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Effectiveness of Tofacitinib in Patients with Psoriatic Arthritis Initiating Monotherapy Versus Combination Therapy: Results from the CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry
This study evaluated the real-world effectiveness of tofacitinib monotherapy versus combination therapy in patients with psoriatic arthritis (PsA) enrolled in the CorEvitas PsA/Spondyloarthritis Registry.
Methods
This study (NCT05195814) included adult patients with PsA initiating tofacitinib (from December 14, 2017 to October 1, 2023) as monotherapy, or in combination with oral small molecules (OSMs: methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, and apremilast). Patients with baseline and 6-month follow-up visits (± 3 months) were included. Outcomes: mean change from baseline (∆) in/proportions achieving, disease activity measures (including body surface area [BSA] = 0%), and patient-reported outcomes. Continuous endpoints at month 6 were analyzed as ∆ with an analysis of covariance model including treatment and baseline value as covariates. ∆ in least squares (LS) means and adjusted LS means/odds ratios are presented.
Results
The study included 141 patients (66/141 monotherapy; 75/141 combination therapy). Patients were predominantly female (61.0%) and white (94.3%), and average age was 56.7 years. More monotherapy initiators were OSM treatment-naïve and had higher mean Patient Global Assessment of Arthritis, compared with combination therapy initiators. By 6 ± 3 months, 28.8% and 25.3% of monotherapy and combination therapy initiators, respectively, discontinued tofacitinib. At 6 ± 3 months, 15.0% of monotherapy initiators achieved minimal disease activity, and 27.1% had BSA = 0%. Corresponding data for combination therapy initiators were 20.7%, and 22.0%, respectively. Differences between groups were not significant. LS mean differences from baseline in overall work impairment/activity impairment were − 13.0/− 21.8 and 1.4/− 2.9 for monotherapy and combination therapy initiators, respectively.
Conclusion
Monotherapy and combination therapy initiators demonstrated improvements across effectiveness outcomes. Tofacitinib monotherapy initiators experienced numerical improvements in overall work impairment/activity impairment. This highlights tofacitinib effectiveness as monotherapy/combination therapy for a diverse PsA population. However, the small sample size limited the statistical power, and so results should be interpreted cautiously.
Prior Presentation: Some of the data reported in this manuscript were previously presented at the American College of Rheumatology Convergence 2024 (Poster 0584; November 14–19, 2024, Washington, DC, USA).
Key Summary Points
Why carry out this study?
Tofacitinib is an oral Janus kinase inhibitor approved for the treatment of psoriatic arthritis (PsA), in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).
A long-term extension sub-study demonstrated that patients with PsA receiving tofacitinib in combination with methotrexate who are in a stable disease state might be able to discontinue methotrexate without an adverse effect on their overall disease activity; real-world data are needed to assess the effectiveness of tofacitinib monotherapy in a setting more representative of clinical practice.
This observational study aimed to evaluate the real-world effectiveness of tofacitinib, both as monotherapy and in combination with oral small molecules (csDMARDs and apremilast), in patients with PsA enrolled in the CorEvitas PsA/Spondyloarthritis Registry.
What was learned from the study?
Generally, tofacitinib monotherapy initiators experienced numerically greater improvements in disease activity and patient-reported outcomes compared with combination therapy initiators (including for overall work impairment and activity impairment); however, after adjustment for potential confounding baseline factors, no significant differences were observed between treatment groups.
The findings of this real-world study suggest that both tofacitinib monotherapy and combination therapy can be effective treatment strategies for PsA in patients with a wide range of disease severity and comorbid conditions; this information could inform treatment decisions for PsA.
Introduction
Psoriatic arthritis (PsA) is a chronic, immune-mediated inflammatory disease characterized by heterogenous manifestations including peripheral arthritis, enthesitis, dactylitis, axial disease, and skin psoriasis (PsO) [1]. It is common for patients with PsO to also have PsA, with approximately 30% of patients with PsO developing PsA [2]. Globally, PsA is reported in approximately 0.1% to 1% of the population [3].
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The treatment strategies for PsA aim to control symptoms, prevent joint damage, and improve quality of life [4]. According to current treatment recommendations, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), in particular methotrexate, can be used as first-line treatment for PsA [5, 6]. If the treatment target of remission or low disease activity (LDA) is not achieved with a csDMARD, biologic (b)DMARDs (including tumor necrosis factor inhibitors [TNFi], and in certain scenarios interleukin [IL]-12/23, IL-17, or IL-23 inhibitors) or Janus kinase (JAK) inhibitors are often given in combination with csDMARDs [5‐7]. For patients with PsA who have an inadequate response to a TNFi, switching to a different TNFi or bDMARD, or a JAK inhibitor, is recommended [5, 6].
In peripheral PsA, there is conflicting evidence regarding the benefit of adding methotrexate to targeted DMARD treatment, and no supportive evidence in patients with axial disease [5]. Therefore, guidelines have limited evidence to recommend the use of csDMARDs for the treatment of peripheral PsA in patients who are treatment-naïve [7]. Conversely, studies of etanercept and golimumab (TNFi) in patients with PsA (golimumab study assessed dactylitis only) have shown that treatment with concomitant methotrexate was more effective than methotrexate monotherapy [8, 9]. In axial disease, treatment with csDMARDs is not recommended in the Group for Research and Assessment of PsO and PsA 2021 guidelines [7].
