Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory disease that develops in up to 30% of patients with psoriasis. It is characterized by diverse clinical features including peripheral and axial arthritis, enthesitis, dactylitis, and nail dystrophy, leading to impaired function and reduced quality of life.[1]Enthesitis, the inflammation at the site of insertion of tendon and ligament into bone, is a hallmark manifestation of PsA and current knowledge supports the idea that enthesitis may be the primary event in PsA.[2,3] The importance of enthesitis in PsA is acknowledged by the inclusion of this clinical manifestation in the Classification Criteria for Psoriatic Arthritis (CASPAR).[4] Furthermore, enthesitis is approved by the Outcome Measures in Rheumatology (OMERACT) to be assessed as one of the core domains in all longitudinal studies and clinical trials on PsA.[5] Several physical examination measures of enthesitis, including the Leeds enthesitis index (LEI), Spondyloarthritis Research Consortium of Canada (SPARCC) index, and Maastricht ankylosing spondylitis enthesitis score (MASES), have been developed and proven reliable in its assessment.[6]

The prevalence of enthesitis in PsA has been reported to range from 19.5% to 65.7% in the US and Europe.[7,8] In an analysis from China, Yang et al[9] observed that enthesitis was present in 26.8% of PsA patients. The clinical features of enthesitis in patients with PsA have been reported in some Western countries.[7,8,10] However, data in China are very limited, hindering the comprehensive understanding of PsA in this region. The Chinese Registry of Psoriatic Arthritis (CREPAR) is a multi-center prospective registry based on the Chinese Rheumatism Data Center (CRDC). Data on enthesitis from the CREPAR have not been reported previously; thus, the present study aimed to determine the demographics, characteristics, and disease associations of enthesitis in Chinese patients with PsA.

Methods Ethical approval

Ethical approval was obtained from the Peking Union Medical College Hospital Ethics Board (No. S-K1811). All patients provided informed consent before data collection.

Patients

The CREPAR, founded in December 2018, is a registry based on the CRDC, which was a clinical research and translational medicine platform under the aegis of the National Health Commission of the People's Republic of China and the national "12th 5-year Plan Period" of the 863 program. Patients in the CREPAR were recruited from 162 hospitals across 31 provinces in China, and their data were collected on each visit. All included centers were tertiary hospitals and researchers were experienced rheumatologists in the fields of PsA. Training programs were used to guide all investigators for clinical assessment and data input, and all centers used the same protocol-directed methods to provide a uniform evaluation and record data. Until June 2021, a total of 1074 patients with PsA according to the CASPAR registered in the CREPAR.[4] Patients who refused musculoskeletal examination were excluded.

Data collection

This was a cross-sectional study. Medical assessment and physical examination were performed by the study physicians in each participating center. Data were collected at the registry enrollment visit, which included demographic information (age, gender, body mass index [BMI], family history, onset age of psoriasis and PsA, and disease duration of PsA), clinical characteristics (clinical subtype including peripheral arthritis, axial involvement [based on the presence of inflammatory back pain according to the Assessment of SpondyloArthritis international Society 2009 criteria or diagnosis confirmed by rheumatologists],[11] dactylitis, enthesitis, nail disease, uveitis, and inflammatory bowel diseases [IBD]), laboratory tests including erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and human leukocyte antigen (HLA)-B27, disease activity measures (swollen joint count [SJC], tender joint count [TJC], Psoriasis Area and Severity Index [PASI], Disease Activity in Psoriatic Arthritis [DAPSA], and Disease Activity Score 28-CRP [DAS28-CRP]), and treatment profiles (current use of non-steroidal anti-inflammatory drugs [NSAIDs], conventional synthetic disease-modifying antirheumatic drugs [csDMARDs], biological DMARDs [bDMARDs], and Janus kinase inhibitors [JAKi]).

