# Response to Tofacitinib in Patients With Psoriatic Arthritis and Probable Anxiety/Depressive Disorder: A Post Hoc Analysis of Phase 3 Trials

Laure Gossec, Agustí Sellas, David Gruben, Mónica Valderrama, Susana Gómez, Cassandra Kinch, Gustavo Citera

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Laure Gossec, Agustí Sellas, David Gruben, Mónica Valderrama, Susana Gómez, et al. Response to Tofacitinib in Patients With Psoriatic Arthritis and Probable Anxiety/Depressive Disorder: A Post Hoc Analysis of Phase 3 Trials. Rheumatology and Therapy, 2025, 12 (6), pp.1175-1186. 10.1007/s40744-025-00800-7. hal-05441248

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1 **Response to Tofacitinib in Patients With Psoriatic Arthritis and Probable**

2 **Anxiety/Depressive Disorder: A Post Hoc Analysis of Phase 3 Trials**

3 Laure Gossec (ORCID ID: 0000-0002-4528-310X)¹,², Agustí Sellas (ORCID ID: 0000-0003-

4 2182-2467)³, David C. Gruben (ORCID ID: 0000-0003-3516-5289)⁴, Mónica Valderrama

5 (ORCID ID: 0009-0009-7863-5456)⁵, Susana Gómez (ORCID ID: 0009-0003-2763-9146)⁵*,

6 Cassandra Kinch (ORCID ID: 0000-0002-2712-1668)⁶† and Gustavo Citera (ORCID ID: 0000-0002-3724-1874)⁷

8 ¹Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique,

9 Paris, France; ²AP-HP, Pitié-Salpêtrière hospital, Rheumatology Department, Paris, France;

10 ³Secció de Reumatologia, University Hospital Vall d'Hebron, Barcelona, Spain; ⁴Pfizer Inc,

11 Groton, Connecticut, USA; ⁵Pfizer SLU, Alcobendas, Madrid, Spain; ⁶Pfizer Canada ULC,

12 Kirkland, Quebec, Canada; ⁷Section of Rheumatology, Instituto de Rehabilitación Psicofísica,

13 Buenos Aires, Argentina

14 *Current affiliation: Hospital Universitario de Salamanca, Salamanca, Spain

15 †Former Pfizer employee

16 **Correspondence to:** Cassandra Kinch, PhD, Tel: (+1) 403 827 3347,

17 kinch.cassandra.d@gmail.com

18

19 **Prior presentation:** This manuscript is based on work previously presented as a poster

20 presentation at the EULAR 2021 Virtual Congress (POS1025)

21 **Target journal:** Rheumatology & Therapy

22 **Article type:** Original Research

23 **Figures/tables:** 5 figures/2 tables (no limited specified); 5 supplementary tables

24 **Word count (abstract):** 271/300 words

25 **Word count (manuscript):** 2884/~4000 words
26 **ABSTRACT**

27 **Introduction:** Mental health status potentially influences treatment responses. The effect of
28 probable anxiety and/or depressive disorder (pADD) on tofacitinib efficacy, patient-reported
29 outcomes (PROs), and safety in psoriatic arthritis (PsA) was assessed.

30 **Methods:** This was a post hoc analysis of two phase 3 trials in patients with PsA receiving
31 tofacitinib, adalimumab, or placebo, and an open-label extension study. Outcomes were stratified
32 by presence/absence of baseline pADD (Short Form-36 Health Survey [SF-36] Mental
33 Component Summary score ≤ 38/ > 38). American College of Rheumatology ≥ 20%, ≥ 50%, and
34 ≥ 70% (ACR20/50/70) responses, remission and/or low disease activity based on Psoriatic
35 Arthritis Disease Activity Score and Disease Activity Index for Psoriatic Arthritis score, minimal
36 disease activity, and PROs (pain/Health Assessment Questionnaire-Disability Index/fatigue)
37 were assessed through month 36. Safety was assessed through month 12.

38 **Results:** Overall, 323/706 (45.8%) patients had baseline pADD; of these, a higher proportion
39 were female versus male (61.9% versus 38.1%). Numerically higher proportions achieved
40 efficacy/PRO responses with tofacitinib versus placebo, regardless of baseline pADD (month 3).
41 Responses with tofacitinib were generally similar in patients with versus without baseline pADD
42 (eg, month 3 ACR20 responses: 54.0% versus 58.5%); some differences were observed at later
43 time points (eg, month 9 minimal disease activity: 25.0% versus 43.8%; p < 0.05). Baseline
44 pADD did not appear to affect the incidence of treatment-emergent adverse events.