Tofacitinib is an oral JAK inhibitor for the treatment of PsA. For PsA, tofacitinib is approved for use in combination with csDMARDs, following an inadequate response or intolerance to ≥ 1 TNFi in the USA [10]. The efficacy of tofacitinib initiated as monotherapy has not been studied in PsA [10]. The efficacy and safety of tofacitinib 5 and 10 mg twice daily (BID) were demonstrated in the global OPAL Broaden and OPAL Beyond phase 3 studies [11, 12], and in a phase 3 study in China (5 mg BID only) [13], as well as in the OPAL Balance long-term extension study [14] in patients with PsA who had an inadequate response to csDMARDs (OPAL Broaden) or TNFi (OPAL Beyond). The long-term safety of tofacitinib has also been compared across several different disease indications using data pooled from global phase 3 and long-term extension studies [15]. In OPAL Broaden and OPAL Beyond, patients were required to remain on a stable dose of one background csDMARD (mostly methotrexate [average of 80% across all studies]) [14]. In a sub-study of the OPAL Balance long-term extension study, the efficacy and safety of tofacitinib 5 mg BID as monotherapy after methotrexate withdrawal, versus tofacitinib 5 mg BID with continued background methotrexate, was assessed. The results from this sub-study support the conclusion that some patients receiving tofacitinib with background methotrexate who are in a stable disease state might be able to discontinue methotrexate to receive tofacitinib monotherapy, without an adverse effect on their overall disease activity [16].
Monotherapy versus combination therapy for the treatment of PsA has been investigated using data from clinical trials. In a recent phase 3b non-inferiority trial, the efficacy of ustekinumab (an IL-12/23 inhibitor) with and without methotrexate was demonstrated in patients with PsA [17]. Similarly, in a pooled analysis from two clinical trials, patients treated with etanercept as monotherapy and in combination with methotrexate achieved PsA response criteria [18]. Moreover, similar observations for etanercept have also been reported when investigating patient-reported outcomes (PROs) in PsA [19].
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Real-world studies are important to complement randomized controlled trial data and assess the effectiveness of a treatment in a setting more representative of clinical practice. A recent analysis of the CorEvitas PsA/Spondyloarthritis (SpA) Registry evaluated the effectiveness of tofacitinib in patients with PsA [20]. In this recent analysis, in which tofacitinib was initiated in combination with oral small molecules (OSMs: csDMARDs [methotrexate, leflunomide, and sulfasalazine] and apremilast) or as monotherapy, effectiveness was analyzed; however, data were not assessed separately or compared between treatment groups [20]. Thus, additional data are needed to understand the effectiveness of tofacitinib in both monotherapy and combination therapy scenarios.
This observational study aimed to evaluate the real-world effectiveness of tofacitinib, both as monotherapy and in combination with OSMs (csDMARDs and apremilast), in patients with PsA enrolled in the CorEvitas PsA/SpA Registry.
Methods
Data Source
The CorEvitas PsA/SpA Registry is a prospective, multicenter, observational disease-based registry that was launched in March 2013. As of November 1, 2023, the CorEvitas dataset included 68 private and academic active clinical sites with over 79 providers throughout 30 states in the USA. CorEvitas has enrolled over 6000 patients with PsA or SpA, and the collection of data from CorEvitas represents 17,000 patient-years. Longitudinal follow-up data were collected from both patients and their treating rheumatologist during routine clinical encounters, using the CorEvitas PsA/SpA Registry questionnaires.
Study Cohort
This study (NCT05195814) included patients aged 18 years or older enrolled in the CorEvitas PsA/SpA Registry with rheumatologist-diagnosed PsA who initiated tofacitinib from December 14, 2017 to October 1, 2023. Patients received tofacitinib as either monotherapy or in combination with OSMs (csDMARDs [methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine] or apremilast). Patients were included if a baseline visit (defined as tofacitinib treatment initiation or up to 4 months prior to initiation if this occurred in between study visits) and 6-month follow-up visit (with a ± 3-month window) were available. Exclusion criteria included a diagnosis of rheumatoid arthritis, lupus, or other forms of autoimmune inflammatory arthritis, or patients taking tofacitinib in combination with any other bDMARD. Tofacitinib dose was not reported. Note that some data were collected prior to the latest tofacitinib prescribing information change which requires an inadequate response or intolerance to ≥ 1 TNFi [10]. There were no set prescribing policies for the investigators within CorEvitas, and as per the protocol, the inclusion of patients was not limited based on prior treatment. JAK inhibitors have typically been used after a TNFi as a result of US Food and Drug Administration (FDA) guidance [21], but occasionally, patients may receive a JAK inhibitor as a first-line agent if they prefer an oral agent, it is recommended by their physician, and their insurance company allows access. Furthermore, it is possible that patients being prescribed tofacitinib have not responded adequately to OSMs.
Outcomes and Assessments
At baseline, data on patient demographics, history of comorbidities, PsA disease activity measures, and PRO measures were collected. Effectiveness outcomes were measured at the 6-month follow-up visit (± 3-month window) and included both disease activity outcomes and PROs. All effectiveness outcomes were stratified by monotherapy and combination therapy initiators.
Change from baseline to 6 ± 3 months was reported for Clinical Disease Activity Index for PsA (cDAPSA), % body surface area (BSA), Health Assessment Questionnaire-Disability Index (HAQ-DI), modified PsA Disease Activity Score (mPASDAS), tender joint count (TJC; 68-joint count), and swollen joint count (SJC; 66-joint count).