Enthesitis was defined as the presence of at least one tender entheseal site. The standardized assessment method for each entheseal site was to use the thumb or index finger and apply about 4 kg/cm2 of pressure (enough to blanch the finger about a fifth of the way from the tip of the fingernail); participants were then asked if they felt any pain to ascertain the presence/absence of enthesitis.[6] The index for evaluating enthesis used in this study was the MASES, which primarily evaluated pain at axial sites, as well as the SPARCC and LEI indices, which evaluated at peripheral sites.[12–14] Axial sites include the spine, chest wall, and pelvis entheses.[15] The MASES assesses tenderness at the following enthesitis sites: bilateral first and seventh costochondral joints, posterior superior iliac spines, anterior superior iliac spines, iliac crests, insertion of the Achilles tendon into the posterior surface of the calcaneus, and the fifth lumbar spinous process. The SPARCC enthesitis index was evaluated at 16 sites: bilateral supraspinatus insertion, lateral and medial epicondyles, greater trochanter, quadriceps insertion, inferior patella, tibial tubercle, Achilles tendon insertion, and plantar fascia insertion (the inferior patella and tibial tuberosity were considered one site because of their anatomical proximity). The LEI consists of six sites: bilateral lateral epicondyles, medial femoral condyles, and Achilles tendon insertion sites. Achilles tendon insertion was included in all enthesitis indices.

Statistical analysis

Analyses were based on observed data with no imputation of missing data. Descriptive statistics were performed with frequencies and percentages for categorical variables and means and standard deviation (SD) for quantitative variables. Means and percentages of enthesitis at individual sites were calculated among the patients with any assessment of entheses. Comparisons of descriptive data between groups were performed using the Student's t-test or the Mann–Whitney U test. Categorical data were compared using the chi-squared or Fisher's exact test. A P-value of <0.05 was considered statistically significant. Multivariable logistic regression analysis was used to assess the demographic and clinical factors associated with enthesitis, where the dependent variable was presence or absence of enthesitis. Variables with P <0.1 in the univariate analysis were included in the multivariable logistic regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were then calculated. Before the construction of a multivariable model, collinearity diagnostics were determined using the variance inflation factor, and variables were accordingly removed from the final model (variance inflation factor >10). We also compared our results with four previous large cohort studies. SPSS (version 24.0; IBM Corp., Armonk, NY, USA) was used for all statistical analyses.

Results Demographics, clinical characteristics, disease activity assessment, and treatment in patients with and without enthesitis

A total of 1074 patients had at least one visit registered in the CREPAR during the years 2018–2021, of which 1031 (96.0%) patients had a record of entheseal assessment and enthesitis was positive in 308 (28.7%) patients. As shown in Table 1, 47.4% of the 308 patients were female, and the mean age was 43.1 ± 12.8 years. Furthermore, the mean BMI was 24.4 ± 5.6 kg/m2. A total of 102 patients (33.1%) reported a family history of psoriasis or PsA. Besides, the onset ages of psoriasis and PsA were 30.0 ± 13.2 years and 36.9 ± 13.1 years, respectively. PsA courses having a duration of >5 years were reported in 134 (43.5%) patients. Compared with those without enthesitis, patients with enthesitis were younger, exhibited an earlier onset both in psoriasis and inflammatory arthritis, and reported a higher proportion with a duration of PsA over 5 years (all P <0.05).

