Psychosocial factors significantly contribute to joint pain persistence in psoriatic arthritis

Psoriatic arthritis (PsA) is one of the most common forms of inflammatory arthritis and while 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. While this is often treated with up-titration or change in immunomodulatory therapy, the drivers of persistent joint pain are unknown. We hypothesize that it is driven primarily by non-inflammatory causes, such as psychologic distress, fatigue, and sleep disturbance. Here we aimed to define the prevalence and clinical characteristics of non-inflammatory persistent joint pain in PsA patients.

Consecutive patients (n=121) were enrolled from the 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 IRB (s20-00084). Full methods can be found in the supplemental material.

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 levels of fibromyalgia, and disease characteristics to those in full remission, including presence of peripheral erosions or axial disease, mean time between symptom onset to diagnosis, and number of past biologics used. Additionally, the groups had a similar proportion of patients with elevated acute phase reactants and currently on biologics. Patients with persistent joint pain had worse physician global scores compared to those in remission (2.5 vs 1.4, p<0.001).

Table 1.

Characteristics of Cross-Sectional Cohort

Characteristic	All (n=95)	Remission (n=70)	Persistent Joint Pain (n=25)	p-value
Demographics and Comorbidities
Age-- mean (SD)	47.8 (13.7)	46.6 (14.0)	51.0 (12.4)	0.16
Female-- n(%)	49 (51.6)	37 (52.9)	12 (48.0)	0.65
Race-- n(%)				0.24
White	76 (80.0)	58 (82.9)	18 (72.0)
Asian	3 (3.2)	2 (2.9)	1 (4.0)
Black	2 (2.1)	2 (2.9)	0 (0.0)
Other	14 (14.7)	8 (11.4)	6 (24.0)
Hispanic-- n(%)	6 (6.3)	3 (4.3)	3 (12.0)	0.36
Cardiovascular disease*—n(%)	39 (41.1)	25 (35.7)	14 (56.0)	0.10
Fibromyalgia—n(%)	1 (1.1)	0 (0.0)	1 (4.0)	0.26
Disease Characteristics
Erosions-- n(%)	25 (26.3)	19 (27.1)	6 (24.0)	> 0.99
Axial disease—n(%)
Radiographic	12 (12.6)	11 (15.7)	1 (4.0)	0.17
Nonradiographic	7 (7.4)	7 (10.0)	0 (0.0)	0.18
Past biologics -- mean (SD)	1.8 (1.9)	2.0 (2.0)	1.4 (1.6)	0.21
Diagnosis Delay (years)-- mean (SD)	2.3 (6.0)	2.4 (6.4)	2.2 (5.1)	0.94
Current Disease Activity
BMI-- mean (SD)	29.3 (7.1)	29.1 (7.6)	29.7 (5.9)	0.72
% BSA-- mean (SD)	1.0 (3.5)	1.1 (4.0)	0.7 (1.3)	0.68
Enthesitis-- n(%)	12 (12.6)	7 (10.0)	5 (20.0)	0.22
Elevated ESR-- n(%)	23 (24.2)	17 (24.3)	5 (20.0)	0.46
Elevated CRP-- n(%)	17 (17.9)	13 (18.6)	4 (16.0)	0.44
Physician Global—mean (SD)	1.7 (1.2)	1.4 (1.1)	2.5 (1.1)	< 0.001
Current biologic-- n(%)	82 (86.3)	60 (85.7)	22 (88.0)	> 0.99

BMI denotes body mass index, %BSA percent of body surface area affected by psoriasis, ESR erythrocyte sedimentation rate, CRP c-reactive protein

^*Cardiovascular disease includes hypertension, hyperlipidemia, coronary artery disease, history of myocardial infraction, history of stroke

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 PsAID; Figure 1A). Global mental health scores (PROMIS10) were also worse in those with persistent pain (49.9 vs. 45.2, P= 0.02, 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, 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 (Table S1, Figure S1).

Figure 1. Increased psychosocial stress in patients with persistent joint pain.

(A) Comparison in patient reported outcomes between those in complete remission (blue) and those with persistent joint pain (purple). On all scales, higher number represents worse outcome. (B) Correlation between number of tender joints in those with persistent pain (but without synovitis) and patient reported outcomes. Acronyms: RAPID3, Routine Assessment of Patient Index Data 3; TJC, tender joint count. ** p<0.01. *** P< 0.001

A second cohort of PAC patients (n=143) with newly diagnosed PsA and at least one 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 persistent joint pain were older, but had similar baseline disease activity (Table S2). 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 (Figure S2).

In a population of patients with PsA that was generally without fibromyalgia, we found that up to a quarter experience persistent joint pain, despite an absence of objective inflammation on exam, 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 co-morbid depression can hamper PsA remission.^7,8 We are limited in the classification of persistent joint, which lacked corresponding radiographic confirmation of the absence of inflammation, and the low prevalence of fibromyalgia, 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 While this may reflect “treatment resistant” PsA, alternatively, it may also represent failure to differentiate between true inflammatory pain from pain perpetuated by other, non-inflammatory factors. While new and potentially effective treatment strategies are emerging,¹⁰ adjuvant therapies (i.e., targeting mental health and sleep) may be necessary to improve outcomes in PsA.

Declaration of interests:

RHH has served as a consultant for Janssen and UCB. SMR has served as a consultant for UCB, Novartis, Amgen, Fresenius Kabi, 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. YZ, SC, AF, KJ have no disclosures.