Additional clinical effectiveness outcomes were measured at month 6 ± 3 among patients who were not in the outcome state at baseline, and included: the proportion of patients achieving LDA as measured by cDAPSA (scores ≤ 13); minimal disease activity (MDA; a composite measure defined as “yes” if a patient met at least five of the seven following criteria: TJC ≤ 1; SJC ≤ 1; BSA ≤ 3%; patient pain Visual Analog Scale [VAS] ≤ 15; patient global assessment VAS ≤ 20; HAQ-DI ≤ 0.5; and tender entheseal points [assessed using SpA Research Consortium of Canada (SPARCC) enthesitis count] ≤ 1); BSA = 0%; mPASDAS < 3.2; resolution of enthesitis (SPARCC = 0); resolution of dactylitis (no dactylitis at follow-up); and Investigator Global Assessment of PsO of “clear” or “almost clear” (0/1). Mean changes from baseline to month 6 ± 3 in patient pain (0–100 VAS) and fatigue (0–100 VAS) scores were assessed among all tofacitinib initiators. In addition, the Work Productivity and Activity Impairment (WPAI) questionnaire was used to assess overall work impairment, work time missed, and impairment while working (in patients reporting current employment only), and activity impairment (in all patients, regardless of employment status).
Therapy status at 6 ± 3 months was also measured (treatment discontinuations at or prior to the 6 ± 3-month follow-up visit and reasons for discontinuation). Safety data were not assessed in this analysis.
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Pfizer’s generative artificial intelligence (AI) assisted technology was used to assist production of the first draft of this manuscript. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.
Statistical Analysis
Descriptive statistics were used to summarize data at baseline and at 6 months, and the change from baseline to 6 months. For binary outcomes, non-response imputation was applied for missing values and for those patients discontinuing therapy prior to follow-up. No imputation was applied for missing continuous outcomes. For binary endpoints, 95% confidence intervals (CIs) using normal approximation to binomial proportions were provided for each group. The 95% CI was also provided for comparisons between groups using normal approximation for the difference in binomial proportions. For continuous variables—such as cDAPSA, DAPSA, mPASDAS, HAQ-DI, BSA, TJC, SJC, patient pain, and patient fatigue—the mean and standard deviation (SD) were calculated at baseline and 6 months. For these continuous endpoints, change from baseline was investigated using an analysis of covariance model adjusted for treatment, baseline value of the outcome variable, age, sex, duration of PsA, bDMARD/targeted synthetic (ts)DMARD-naïve versus experienced, and prior number of OSM treatments (0, 1, 2+) as covariates, and delta least squares (LS) means (95% CI) are presented to show the comparison between these groups. Additionally, treatment differences between groups in binary outcomes were assessed using logistic regression models; these models included the following independent variables: treatment group, age, sex, duration of PsA, prior b/tsDMARD use, prior number of OSM treatments (0, 1, 2+), and baseline value of the outcome variable (with the exception of MDA, enthesitis, and dactylitis, as these outcomes did not have an appropriate continuous baseline value to include). Including covariate adjustment in the outcome models reduced the potential for confounding by controlling for potential differences in patient characteristics at baseline. This study employed a complete case method in multivariable models. P values were a descriptive measure.
Ethical Approval
The study was performed in accordance with Good Pharmacoepidemiology Practice. Sponsor approval and continuing review were obtained through a central Institutional Review Board (IRB), WCG IRB (no. 120160070). All registry participants provided informed consent and authorization prior to participation. CorEvitas PsA/SpA Registry data used in this analysis were provided in an anonymized structured format and did not contain any patient personal information. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
Results
Baseline Demographics, and Patient and Disease Characteristics
In total, 141 patients were included in the analysis. Of these, 66 patients received monotherapy and 75 patients received combination therapy (see Fig. S1 in the electronic supplementary material). The majority of patients were typically on the approved dose, and there was very little variability in dosing, with more than 90% of tofacitinib initiators receiving 11 mg once daily. There were six patients who initiated tofacitinib in combination with multiple csDMARDs.
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At baseline in the overall population, the mean (SD) age was 56.7 (11.3) years, the majority of patients were female (61.0%) and white (94.3%), and mean time since PsA diagnosis was 8.7 years. Demographics and baseline disease characteristics were generally similar for monotherapy and combination initiators, with some exceptions. More monotherapy initiators were OSM treatment-naïve and had higher mean Patient Global Assessment of Arthritis, higher baseline morning stiffness, higher pain VAS, and higher WPAI component scores compared with combination therapy initiators (Table 1). In total, 7/66 monotherapy initiators and 2/75 combination therapy initiators were naïve to both OSMs and b/tsDMARDs at tofacitinib initiation (Table 1). Additional demographics and baseline characteristics are reported in Table S1 in the electronic supplementary material.
