FormalPara Key Summary Points

Why carry out this study?

Attenuated responses to tumor necrosis factor inhibitors (TNFi) were reported in current or past smokers versus never smokers in routine care studies of patients with psoriatic arthritis (PsA) or ankylosing spondylitis (AS); however, studies assessing responses to other advanced PsA and AS treatments by smoking status are limited.

This post hoc analysis evaluated the efficacy and safety of tofacitinib in patients with PsA or AS by patient-reported cigarette smoking status at trial screening, using data from randomized controlled trials (PsA and AS) and a long-term extension trial (PsA only).

What was learned from this study?

Tofacitinib efficacy was comparable in current/past and never smokers, which contrasts with data from tumor necrosis factor inhibitors in routine care studies.

Complementing reports of smoking and comorbidities association in spondyloarthritis, current/past smokers had higher rates of adverse events than never smokers.

Introduction

Psoriatic arthritis (PsA) and ankylosing spondylitis (AS) are chronic inflammatory diseases with long-term impacts on physical function and health-related quality of life [1, 2]. PsA predominantly manifests as psoriasis, nail lesions, peripheral joint and axial diseases, dactylitis, and enthesitis [1]. AS symptoms include back pain, morning stiffness, and spinal rigidity, though peripheral (arthritis/enthesitis) and extra-musculoskeletal manifestations may be present [2].

Inflammation and disease activity control are important for PsA and AS disease management, given their link to adverse outcomes [3]. The European Alliance of Associations for Rheumatology recommends encouraging patients with rheumatic and musculoskeletal diseases to stop smoking due to its negative impact on symptoms, physical function, disease activity and progression, and comorbidities [4]. Smoking may impact disease control in patients with PsA/AS, as attenuated responses to tumor necrosis factor inhibitors (TNFi) were reported in current and past smokers versus never smokers in routine care studies [5, 6], although data describing responses to other advanced PsA and AS treatments by smoking status are limited.

The efficacy and safety of tofacitinib 5 and/or 10 mg twice daily (BID) in PsA were demonstrated in two global phase 3 randomized controlled trials (RCTs) [7, 8], one phase 3 RCT in China [9], and one open-label long-term extension (LTE) trial [10]. Efficacy and safety of tofacitinib 5 mg BID in AS were demonstrated in one phase 2 and one phase 3 RCT [11, 12]; tofacitinib 2 and 10 mg BID doses were also investigated in the phase 2 RCT.

Previously, tofacitinib efficacy was shown to be comparable in rheumatoid arthritis (RA) and ulcerative colitis regardless of baseline smoking status [13, 14]. Here, we assessed tofacitinib efficacy and safety in patients with PsA or AS by patient-reported cigarette smoking status at trial screening using RCT and LTE (PsA only) trial data.

Methods

Post Hoc Analysis

This post hoc analysis included pooled data from three phase 3 placebo-controlled RCTs (OPAL Broaden, OPAL Beyond, and a trial in China) and one LTE trial (OPAL Balance; safety only) in patients with PsA. For patients with AS, data were pooled from one phase 2 and one phase 3 placebo-controlled RCT. Trial details are published [7,8,9,10,11,12] (see the electronic supplementary material).

Patients were categorized by their reported cigarette smoking status (current/past or never) at trial screening. Efficacy and safety data from RCTs were analyzed by treatment and by current/past or never smoker status. Efficacy data from the RCTs were assessed for patients with PsA receiving tofacitinib 5 or 10 mg BID to month 6, or placebo to month 3. Efficacy data were assessed for patients with AS receiving tofacitinib 5 mg BID or placebo in the phase 3 trial, to week 16. Due to the study design, efficacy for patients with AS enrolled in the phase 2 trial was assessed to week 12 only. Safety in the RCTs was assessed in patients with PsA receiving tofacitinib 5 or 10 mg BID or placebo to month 3, and in patients with AS receiving tofacitinib 5 mg BID or placebo to week 12.

Additionally, the long-term safety of tofacitinib was assessed by current/past versus never smoker status in patients receiving ≥ 1 tofacitinib dose using data from RCTs and the LTE trial (PsA only) up to month 48 for PsA, and week 48 for AS. Data from patients with PsA were assessed as ‘average tofacitinib 5 mg BID’ (average total daily dose < 15 mg), ‘average tofacitinib 10 mg BID’ (average total daily dose ≥ 15 mg), and ‘all tofacitinib’ (received ≥ 1 tofacitinib 5 or 10 mg BID dose). In patients with AS, data were assessed as ‘tofacitinib 5 mg BID’ (received ≥ 1 tofacitinib 5 mg BID dose) and ‘all tofacitinib’ (received ≥ 1 tofacitinib 2, 5, or 10 mg BID dose). Efficacy outcomes by current, past, and never smoker status at month 3 (PsA) and week 12 (AS) were reported.

