Clinical Enthesitis in a Prospective Longitudinal Psoriatic Arthritis Cohort: Incidence, Prevalence, Characteristics, and Outcome

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1 Arthritis Care & Research Vol. 69, No. 11, November 2017, pp DOI /acr , American College of Rheumatology ORIGINAL ARTICLE Clinical Enthesitis in a Prospective Longitudinal Psoriatic Arthritis Cohort: Incidence, Prevalence, Characteristics, and Outcome ARI POLACHEK, 1 SUZANNE LI, 2 VINOD CHANDRAN, 3 AND DAFNA D. GLADMAN 4 Objective. To evaluate the incidence, prevalence, characteristics, disease associations, risk factors, and outcome of clinical enthesitis in patients with psoriatic arthritis (PsA). Methods. The study included patients with PsA followed prospectively. Enthesitis was defined as the presence of at least 1 tender enthesis at 1 of the 18 entheseal sites of the Spondyloarthritis Research Consortium of Canada enthesitis index. Results. Between 2008 and 2014, 281 of 803 patients had enthesitis, providing a prevalence of 35%. A total of 192 patients developed enthesitis during the course of followup, with an annual incidence of 0.9%. Most of the patients had 1 (48.4%) or 2 (32.2%) tender entheseal sites, and the mean SD number of sites per visit was The 3 most common sites were at the insertions of the Achilles tendon, plantar fascia on the calcaneus, and the lateral epicondyles (24.2%, 20.8%, and 17.2%, respectively). More active disease (higher actively inflamed joint count, tenosynovitis, and dactylitis), more pain, and less clinical damage were associated with enthesitis. Higher body mass index, more actively inflamed joints, and younger age were risk factors for developing this condition. Enthesitis resolved in most patients without changing treatment. Conclusion. Clinical enthesitis is common, with a period prevalence of 35% of PsA patients. It usually involves only 1 or 2 sites simultaneously. The most common tender sites are at the insertions of the Achilles tendon, plantar fascia, and the lateral epicondyles. More active disease and more pain are associated with enthesitis. INTRODUCTION Psoriatic arthritis (PsA) is a heterogeneous disease whose manifestation includes involvement of peripheral and axial skeleton, skin, nails, eyes, mucous membrane ulcers, and the gastrointestinal tract (1). The musculoskeletal involvement can affect the synovium, bone, fat pad, bursae, adjacent tendons, and entheses (2). Enthesitis signifies inflammation at the insertion of tendons, ligaments, joint capsule fibers, or fascia insertion sites into bone, either in appendicular or axial skeleton (3). Over time, it can cause inflammatory and structural changes, causing cystic and erosive reactions with subsequent periostitis and the formation of spurs and syndesmophytes (4). The main consequences of these are pain and disability. The growing use of ultrasound and magnetic resonance imaging (MRI) has helped to improve detection and understanding of the underlying mechanism of enthesitis (5,6). Furthermore, there are several imaging-based studies that show preclinical enthesitis in psoriasis patients (7,8). In line with this finding, the primacy of enthesitisrelated inflammation in the pathogenesis of PsA was suggested by animal models of inflammatory spondyloarthritis (SpA) (9 11). The importance of clinical enthesitis in classifying PsA was reaffirmed by inclusion of this feature as one of the stem requirements of the Classification Criteria for Psoriatic Arthritis (CASPAR) criteria (12,13). However, little is known about clinical enthesitis in PsA, and thus the aim of this study was to determine the prevalence, Supported by a grant from the Krembil Foundation. Dr. Polachek s work was supported by an educational grant from Janssen Canada. 1 Ari Polachek, MD: University of Toronto, Toronto Western Hospital, and Centre for Prognosis Studies in the Rheumatic Diseases, Toronto, Ontario, Canada; 2 Suzanne Li, MMath: Centre for Prognosis Studies in the Rheumatic Diseases, Krembil Research Institute, and University Health Network, Toronto, Ontario, Canada; 3 Vinod Chandran, MD, DM, PhD: University of Toronto, Centre for Prognosis Studies in the Rheumatic Diseases, Krembil Research Institute, and University Health Network, Toronto, Ontario, Canada; 4 Dafna D. Gladman, MD, FRCPC: University of Toronto, Krembil Research Institute, Center for Prognosis Studies in the Rheumatic Diseases, and Toronto Western Hospital, Toronto, Ontario, Canada. Address correspondence to Dafna D. Gladman, MD, FRCPC, Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Research Institute, University Health Network, 399 Bathurst Street 1E-410B, Toronto, Ontario, Canada, M5T 2S8. dafna.gladman@utoronto.ca. Submitted for publication June 21, 2016; accepted in revised form December 13,

