Characterization of Super-Responder Profile in Patients with Psoriatic Arthritis Treated with b/tsDMARDs: A Retrospective Study of a Longitudinal Cohort

Abstract

Introduction

Psoriatic arthritis (PsA) is a complex disease in which remission or low disease activity is now an achievable target. This study aimed to evaluate “super-responders” (SR) among patients with PsA treated with advanced therapies and to explore possible clinical factors associated with the SR phenotype.

Methods

This is a retrospective analysis of a longitudinal cohort of patients diagnosed with PsA and treated with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs), with at least 2 years of follow-up. SR were defined as patients achieving very low disease activity (VLDA) within 6 months of therapy initiation and maintaining VLDA for at least 2 years. Data from all clinical visits were reviewed to confirm response patterns. Patients who initiated treatment for PsA were included, regardless of prior biologic use for psoriasis. SR were compared with non-SR patients to identify clinical differences. Logistic regression was performed to evaluate features associated with SR.

Results

Among 177 evaluated patients, 29 (16.3%) were classified as SR. SR patients were more often of male sex, had significantly lower baseline pain visual analogue scale scores (p < 0.01), Patient Global Assessment score (p = 0.04), and shorter intervals between psoriasis and PsA diagnosis (p = 0.04). They were more frequently treated with interleukin-17 (IL-17) inhibitors at baseline (37.9% vs. 19.5%, p = 0.04) and had absence of cardiometabolic comorbidities. Logistic regression analysis confirmed associations between SR status and IL-17 treatment, absence of cardiometabolic comorbidities, and lower pain scores.

Conclusion

This study may identify a distinct subset of patients with PsA demonstrating rapid and sustained response to treatment. While promising, the clinical utility of the SR concept requires cautious interpretation, especially regarding potential treatment de-escalation. Further validation in multicenter prospective studies may be essential.

Key Summary Points

Why carry out this study?

Remission or low disease activity are achievable targets in psoriatic arthritis (PsA); however, deep, rapid, and sustained remission might not often be achieved.

This preliminary study investigated the “super-responder” profile in patients with PsA, showing the rate of patients achieving this condition and potential associated factors.

What was learned from the study?

A shorter interval between the onset of psoriasis and the diagnosis of PsA, the absence of cardiometabolic comorbidities, and treatment with interleukin-17 inhibitors seem to be significantly associated with a “super-responder” profile.

Identifying “super-responder” patients with PsA may improve the management of patients and, potentially, reduce healthcare costs and resource utilization.

Introduction

Psoriatic arthritis (PsA) is a complex, heterogenous, and chronic inflammatory disease characterized by coexistence of psoriasis (PsO), musculoskeletal manifestations such as arthritis, enthesitis, and dactylitis, extra-articular manifestations and comorbidities [1]. To date, remission and low disease activity are the targets of treatment in PsA, as recommended by the European Alliance of Association for Rheumatology (EULAR) [2]. These conditions can be achieved in 40–70% of patients treated with advanced therapies in real-life clinical studies [3–5]. However, in a multifaceted disease like PsA, the possibility to achieve a “deep” remission in all domains is still low, with some studies reporting rates of 10–20%, but some patients may achieve a deeper, faster, and sustained remission across multiple disease domains. In dermatology, the term “super-responder” (SR) has been applied to patients who achieve rapid and complete skin clearance with biologic therapy. There are different definitions of SR patients with PsO in the literature [6–8]. Marcelli et al. [6] proposed, as a definition, patients who achieved complete skin clearance (Psoriasis Severity Area Index = 0) at 20 weeks of treatment. Identification of SR patients with PsO has potential benefits in dermatological clinical practice, in the light of possible management of treatment strategies. To our knowledge, despite the number of papers exploring the effectiveness of advanced treatments in PsA, this concept has not yet been clearly established.

In this context, the aim of our study was to evaluate the SR profile in patients with PsA treated with biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs), and to explore associated clinical factors. We also discussed the feasibility and implications of tailoring treatment strategies based on SR status.

Methods

Study Design and Participants

This was a retrospective analysis of a longitudinal observational cohort of patients diagnosed with PsA according to the classification criteria for PsA (CASPAR) [9] and treated with b/tsDMARDs, who attended the PsA clinic at the University of Molise between January 1, 2018 and December 31, 2023. Our research was planned with the intention to collect a large number of variables, without prespecified hypothesis. Patients were treated according to the current standard of care, following the GRAPPA and EULAR treatment recommendations [2, 10]. Data presented were restricted to the baseline visit and the last follow-up in our unit. Clinical data were collected from medical records at all available timepoints. Usually, patients in our unit are followed up every 3–6 months. Missing data were not imputed.