Table 1
Demographics and baseline characteristics, stratified by monotherapy and combination therapy
Monotherapy
(N = 66)
Combination therapy
(N = 75)
Overall
(N = 141)
Demographics
Age (years), mean (SD)
55.9 (11.8)
57.5 (10.7)
56.7 (11.3)
Female, n (%)
41 (62.1)
45 (60.0)
86 (61.0)
White, n (%)
64 (97.0)
69 (92.0)
133 (94.3)
Hispanic ethnicity, n/N (%)
4/58 (6.9)
3/67 (4.5)
7/125 (5.6)
Smoking status, n (%)
Never
39 (59.1)
47 (62.7)
86 (61.0)
Former
21 (31.8)
16 (21.3)
37 (26.2)
Current
6 (9.1)
12 (16.0)
18 (12.8)
BMI (kg/m2), mean (SD) [N1]
31.2 (6.6) [64]
33.9 (10.3) [74]
32.6 (8.8) [138]
History of comorbidities, n (%)
Cardiovascular diseasea
11 (16.7)
6 (8.0)
17 (12.1)
Malignancyb
5 (7.6)
6 (8.0)
11 (7.8)
NMSC
4 (6.1)
1 (1.3)
5 (3.5)
Hypertension
19 (28.8)
31 (41.3)
50 (35.5)
Diabetes
11 (16.7)
12 (16.0)
23 (16.3)
Fibromyalgiac
12 (18.2)
12 (16.0)
24 (17.0)
Depression
17 (25.8)
12 (16.0)
29 (20.6)
Anxiety
7 (10.6)
5 (6.7)
12 (8.5)
Uveitis
1 (1.5)
1 (1.3)
2 (1.4)
Inflammatory bowel diseased
1 (1.5)
3 (4.0)
4 (2.8)
Psoriatic nail dystrophy
6 (9.1)
6 (8.0)
12 (8.5)
Osteoporosis
2 (3.0)
1 (1.3)
3 (2.1)
Metabolic syndromee
35 (53.8)
40 (54.1)
75 (54.0)
Duration of PsA symptoms (years), mean (SD) [N1]
13.8 (11.3) [64]
13.4 (10.5) [73]
13.6 (10.9) [137]
Time since PsA diagnosis (years), mean (SD) [N1]
9.1 (8.9) [64]
8.4 (8.9)
8.7 (8.9) [139]
Disease
characteristics
TJC (0–68), mean (SD) [N1]
9.2 (12.0) [63]
8.6 (10.5)
8.9 (11.2) [138]
SJC (0–66), mean (SD) [N1]
3.8 (6.0)
3.2 (4.1)
3.5 (5.0) [138]
Physician Global Assessment of Arthritis (0–100 VAS), mean (SD)
37.7 (24.8)
33.5 (23.1)
35.4 (23.9)
Physician Global Assessment of Arthritis and Psoriasis (0–100 VAS), mean (SD) [N1]
42.1 (24.9) [65]
37.5 (25.6) [74]
39.6 (25.3) [139]
Enthesitis, n (%)
24 (36.4)
30 (40.0)
54 (38.3)
Dactylitis, n (%)
7 (10.6)
11 (14.7)
18 (12.8)
mPASDAS, mean (SD) [N1]
4.8 (1.3) [43]
4.5 (1.6) [59]
4.6 (1.4) [102]
cDAPSA, mean (SD) [N1]
24.6 (17.1) [62]
21.4 (15.1)
22.9 (16.1) [137]
MDA, n (%)
6 (9.1)
17 (22.7)
23 (16.3)
VLDA, n (%)
1 (1.6)
5 (6.8)
6 (4.4)
BSA category (%), n/N (%)
0
17/65 (26.2)
32/73 (43.8)
49/138 (35.5)
0 to < 3
26/65 (40.0)
17/73 (23.3)
43/138 (31.2)
≥ 3 to < 10
17/65 (26.2)
18/73 (24.7)
35/138 (25.4)
≥ 10
5/65 (7.7)
6/73 (8.2)
11/138 (8.0)
HAQ-DI, mean (SD) [N1]
1.0 (0.6) [65]
0.8 (0.6)
0.9 (0.6) [140]
DAPSA, mean (SD) [N1]
27.0 (19.4) [43]
21.6 (13.8) [59]
23.9 (16.5) [102]
Patient pain (0–100 VAS), mean (SD)
61.4 (25.5)
52.2 (27.0)
56.5 (26.6)
Patient Global Assessment of Arthritis (0–100 VAS), mean (SD) [N1]
54.6 (26.8) [65]
45.7 (25.8)
49.8 (26.6) [140]
Patient fatigue (0–100 VAS), mean (SD)
58.3 (27.2)
50.9 (27.1)
54.4 (27.3)
Patient morning stiffness (0–100 VAS), mean (SD)
62.5 (28.5)
50.6 (29.5)
56.1 (29.5)
WPAI domain (%), mean (SD) [N1]
Work time missedf
11.5 (18.0) [31]
2.6 (7.0) [32]
7.0 (14.2) [63]
Impairment while workingf
41.5 (26.2) [32]
22.0 (19.9) [34]
31.5 (25.0) [66]
Overall work impairmentf
48.1 (28.2) [31]
24.3 (21.0) [32]
36.0 (27.4) [63]
Activity impairment
46.8 (28.2) [32]
25.4 (20.6) [35]
35.6 (26.6) [67]
Prior and concomitant treatmentg
Number of prior OSM treatments, n (%)h
0
19 (28.8)
6 (8.0)
25 (17.7)
1
25 (37.9)
39 (52.0)
64 (45.4)
2+
22 (33.3)
30
(40.0)
52 (36.9)
Number of prior b/tsDMARDs, n (%)
0
13 (19.7)
24 (32.0)
37 (26.2)
1
13 (19.7)
14 (18.7)
27 (19.1)
2+
40 (60.6)
37 (49.3)
77 (54.6)
Number of prior TNFi, n (%)
0
17 (25.8)
27 (36.0)
44 (31.2)
1
21 (31.8)
24 (32.0)
45 (31.9)
2+
28 (42.4)
24 (32.0)
52 (36.9)
Number of prior non-TNFi, n (%)i
0
34 (51.5)
44 (58.7)
78 (55.3)
1
16 (24.2)
24 (32.0)
40 (28.4)
2+
16 (24.2)
7 (9.3)
23 (16.3)
Current prednisone use, n (%)
Dose ≤ 10 mg
1 (1.5)
5 (6.7)
6 (4.3)
Dose > 10 mg
0 (0.0)
1 (1.3)
1 (0.7)
No use
65 (98.5)
69 (92.0)
134 (95.0)
bDMARD biologic disease-modifying antirheumatic drug, BMI body mass index, BSA body surface area, cDAPSA Clinical Disease Activity Index for Psoriatic Arthritis, DAPSA Disease Activity Index for Psoriatic Arthritis, HAQ-DI Health Assessment Questionnaire-Disability Index, MDA minimal disease activity, mPASDAS, modified Psoriatic Arthritis Disease Activity Score, N total number of patients, N1 number of evaluable patients, n number of patients with each characteristic, NMSC non-melanoma skin cancer, OSM oral small molecule, PsA psoriatic arthritis, SD standard deviation, SJC swollen joint count, TJC tender joint count, TNFi tumor necrosis factor inhibitor, tsDMARD targeted synthetic disease-modifying antirheumatic drug, VAS Visual Analog Scale, VLDA very low disease activity, WPAI Work Productivity and Activity Impairment