45 **Conclusion:** Baseline pADD was frequent in patients with PsA initiating tofacitinib and
46 higher in females. Tofacitinib-treated patients had generally similar efficacy/safety
47 outcomes, regardless of baseline pADD. Some differences in efficacy outcomes were noted
48 longer-term (9–12 months). Limitations: small numbers in some analyses; use of SF-36 as
49 pADD proxy.

50 **Trial registration:** ClinicalTrials.gov: NCT01877668; NCT01882439; NCT01976364

51 **Keywords:** Anxiety, depression, psoriatic arthritis, tofacitinib

52
53 KEY SUMMARY POINTS

54 Why carry out this study?

55 • Changes in mental health can negatively impact health-related quality of life and may
56 influence clinical outcomes in patients with psoriatic arthritis (PsA).

57 • This post hoc analysis of two phase 3 trials assessed the effect of probable anxiety and/or
58 depressive disorder (pADD) on tofacitinib efficacy, patient-reported outcomes (PROs),
59 and safety in PsA.

60 What was learned from this study?

61 • Tofacitinib-treated patients with PsA had generally similar efficacy, PROs, and safety
62 outcomes, regardless of baseline pADD status; however, some attenuated responses at
63 later time points (9–12 months) were observed in patients with versus without pADD.

64 • The results of this study indicate that tofacitinib can be considered for use regardless of
65 psychological status, although more research is required to evaluate the correlation
66 between PsA and anxiety/depression using a gold standard psychiatric assessment.
## INTRODUCTION

Psoriatic arthritis (PsA) is an inflammatory disease characterized by skin psoriasis, nail disease, peripheral joint inflammation, and manifestations including enthesitis, dactylitis, and/or axial disease [1, 2]. For many patients, the burden of PsA features psychological distress, with at least half experiencing depression or anxiety [3]. The combination of joint and skin symptoms may contribute to depression and/or anxiety in PsA [2], although the relationship between these comorbidities and inflammation is complex, and yet to be fully elucidated [4].

In patients with PsA, changes in mental health can negatively impact health-related quality of life and may influence clinical outcomes [2, 3, 5, 6]. Anxiety and depression are highly prevalent in patients with PsA. In a meta-analysis of 24 studies including 31,227 patients with PsA, the prevalence of anxiety ranged from 4–61% and depression from 5–51% [3]. Studies in patients with PsA report that the likelihood of achieving minimal disease activity (MDA) or joint remission is reduced in patients with depression/anxiety [5, 6].

Self-reported assessment tools are commonly used to evaluate anxiety/depression as surrogate measures [4]. One tool is the Short Form-36 Health Survey (SF-36) Mental Component Summary (MCS) score, which has been used to evaluate anxiety/depression in patients with rheumatoid arthritis (RA) and PsA [5]. However, the SF-36 has not been validated against the gold standards for detection of anxiety/depression in clinical practice.

Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of PsA. The efficacy and safety of tofacitinib 5 and 10 mg twice daily (BID) has been demonstrated in two global phase 3 randomized controlled trials (RCTs) [7, 8] of patients with active PsA, and in an open-label, long-term extension (LTE) [9] study, in which safety was consistent with the phase 3 studies. To date, there are no data examining the impact of probable anxiety and/or depressive disorder (pADD) on the efficacy/safety of JAK inhibitors in patients with PsA. The objective of this post hoc analysis was to assess the impact of baseline pADD on efficacy, patient-reported outcomes (PROs) and safety in patients with active PsA receiving tofacitinib in an RCT setting.

## METHODS

### Patients

This post hoc analysis included data from patients with active PsA in the OPAL Broaden (NCT01877668; Date of registration: June 12, 2013) [7], OPAL Beyond (NCT01882439; Date of registration: June 18, 2013) [8], and OPAL Balance (NCT01976364; Date of registration: October 29, 2013) studies [9]. OPAL Broaden was a phase 3 trial of tofacitinib (duration: 12 months) in patients who were tumor necrosis factor inhibitor (TNFi)-naïve and had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) [7]. OPAL Beyond was a phase 3 trial of tofacitinib (duration: 6 months) in patients who had an inadequate response to TNFi [8]. In both studies, patients received tofacitinib 5 mg BID, tofacitinib 10 mg BID, adalimumab 40 mg administered subcutaneously once every 2 weeks (OPAL Broaden only), or placebo (switching to tofacitinib 5 or 10 mg BID at month 3), all in combination with a csDMARD [7, 8]. Participant race/ethnicity were self-reported from fixed categories including ‘Other’, where the patient could specify.
107 Patients in OPAL Broaden or OPAL Beyond fulfilled the Classification Criteria for
108 Psoriatic Arthritis (CASPAR), and could enter the open-label LTE study, OPAL Balance, where
109 patients received tofacitinib 5 mg BID (see Supplementary Methods in the electronic
110 supplementary material) [9].