Inclusion criteria were:

1. Age ≥ 18 years

2. At least 2 years of follow-up in our center

3. Availability of clinical data

Individuals receiving biologic therapy for psoriasis before PsA onset were also included. Patients with PsA preceding psoriasis were retained, and time intervals were managed accordingly.

Data Collection

A detailed medical history and physical examination were collected for all recruited patients. Details for the data collection were also published elsewhere [11]. Demographics and disease characteristics including sex, age, disease duration, level of education, time between the onset of PsO and the diagnosis of PsA, and pattern of articular manifestations were evaluated. C-reactive protein performed within 1 month from clinical assessment was also collected. Treatment history, including conventional synthetic DMARDs, tumor necrosis factor (TNF) inhibitors, interleukin (IL)-17/IL-12/23 inhibitors, and phosphodiesterase 4 inhibitor (PDE4) inhibitors, was collected.

Comorbidities (including obesity, defined as body mass index ≥ 30 kg/m²) and presence of extra-articular manifestations were collected. Comorbidities were stratified into cardiometabolic (e.g., obesity, hypertension, diabetes, dyslipidemia, prior cardiovascular events) and others. Among comorbidities, fibromyalgia was assessed by physician judgement. The clinical assessment encompassed the number of 68 tender and 66 swollen joints, enthesitis and dactylitis. Entheseal involvement was clinically assessed by using the Leeds Enthesitis Index (LEI) [12], and dactylitis as presence/absence in each finger (digit score 0–20). The Patient Global Assessment (PtGA), pain assessment on visual analogue scale (VAS), and the physician’s global evaluation (PhGA) of disease activity on a VAS were also recorded [13, 14]. The Disease Activity score for Psoriatic Arthritis (DAPSA) was performed [15]. The patient acceptable symptom state (PASS) was also collected [16]. The Health Assessment Questionnaire Disability Index (HAQ-DI) was evaluated as a measure of function [17].

Definition of SR Patients with PsA

There is no consensus on the definition of SR in PsA. For the purpose of this study, we defined SR as patients who achieved very low disease activity (VLDA according to Coates et al.) [18, 19] within 6 months from the introduction of advanced treatment and maintenance of VLDA at all subsequent visits for at least 2 years.

VLDA was defined when patients met 7/7 of the following criteria: tender joint count ≤ 1; swollen joint count ≤ 1; PASI ≤ 1 or body surface area ≤ 3; patient pain on VAS score of ≤ 15; PtGA on VAS score of ≤ 20; HAQ score ≤ 0.5; tender entheseal points ≤ 1 [18].

VLDA and the aforementioned clinical characteristic of patients were collected at each visit.

We chose to utilize the VLDA because it should potentially avoid residual disease activity in PsA clinical domains [11].

We also chose to compare the SR group to only the non-SR patients in order to potentially identify a phenotype of patients with persistently very low disease activity, distinguishing them from those who experienced at least one remission and those who did not adequately respond to treatment.

Ethical Approval

The study was approved by the institutional review board of the University of Molise (protocol no. 0001-017-2021) and performed according to the Helsinki declaration. Written informed consent to use clinical data was obtained from all participants.

Statistical Analysis

Data were analyzed using IBM SPSS v26.0. Continuous variables were assessed for normality by using the Kolmogorov–Smirnov test. Normally distributed variables were summarized using the mean ± standard deviation (SD), and non-normally distributed variables by the median and interquartile range (IQR). Descriptive statistics, Mann–Whitney U test, chi-square test, or Fisher’s exact test (as appropriate) were used to compare SR and non-SR groups. Variables with p ≤ 0.15 in univariate analyses were entered into binary logistic regression models. Odds ratios (OR) and standard error (SE) were reported. Missing data were not imputed. P values less than 0.05 were considered significant.

Results

Of 225 patients with PsA in our database, 177 patients fulfilled the inclusion criteria and were evaluated. Of these, 99 (55.9%) were male and 78 (44.1%) female. At baseline, median (IQR) age was 55 (43–62) years and median disease duration was 3 (0.5–9) years. At last follow-up in our unit, 35 (19.4%) patients reached VLDA in at least one visit during follow-up. Of these, 29 (16.3%) patients fulfilled the criteria for SR patients with sustained VLDA. Table 1 compares the baseline demographics and disease characteristics between SR and non-SR patients. SR patients showed a significantly lower value of baseline pain on VAS (p < 0.01) and PtGA (p = 0.04). Furthermore, SR showed a tendency toward a lower median number of tender joints (p = 0.07) at baseline. However, no significant differences were found in the PhGA of disease activity at baseline. Interestingly, SR patients with PsA showed a significantly shorter interval between PsO and the diagnosis of PsA in comparison to non-SR (p = 0.04). SR patients also tended to be of male sex (72.4% vs. 52%, p = 0.06). SR patients were significantly more likely to have been treated with IL-17 inhibitors (37.9% vs. 19.5%, p = 0.04) while no differences in the rate of prescription of other medications were found between SR and non-SR (Table 1).