aHistory of cardiovascular disease includes history of: cardiac revascularization procedure, ventricular arrythmia, cardiac arrest, myocardial infarction, acute coronary syndrome, unstable angina, congestive heart failure (with and without hospitalization), stroke, transient ischemic attack, other cardiovascular disease, deep vein thrombosis, peripheral arterial disease, peripheral arterial thrombosis, urgent peripheral revascularization, peripheral ischemia/gangrene, pulmonary embolism, carotid artery disease, and hemorrhage
bMalignancy includes breast cancer, lung cancer, lymphoma, skin cancer (excluding NMSC), and other cancers
cIf reported on either physician or patient forms, or if the definition of fibromyalgia [22] was met using the Widespread Pain Index and Symptom Severity Scale measures
dCrohn’s disease and ulcerative colitis
eMetabolic syndrome is defined as presence of: at least three of hypertension, hyperlipidemia, diabetes, and obesity
fAmong patients reporting current employment
g7/66 monotherapy initiators and 2/75 combination therapy initiators were naïve to both OSMs and b/tsDMARDs at tofacitinib initiation
hMethotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or apremilast
iNon-TNFi treatments included secukinumab, ixekizumab, ustekinumab, and abatacept
Therapy Status
Of the 141 patients in the overall group, 103 patients (73.0%) remained on tofacitinib, while 38 patients (27.0%) had discontinued at, or before, the 6 ± 3-month follow-up visit (Table 2). Among those who discontinued, 22 patients (57.9%) switched to a b/tsDMARD; of these, 5 patients (22.7%) switched to a TNFi, 13 patients (59.1%) switched to a non-TNFi, and 4 patients (18.2%) switched to another tsDMARD. Additionally, in the overall group, 3 patients (2.1%) added an OSM and 20 patients (14.2%) discontinued a concomitant OSM. Of those who discontinued an OSM, the reasons were not reported for 15 patients (75.0%), while 3 patients (15.0%) discontinued because of efficacy reasons and 2 patients (10.0%) discontinued for safety reasons (both due to minor adverse events).
Table 2
Treatment status at 6 months,a stratified by monotherapy and combination therapy
Monotherapy
(N = 66)
Combination therapy
(N = 75)
Overall
(N = 141)
Remained on tofacitinib, n (%)
47 (71.2)
56 (74.7)
103 (73.0)
Discontinued tofacitinib, n (%)
19 (28.8)
19 (25.3)
38 (27.0)
Switched to a b/tsDMARD, n (%)
14 (73.7)
8 (42.1)
22 (57.9)
Switched to a TNFi, n (%)
2 (14.3)
3 (37.5)
5 (22.7)
Switched to a non-TNFi, n (%)b
10 (71.4)
3 (37.5)
13 (59.1)
Switched to a tsDMARD, n (%)c
2 (14.3)
2 (25.0)
4 (18.2)
Added OSM treatment, n (%)d
1 (1.5)
2 (2.7)
3 (2.1)
Discontinued OSM treatment, n (%)d
–
20 (26.7)
20 (14.2)
No reason reported
–
15 (75.0)
15 (75.0)
Efficacy
–
3 (15.0)
3 (15.0)
Safety
–
2 (10.0)e
2 (10.0)e
Other
–
0 (0.0)
0 (0.0)
bDMARD biologic disease-modifying antirheumatic drug, N number of evaluable patients, n number of patients with each status, OSM oral small molecule, TNFi tumor necrosis factor inhibitor, tsDMARD targeted synthetic disease-modifying antirheumatic drug
aDiscontinuation or switching treatments occurred at or prior to the 6-month follow-up visit; follow-up visits occurred at 6 ± 3 months and could, therefore, have taken place between 3 and 9 months
bNon-TNFi treatments included secukinumab, ixekizumab, ustekinumab, and abatacept
ctsDMARDs included upadacitinib
dMethotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or apremilast
eDue to minor adverse events
Similar proportions of patients in the monotherapy versus combination therapy groups remained on tofacitinib (71.2% vs. 74.7%, respectively) at the 6 ± 3-month follow-up. Among those who discontinued, 14 patients (73.7%) in the monotherapy group switched to a b/tsDMARD compared with 8 (42.1%) patients in the combination therapy group. Of the patients who switched to a b/tsDMARD, 10/14 patients (71.4%) in the monotherapy group versus 3/8 patients (37.5%) in the combination therapy group switched to a non-TNFi bDMARD (Table 2); in contrast, a higher proportion of patients in the combination therapy group versus monotherapy group discontinued as a result of switching to a TNFi (3/8 patients [37.5%] vs. 2/14 patients [14.3%], respectively). Additionally, 2 patients (2.7%) added an OSM in the combination therapy group versus 1 patient (1.5%) in the monotherapy group (overall: 3 patients [2.1%]) (Table 2).