111 Trials were conducted in accordance with the International Council for Harmonisation
112 Good Clinical Practice guidelines and the Declaration of Helsinki. The trial
113 protocols/documentation were approved by the institutional review board or independent ethics
114 committee at each site; details of all study sites have been previously published [7-9].
115 All patients provided written, informed consent.

116 Assessment of pADD

117 pADD was assessed at baseline, and the proportion of patients with/without pADD was assessed
118 over time, up to month 36 (Supplementary Information). Presence of pADD was defined as
119 SF-36 MCS ≤ 38 and absence of pADD was defined as SF-36 MCS > 38, based on published
120 criteria [5, 10].

121 Efficacy and PRO Assessments

122 Efficacy outcomes, stratified by baseline pADD status, included patients who achieved ≥ 20%,
123 ≥ 50%, and ≥ 70% improvements in American College of Rheumatology criteria (ACR20/50/70
124 responses, respectively), Psoriatic Arthritis Disease Activity Score (PASDAS) ≤ 3.2,
125 Disease Activity Index for Psoriatic Arthritis (DAPSA) remission (defined as DAPSA score ≤ 4),
126 DAPSA low disease activity (LDA; defined as DAPSA score ≤ 14), and MDA. In addition, least
127 squares (LS) mean changes from baseline in PASDAS, DAPSA, C-reactive protein, tender joint
128 count, and swollen joint count were evaluated. PROs included the proportion of patients
129 achieving minimal clinically important differences (MCID) in patient assessment of arthritis
130 pain visual analog scale (pain VAS; improvement in pain VAS score of ≥ 10 units) [11], Health
131 Assessment Questionnaire-Disability Index (HAQ-DI; score improvement ≥ 0.35) [12], and
132 Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; score improvement ≥ 4)
133 [13], and LS mean changes from baseline in Patient Global Assessment of Disease Activity
134 (PtGA), pain VAS, HAQ-DI, and FACIT-F.

135 Changes in pADD status over time were also assessed.

136 Safety Assessments

137 Safety outcomes included treatment-emergent adverse events (TEAEs; all-causality), serious
138 AEs (SAEs), discontinuations due to AEs, deaths, and AEs of special interest.

139 Analysis

140 Data were analyzed for both tofacitinib doses combined using pooled data from OPAL Broaden
141 and OPAL Beyond (demographics and baseline characteristics, efficacy, PROs, and safety),
142 and separately, for all patients receiving tofacitinib in OPAL Balance (efficacy and PROs)
143 (see the Supplementary Information for time points).

144 Efficacy, PROs, and safety data were analyzed descriptively based on the full analysis set
145 (randomized patients who received ≥ 1 dose of treatment) and there was the further requirement
146 that a patient had no missing SF-36 MCS data at baseline so that pADD could be determined.
Models comparing efficacy outcomes and PROs were run based on treatment group (pooled OPAL Broaden and OPAL Beyond data), and treatment sequence (OPAL Balance data [see the Supplementary Information]). The adalimumab arm was included to help yield better estimates of the variance parameters of the model; however, the focus of the analysis was on the tofacitinib combined data. Therefore, only select adalimumab results are described in the main article; however, the remainder of these results are reported in the Supplementary Information.
Differences between tofacitinib/adalimumab and placebo at month 3 are described descriptively as numerically higher/lower. At each visit, comparisons between patients with/without baseline pADD within treatment groups were performed, with descriptive *p* values, odds ratios, and 95% confidence intervals calculated. Differences where *p* < 0.05 are described as higher/lower, differences where *p* ≥ 0.05 are described as numerically higher/lower. There was no adjustment for multiple comparisons.

## RESULTS

### Baseline Demographics and Disease Characteristics

In total, 470, 106, and 236 patients were included in the tofacitinib, adalimumab, and placebo groups, respectively (pooled OPAL Broaden and OPAL Beyond). From OPAL Balance, 682 patients were included.

Of 706 patients receiving tofacitinib or placebo and with active PsA included in this analysis (OPAL Broaden and OPAL Beyond), 323 (45.8%) had pADD identified at baseline: 45.5% (214/470) of patients in the tofacitinib group and 46.2% (109/236) of patients in the placebo group. Baseline characteristics were generally similar for patients with/without pADD at baseline; however, there were more female patients with versus without pADD, and patients with pADD had higher pain VAS scores (Table S1 in the electronic supplementary material).