Table 1.

PsA characteristics

	Patients (n = 177)		p value
	SR (n = 29)	Non-SR (n = 148)
Demographic, physical characteristics
Sex (male), n (%)	22 (75.8)	77 (52)	0.06
Age, years median (IQR)	51 (39–58)	55 (47–65)	0.39
BMI (kg/m2), median (IQR)	26.3 (23.6–28.9)	26.7 (23.8–30.2)	0.70
Clinical PsA characteristics
Median follow-up, years (IQR)	4 (2–6)	4 (2–6)	1
Disease duration, months, median (IQR)	46 (9.7–123)	36 (4–119)	0.8
Time between PsO onset and PsA diagnosis, years, median (IQR)	14 (6–33)	27 (9–49)	0.04*
PsA subset
Axial involvement, n (%)	3 (11.1)	12 (8.1)	0.34
Monoarticular, n (%)	3 (7.9)	6 (4.1)
Oligoarticular, n (%)	8 (27.5)	42 (28.3)
Polyarticular, n (%)	11 (37.9)	53 (35.8)
Uveitis present or past, n (%)	0 (0)	2 (1.3)	1
Crohn disease, n (%)	0 (0)	3 (2)	1
Ulcerative colitis, n (%)	0 (0)	1 (0.7)	1
Nail involvement, n (%)	6 (20.6)	34 (22.9)	0.74
BSA, median (IQR)	1 (0–4)	1 (1–3)	0.77
Tender Joints (out of 68), median (IQR)	3 (0–4.5)	4 (1–6)	0.07
Swollen joints (out of 66), median (IQR)	1 (0–2)	1 (0–2)	0.89
Patient Global Assessment, median (IQR)	5 (1–6)	6 (4–7)	0.04*
Patient pain on VAS, median (IQR)	5 (1–6)	6 (4–8)	< 0.01*
Dactylitis, n (%)
Past or present	9 (31)	25 (16.8)	0.11
CRP (mg/dl), median (IQR)	0.2 (0.17–0.7)	0.2 (0.2–0.6)	0.46
DAPSA, median (IQR)	15.2 (10.4–25.6)	15.6 (8.4–22)	0.70
LEI, median (IQR)	1 (0–1)	1 (0–2)	0.67
PsA function and impact
PsAID, median (IQR)	6.1 (4.8–8.7)	5.30 (3.9–8.2)	0.45
HAQ-DI, median (IQR)	0.75 (0.5–1.25)	1 (0.5–1.25)	0.08*
Comorbidities and treatment at baseline
Cardiometabolic comorbidities, n (%)	11 (37.9)	79 (53.4)	0.15
Other comorbidities, n (%)	5 (17.2)	30 (20.3)	0.43
Presence of fibromyalgia, n (%)	1 (3.4)	15 (10.1)	0.40
Concomitant csDMARDs, n (%)	5 (17.2)	31 (20.9)	0.80
Anti-TNF	11 (37.9)	50 (33.7)	0.67
Anti-IL-12/23	1 (3.4)	7 (4.7)	1
Anti-IL-17	11 (37.9)	29 (19.5)	0.04*
Anti-IL-23	2 (6.8)	12 (8.1)	1
JAKi	0 (0)	4 (2.7)	1
PDE4i	1 (3.4)	12 (8.1)	1

SR super responders, BMI body mass index, IQR interquartile range, PsA psoriatic arthritis, BSA body surface area, VAS visual analogue scale, CRP C-reactive protein, DAPSA Disease Activity Index for Psoriatic Arthritis, PsAID Psoriatic Arthritis Impact of Disease, HAQ-DI Health Assessment Questionnaire Disability Index, csDMARD conventional synthetic disease-modifying anti-rheumatic drugs, TNF tumor necrosis factor, IL interleukin, JAKi Janus kinase inhibitors, PDE4i phosphodiesterase 4 inhibitor

*Statistically significant

Binary logistic regression identified treatment with IL-17 inhibitors (OR 2.47, 95% CI 1.01–6.06, p = 0.04), absence of cardiometabolic comorbidities (OR 2.71, 95% CI 1.09–6.74, p = 0.03), and lower pain VAS at baseline (OR 0.96 per unit increase, p = 0.01) as independently associated with SR status. Table 2 presents the full model.

