To the Editor:

Psoriatic arthritis (PsA) is one of the most common forms of inflammatory arthritis and although advances in psoriasis therapeutics have led to skin clearance in many patients using targeted biologics, joint efficacy lags behind.1-4 Even in patients with seemingly controlled inflammation, up to half continue to experience residual pain.5,6 Clinically, patients may present with continued tender joints after treatment without any evidence of active swelling or inflammation. Even though this is often treated with uptitration or change in immunomodulatory therapy, the drivers of persistent joint pain are unknown. We hypothesize that it is driven primarily by noninflammatory causes, such as psychologic distress, fatigue, and sleep disturbance. Here we aimed to define the prevalence and clinical characteristics of noninflammatory persistent joint pain in patients with PsA.

Consecutive patients (n = 121) were enrolled from the New York University (NYU) Psoriatic Arthritis Center (PAC) into an observational cohort. Patients were defined as active (≥ 1 swollen joint), in remission (0 swollen and tender joints), or having persistent joint pain (0 swollen joints, ≥ 1 tender joint). This study was approved by the NYU Institutional Review Board (i20-00084). Full methods can be found in the Supplementary Material (available with the online version of this article).

At time of evaluation, 26/121 (21.5%) participants had active disease and 95 (78.5%) had no swollen joints or evidence of active synovitis as assessed by physical exam. Of those without swollen joints, 70 (73.7%) were in full remission and 25 (26.3%) had persistent joint pain with an average of 3.0 tender joints (SD 2.8; Table 1). Patients with persistent joint pain had similar demographics, low prevalence of fibromyalgia (FM), and disease characteristics, including presence of peripheral erosions or axial disease, mean time between symptom onset to diagnosis, and number of past biologics used, to those in full remission. Additionally, the groups had a similar proportion of patients who had elevated acute-phase reactants and were currently on biologics. Patients with persistent joint pain had worse physician global assessment scores compared to those in remission (2.5 vs 1.4, P < 0.001).

Characteristics of the cross-sectional cohort.

Despite these similarities, patients with persistent joint pain had higher levels of fatigue, depression, and anxiety compared to those in remission, as well as worse coping mechanisms, more impact on their work and social life, and increased sleep disturbance (as measured by the PsA Impact of Disease [PsAID]; Figure 1A). Global mental health scores (10-item Patient Reported Outcomes Measurement Information System [PROMIS10]) were also worse in those with persistent pain (49.9 vs 45.2, P = 0.02, with lower scores indicating decreased mental health). In patients with persistent joint pain, the number of tender joints was moderately correlated with level of fatigue, function, sleep disturbance, coping difficulties, and anxiety, and weakly correlated with depression, but not with age (Figure 1B). Patients with persistent joint pain had similar patient-reported outcomes to those with active inflammatory disease (Supplementary Table S1 and Figure S1, available with the online version of this article).

Increased psychosocial stress in patients with persistent joint pain. (A) Comparison in PROs between those in complete remission and those with persistent joint pain. On all scales, higher numbers represent worse outcomes. (B) Correlation between number of tender joints in those with persistent pain (but without synovitis) and PROs. ** P < 0.01. *** P < 0.001. PRO: patient-reported outcome; RAPID3: Routine Assessment of Patient Index Data 3; TJC: tender joint count.

A second cohort of patients within PAC (n = 143) with newly diagnosed PsA and at least 1 subsequent visit was followed for an average of 7.9 months (SD 7.6) to assess for disease outcome (active, remission, persistent joint pain) after initiation of treatment. At follow-up, 59 participants were active, 56 were in remission, and 28 had persistent joint pain. Patients with active disease were older than those in remission, but all groups had similar baseline disease activity (Supplementary Table S2, available with the online version of this article). Self-reported depression ever (odds ratio [OR] 2.45, 95% CI 0.92-6.50) and an increased tender and swollen joint count difference at baseline (OR 1.09, 95% CI 0.99-1.20) were the most predictive of having later persistent joint pain compared to continued activity or remission, even after adjustment for age, although neither achieved statistical significance (Supplementary Figure S2).

In a population of patients with PsA that was generally without FM, we found that up to a quarter experience persistent joint pain, despite an absence of objective inflammation on examination, underlining the pervasiveness of this clinical scenario. Those with remaining tender joints reported more fatigue, sleep disturbance, depression, and anxiety, and worse ability to cope than those without, although we cannot determine the directionality of this relationship from a cross-sectional analysis. However, our longitudinal cohort did find that those with a history of depression were more likely to have persistent joint pain after initiation of treatment than those without, in line with previous studies showing that comorbid depression can hamper PsA remission.7,8 We are limited in the classification of persistent joint pain, which lacked corresponding radiographic confirmation of the absence of inflammation, and the low prevalence of FM, preventing the detection of its possible contribution.

Understanding the modulators of residual joint pain is of critical importance to improve outcomes in PsA. In patients initiating their second or later biologic, only a minority will remain on the drug and achieve remission.9 Although this may reflect treatment-resistant PsA, alternatively, it may also represent failure to differentiate between true inflammatory pain and pain perpetuated by other, noninflammatory factors. Although new and potentially effective treatment strategies are emerging,10 adjuvant therapies (ie, targeting mental health and sleep) may be necessary to improve outcomes in PsA.

This study was funded by the National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS 1UC2AR081029 to JUS; T32-AR-069515 to RHH and JUS; 5UC2AR081039-02S1 to JUS and RHH), NYU Colton Center for Autoimmunity, Rheumatology Research Foundation, National Psoriasis Foundation, Beatrice Snyder Foundation, and Riley Family Foundation.

RHH has served as a consultant for Janssen and UCB. SMR has served as a consultant for UCB, Novartis, Amgen, Fresenius Kabi, and AbbVie; and has received clinical research support from Pfizer, Janssen, and Eli Lilly. JUS has served as a consultant for Janssen, Novartis, Pfizer, Sanofi, Amgen, UCB, BMS, and AbbVie; and has received funding for investigator-initiated studies from Janssen and Pfizer. The remaining authors declare no conflicts of interest relevant to this article.