Outcomes

Efficacy outcomes assessed in patients with PsA included American College of Rheumatology ≥ 20% and ≥ 50% responses (ACR20 and ACR50, respectively), minimal disease activity (MDA), PsA Disease Activity Score (PASDAS) ≤ 3.2 [15], ≥ 75% improvement in Psoriasis Area and Severity Index (PASI) response (assessed in patients with baseline body surface area ≥ 3% and baseline PASI > 0), ≥ 50% improvement in pain visual analog scale, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) ≥ 40.1 rates [16], and change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI).

Efficacy outcomes assessed in patients with AS included ≥ 20% and ≥ 40% improvement in Assessment of SpondyloArthritis international Society responses (ASAS20 and ASAS40, respectively), AS Disease Activity Score (ASDAS) < 2.1 [17], Bath Ankylosing Spondylitis Disease Activity Index 50 response (BASDAI50), ≥ 50% improvement in back pain, and FACIT-F ≥ 40.1 rates [16].

Safety outcomes assessed in patients with PsA and AS included treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and discontinuations due to AEs. In addition, AEs of special interest (AESI), which included serious infections, herpes zoster infections (serious and non-serious), major adverse cardiovascular events (MACE), malignancies excluding non-melanoma skin cancer (NMSC), NMSC, venous thromboembolism (including deep vein thrombosis and pulmonary embolism), and arterial thromboembolism, were evaluated up to month 48 for patients with PsA, and up to week 48 for patients with AS.

Statistical Analyses

All PsA analyses were based on the final datasets. Phase 2 AS data are from the final dataset. Phase 3 AS data are based on two databases: efficacy data are from the week 16 analysis (database cut-off: December 19, 2019; data snapshot: January 29, 2020), and all other data are from the final week 48 analysis.

Binary and continuous outcomes were assessed using longitudinal logistic regression models and longitudinal mixed-effects linear models, respectively, fitted to include treatment, visit, smoking status, median body mass index (BMI) status (i.e., BMI compared with the baseline median value; < 27.8 and ≥ 27.8 kg/m2 for patients with PsA and < 26.2 and ≥ 26.2 kg/m2 for patients with AS), age, sex, trial, prior TNFi use, and geographic regions at baseline, and all-way interactions of smoking status among median BMI status at baseline, visit, and treatment; and for continuous models, the baseline value of the dependent variable was included. BMI was included in the model due to the relationship between smoking and BMI [18], and for simplicity the two-category median BMI status was used.

Adjusted rates (standard error [SE]) and odds ratios (ORs; 95% confidence intervals [CIs]) versus placebo for binary outcomes and adjusted means (SE) and differences in adjusted means (95% CIs) for continuous outcomes were reported.

Adjusted incidence rates (IRs; number of patients with events/100 patient-years) and associated 95% CIs for safety outcomes were estimated using Poisson regression models, fitted to include treatment, smoking status, median BMI status, sex, trial, and treatment, and smoking status interaction. For several outcomes, models failed to converge; therefore, unadjusted IRs and associated 95% CIs (based upon inverting the Chi-square approximation to the Poisson mean) were also reported.

Data were as observed; missing data were not imputed. p values and 95% CIs were not adjusted for multiple comparisons and were considered descriptive. Numerical differences in adjusted response rates and means with tofacitinib and placebo were noted. The magnitude of treatment response between tofacitinib versus placebo (binary outcomes: OR [95% CI]; continuous outcomes: differences in adjusted means [95% CI]) were assessed between current/past versus never smokers; comparisons with overlapping 95% CIs were considered as similar. Adjusted response rates and means differences between current/past versus never smokers were based on nominal p < 0.05. Safety outcome comparisons between current/past and never smokers were described as higher or lower if the 95% CIs of the unadjusted or adjusted IRs did not overlap.

Additional details on the statistical analysis are in the electronic supplementary material.

Ethics Approval

All studies were conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines of the International Council for Harmonisation, and were approved by the relevant Institutional Review Board and/or Independent Ethics Committee at each investigational site [7,8,9,10,11,12]. Patients provided written, informed consent.

Results

Patients

Overall, 914 patients with PsA (342 current/past and 572 never smokers) and 372 patients with AS (178 current/past and 194 never smokers) were included. Demographics and baseline characteristics were generally similar regardless of smoking status; however, fewer patients were female, and disease duration was longer in current/past versus never smokers (Table S1 in the electronic supplementary material).

Efficacy by Smoking Status

Across outcomes to month 3 (PsA) and week 16 (AS), tofacitinib efficacy was generally greater versus placebo in current/past and never smokers, except for FACIT-F ≥ 40.1 rates, which were similar with tofacitinib and placebo (Fig. 1; Fig. S1 and S2 in the electronic supplementary material). The magnitude of treatment response (i.e., tofacitinib versus placebo) was generally similar regardless of smoking status across all outcomes in PsA and AS (Fig. 1; Fig. S1 and S2 in the electronic supplementary material).