Clinical Effectiveness Outcomes
Disease Activity and Patient-Reported Outcomes
Across treatment groups, numerical improvements from baseline in disease activity outcomes were observed at 6 ± 3 months. Overall, there was a change from baseline of − 6.1 in cDAPSA, − 7.2 in DAPSA, and − 8.9 in patient pain (Fig. 1a). Across outcomes, there was a larger numerical change from baseline in the monotherapy group versus the combination therapy group. Specifically, for cDAPSA, there was a change from baseline of − 8.2 in the monotherapy group and − 4.4 in the combination therapy group. For the DAPSA outcome, there was a change from baseline of − 10.7 in the monotherapy group versus − 4.9 in the combination therapy group, and for patient pain, − 13.7 in the monotherapy group versus − 4.7 in the combination therapy group. After adjustment for differences at baseline between the two groups, the differences in LS means were not significant (Fig. 1a).
Fig. 1
a) Effectiveness outcomes and patient-reported outcomes at 6 ± 3 months, and b) proportion of patientsa achieving effectiveness outcomes at 6 ± 3 months, stratified by monotherapy and combination therapy.baResponse rates were calculated for patients not in the outcome achievement state at baseline and non-response was imputed for those with missing values or for patients discontinuing tofacitinib prior to 6 months. 95% CI were based on normal approximation to binomial proportions. bTofacitinib plus csDMARD (methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or apremilast). cThe raw mean differences (rather than LS means) are presented for the overall group. dLS mean change from baseline for monotherapy versus combination therapy from linear regression models with independent variables: treatment group (reference = combination therapy), age, sex, duration of PsA, prior b/tsDMARD (naïve vs. experienced), prior number of OSM treatments (0, 1, 2+), and baseline value of the outcome variable. eMDA was defined as “yes” if a patient met at least five of the seven following criteria: TJC ≤ 1, SJC ≤ 1, BSA ≤ 3%, patient pain VAS ≤ 15, patient global assessment VAS ≤ 20, HAQ-DI ≤ 0.5, and SPARCC enthesitis count ≤ 1. fORs (95% CI) from logistic regression models with independent variables: treatment group (reference = combination therapy), age, sex, duration of PsA, prior b/tsDMARD (naïve vs. experienced), prior number of OSM treatments (0, 1, 2+), and baseline value of the outcome variable (with the exception of MDA, enthesitis, and dactylitis since these outcomes did not have an appropriate continuous baseline value to include). gEstimate not calculated due to sparse data available. ∆ change from baseline, bDMARD biologic disease-modifying antirheumatic drug, BSA body surface area, cDAPSA Clinical Disease Activity Index for Psoriatic Arthritis, CI confidence interval, csDMARD conventional synthetic disease-modifying antirheumatic drug, DAPSA Disease Activity Index for Psoriatic Arthritis, HAQ-DI Health Assessment Questionnaire-Disability Index, LDA low disease activity, LS least squares, MDA minimal disease activity, mPASDAS modified Psoriatic Arthritis Disease Activity Score, OR odds ratio, OSM oral small molecule, PRO patient-reported outcome, PsA psoriatic arthritis, PsO psoriasis, SE standard error, SJC swollen joint count, SPARCC Spondyloarthritis Research Consortium of Canada, TJC tender joint count, tsDMARD targeted synthetic disease-modifying antirheumatic drug, VAS Visual Analog Scale
Overall, at 6 ± 3 months, 26.0% (95% CI 17.7, 35.7) of patients achieved LDA as measured by cDAPSA; specifically, in the monotherapy group, 31.3% of patients achieved cDAPSA LDA (95% CI 19.1, 46.4) versus 21.2% (95% CI 11.5, 35.1) in the combination therapy group (Fig. 1b). In total, 24.7% (95% CI 16.2, 35.0) of patients achieved BSA = 0%, with a numerically higher proportion of patients in the monotherapy group versus the combination therapy group (27.1% [95% CI 15.7, 42.1] and 22.0% [95% CI 11.1, 38.0], respectively). MDA was achieved by 17.8% (95% CI 11.4, 25.9) of patients overall at 6 ± 3 months, with 15.0% (95% CI 7.5, 27.1) of patients in the monotherapy group versus 20.7% (95% CI 11.6, 33.7) in the combination therapy group. Similar proportions of patients in the monotherapy group and combination therapy group achieved mPASDAS < 3.2, resolution of enthesitis, resolution of dactylitis, and Investigator Global Assessment of PsO score of “clear” or “almost clear” (0/1). Monotherapy and combination therapy groups did not differ significantly across any outcome measure after adjustment (Fig. 1b).
Work Productivity and Activity
After 6 ± 3 months, the LS mean difference from baseline in overall work impairment was − 13.0 (standard error [SE] 4.3) for the monotherapy group and 1.4 (SE 4.4) for the combination therapy group among the subset of initiators reporting current employment (Fig. 2). The LS mean difference in activity impairment between baseline and 6 months was − 21.8 (SE 4.5) for the monotherapy group and − 2.9 (SE 4.3) for the combination therapy group (Fig. 2). When the LS means were adjusted for independent variables including treatment group, the observed differences between monotherapy and combination therapy were not significant.