2 1686 Polachek et al Significance & Innovations Clinical enthesitis is a common finding, occurring in a third of psoriatic arthritis patients. The Achilles tendon, plantar fascia, and lateral epicondyles are the most commonly detected enthesitis sites. More active disease and more pain are associated with this condition. The risk factors for developing enthesitis are more actively inflamed joints, higher body mass index, and younger age at detection. incidence, characteristics, disease associations, risk factors, and outcome of enthesitis in PsA patients. PATIENTS AND METHODS Setting. The study population included patients from the University of Toronto PsA cohort that was established in The PsA clinic is a tertiary-care facility affiliated with the University of Toronto. It also serves as a primaryand secondary-care referral center in downtown Toronto. The clinic s patients therefore range from those with severe disease to patients with inactive disease taking maintenance therapy to patients in complete remission and off all therapy. According to the PsA Assessment in Rheumatology study, our patients were similar to clinical trials and practices in different clinics across Canada (14). The patients fulfilled the CASPAR criteria and were followed prospectively at 6 12-month intervals according to a standard protocol (1). At each visit, patients were assessed clinically with a complete history and physical examination that included actively inflamed (tender and/ or swollen) and clinically damaged joint counts (15), assessment of dactylitis, tenosynovitis, enthesitis, spinal mobility measures, fibromyalgia, body surface area of psoriasis, psoriasis area and severity index, modified nail psoriasis severity index, and detailed medication history. In addition, blood tests (including acute-phase reactants) were taken at each visit, and radiographs were taken every 2 years and scored according to the modified Steinbrocker method (16). Sacroiliac joints were scored according to the New York criteria, and syndesmophytes were scored using the modified Stokes Ankylosing Spondylitis Spinal Score (17). Sacroiliitis of grade 2 was considered sacroiliitis. Patient-reported outcome measures collected included the Health Assessment Questionnaire, Medical Outcomes Survey Short Form 36, and pain measured on a 0 10 scale in the patient global assessment questionnaire. Patient selection. PsA patients attending the clinic between January 2008 and December 2014 who had evidence of enthesitis as measured by the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index were identified (18). The first visit after January 1, 2008 would be the first recruitment visit. Patients without enthesitis served as controls. Enthesitis assessment. The SPARCC enthesitis index assesses tenderness at the following enthesitis sites bilaterally: supraspinatus insertion, lateral and medial epicondyles, greater trochanter, quadriceps insertion, inferior patella, tibial tubercle, Achilles tendon insertion, and plantar fascia insertion. The SPARCC enthesitis index has been proven valid and reliable, particularly for patients with PsA (19). Outcome. Enthesitis was defined as the presence of at least 1 tender entheseal site of the 18 entheseal insertion sites of the SPARCC enthesitis index. The total number of involved sites per visit was based on counting each site (18). The SPARCC enthesitis score ranges 0 16, as only one of the inferior patella or tibial tubercle site is included in the score if both are affected. For the outcome analysis, enthesitis resolution was defined as the absence of tenderness at any entheseal site within 18 months of enthesitis detection. Treatment change was defined as either an increased dose of current