Fig. 1
figure 1

Efficacy outcomes in PsA and AS by current/past and never smoker status at trial screening. ACR20 response, HAQ-DI, and ASAS20 response (primary outcomes from the pivotal trials) are described in the electronic supplementary material (Supplementary Fig. 1). *p < 0.05 for current/past versus never smokers. aDue to the presence of zero rates, baseline values were omitted to improve the model fit. b1 and 3 never smokers who received tofacitinib 10 mg BID and placebo, respectively, had minimal disease activity at baseline. c1 current/past and 1 never smoker who received tofacitinib 5 mg BID had baseline ASDAS < 2.1. ACR20/50 American College of Rheumatology ≥ 20%/ ≥ 50% response, AS ankylosing spondylitis, ASAS20/40 ≥ 20/ ≥ 40% improvement in Assessment of SpondyloArthritis international Society, ASDAS Ankylosing Spondylitis Disease Activity Score, BID twice daily, CI confidence interval, HAQ-DI Health Assessment Questionnaire-Disability Index, MDA minimal disease activity, n number of patients with response, N number of evaluable patients, OR odds ratio, PsA psoriatic arthritis, SE standard error

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Tofacitinib efficacy to month 6 (PsA) or week 16 (AS) was comparable in current/past versus never smokers across most timepoints (Fig. 1; Fig. S1 and S2 in the electronic supplementary material).

When categorized as current, past, or never smokers, generally, trends toward greater efficacy at month 3 (PsA) or week 12 (AS) with tofacitinib versus placebo were observed (ORs ≥ 1 but CIs included 1 in some instances) and the magnitude of treatment response was similar regardless of smoking status, although patient numbers were small (Table S2 in the electronic supplementary material).

Tofacitinib efficacy at month 3 (PsA) or week 12 (AS) was generally comparable in current, past, or never smokers (Table S2 in the electronic supplementary material).

Safety by Smoking Status

Compared with placebo, TEAE adjusted IRs were higher with tofacitinib to month 3 in current/past and never smokers with PsA, and to week 16 in never smokers with AS; TEAE adjusted IRs were higher in current/past versus never smokers across all treatment groups, including placebo (Table S3 in electronic supplementary material). There were no consistent trends across treatments and smoking status for SAEs and discontinuations due to AEs adjusted IRs (Table S3 in electronic supplementary material).

In PsA, TEAE and SAE adjusted IRs to month 48 were higher in current/past versus never smokers across all tofacitinib treatment groups; trends were similar for discontinuation due to AEs, serious infections, and herpes zoster in the average tofacitinib 5 mg BID and all tofacitinib groups (Table 1). Other AESI occurred in current/past and never smokers with PsA, although low event numbers limit interpretation (Table 1).

Table 1 Safety to month 48 (PsA) and week 48 (AS) by current/past versus never smoker status at trial screening
Full size table

In AS, TEAE adjusted IRs to week 48 were higher in current/past versus never smokers in the tofacitinib 5 mg BID and all tofacitinib groups; adjusted IRs for SAEs and discontinuation due to AEs were higher in never versus current/past smokers in the tofacitinib 5 mg BID group but similar in the all tofacitinib group, which included more patients/exposure (Table 1). Across both AS groups, serious infections and herpes zoster occurred in current/past or never smokers; no MACE, malignancies excluding non-melanoma skin cancer (NMSC), venous thromboembolism, or other AESI were reported (Table 1).

Discussion

This post hoc analysis assessed tofacitinib efficacy and safety in patients with PsA or AS by smoking status. To our knowledge, this is the first analysis investigating the impact of cigarette smoking on the benefit/risk of a Janus kinase (JAK) inhibitor in patients with PsA or AS.

Regardless of smoking status, tofacitinib generally demonstrated greater efficacy versus placebo across all outcomes to month 3 (PsA) and week 16 (AS), except for FACIT-F ≥ 40.1 rates; efficacy was generally comparable across current/past and never smokers.

Differences in TNFi response by smoking status were reported in the DANBIO registry [5, 6]. TNFi-treated patients with PsA or AS who smoked had worse baseline patient-reported outcomes and shorter treatment adherence when compared with non-smokers [5, 6]. In patients with PsA, lower responses were reported in current/past versus never smokers and were most pronounced in male smokers [5]. Similarly, in patients with AS, TNFi responses were lower in current/past versus never smokers; improvements in patient-reported outcomes were smaller in current versus never smokers [6]. Disease activity tends to be higher in smokers [19], which may have led to treatment response reduction in this registry [5, 6]. Conversely, tofacitinib efficacy in the current analysis was similar regardless of smoking status; however, studies should be compared with caution due to confounders present in routine care versus RCT settings. Furthermore, the mechanisms of action of JAK inhibitors and TNFi may contribute to treatment response differences in current/past and never smokers. Smoking increases inflammation by stimulating pro-inflammatory cytokine release [20]. Since several cytokines utilize JAK signaling, the impact of smoking on treatment responses may be dampened in patients receiving JAK inhibitors versus TNFi, which only affect TNF [21]; however, further studies are needed to explore this hypothesis.

