeated measurements, with treatment, geographical region, disease duration, visit, and treatment-by-visit interaction included with the baseline value as covariates, and subjects as random effect. LS mean changes from baseline for the placebo group are shown for comparison. *p < 0.05, **p < 0.01, ***p < 0.001 for comparison versus placebo. BID twice daily, CDAI Clinical Disease Activity Index, CI confidence interval, DAS28-4(ESR) Disease Activity Score in 28 joints, erythrocyte sedimentation rate, FAS full analysis set, LS least squares

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Fig. 4
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Placebo-adjusted LS mean changes from baseline, and LS mean changes from baselinea in a HAQ-DI and b Pain (VAS) at month 3 in the tofacitinib 5 mg BID, tofacitinib 10 mg BID, and adalimumab treatment groups, stratified by self-reported race (FAS). aPlacebo-adjusted LS mean and LS mean change from baseline (95% CI) were obtained from a mixed-effect model of repeated measurements, with treatment, geographical region, disease duration, visit, and treatment-by-visit interaction included with the baseline value as covariates, and subjects as random effect. LS mean changes from baseline for the placebo group are shown for comparison. *p < 0.05, **p < 0.01, ***p < 0.001 for comparison versus placebo. BID twice daily, CI confidence interval, FAS full analysis set, HAQ-DI Health Assessment Questionnaire-Disability Index, LS least squares, VAS Visual Analog Scale

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At month 3, LS mean changes from baseline in CDAI, DAS28-4(ESR), HAQ-DI, and Pain (VAS) were generally greater with tofacitinib and adalimumab versus placebo in White/Asian/Other patients (Figs. 3 and 4). These trends were largely present at earlier time points (Fig. S3 and Table S6, electronic supplementary material). From month 3, LS mean changes from baseline in DAS28-4(ESR) were mostly comparable between racial groups across active treatments, whereas LS mean changes from baseline in CDAI, HAQ-DI, and Pain (VAS) were typically numerically greater in Black versus White/Other patients with all tofacitinib (Fig. 3 and 4; Fig. S3 and Table S6, electronic supplementary material). In placebo-treated patients, LS mean changes from baseline in CDAI, DAS28-4(ESR), HAQ-DI, and Pain were numerically greater in Black versus White/Asian/Other patients at month 3 (Figs. 3 and 4); these trends were largely consistent with those observed at earlier time points (Fig. S3 and Table S6, electronic supplementary material).

Clinical Efficacy Outcomes Stratified by Race and Geographic Region

Some differences in outcomes were observed within racial groups when stratified by geographical region, with numerically higher responses observed in Latin America versus Europe or the US (Table S7, electronic supplementary material).

Safety

A trend toward higher AE IRs was observed in Black/Other patients versus White/Asian patients with tofacitinib, while similar AE IRs were largely observed across racial groups for adalimumab, although the number of evaluable patients in each racial group was small (Fig. 5a). AE IRs were similar across White/Asian/Other patients receiving placebo with higher IRs observed for Black patients. IRs for SAEs were mostly comparable across treatments and racial groups (Fig. 5b). Across treatment groups, IRs for discontinuation due to AEs were numerically higher in Asian versus White/Other patients (Fig. 5c) and were generally lowest for Other patients.

Fig. 5
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IRs (95% CI) for a AEs, b SAEs, and c discontinuations due to AEs in the tofacitinib 5 mg BID, tofacitinib 10 mg BID, adalimumab, and placebo treatment groups, stratified by self-reported race (SAS). IRs were calculated as the number of unique patients (per 100 PY of exposure) with events during the time between first and last dose plus 28 days, divided by the patient time accrued between first and last dose plus 28 days, or up to first event, data cut-off, whichever occurred earlier. PY are total follow-up time calculated up to the day of the first event, subject to a risk period of up to 28 days beyond the last dose or to the data cut-off date (28-day algorithm). AE adverse event, BID twice daily, CI confidence interval, IR incidence rate, PY patient-years, SAE serious adverse event, SAS safety analysis set

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Across treatment groups, IRs for AEs of special interest were generally comparable between racial groups (Fig. 6; Fig. S4 and S5, electronic supplementary material), though some exceptions were observed. IRs for serious infections trended higher in Asian versus White patients following treatment with tofacitinib or adalimumab (Fig. 6a). Incidences of tuberculosis were only reported in Asian patients receiving tofacitinib 10 mg BID (IR, 1.81; 95% CI 0.83–3.43; n = 9; Fig. S5b, electronic supplementary material) and White patients receiving tofacitinib 5 mg BID (IR, 0.12; 95% CI 0.01–0.43; n = 2; Fig. S5b, electronic supplementary material). In patients treated with tofacitinib, numerically higher IRs for herpes zoster (Fig. 6b) and hepatic disorders (Fig. 6c) were observed in Asian versus White/Other and in Asian/Other versus White patients, respectively. IRs for MACE, VTE, malignancies, and all-cause mortality did not display any notable trends (Fig. S4, electronic supplementary material).