medication (nonsteroidal antiinflammatory drugs, disease-modifying antirheumatic drugs [DMARDs], or biologic agents) or addition or change to a new medication. Statistical analysis. Descriptive statistics are provided. Incidence was calculated per patient-year of followup, counting only the first enthesitis event after the first visit for each patient. To account for repeated occurrence of enthesitis, a generalized estimating equation (GEE) logistic model was used for determining characteristics associated with enthesitis. The presence of enthesitis at each followup visit was used as the outcome. Cox regression analysis was used to identify predictors for the development of enthesitis in those without enthesitis at baseline. For this analysis, time-dependent variables were used. The selection of variables for the GEE and Cox models reflects clinical factors that may influence enthesitis, including demographics, active inflammation, damage, chronic pain syndrome, and treatment. A chisquare test of independence was used to examine the association between enthesitis resolution and change of treatment. Missing data were imputed from the closest visit to the index visit. RESULTS Baseline characteristics of the entire cohort. Between January 2008 and December 2014, 803 patients with PsA attended the PsA clinic. During this time frame, the mean SD followup was years. A total of 470 patients (58.5%) started their followup before 2008, and 333 (41.5%) were enrolled since January 1, For the 470 patients who had been followed prior to 2008, only the information collected after January 1, 2008 was included in this study. Of the 803 patients, 57% were male, and the mean SD age was years. The

3 Enthesitis in Psoriatic Arthritis 1687 mean SD PsA and psoriasis duration was and years, respectively. Incidence and prevalence. Of the 803 patients who were evaluated during the study period, 281 had enthesitis on at least 1 visit, with a prevalence of 35%. A total of 128 patients had enthesitis at their first visit after January 1, 2008, and 192 patients developed enthesitis during the course of followup, with 2,140 patient-years, providing an annual incidence of 0.9%. Baseline and disease-related characteristics at enthesitis detection. Among the 281 patients with enthesitis, the mean SD age at enthesitis detection was years, and PsA duration was years (Table 1). Table 1. Baseline characteristics at enthesitis detection* Characteristics Values Age Male, no. (%) 151 (54) Psoriatic arthritis duration Psoriasis skin disease duration Body mass index (BMI) Normal BMI <25, % 24 BMI 26 30, % 29 BMI >30, % 47 SPARCC enthesitis score Actively inflamed joints (tender and/or swollen) Damaged joints Presence of tenosynovitis, no. (%) 64 (23) Presence of dactylitis, no. (%) 52 (19) Psoriasis body surface area Psoriasis area severity index Modified nail psoriasis severity index Patient-reported outcome Health Assessment Questionnaire Short Form 36 physical component score Short Form 36 mental component score Pain (scale 0 10) Comorbidities, no. (%) Diffuse idiopathic skeletal hyperostosis 20 (7) Osteoarthritis 31 (11) Diabetes mellitus 33 (12) Fibromyalgia 42 (15) Laboratory and radiograph tests, no. (%) Elevated ESR (males >13, females >20) 81 (31) Elevated C-reactive protein 115 (41) HLA B*27 positive 40 (14) Modified Steinbrocker score Presence of plantar spurs, no. (%) 143 (53) Presence of Achilles spurs, no. (%) 99 (37) Presence of sacroiliitis, no. (%) 116 (42) Treatment at detection, no. (%) Nonsteroidal antiinflammatory drug 205 (73) Disease-modifying antirheumatic drug 154 (55) Biologic agents 95 (34) * Values are the mean SD unless indicated otherwise. SPARCC = Spondyloarthritis Research Consortium of Canada; ESR = erythrocyte sedimentation rate. At the time of enthesitis, the mean SD body mass index (BMI) was , and 47% of the patients were obese (BMI >30). The mean SD number of actively inflamed joints was , and the mean SD damaged joint count was Laboratory tests revealed that 81 patients (31%) had an elevated erythrocyte sedimentation rate, 115 patients (41%) had elevated C-reactive protein levels, and 14% were positive for HLA B*27 (Table 1). The radiologic evaluation revealed plantar spurs in 143 patients (53%), Achilles spurs