Table 1 - Demographics, clinical characteristics, disease activity assessment, and treatment in PsA patients with and without enthesitis. Variables Patients with enthesitis Patients without enthesitis t/z/ χ 2-value P-value (N = 308) (N = 723) Demographics Age (years) 43.1 ± 12.8 45.3 ± 12.9 2.507* 0.012 Female 146 (47.4) 327 (45.2) 0.411† 0.521 BMI (kg/m2) 24.4 ± 5.6 24.5 ± 6.1 0.166* 0.868 Family history 102 (33.1) 196 (27.1) 3.793† 0.051 Onset age of PsA (years) 36.9 ± 13.1 40.0 ± 13.0 3.550* <0.001 Onset age of psoriasis (years) 30.0 ± 13.2 32.4 ± 13.4 2.486* 0.013 Course of PsA (>5 years) 134 (43.5) 265 (36.7) 4.277† 0.039 Clinical characteristics Dactylitis 135 (43.8) 323 (44.7) 0.062† 0.803 Nail disease 197 (64.0) 449 (62.1) 0.319† 0.572 Uveitis 19 (7.0) 29 (4.3) 2.842† 0.092 IBD 12 (4.4) 31 (4.6) 0.021† 0.886 Peripheral arthritis 281 (91.2) 638 (88.2) 1.995† 0.158 Axial involvement 169 (55.0) 253 (35.0) 35.841† <0.001 HLA-B27 positive 73 (23.9) 138 (19.4) 2.727† 0.099 ESR (mm/1 h) 20.0 (10.0, 42.0) 20.0 (9.0, 39.0) -1.167‡ 0.243 CRP (mg/L) 9.1 (3.2, 23.7) 7.0 (2.5, 18.7) -2.550‡ 0.011 Disease activity assessment PASI 1.6 (0.0, 7.8) 0.3 (0.0, 3.7) -3.645‡ <0.001 SJC66 4.0 (1.0, 9.0) 2.0 (0.0, 7.0) -3.199‡ 0.001 TJC68 4.0 (1.0, 10.0) 2.0 (0.0, 7.0) -5.272‡ <0.001 DAS28-CRP 3.7 (2.6, 4.7) 3.2 (2.4, 4.1) -4.275‡ <0.001 DAPSA 21.8 (13.4, 36.3) 15.8 (8.7, 26.2) -5.761‡ <0.001 Treatment NSAIDs 142 (46.1) 266 (36.8) 7.833† 0.005 Glucocorticoid 33 (10.7) 66 (9.1) 0.626† 0.429 csDMARDs 211 (77.6) 481 (80.0) 0.689† 0.407 MTX 170 (62.5) 399 (66.4) 1.248† 0.264 LEF 45 (16.5) 116 (19.3) 0.946† 0.331 SASP 33 (12.1) 47 (7.8) 4.183† 0.041 bDMARDs 104 (38.2) 207 (34.4) 1.175† 0.278 TNFi 85 (31.3) 164 (27.3) 1.442† 0.230 IL-17i 19 (7.0) 43 (7.2) 0.008† 0.928 JAK inhibitors 18 (6.6) 32 (5.3) 0.580† 0.447

Data are presented as n (%), mean ± standard deviation, or median (Q1, Q3);*t value; †χ2 value; ‡z value. bDMARDs: Biological DMARDs; BMI: Body mass index; CRP: C reactive protein; csDMARDs: Conventional synthetic disease-modifying antirheumatic drugs; DAPSA: Disease Activity in Psoriatic Arthritis; DAS28-CRP: Disease Activity Score 28-CRP; ESR: Erythrocyte sedimentation rate; HLA-B27: Human leukocyte antigen; IBD: Inflammatory bowel diseases; IL-17i: Interleukin-17 inhibitors; JAK: Janus kinase inhibitors; MTX: Methotrexate; NSAIDs: Non-steroidal antiinflammatory drugs; PASI: Psoriasis Area and Severity Index; PsA: Psoriatic arthritis; SASP: Sulfasalazine; SJC: Swollen joint count; TNFi: Tumor necrosis factor inhibitors; TJC: Tender joint count.

In terms of clinical characteristics and disease activity, patients with enthesitis had a higher percentage of axial involvement (55.0% [169/308] vs. 35.0% [253/723], χ2= 35.841, P <0.001) and greater disease activity as reflected by greater TJC, SJC, higher CRP, PASI, DAS28-CRP, and DASPSA scores (all P <0.05) than those in the group without enthesitis. The prevalence of other PsA manifestations including peripheral arthritis, dactylitis, nail disease, uveitis, and IBD was an approximately comparable percentage in the two groups. As for laboratory results, 73 (23.9%) were HLA–B27 positive in patients with enthesitis, which was higher than that in patients without enthesitis (138, 19.4%). ESR was also higher in the group with enthesitis. However, these indicators did not reach statistical significance.

For treatment, patients with enthesitis were more likely to use NSAIDs compared to those without enthesitis (χ2=7.833, P = 0.006). The proportion of patients receiving csDMARDs, including methotrexate and leflunomide, remained insignificantly different between the two groups. However, a greater proportion of patients with enthesitis received sulfasalazine than patients without enthesitis (χ2=4.183, P = 0.041). Besides, bDMARDs usage was observed to be slightly higher in the enthesitis group than in the non-enthesitis group, of which TNF inhibitors were the most used, and the rates of IL-17 inhibitors were approximately equal in both groups. However, these differences were not statistically significant.