Fig. 2
Change from baseline in Work Productivity and Activity Impairment domains at 6 ± 3 months, stratified by monotherapy and combination therapy.aaDiscontinuation or switching treatments occurred at or prior to the 6-month follow-up visit; follow-up visits occurred at 6 ± 3 months and could, therefore, have taken place between 3 and 9 months. bMethotrexate, leflunomide, sulfasalazine, hydroxychloroquine, or apremilast. cAmong those reporting current employment. dLS mean change from baseline for monotherapy versus combination therapy from linear regression models with independent variables: treatment group (reference = combination therapy), age, sex, duration of PsA, prior b/tsDMARD (naïve vs. experienced), prior number of OSM treatments (0, 1, 2+), and baseline value of the outcome variable. bDMARD biologic disease-modifying antirheumatic drug, CI confidence interval, LS least squares, OSM oral small molecule, PsA psoriatic arthritis, SE standard error, tsDMARD targeted synthetic disease-modifying antirheumatic drug
This real-world study compared the effectiveness of tofacitinib monotherapy versus combination therapy among patients with PsA who initiated tofacitinib and had a 6-month follow-up visit. The study utilized the CorEvitas PsA/SpA Registry, a patient data collection and analysis resource. Generally, tofacitinib monotherapy initiators experienced numerically greater improvements in disease activity and PROs compared with combination therapy initiators; however, after adjustment for potential confounding baseline factors, no significant differences were observed between therapy groups. Overall, more than 90% of tofacitinib initiators received the approved dose of 11 mg once daily, while six patients received tofacitinib in combination with multiple csDMARDs. Consequently, no differences in mean dose distribution between the monotherapy and combination therapy groups were expected. The majority of patients in both the monotherapy and combination therapy groups were not b/tsDMARD-naïve. Therefore, the mean PRO differences were achieved despite monotherapy initiators receiving prior treatment.
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Similar proportions of patients in the monotherapy and combination therapy groups remained on tofacitinib at 6 ± 3 months. However, more patients in the monotherapy group switched to a b/tsDMARD compared with patients in the combination therapy group. The overall discontinuation rate in this analysis (27%) was not unexpected, based on results for other advanced PsA treatments in the CorEvitas PsA/SpA Registry (apremilast, 44% at 6 months; TNFi, 43.9–54.4% during follow-up) [23, 24]. Furthermore, persistence with tofacitinib at 6 months ranged from 53.1% to 70.4% in an analysis of claims databases [25].
The most common reason for discontinuing OSM treatment reported in both groups was “efficacy”, followed by “safety”. However, in the majority of cases, the reasons for switching were not reported. This finding is in line with other reports in patients with PsA. In a retrospective cohort study in patients with PsA, 79 patients (67.5%) switched bDMARD treatment because of inefficacy and 38 patients (25.7%) due to of adverse events [26]. Moreover, a review of numerous real-world studies in patients with PsA observed that the main reason for switching to a second TNFi was lack of effectiveness, followed by inefficacy and adverse events [27].
The adjusted differences in outcomes between monotherapy and combination therapy initiators were modest and not statistically significant, which is consistent with prior studies. Previously published meta-analyses of randomized clinical trials and real-world studies have evaluated the use of biologics as monotherapy and in combination with methotrexate, and generally found no difference in outcomes between the two groups. In a meta-analysis of data from 15 randomized controlled trials, there was no significant difference in PsA clinical efficacy outcomes measured at week 24 [28]. In a more recent network meta-analysis of 17 clinical trials, no significant difference in achieving American College of Rheumatology response rates was reported in patients with PsA treated with biologic monotherapy compared with those receiving biologic therapy in combination with methotrexate [29]. Real-world evidence also supports the findings reported in this current study. An analysis that combined European biologics registry data (including the ATTRA registry from the Czech Republic and the Bath, UK, PsA cohort) to investigate the comparative effectiveness of TNFi monotherapy versus combination therapy in patients with PsA found that combination TNFi and csDMARD therapy did not improve disease activity or physical function, compared with TNFi monotherapy. However, investigators reported that patients receiving combination therapy persisted longer on their first TNFi [30]. In another real-world study that utilized the CorEvitas PsA/SpA Registry, patients with PsA receiving TNFi and csDMARD combination therapy showed no significant difference in TNFi persistence and time to remission compared with TNFi monotherapy [31].
Similar to the current study, it was reported in a recent analysis of tofacitinib monotherapy and combination therapy for PsA from the CorEvitas PsA/SpA Registry that treatment with tofacitinib led to improvements in multiple PsA domains, and PROs, including work productivity [20]. However, this current study also provides valuable comparative evidence of tofacitinib monotherapy and combination therapy for PsA.
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Furthermore, we found that the improvements in disease activity and PROs of the current study were consistent with those for guselkumab, a biologic treatment used in patients with PsA from the CorEvitas PsA/SpA Registry [32]. For patients receiving guselkumab, with patient-reported pain ≥ 15 mm at baseline, 40.2% achieved at least 15-mm reductions at 6 months [32]. In the current study, patients receiving tofacitinib monotherapy reported a LS mean change from baseline in patient pain of − 13.7 at 6 ± 3 months. In patients receiving guselkumab, with HAQ-DI scores of at least 0.35 at baseline, 30.4% achieved significant improvements of at least 0.35 at 6 months [32]. Similarly, in the current study, patients receiving tofacitinib monotherapy reported a LS mean change from baseline of − 0.15, indicating improvement in disability. The consistency of results across single-arm observational studies is reassuring; however, there are likely differences in the baseline characteristics of the study populations that, without proper adjustment, should not be compared directly.
To our knowledge, this is the first real-world study in patients with PsA comparing work productivity and activity between tofacitinib monotherapy and combination therapy initiators. However, real-world data have been gathered on work productivity, activity impairment, and disease activity in patients with PsA treated with TNFi therapy [33]; similar to our findings, all of these domains improved over 9 months of treatment. Other real-world studies with golimumab [34], adalimumab [35], and ustekinumab [36] have observed similar trends.