in 99 (37%), and sacroiliitis in 116 (42%). Enthesitis characteristics. The mean SD number of affected entheseal sites was , with a mean SD SPARCC score of Most of the patients (80.6%) had 1 or 2 (110 and 99 patients, respectively) tender entheseal sites at first detection (Figure 1), while 10.6% had 3 or 4 sites, and the rest (8.8%) had between 5 and 14 tender sites. During the entire followup, similar involvement was observed, with most patients continuing to have 1 or 2 tender entheseal sites (74.3% of the patients). The 3 most common tender entheseal sites were Achilles tendon insertion, plantar fascia, and lateral epicondyles (24.2%, 20.8%, and 17.2%, respectively) (Figure 2). A total of 58 patients (20.6%) had bilateral involvement of the Achilles tendon, 55 (19.6%) of the plantar fasciae, and 45 (16%) of the lateral epicondyles. The majority (64.7%) had more active sites in the lower body part compared to the upper part. Disease association. To identify factors associated with enthesitis, demographic and disease-related features were investigated using a GEE logistic model. The following 5 features were independently associated with enthesitis: higher actively inflamed joint count (odds ratio [OR] 1.06; P = ), presence of dactylitis (OR 2.5; P = 0.02), presence of tenosynovitis (OR 5.3; P < ), less clinical damage (OR 0.9; P = 0.04), and more pain (OR 1.14; P = 0.01) (Table 2). Risk factors. Risk factors for detection of enthesitis on followup were evaluated using Cox regression analysis with time-dependent covariates. Multivariate analyses revealed 3 independent risk factors for enthesitis: higher Figure 1. The number of positive enthesitis sites at first detection.

4 1688 Polachek et al BMI (hazard ratio [HR] 1.04; P = 0.02), higher actively inflamed joint count (HR 1.05; P ), and younger age (HR 0.98; P = 0.02) (Table 3). Outcome. The median duration to enthesitis resolution was 7.5 months (range 4.5 months to 5.5 years). Of 227 patients (80.1%) with enthesitis who were followed for >1 visit, it resolved in 215 (95%), of whom 197 patients were treated with medications. However, most patients (139 [70.5%]) improved without changing treatment. A chi-square test of independence indicates that there was no association between enthesitis resolution and change of treatment (P = 0.8). Moreover, both the GEE analysis and the Cox regression models failed to identify any treatment to be associated with or predict enthesitis. However, it should be noted that this was not a therapeutic trial, and there was no specific protocol used specifically for the enthesitis. Figure 2. The distribution of positive enthesitis sites. Percentages refer to either right, left, or both sites. Adapted with permission from Oxford University Press (ref. 40). Table 2. Features associated with enthesitis at occurrence (GEE model)* Features OR (95% CI) P Demographics Age at study entry 0.99 ( ) 0.07 Sex 0.6 ( ) 0.08 Psoriatic arthritis 1.01 ( ) 0.5 duration Psoriasis duration 1.01 ( ) 0.4 Body mass index 1.03 ( ) 0.1 Disease-related characteristics Actively inflamed joint 1.06 ( ) count Presence of dactylitis 2.5 ( ) 0.02 Presence of tenosynovitis 5.3 ( ) < Presence of sacroiliitis 1.4 ( ) 0.2 Damaged joint count 0.9 ( ) 0.04 Steinbrocker score 1.06 ( ) 0.4 PASI score 0.97 ( ) 0.3 Nail disease 1.07 ( ) 0.8 Pain score 1.15 ( ) 0.01 Presence of fibromyalgia 1.6 ( ) 0.2 Treatment NSAIDs vs. no treatment 2.3 ( ) 0.2 DMARDs vs. no treatment 1.6 ( ) 0.4 Biologic agents vs. no treatment 1.6 ( ) 0.4 * GEE = generalized estimating equation; OR = odds ratio; 95% CI = 95% confidence interval; PASI = Psoriasis Area and Severity Index; NSAIDs = nonsteroidal antiinflammatory drugs; DMARDs = disease-modifying antirheumatic drugs. DISCUSSION Enthesitis is an important feature of PsA (12) and is recognized as part of the stem of the CASPAR criteria (13). Our study demonstrates that clinical enthesitis is a common condition, occurring in 35% of PsA patients. The Achilles tendon, plantar fascia, and lateral epicondyles are the most commonly detected sites, and these locations are often bilateral. The features associated with enthesitis are more active disease, more pain, and less damage, and the risk factors for developing it are more actively inflamed