Enthesitis characteristics

Among the 308 patients with enthesitis at the time of enrollment, the average number of enthesitis sites was 3.3 ± 2.8 (range: 1.0–18.0). More than half of the patients (53.6%) had 1 or 2 tender entheseal sites (73 and 92 patients, respectively), 86 (27.9%) patients had 3 or 4 sites, and the rest (57, 18.5%) had between 5 and 18 tender sites.

The distribution and prevalence of enthesitis sites according to the MASES, SPARCC, and LEI indices are given in Table 2. The most common enthesitis site was iliac crest (left 88 [28.6%]; right 82 [26.6%]; bilateral 78 [25.3%]), followed by anterior superior iliac spine (left 84 [27.3%]; right 70 [22.7%]; bilateral 65 [21.1%]) and first costo-condral (left 63 [20.5%]; right 61 [19.8%]; bilateral 55 [17.9%]) when using MASES, while the top three tender entheseal sites were plantar fascia (left 40 [13.0%]; right 38 [12.3%]; bilateral 30 [9.7%]), Achilles tendon insertion (left 25 [8.1%]; right 23 [7.5%]; bilateral 17 [5.5%]), and lateral epicondyles (left 18 [5.8%]; right 18 [5.8%]; bilateral 11 [3.6%]) according to the SPARCC index. When assessed by LEI, the more common enthesitis sites were Achilles tendon and lateral epicondyles, and the medial femoral condyles (left 14 [4.5%]; right 14 [4.5%]; bilateral 7 [2.3%]) was the third. It can be seen that the prevalence of axial entheseal sites was higher than that of peripheral sites.

Table 2 - Distribution of enthesitis in patients with PsA. Enthesitis sites Left Right Bilateral SPARCC Supraspinatus 11 (3.6) 15 (4.9) 9 (2.9) Medial epicondyle 7 (2.3) 5 (1.6) 3 (1.0) Lateral epicondyle 18 (5.8) 18 (5.8) 11 (3.6) Greater trochanter 5 (1.6) 7 (2.3) 5 (1.6) Superior pole of the patella 8 (2.6) 8 (2.6) 4 (1.3) Inferior pole of patella or tibial tuberosity 10 (3.2) 13 (4.2) 10 (3.2) Achilles tendon 25 (8.1) 23 (7.5) 17 (5.5) Plantar fascia insertion to calcaneum 40 (13.0) 38 (12.3) 30 (9.7) MASES First costo-condral 63 (20.5) 61 (19.8) 55 (17.9) Seventh costo-condral 44 (14.3) 39 (12.7) 35 (11.4) Anterior superior iliac spine 84 (27.3) 70 (22.7) 65 (21.1) Posterior superior iliac spine 43 (14.0) 42 (13.6) 35 (11.4) Iliac crest 88 (28.6) 82 (26.6) 78 (25.3) Achilles tendon 25 (8.1) 23 (7.5) 17 (5.5) Lumbar fifth spinous process – – 57 (18.5) LEI Lateral epicondyles 18 (5.8) 18 (5.8) 11 (3.6) Medial femoral condyles 14 (4.5) 14 (4.5) 7 (2.3) Achilles tendon 25 (8.1) 23 (7.5) 17 (5.5)

Data were presented as n (%). LEI: Leeds enthesitis index; MASES: Maastricht Ankylosing Spondylitis Enthesitis Score; PsA: Psoriatic arthritis; SPARCC: Spondyloarthritis research consortium of Canada. –: Not applicable.

Disease association

Univariate analyses indicated 14 variables with P-values<0.1. Based on the results, these variables were included in the multivariable regression models to identify factors related to enthesitis. The DAPSA was not included in the model because of its co-linearity [Supplementary Tables 1 and 2, https://links.lww.com/CM9/B495]. The following three features were found independently associated with enthesitis: axial involvement (OR: 2.21, 95% CI: 1.59–3.08, P <0.001), PASI (OR: 1.03, 95% CI: 1.01–1.04, P = 0.002), and DAS28-CRP (OR: 1.25, 95% CI: 1.01–1.55, P = 0.037) [Table 3].