Fig. 6
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IRs (95% CI) for a serious infections, b herpes zoster (serious and non-serious), and c hepatic disorders in the tofacitinib 5 mg BID, tofacitinib 10 mg BID, adalimumab, and placebo treatment groups, stratified by self-reported race (SAS). IRs were calculated as the number of unique patients (per 100 PY of exposure) with events during the time between first and last dose plus 28 days, divided by the patient time accrued between first and last dose plus 28 days, or up to first event, data cut-off, whichever occurred earlier. PY are total follow-up time calculated up to the day of the first event, subject to a risk period of up to 28 days beyond the last dose or to the data cut-off date (28-day algorithm). BID twice daily, CI confidence interval, IR incidence rate, PY patient-years, SAS safety analysis set

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Discussion

To our knowledge, this is the first peer-reviewed publication to evaluate the impact of race on the efficacy and safety of a JAK inhibitor in RA. Across racial groups, tofacitinib efficacy and safety were consistent with previous overall and regional findings from the tofacitinib RA clinical program [17,18,19,20,21,22,23,24,25,26,27,28,29,30].

Different efficacy and safety trends were observed across racial groups with active treatment. Higher treatment effects, evidenced by numerically higher ORs for ACR20/50/70 responses and CDAI/DAS28-4(ESR) LDA rates at month 3, were observed in White/Asian/Other versus Black tofacitinib-treated patients. Furthermore, higher treatment effects for ACR20 response and CDAI-defined LDA rates, and placebo-adjusted improvements in DAS28-4(ESR), HAQ-DI, and Pain (VAS), were generally observed at month 3 in Asian versus White patients. Trends toward slightly lower tofacitinib treatment effect in Black versus White/Asian/Other patients and White versus Asian patients may be attributable to differences in patient demographics, such as age, smoking history, bDMARD exposure (potentially driven by differing regional practice norms), and comorbidities. It is well established that racial differences in the clinical management of patients with RA exist [13, 31] wherein physician-reported measures may be influenced by implicit bias, while racial disparities in patients’ attitudes to treatment [12, 32], beliefs, and coping strategies [33] may contribute to differences in patient outcomes [34]. Trends for adalimumab appear similar to tofacitinib, although low patient numbers in the adalimumab group limits interpretation.

Racial disparities in pain responses between African-American, Caucasian, and Hispanic patients with RA have been reported [6], complementing the observed pain response differences between Black and White patients in our analysis. Given that disease characteristics were generally similar between Black and White patients in the current analysis, other factors, such as social context, may have contributed to differences in pain response. Previous analyses in RA populations observed that lower socioeconomic status (income level, education level, occupation) was associated with higher disease activity, physical disability [35, 36], and pain at baseline [35], and lower educational attainment negatively impacts physical function and pain levels [37]. Additionally, these differences in pain are unlikely to be due to pharmacokinetic variation, consistent with the concept that race is a social rather than a biologic construct. No major differences in variation in tofacitinib exposure have been demonstrated between races in patients with RA [38, 39]. Further exploration of racial disparities in pain responses is warranted, particularly around the greater pain improvements observed in Asian patients.

Across efficacy outcomes, Black patients receiving placebo typically had numerically higher responses versus White/Asian/Other patients. This may reflect demographic differences, notably country of enrollment, across the racial groups participating in the randomized controlled trials; some differences in outcomes were observed within racial groups when stratified by geographical region. Increasing placebo responses in RA clinical trials have been observed over time; a meta-analysis of 32 randomized clinical trials between 1999–2018 reported significant increases in placebo ACR50 and ACR70 responses during this time period [40]. In this analysis, most (67.1%) Black patients enrolled from the US, where standard of care and access to treatment may differ versus other global regions. Black patients in the current analysis were more likely to be exposed to tumor necrosis factor inhibitors and less likely to have received csDMARDs, other than methotrexate, compared with Asian and Other patients. Therefore, the increased placebo response observed in this racial group may have been driven by this regional cohort. Indeed, previous studies have observed higher placebo responses driven by specific regional cohorts; a phase 3 study of filgotinib in patients with RA observed elevated ACR20 response rates in the placebo arm, which was attributed to high placebo response rates in patients from Eastern Europe, Mexico, and Argentina [41]. Additionally, higher ACR20 response rates were observed in Latin American patients with psoriatic arthritis receiving placebo versus patients from North America or Europe [42]. Furthermore, access-to-care barriers may be partially removed through participation in a clinical trial; it is possible that addressing social determinants of health may contribute to higher placebo responses observed in Black patients. Real-world data may provide more insight since social determinants are likely to be less mitigated in a real-world clinical setting.