joints, higher BMI, and younger age at detection. Ranza et al (20) demonstrated a similar frequency (30%) in a cross-sectional study. A lower prevalence was detected in population-based studies from Iceland (8%) and Olmstead County (23%) (21,22). A higher prevalence of enthesitis (53.8%) was reported from a multicenter SpA study (23). These discrepancies can be attributed to the use of different enthesitis indices. The current study used the SPARCC enthesitis index, which demonstrated good reliability in the International Spondyloarthritis Interobserver Reliability Exercise (INSPIRE) (19). SPARCC functioned better than the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in the INSPIRE study, and similar to the Leeds Enthesitis Index (LEI). This difference may explain both the closer numbers to the Ranza et al study, which used the LEI and the difference from the Carneiro et al study (23), which used the MASES index. Most patients in our study had up to 2 tender enthesitis sites. This number is similar to the INSPIRE study, which reported a median of 1.8 enthesitis sites among PsA patients, and to another study that reported a mean of 2.1 affected entheseal sites among a large study (1,505 participants) of heterogeneous SpA patients (19,23). Interestingly, bilateral involvement was detected in up to one-fifth of the patients with enthesitis. The Achilles tendon insertion site, planter fascia, and lateral epicondyles were the most commonly involved enthesitis sites. The SPARCC enthesitis index does not include the medial femoral condyle, which is included in

5 Enthesitis in Psoriatic Arthritis 1689 Table 3. Risk factors for enthesitis (Cox regression model)* Univariate Reduced Features HR (95% CI) P HR (95% CI) P Demographics Age at study entry 0.98 ( ) ( ) 0.01 Sex 0.7 ( ) 0.2 Psoriatic arthritis duration 0.98 ( ) 0.2 Psoriasis duration 1.01 ( ) 0.1 Body mass index 1.05 ( ) ( ) 0.02 Disease-related characteristics Actively inflamed joint count 1.05 ( ) < ( ) Presence of dactylitis 0.9 ( ) 0.8 Presence of tenosynovitis 1.8 ( ) 0.08 Presence of sacroiliitis 1.2 ( ) 0.4 Damaged joint count 0.97 ( ) 0.08 Steinbrocker score 1.02 ( ) 0.2 PASI score 0.98 ( ) 0.6 Nail disease 1.25 ( ) 0.3 Presence of fibromyalgia 0.4 ( ) 0.1 Treatment NSAIDs vs. no treatment 1.6 ( ) 0.4 DMARDs vs. no treatment 1.3 ( ) 0.5 Biologic agents vs. no treatment 1.3 ( ) 0.6 *HR= hazard ratio; 95% CI = 95% confidence interval; PASI = Psoriasis Area and Severity Index; NSAIDs = nonsteroidal antiinflammatory drugs; DMARDs = disease-modifying antirheumatic drugs. the LEI. The lower body sites were more commonly involved, though this involvement could reflect the higher representation of this region in the SPARCC enthesitis index. A few imaging-based studies support this predilection, which is pronounced around the heel (24 26). The reason behind this predilection to lower-extremity enthesitis might be the higher load that causes more repetitive biomechanical stress at the enthesis, leading to an inflammatory reaction in the joint and the attachment sites, which may be more pronounced in the lower extremities (27). Since the vast majority of clinicians do not use imaging techniques on a regular basis, due to unavailability, lack of training, time constraints, or cost, we aimed to describe the clinical evaluation of enthesitis in a large, longitudinal prospective PsA cohort. Benjamin and McGonagle proposed the concept of an entheseal organ, representing pathologic changes that extend from the enthesis to the adjacent bone and soft tissues (28). In line with this idea, previous studies suggested that enthesitis is the primary lesion in SpA, which may lead to further inflammation in the synovial membrane (the concept of synovio-entheseal complex) (11,29). Our study demonstrated an association between clinical enthesitis and features of more active inflammatory disease, including higher actively inflamed joint count, tenosynovitis, and dactylitis. Studies in PsArelated diseases have shown similar results. In SpA patients with enthesitis, a significantly higher frequency of tender and swollen joint counts as well as more inflammatory axial symptoms have been found (23). Studies in ankylosing spondylitis (AS) patients revealed a correlation between