Table 3 - Multivariable analysis in PsA patients with enthesitis. Variables OR 95% CI P-value Age 1.00 0.96–1.04 0.967 Family history 1.15 0.80–1.64 0.452 Onset age of PsA 0.98 0.95–1.02 0.417 Onset age of psoriasis 1.00 0.98–1.02 0.814 Course of PsA (>5 years) 0.97 0.59–1.61 0.914 Uveitis 1.40 0.70–2.79 0.338 Axial involvement 2.21 1.59–3.08 <0.001 PASI 1.03 1.01–1.04 0.002 SJC66 1.00 0.98–1.03 0.796 TJC68 1.01 0.98–1.04 0.525 HLA-B27 positive 0.97 0.64–1.47 0.881 CRP 1.00 0.99–1.00 0.173 DAS28-CRP 1.25 1.01–1.55 0.037

CI: Confidence interval; CRP: C reactive protein; DAS28-CRP: Disease Activity Score 28-CRP; HLA-B27: Human leukocyte antigen; OR: Odds ratio; PASI: Psoriasis Area and Severity Index; PsA: Psoriatic arthritis; SJC: Swollen joint count; TJC: Tender joint count.

Comparison of main characteristics of PsA patients with enthesitis in several large cohorts

Table 4 provides published data related to enthesitis in PsA cohorts in the US,[7] Denmark,[8] Canada,[16] and Turkey,[10] and we compared these with our data. The prevalence of enthesitis varied widely among different studies: 19.5% in the US, 65.7% in Denmark, and 28.7% in between in China. These discrepancies can be attributed to the different enthesitis indices used: MASES in Turkey, SPARCC in Denmark, Canada, and the US, and all by us. The distribution was somewhat higher in men than in women in Chinese and Canadian patients, but lower in Turkish and American patients. Besides, Chinese patients had a lower BMI (24.4 kg/m2) compared to patients in other countries (28.6–31.6 kg/m2). The disease duration of Chinese patients was 6.2 years, longer than that in Denmark and Turkey, but shorter than that in Canada and the US. Moreover, participants in China had the highest rate of positive HLA-B27 (23.9% vs. 14–18.7%). The prevalence of dactylitis ranged between 13.1% and 19%, except in China, where the prevalence was higher (43.8%). As for the involved entheseal sites, the most common site was Achilles tendon insertion in Denmark, Canada, and Turkey, whereas it was lateral epicondyles in the US; however, in China, iliac crest was more common. In terms of treatment, more than two-thirds of Chinese patients received csDMARDs (77.6%) compared to 14% of Canadian, 17.5% of Danish, and 21.7% of American patients. In addition, bDMARDs were used in over a third of patients in China (38.2%), compared to 34% of Canadian patients, and were more prevalent in 61.5% of American patients.

Table 4 - Comparison of the PsA cohorts evaluating enthesitis. Variables CREPAR Mathew et al [8] Polachek et al [16] Mease et al [7] Sunar et al [10] Country China Denmark Canada The United States Turkey Date 2018–2021 2010–2020 2008–2014 2013–2018 2018–2019 No. of patients 1074 1037 803 2003 1130 No. enthesitis positive, n (%) 308 (28.7) 681 (65.7) 281 (34.9) 391 (19.5) 251 (22.2) Age (years) 43.1 ± 12.8 46.8 ± 13.1 49.0 ± 12.7 52.7 ± 12.6 – Male, n (%) 162 (52.6) 268 (39.4) 151 (54) 146 (37.0) – Disease duration (years) 6.2 ± 7.3 (mean) 2.34 ± 5.58 (mean) 11.4 ± 11.3 (mean) 7.0 ± 8.0 (mean) 3 (median) BMI (kg/m2) 24.4 ± 5.6 28.6 ± 5.9 30.0 ± 6.4 31.6 ± 7.0 29.12 ± 4.72 HLA-B27 positive, n (%) 73 (23.9) 56 (18.7) 40 (14) – – Dactylitis, No. (%) 135 (43.8) – 52 (19) 55 (14.1) 33 (13.1) Measure of enthesitis SPARCC + MASES + LEI