Safety outcomes were broadly similar across racial groups with tofacitinib, with some exceptions. Higher IRs for AEs were observed in Black versus White/Asian patients with both tofacitinib doses, although this might be accounted for by the higher proportion of Black patients with baseline cardiovascular risk factors in the tofacitinib groups. Patients in the Other subgroup had the second highest IR for AEs, but this group also generally had the lowest IR for discontinuations due to AEs. This might suggest a trend for a reporting and retention bias in patients enrolling from countries in Latin America, which accounted for the majority of study centers in the Other patient subgroup, or result from differences in the manageability of AEs between racial groups (i.e., it may be possible that Other patients experienced a high number of AEs that were more manageable vs. those experienced by other racial groups). Considering AEs of special interest, IRs for serious infections, herpes zoster, and hepatic disorders were higher in Asian patients versus other racial groups with tofacitinib. Additionally, the IR of tuberculosis was higher in Asian patients receiving tofacitinib 10 mg BID (n = 9) versus other racial groups. These findings were not unexpected as previous analyses of the tofacitinib RA clinical program identified enrollment from an Asian location (vs. US/Canada) as a risk factor for serious infections [43], herpes zoster [43], and tuberculosis [44], and increased incidence of elevated transaminases have been reported in Asian patients receiving tofacitinib compared with other racial groups [45]. Differences in IRs for malignancies (excluding NMSC), MACE, VTE (DVT and/or PE), and gastrointestinal perforations were not observed across racial groups.

Limitations of this analysis included a high correlation between race and region (e.g., largely, Black patients were from the US, Asian patients were from Asia, and Other patients were from Latin America). Thus, this may not reflect the prevalence of racial groups within an individual country. However, additional analyses stratifying by both race and geographic region were also conducted to allow for assessment of any regional differences. Three of the included trials only recruited patients from a single country, although all trials were broadly similar in terms of inclusion and exclusion criteria. The low patient numbers in some treatment/racial groups were previously noted. Accordingly, the number of variables that could be included in the statistical models were limited. The small group size was particularly marked with Black patients; therefore, findings for this racial group must be interpreted with particular caution. However, in this analysis, the proportions of Black patients enrolled at sites in the US across all treatment groups (8.5–12.5%) were similar to the US census 2010 population estimates (13.6%) [46]. Furthermore, analysis of Pfizer-sponsored US clinical trials across therapeutic areas demonstrated equitable representation across race/ethnicity, sex, and age [47]. Nevertheless, inherent barriers to participation in clinical trials (e.g., access to clinical trial sites and time and financial challenges associated with research participation) still exist for some racial/ethnic minoritized groups. Patients of certain racial/ethnic backgrounds may also be less willing to participate due to mistrust of medical research or political influence, as observed for some coronavirus (COVID-19) vaccine trials and vaccination uptake rates [48]. The resulting limitations of our data reinforce the importance of improving engagement with, and increasing the inclusion of, minoritized groups in RA randomized controlled trials to better understand therapeutic outcomes across a diverse range of patients. A further limitation was the use of self-reporting race and the heterogenous nature of the Other patients subgroup. Considering that race is socially constructed, patients’ understanding of race may vary across regions. Additionally, data on patients’ socioeconomic status as well as patients’ social determinants of health are not available, as these variables were not captured in the primary studies. It is likely that these factors would have had a greater impact on efficacy and safety outcomes with tofacitinib than patient race. Therefore, the authors recommend that future studies ensure capture of social determinants of health at baseline to enable a greater understanding of the factors that drive demographic disparities in controlled settings and to better inform on the benefit/risk of RA therapies.

Conclusions

This post hoc analysis showed tofacitinib is efficacious across racial groups, with similar safety outcomes. Some racial differences were observed in clinical outcomes; these are unlikely to arise due to race itself, but they reveal potential inequities in regional patient demography and clinical management of RA. For example, the higher treatment effect in Asian versus White patients may be due to the lower bDMARD exposure in this population; Black patients were largely from the US where higher responses to placebo are generally expected, which likely accounts for the numerically lower treatment effect in this group; Other patients were largely from Latin America where patient discontinuation rates were generally lower and response rates higher, which may suggest retention in clinical trials. Additionally, Asian patients are generally more prone to herpes zoster and certain endemic infections which may account for the increased AE IRs in this population. Further studies on the impact of socioeconomic, cultural, genetic, and practice-based differences are required to better understand the factors that may underpin the racial discrepancies seen with tofacitinib and other advanced therapies for RA.