### Efficacy Outcomes

Regardless of baseline pADD status, efficacy improvements to month 3 were numerically greater with tofacitinib versus placebo (Fig. 1; Table S2 in the electronic supplementary material).

Across outcomes (ACR20/50/70, PASDAS ≤ 3.2, MDA, DAPSA-remission, and DAPSA-LDA), response rates were mostly similar in patients with/without baseline pADD at months 3 and 6 (Fig. 1; Fig. S1 in the electronic supplementary material). At later time points, some differences in responses were noted, with higher proportions of patients without baseline pADD achieving PASDAS ≤ 3.2 (months 9 and 12) or MDA (month 9) (Fig. 1).

At month 3, efficacy improvements were generally numerically greater with adalimumab versus placebo, regardless of baseline pADD status (Fig. S2, Fig. S3, and Table S2 in the electronic supplementary material). Response rates with adalimumab were generally similar across outcomes (ACR20/50/70, PASDAS ≤ 3.2, MDA, DAPSA-remission, and DAPSA-LDA) between patients with/without baseline pADD (Fig. S2, Fig. S3, and Table S2 in the electronic supplementary material).

In OPAL Balance, efficacy improvements to month 36 in patients receiving tofacitinib were generally similar between those with/without baseline pADD and were generally consistent over time (Table S3, Fig. S4, and Fig. S5 in the electronic supplementary material).
<caption>Fig. 1 Proportions of patients achieving a, ACR20 response<sup>a</sup>; b, PASDAS ≤ 3.2; c, MDA<sup>b</sup>; and d, DAPSA-remission<sup>c</sup></caption>

■ Combined tofacitinib doses - patients with pADD ■ Placebo - patients with pADD
■ Combined tofacitinib doses - patients without pADD ■ Placebo - patients without pADD

<figure><img src="image_2.png" /></figure>

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

189 Tofacitinib combined doses included data pooled from patients receiving tofacitinib 5 or 10 mg BID. Error bars
190 represent standard error (SE). SEs from the repeated measures mixed-effects model for proportions may not have
191
192 been estimable for any given treatment group. The SEs for differences between treatment groups (odds ratios) are
193 estimable, as well as their 95% CIs. Data for months 3 and 6 are pooled for OPAL Broaden and Beyond; data for
194 months 9 and 12 are for OPAL Broaden only. Patients who initially received placebo and switched to tofacitinib at
195 month 3 had their post-month 3 values excluded from the analysis. n and N represent observed counts. Odds ratios
196 represent differences (expressed as ratios) between patients with and without baseline pADD. Response rates and
197 odds ratios are estimated from the model. *p* < 0.05, patients with<sup>d</sup> versus without<sup>e</sup> baseline pADD. <sup>a</sup>≥ 20%
198 improvement in ACR criteria. <sup>b</sup>MDA defined as achieving 5 of the 7 following criteria: TJC ≤ 1; SJC ≤ 1; PASI ≤ 1
199 or BSA ≤ 3%; pain VAS ≤ 15; PtGA VAS ≤ 20 mm; HAQ-DI ≤ 0.5; LEI ≤ 1. <sup>c</sup>DAPSA score ≤ 4. <sup>d</sup>SF-36 MCS
200 score ≤ 38. <sup>e</sup>SF-36 MCS score > 38. <sup>ACR</sup> American College of Rheumatology, <sup>BID</sup> twice daily, <sup>BSA</sup> body surface
201 area, <sup>CI</sup> confidence interval, <sup>DAPSA</sup> Disease Activity Index for Psoriatic Arthritis, <sup>HAQ-DI</sup> Health Assessment
202 Questionnaire-Disability Index, <sup>LEI</sup> Leeds Enthesitis Index, <sup>MCS</sup> Mental Component Summary, <sup>MDA</sup> minimal
disease activity, <sup>n</sup> number of patients meeting response criteria, <sup>N</sup> number of patients evaluable at each time point
203 stratified by patients with<sup>d</sup> versus without<sup>e</sup> baseline pADD, <sup>pADD</sup> probable anxiety and/or depressive disorder,
204 <sup>PASDAS</sup> Psoriatic Arthritis Disease Activity Score, <sup>PASI</sup> Psoriasis Area Severity Index, <sup>PtGA</sup> Patient Global
205 Assessment of Disease, <sup>SF-36</sup> Short Form-36 Health Survey, <sup>SJC</sup> swollen joint count, <sup>TJC</sup> tender joint count,
206 <sup>VAS</sup> visual analog scale.
208 **Patient-Reported Outcomes**