Table 2.

Logistic regression analysis of factors potentially associated with SR

	Beta	Standard error	P value	Odds ratio
Sex (male)	− 0.83	0.54	0.12	0.43
Pain VAS	− 0.25	0.09	0.006	0.77
Number of tender joints	− 0.76	0.42	0.18	0.39
Cardiometabolic comorbidities	− 0.83	0.48	0.04	0.43
Naïve to b/tsDMARDs	0.50	0.48	0.29	1.66
Treatment with IL-17i	1.89	0.65	0.004	6.66

SR super responders, VAS visual analogue scale, b/tsDMARDs biologic/targeted synthetic disease-modifying anti-rheumatic drugs, IL-17i interleukin-17 inhibitors

Discussion

The growing emphasis on personalized medicine and patient-centered care has brought the need to evaluate the presence of disease phenotypes which may better respond to advanced treatment strategies to improve the management of patients. Our study may contribute to this interesting topic. In this context the characterization of SR patients with PsA could be of particular interest.

This study presents one of the first efforts to identify a SR phenotype in PsA. Our findings suggest that patients with fewer comorbidities, early PsA diagnosis relative to psoriasis onset, and IL-17 inhibitor therapy may have a higher likelihood of achieving SR status.

The term SR is borrowed from dermatology, though it lacks consensus in rheumatology. This construct may help identify patients for personalized treatment approaches. Our results support the feasibility of identifying high-performing patient subgroups but still do not support de-escalation of therapy without prospective trials.

We also noted that lower baseline pain values were a key differentiator of SR status.

Our results are partially in keeping with a recent meta-analysis, in which higher baseline DAPSA score, female sex, and higher baseline tender joint count were negatively associated with treatment response [20]. Interestingly, this study showed that a shorter interval between the PsO onset and PsA diagnosis may be associated with a SR condition. This data should be investigated more in dept but could be in keeping with the growing interest in the transition phase from PsO to PsA as main treatment target [21].

Finally, the presence of comorbidities and in particular cardiometabolic comorbidities is negatively associated with the possibility to achieve SR. This is in keeping with the complexity of psoriatic disease in which multimorbidity may influence disease activity [22]. However, fibromyalgia was not negatively associated with SR, probably because of its lower prevalence in our group. It is possible that fibromyalgia in female sex may play a role as a factor predicting a worse response in the non-SR group; however, in our bivariate and multivariable analyses, fibromyalgia did not emerge as a strong predictive factor. Another interesting aspect is related to the potential role of anti-IL-17 treatment as a factor determining the SR profile. The SPIRIT H2H study with ixekizumab demonstrated the superiority of IL-17 treatment, compared to adalimumab, in the achievement of the combined response ACR50 + PASI100 [23]. Our results could be in keeping with these findings, but they should be carefully interpreted because of the possibility that IL-17 inhibitor significance may be related to a type 2 error.

Limitations include the retrospective, single-center nature of the study, non-imputation of missing data, and the reliance on LEI for enthesitis. Some patients may have had structural damage limiting HAQ-DI improvement (floor effect), possibly excluding them from SR classification. Future studies might compare SR classification using the minimal disease activity (MDA) criteria instead of VLDA to evaluate potential differences. Moreover, the relative stringency of the statistical significance on the results of the multivariate statistical model may have influenced the results.

Finally, the assessment of potential predictors for SR may be of particular interest in the near future when trying to identify patients with very good outcomes in which treatment strategies may be adjusted. Moreover, another interesting aspect was the management of patients that need escalation of therapy to achieve sustained remission.

Conclusion

A distinct subgroup of patients with PsA designed as “super-responders” may achieve sustained VLDA early in treatment. These patients tend to have fewer cardiometabolic comorbidities, shorter disease duration, and greater responsiveness to IL-17 inhibitors. Prospective validation is necessary before clinical application.

Author Contributions

Fabio Massimo Perrotta and Ennio Lubrano have made substantial contributions to all of these sections: conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article, revising it critically for important intellectual content and final approval of the version to be submitted. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

The datasets generated during and/or analyzed during the current study may be available from the corresponding author on reasonable request.

Declarations

Conflict of Interest

Ennio Lubrano and Fabio Massimo Perrotta are members of the Editorial Board of Rheumatology and Therapy. Ennio Lubrano and Fabio Massimo Perrotta were not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions.

Ethical Approval

The study was approved by the institutional review board of the University of Molise (protocol no. 0001-017-2021) and performed according to the Helsinki declaration. Written informed consent to use clinical data of all participants was obtained.