A strength of this current study is that a broader range of disease activity outcomes and PROs were investigated than in previous real-world studies in PsA. Additionally, this study focused on a broad population of tofacitinib initiators, with a wide range of disease severity and with comorbid conditions. The CorEvitas PsA/SpA Registry study provides valuable insights into the treatment of PsA; however, limitations must be considered when interpreting its findings. Firstly, the study had low patient numbers, which limited the statistical power and the ability to detect significant differences or associations. Secondly, there may have been channeling bias in terms of who received tofacitinib monotherapy versus combination therapy, limiting the ability to directly compare the two groups. Moreover, the patient sample may not have been representative of the broader population of adults with PsA in the USA or globally. Lastly, the study did not include measures of patients’ adherence to their medication regimen. Non-adherence is a common issue in chronic diseases like PsA and can significantly impact treatment outcomes [37, 38]; however, patients with PsA generally prefer oral therapies to other modes of administration [39]. The lack of adherence data in the study limits the ability to fully understand and interpret the effects of the treatment regimens being evaluated. Medication adherence beyond what was recorded by the physician (starts, stops, and interruptions in tofacitinib use) was not recorded. Notably, no major disruptions in medication use due to the SARS-CoV-2 (COVID-19) pandemic were observed, and any disruptions due to other reasons (e.g., FDA-mandated revisions to the boxed warnings for JAK inhibitors) would have been captured in the stop dates reported by the physician, and reflected in this analysis. No major differences in the “reasons for discontinuation” were observed between the cohorts, although it should be noted that many patient records did not report a reason for discontinuation of the study drug. There were no reports of safety or COVID-19 concerns.
Conclusions
The findings of this real-world study suggest that both monotherapy and combination therapy can be effective treatment strategies for PsA and this information could inform treatment decisions for PsA. This analysis highlights the use of tofacitinib in a broad population of initiators and underscores its effectiveness both as monotherapy and in combination with other OSMs. However, the small sample size limited the statistical power, and so results should be interpreted cautiously. Further research is warranted to confirm these results.
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Acknowledgements
We thank the participants of the study.
Medical Writing/Editorial Assistance
Medical writing support, under the direction of the authors, was provided by Caitlin Duncan, PhD, CMC Connect, a division of IPG Health Medical Communications, and was funded by Pfizer, New York, NY, USA, in accordance with Good Publication Practice (GPP 2022) guidelines (Ann Intern Med. 2022;175:1298–304). Pfizer’s generative artificial intelligence (AI) assisted technology was used to assist production of the first draft of this manuscript. After using this tool/service, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. All authors approved the final version of the article, including the authorship list. Pfizer was given the opportunity to review the article.
Declarations
Conflict of Interest
Alexis Ogdie has received consultancy fees for AbbVie, Amgen, Bristol Myers Squibb, Celgene, CorEvitas, LLC, Gilead, GSK, Janssen, Lilly, Novartis, Pfizer Inc, Takeda, TREG, and UCB, and research grants for AbbVie, Amgen, Bristol Myers Squibb, Forward/National Databank for Rheumatic Diseases, Janssen, NIH/NIAMS, Novartis, Pfizer Inc, and Rheumatology Research Foundation. Nicole Middaugh is an employee of CorEvitas, LLC (CorEvitas has been supported through contracted subscriptions in the past 2 years by AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Lilly, Genentech, GSK, Janssen, LEO Pharma, Novartis, Ortho Dermatologics, Pfizer Inc, Sun Pharmaceutical Industries Ltd, and UCB). Taylor Blachley is an employee of CorEvitas, LLC (CorEvitas has been supported through contracted subscriptions in the past 2 years by AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Lilly, Genentech, GSK, Janssen, LEO Pharma, Novartis, Ortho Dermatologics, Pfizer Inc, Sun Pharmaceutical Industries Ltd, and UCB). Tran Bourgeois was an employee of CorEvitas, LLC, at the time of the study (CorEvitas has been supported through contracted subscriptions in the past 2 years by AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Lilly, Genentech, GSK, Janssen, LEO Pharma, Novartis, Ortho Dermatologics, Pfizer Inc, Sun Pharmaceutical Industries Ltd, and UCB), and is now an employee of the Children’s Hospital of Philadelphia, PA, USA. You-Li Ling is an employee and stockholder of Pfizer Inc. Rajiv Mundayat, Princeton, NJ, USA, is a stockholder of Pfizer Inc and was an employee of Pfizer Inc at the time of the study. Lara Fallon is an employee and stockholder of Pfizer Inc. Karim R. Masri is a stockholder of Pfizer Inc and was an employee of Pfizer Inc at the time of the study, and is now an employee of Candid Therapeutics. Philip J. Mease has been advisor or review panel member for Genascence–Safety Monitoring Board, has received consultancy fees from AbbVie, Acelyrin, Aclaris, Alumis, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Lilly, Inmagene, Janssen, MoonLake, Novartis, Pfizer Inc, Takeda, UCB, and Ventyx, has been an officer and board member for Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), OMERACT, and SPARTAN, and has received grant/research support from Amgen, Acelyrin, Bristol Myers Squibb, Lilly, Janssen, Novartis, Pfizer Inc, and UCB.
Ethical Approval
The study was performed in accordance with Good Pharmacoepidemiology Practice. Sponsor approval and continuing review were obtained through a central Institutional Review Board (IRB), WCG IRB (no. 120160070). All registry participants provided informed consent and authorization prior to participation. CorEvitas PsA/SpA Registry data used in this analysis were provided in an anonymized structured format and did not contain any patient personal information. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments.
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Effectiveness of Tofacitinib in Patients with Psoriatic Arthritis Initiating Monotherapy Versus Combination Therapy: Results from the CorEvitas Psoriatic Arthritis/Spondyloarthritis Registry
Verfasst von
Alexis Ogdie
Nicole Middaugh
Taylor Blachley
Tran Bourgeois
You-Li Ling
Rajiv Mundayat
Lara Fallon
Karim R. Masri
Philip J. Mease
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