209 At month 3, numerically greater improvements in PROs were observed with tofacitinib versus
210 placebo, regardless of baseline pADD status (Fig. 2; Table S2 in the electronic supplementary
211 material). However, the proportion of patients achieving MCID for pain VAS (≥ 10 units) was
212 lower (months 6 and 12) or numerically lower (months 3 and 9) in those with versus without
213 baseline pADD (Fig. 2). Across all time points, proportions of tofacitinib-treated patients
214 achieving MCID for HAQ-DI and FACIT-F were generally similar for those with versus without
215 baseline pADD (Fig. 2).

216 Similarly, at month 3, numerically greater improvements in PROs were observed with
217 adalimumab versus placebo, regardless of baseline pADD status (Fig. S6 and Table S2 in the
218 electronic supplementary material). Across time points, improvements in PROs for adalimumab
219 were mostly similar between patients with/without baseline pADD; however, the proportion of
220 patients achieving MCID for FACIT-F (months 3–12) and HAQ-DI (months 6–12) were
221 numerically higher in those with versus without baseline pADD (Fig. S6 and Table S2 in the
222 electronic supplementary material).

223 In OPAL Balance, improvements in PROs to month 36 in patients receiving tofacitinib
224 were generally similar between those with/without baseline pADD (Table S3 and Fig. S7 in the
225 electronic supplementary material).
226

**Fig. 2** Proportions of patients achieving the MCID for a, pain; b, HAQ-DI; and c, FACIT-F

<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

227

228

229

230

231

232

Tofacitinib combined doses included data pooled from patients receiving tofacitinib 5 or 10 mg BID. Error bars represent standard error (SE). Data for months 3 and 6 are pooled for OPAL Broaden and Beyond; data for months 9 and 12 are for OPAL Broaden only. Patients who initially received placebo and switched to tofacitinib at month 3 had their post-month 3 values excluded from the analysis. *n* and *N* represent observed counts. Odds ratios represent differences (expressed as ratios) between patients with and without baseline pADD. Rates of MCID and odds ratios
233 are estimated from the model. *p* < 0.05, patients withª versus withoutᵇ baseline pADD. SF-36 MCS score ≤ 38.

234 SF-36 MCS score > 38. BID twice daily, CI confidence interval, FACIT-F Functional Assessment of Chronic

235 Illness Therapy-Fatigue, HAQ-DI Health Assessment Questionnaire-Disability Index, MCID minimal clinically

236 important difference, MCS Mental Component Summary, n number of patients meeting response criteria, N number

237 of patients evaluable at each time point stratified by patients withª versus withoutᵇ baseline pADD, pADD probable

238 anxiety and/or depressive disorder, SF-36 Short Form-36 Health Survey, VAS visual analog scale
239 **Changes in pADD Over Time**

240 The proportion of patients with pADD reduced by 57% from baseline to month 12 in OPAL

241 Broaden and OPAL Beyond (Fig. S8a [combined tofacitinib doses] and Fig. S9a [adalimumab]

242 in the electronic supplementary material). In OPAL Balance, the proportion of patients with

243 pADD remained stable from months 6 to 36 (Fig. S10a in the electronic supplementary material).

244 Most patients (> 82%) without pADD at baseline remained without pADD from baseline to

245 month 12 (Fig. S8b and Fig. S9b in the electronic supplementary material). Similar trends were

246 observed in OPAL Balance from months 6 to 36 (Fig. S10b in the electronic supplementary

247 material).

248 **Safety**

249 Up to month 3, the incidence of TEAEs, SAEs, and discontinuations due to AEs were generally

250 similar between tofacitinib- and placebo-treated patients (Table 1). Up to months 3 and 12, there

251 were no notable differences in safety outcomes with tofacitinib, according to baseline pADD

252 (Table 1). The incidence of AEs of special interest was reported according to baseline pADD