Here, in the all tofacitinib group, adjusted IRs for TEAEs, SAEs, and discontinuation due to AEs in PsA trials to month 48 were higher in current/past versus never smokers, while in AS trials to week 48, TEAE adjusted IRs were higher in current/past versus never smokers but similar for SAEs and discontinuation due to AEs. Differences in SAEs and discontinuations due to AE adjusted IRs in AS between the all tofacitinib versus tofacitinib 5 mg BID groups were likely due to lower patient numbers and exposure in the tofacitinib 5 mg BID group. Of interest, no malignancies were reported in the AS groups, and very few were reported in the PsA groups. As reported previously for the tofacitinib PsA program, none of these were lung cancer cases [22]. Note that in contrast to efficacy, safety data for current/past smokers was not analyzed by current and past smoker status, due to the limited number of safety events.

A higher risk of cardiovascular diseases (CVD) compared with the general population has been documented in patients with RA, PsA and AS [3, 23,24,25,26]. In the general RA population, smoking has been associated with higher risk of comorbidities (i.e., CVD, mortality, pulmonary diseases, infections, and osteoporosis [4, 27]). However, the effect of smoking on inducing autoantigen citrullination in the lungs among patients with the HLA-DRB1 shared epitope, which increases the risk for seropositive RA [4], should be considered. Several psoriatic comorbidities (i.e., MACE, inflammatory bowel diseases, and respiratory-tract-related malignancies) were linked to smoking [28]. Studies on the impact of smoking in patients with spondyloarthritis specifically are limited, although associations between smoking and comorbidities (including metabolic syndrome, depression, pulmonary disease, and CVD in PsA, and higher number of comorbidities in axial spondyloarthritis) have been reported [28, 29]. Furthermore, increased disease activity and inflammation in PsA and AS may likewise contribute to increased CVD risk in smokers [3].

In a post hoc analysis of ORAL Surveillance, a post-authorization safety study in patients with RA aged ≥ 50 years and ≥ 1 additional cardiovascular risk factor, increased risk of MACE and malignancies excluding NMSC (co-primary endpoints) as well as myocardial infarction, venous thromboembolism, and all-cause death (secondary endpoints) with tofacitinib versus TNFi were identified in patients aged ≥ 65 years or who had ever smoked [30]. However, there was no detectable risk increase of these AESIs between tofacitinib versus TNFi in ORAL Surveillance in patients aged < 65 years and who had never smoked; the absolute risk remained low and was corroborated across tofacitinib clinical development programs from other indications, including PsA, in the overall population and patients aged < 65 years who had never smoked [30]. There may be a possible interaction between these AESIs and the underlying inflammatory disorder, as there is more evidence supporting the association between increased CVD and malignancies risk and RA, compared with PsA and AS [3, 31]. Nevertheless, most patients in the tofacitinib PsA program were aged < 65 years [30]; therefore, smoking status may play a key role in absolute risk reduction in this study population.

Limitations included the post hoc nature of the analysis, the use of as-observed data, and the small patient and event numbers for some subgroups. Additionally, long-term efficacy was not characterized, no active comparator group was included, and patients enrolled in RCTs may not represent those in routine practice. As noted previously, in the DANBIO registry of patients with PsA or AS, smokers had worse baseline patient-reported outcomes and shorter treatment adherence [5, 6], factors that may be controlled in RCTs. Therefore, these results may not be fully representative of the effects of smoking status on tofacitinib efficacy/safety in a real-world setting. Further limitations of utilizing RCT data for secondary analyses include the often restrictive sample sizes and the likelihood that the trial was originally designed and powered to answer a different research question. Future registry analyses will be important to further elucidate the real-world use of tofacitinib/JAK inhibitors for PsA/AS when compared to other treatments, such as TNFi.

Conclusions

In this analysis, tofacitinib efficacy was greater than placebo, and comparable in current/past versus never smokers in RCT settings, which differs from TNFi routine care studies. In tofacitinib-treated patients, adjusted IRs in RCTs/LTE trial (PsA only) were higher in current/past versus never smokers for TEAEs, SAEs, and discontinuations due to AEs in PsA, and for TEAEs in AS, complementing reports of associations between smoking and comorbidities in spondyloarthritis. These findings support increased surveillance and caution for patients with PsA or AS with smoking history; smoking cessation should be recommended to all patients, consistent with available guidelines [4, 32].