253 status (Table 1).
<table><caption>**Table 1** Safety events in patients with<sup>a</sup> and without<sup>b</sup> baseline pADD receiving tofacitinib and placebo</caption><thead><tr><th rowspan="3">Patients with<br>events, n (%)</th><th colspan="3">Up to month 3</th><th colspan="3">Up to month 12</th></tr><tr><th colspan="2">Combined<br>tofacitinib doses<br>(5 or 10 mg BID)</th><th rowspan="2">Placebo</th><th colspan="2">Combined<br>tofacitinib doses<br>(5 or 10 mg BID)</th></tr><tr><th>With<br>pADD<sup>a</sup><br>(N = 214)</th><th>Without<br>pADD<sup>b</sup><br>(N = 256)</th><th>With<br>pADD<sup>a</sup><br>(N = 109)</th><th>Without<br>pADD<sup>b</sup><br>(N = 127)</th><th>With<br>pADD<sup>a</sup><br>(N = 214)</th><th>Without<br>pADD<sup>b</sup><br>(N = 256)</th></tr></thead><tbody><tr><td>TEAEs</td><td>98 (45.8)</td><td>130<br>(50.8)</td><td>47 (43.1)</td><td>48 (37.8)</td><td>146<br>(68.2)</td><td>184<br>(71.9)</td></tr><tr><td>SAEs</td><td>1 (0.5)</td><td>7 (2.7)</td><td>3 (2.8)</td><td>1 (0.8)</td><td>9 (4.2)</td><td>15 (5.9)</td></tr><tr><td>Discontinuations due<br>to AEs</td><td>4 (1.9)</td><td>6 (2.3)</td><td>1 (0.9)</td><td>3 (2.4)</td><td>9 (4.2)</td><td>13 (5.1)</td></tr><tr><td>Deaths (all cause)</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>AEs of special<br>interest</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Serious infections</td><td>0</td><td>2 (0.8)</td><td>0</td><td>0</td><td>1 (0.5)</td><td>4 (1.6)</td></tr><tr><td>HZ (serious and<br>non-serious)<sup>c</sup></td><td>2 (0.9)</td><td>1 (0.4)</td><td>0</td><td>0</td><td>3 (1.4)</td><td>4 (1.6)</td></tr><tr><td>OIs<sup>c</sup> (excl.<br>tuberculosis)</td><td>1 (0.5)</td><td>0</td><td>0</td><td>0</td><td>1 (0.5)</td><td>0</td></tr><tr><td>Tuberculosis<sup>c</sup></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>MACE<sup>c</sup></td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (0.5)</td><td>0</td></tr><tr><td>Malignancies<br>(excl. NMSC)<sup>c</sup></td><td>0</td><td>2 (0.8)</td><td>0</td><td>0</td><td>0</td><td>3 (1.2)</td></tr><tr><td>NMSC<sup>c</sup></td><td>0</td><td>0</td><td>0</td><td>0</td><td>1 (0.5)</td><td>0</td></tr><tr><td>GI perforation<sup>c</sup></td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Thromboembolism<sup>d</sup></td><td>0</td><td>1 (0.4)<sup>e</sup></td><td>0</td><td>0</td><td>0</td><td>1 (0.4)<sup>e</sup></td></tr></tbody></table>

Data for 'Up to month 3' includes data pooled for OPAL Broaden and Beyond up to month 3, with tofacitinib groups combined. Data for 'Up to month 12' includes data from OPAL Broaden and Beyond, combining all tofacitinib, that combination also including patients randomized to placebo (but including only their tofacitinib exposure)
260 SF-36 MCS score ≤ 38

261 SF-36 MCS score > 38

262 Adjudicated events

263 Includes deep vein thrombosis, pulmonary embolism, and arterial thromboembolism

264 One event of arterial thromboembolism

265 AE adverse event, BID twice daily, GI gastrointestinal, HZ herpes zoster, MACE major adverse cardiovascular

266 events, MCS Mental Component Summary, n number of patients with event, N number of evaluable patients, NMSC

267 non-melanoma skin cancer, OI opportunistic infection, pADD probable anxiety and/or depressive disorder, SAE

268 serious adverse event, SF-36 Short Form-36 Health Survey, TEAE treatment-emergent adverse event

269
270 DISCUSSION

271 This analysis demonstrated that anxiety and depression are frequent in patients with active PsA
272 initiating clinical trials of tofacitinib, with nearly half of all patients having pADD at baseline
273 and, of those, the majority were female. At baseline, patients with baseline pADD had higher
274 pain VAS scores than patients without pADD. These results suggest that rates of clinical
275 improvement with tofacitinib were numerically greater than with placebo up to month 3 in both
276 subgroups. No effect of baseline pADD on responses to tofacitinib was observed over the short
term (to month 3), although longer-term efficacy appeared slightly lower at selected time points
277 and for selected outcomes in patients with versus without pADD. Safety findings were generally
278 consistent regardless of baseline pADD status at months 3 and 12 and were noted in the
279 incidence of AEs of special interest; however, the number of events was small across groups, and
280 no comparison was possible. To our knowledge, this is the first report focusing on the effects of
281 baseline pADD on the efficacy/safety of a JAK inhibitor in patients with PsA, and these findings
282 indicate that tofacitinib can be considered regardless of psychological status.
283

284 The frequency of anxiety/depression at baseline in this analysis was in the range reported
285 previously in PsA [3]. Patients enrolling in tofacitinib clinical trials in PsA had active disease [7-
286 9], which may have impacted their mood. Generally, profiles of patients participating in clinical
287 trials are not necessarily characteristic of those in routine care, as they are likely to have more
288 severe disease and potentially a lower comorbidity burden (excluding pADD). Therefore, the
289 proportion of patients with pADD, and the clinical outcomes in patients with pADD, may differ
290 between a clinical trial setting and routine care. Furthermore, the method used to detect pADD in
291 this analysis (SF-36 MCS) may yield different results versus other tools designed to identify
292 anxiety/depression. This highlights the importance of assessing prevalence and impact of
293 depression and/or anxiety in patients with PsA treated with advanced therapies, using clinically
294 established diagnostic measures. Most patients without pADD at baseline remained without
295 pADD over time, although the proportion of patients with pADD decreased following treatment
296 initiation, which may be attributed to the promise of initiating new treatment and/or alleviation
297 of symptoms.
298

298 A difference in MDA was observed at a later time point (month 9) with tofacitinib in
299 OPAL Broaden and OPAL Beyond in those with versus without baseline pADD. A routine-care
300 study that used the same SF-36 MCS thresholds to indicate anxiety/depression status reported a
301 reduced probability of achieving MDA in patients with PsA and symptoms of anxiety/depression
302 [6]. Here, differences in responses to tofacitinib at later time points were also observed in OPAL
303 Broaden and OPAL Beyond, with lower proportions of patients with pADD versus those without
304 pADD achieving PASDAS ≤ 3.2 (at months 9 and 12) and the MCID for pain VAS (≥ 10 units)
305 (months 6 and 12). Differences being observed at later time points could be due to the high
306 expectations for the new treatment having worn off, and as improvements are reaching a plateau
307 and are not expected to continue to improve, mood may play a larger role in the perceived
308 symptom improvement. The presence of anxiety and depression (according to the SF-36 MCS
309 ≤ 38 criterion) has also been reported to be a negative predictor for achieving DAPSA-defined
310 remission [5]. However, in this analysis, similar rates of DAPSA-defined remission were
311 generally achieved regardless of baseline pADD status. The differences between these findings
312 and results from real-world studies may reflect the nature of the study designs, with patients
313 enrolled in RCTs more likely to receive monitoring/management of anxiety/depression than
314 those in routine care. Notably, the outcomes with heavier weighting on tender/swollen joint
315 counts (ACR20/50/70 and DAPSA-defined remission) did not show differences based on
316 presence/absence of pADD. However, MDA and PASDAS, which place less emphasis on
317 tender/swollen joint counts, and incorporate PROs, such as pain (MDA), PtGA (MDA and
318 PASDAS), SF-36 Physical Component Summary (PCS; PASDAS), as well as other psoriatic
319 domains, did show a difference. Therefore, further research in this area is warranted.

320 Enhanced pain sensitization has been reported in patients with RA, and due to changes in
321 cortical opioid receptor binding, may be associated with low mood [14]. Furthermore, a previous
322 longitudinal study of patients with PsA over a mean period of 7.5 years identified a small but
323 consequential bidirectional relationship between depressive symptoms and pain [15]. Here, a
324 trend toward lower pain response was observed in patients with versus without baseline pADD.

325 The impact of depression (using SF-36 MCS) on the efficacy of tofacitinib in RA was
326 evaluated in a post hoc analysis of pooled data from RCTs [16]. Consistent with this analysis in
327 PsA, tofacitinib efficacy, including ACR20/50/70 response and LS mean change from baseline in
328 HAQ-DI, was generally similar in patients with/without baseline pADD [16].

329 Here, the impact of pADD on safety outcomes was investigated. Regardless of baseline
330 pADD status, the incidences of TEAEs, SAEs, discontinuations due to AEs, and AEs of special
331 interest were similar for patients treated with tofacitinib or placebo.

332 These findings may be limited by the post hoc nature of this analysis and the small
333 numbers in some of the analyses. Furthermore, findings from clinical trial data may not be
334 representative of real-world practice. The OPAL Broaden, OPAL Beyond, and OPAL Balance
335 studies were not designed to identify anxiety and/or depression in patients with PsA, and the
336 current study was not designed for comparisons between tofacitinib and adalimumab. The results
337 can only be considered as indicative and exploratory in nature, as there was no adjustment for
338 multiple comparisons, and several endpoints in the analysis are positively correlated.
339 Additionally, the placebo period was shorter than for active treatment, and the analyses beyond
340 month 6 included data from OPAL Broaden only. The patients included in this analysis were
341 identified as being at risk for pADD by using SF-36 MCS, rather than by a confirmed clinical
342 diagnosis. Therefore, in order to validate the use of SF-36 MCS, more research is required to
343 evaluate the correlation between PsA and anxiety/depression by using a gold standard psychiatric
344 assessment.

345 **Conclusions**

346 In conclusion, these results suggest that efficacy, PROs, and safety in tofacitinib-treated
347 patients with PsA are generally similar in patients regardless of pADD status, although some
348 attenuated responses at later time points were observed in patients with versus without pADD.
349 These findings indicate that tofacitinib can be considered for use regardless of psychological
350 status; however, specially designed studies using gold standard psychiatric assessments are

351 warranted In addition, future research should further evaluate the relationship between clinical

352 anxiety and depression, and adverse treatment outcomes in PsA.
353 ACKNOWLEDGMENTS

354 We thank the participants of the study.

355 **Author Contributions.** David C. Gruben conceptualized and designed the study, acquired data,

356 and contributed to data analysis and interpretation. Agustí Sellas, Mónica Valderrama, Susana

357 Gómez, Cassandra Kinch, and Gustavo Citera conceptualized and designed the study and

358 contributed to analysis and interpretation of the data. Laure Gossec contributed to analysis and

359 interpretation of the data. All named authors meet the International Committee of Medical

360 Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the
361 integrity of the work as a whole, and have given their approval for this version to be published.

362 **Funding.** This study was sponsored by Pfizer. Medical writing support was funded by Pfizer.

363 The journal's Rapid Service and Open Access fees for this article were also funded by Pfizer.

364 **Medical Writing/Editorial Assistance.** Medical writing support, under the direction of the
365 authors, was provided by Tanya Guha, PhD, Lauren Hogarth, MSc, and Kimberley Haines, MSc,

366 CMC Connect, a division of IPG Health Medical Communications, and was funded by Pfizer,

367 New York, NY, USA, in accordance with Good Publication Practice (GPP 2022) guidelines

368 (Ann Intern Med 2022;175:1298–304).

369 **Data Availability.** Upon request, and subject to review, Pfizer will provide the data that support
370 the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also
371 provide access to the related individual de-identified participant data. See

372 https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

373 **Declarations**

374 **Ethical Approval.** Trials were conducted in accordance with the International Council for
375 Harmonisation Good Clinical Practice guidelines and the Declaration of Helsinki. The trial
376 protocols/documentation were approved by the institutional review board or independent ethics
377 committee at each site; details of all study sites have been previously published [7-9].

378 All patients provided written, informed consent.

379 **Conflict of Interest.** Laure Gossec has received grants or research support from AbbVie, Biogen,
380 Eli Lilly, Novartis, Sandoz, and UCB; consulting fees from AbbVie, Bristol Myers Squibb,

381 Celltrion, Galapagos, Janssen, Novartis, Pfizer Inc, and UCB; honoraria for lectures from
382 AbbVie, Amgen, Celltrion, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Pfizer Inc, Sandoz,
383 and UCB; support for attending meetings and/or travel from MSD, Novartis, and Viatris; and has
384 received medical writing support from AbbVie, Janssen, Pfizer Inc, and UCB. Agustí Sellas has
385 received support from Janssen and Novartis; honoraria for lectures from AbbVie, Amgen, Eli

386 Lilly, GlaxoSmithKline, Janssen, MSD, Novartis, and UCB; and has received support for
387 attending meetings and/or travel from AbbVie and Eli Lilly. David C. Gruben and Mónica

388 Valderrama are employees and stockholders of Pfizer Inc. Susana Gómez was an employee and
389 stockholder of Pfizer Inc at the time of the analysis, and at her current institute has received grant
390 and/or research support from Amgen, Bristol Myers Squibb, Galapagos, and Novartis. Cassandra

391 Kinch was an employee and stockholder of Pfizer Inc at the time of the analysis. Gustavo Citera
392 has received grants and/or research support from AbbVie, Amgen, Eli Lilly, Gema, Genzyme,
393 Novartis, Pfizer Inc, and Sanofi Genzyme; and has acted as a consultant for AbbVie, Amgen,

394 Eli Lilly, Gema, Genzyme, Novartis, Pfizer Inc, and Sanofi Genzyme.
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