enthesitis and higher disease activity (measured by the Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]) (30 32). Pain is one of the consequences of enthesitis, and the current study demonstrated an association between the presence of enthesitis and higher pain scores. Rezvani et al (32) found a positive correlation between enthesitis to the fourth question in the BASDAI questionnaire (level of discomfort from any areas tender to touch or pressure) that refer to entheseal pain among 421 AS patients. Additional support for this point derives from studies in juvenile patients with enthesitis-related arthritis (ERA) (33,34). The patients in these studies had increased pain compared with the other subtypes of juvenile idiopathic arthritis. Given the fact that pain is an important component of the quality of life, it is not surprising that these 2 ERA studies, as well as others, showed worse quality of life in patients with enthesitis compared with patients who did not have it (30,31). Active enthesitis might cause chronic lesions such as erosions and enthesophytes, leading to chronic damage and disability (4,5). In addition, according to the synovio-entheseal complex theory, the spread of the inflammation from the entheses to the synovial membrane might lead to chronically damaged joints (27). In our study, acute clinical enthesitis was associated with less peripheral joint damage. The reason for that requires further investigation. McGonagle et al (35) suggested that high biomechanical stress at the enthesis triggers an inflammatory response that results in enthesitis. In line with this theory, our study revealed that higher BMI is a risk factor for developing enthesitis. Schenck et al (36) showed

6 1690 Polachek et al recently in a large national German pediatric rheumatology database that those with ERA and systemic arthritis had the highest prevalence of overweight and obesity among juvenile idiopathic arthritis patients. Indeed, in a study of ultrasound to determine whether the Madrid Enthesitis Index could identify patients with psoriasis destined to develop PsA, results showed that in patients with a high BMI (>30) there was no difference between patients with PsA, patients with psoriasis alone, or healthy controls (26). Of particular note, MRI and ultrasound studies have both shown that there is an age-related thickening of the normal enthesis and ligaments, often observed after age 40 years (37). While the relationship between younger age and enthesitis in our study is unclear, it suggests that we have identified acute enthesitis as opposed to agerelated enthesopathy (37). One of the difficulties in assessing the enthesitis process is the differentiation from fibromyalgia. The current study identified 15% of PsA patients who were diagnosed with fibromyalgia in addition to enthesitis. Marchesoni et al (38) compared 266 patients with PsA to 120 fibromyalgia patients and showed that the presence of 6 fibromyalgia-associated symptoms and 8 tender points were the best discriminating factors between these 2 conditions. In our study, the most commonly detected sites are clearly distinguished clinically from the fibromyalgia tender points. Moreover, the vast majority (89.3%) had <4 active enthesitis sites, and our analyses did not reveal a significant association between enthesitis and fibromyalgia. The treatment data for enthesitis derive from controlled studies that showed efficacy of tumor necrosis factor inhibitors, ustekinumab (anti interleukin [IL]-12/ IL-23), secukinumab and ixekizumab (anti IL-17A), and apremilast (anti phosphodiesterase 4) (39). Although the majority of the patients in our study were treated with medications, most of them improved without changing treatment. However, this study was not designed to address treatment efficacy for enthesitis. Most patients were already treated, and only a minority had treatment changes during followup, so that it was difficult to evaluate the treatment influence and to differentiate between the various treatments. A limitation of this study is that it relied on the clinical measurement of enthesitis. However, the INSPIRE study demonstrated high agreement for the SPARCC enthesitis index among assessors, and the senior investigators in the current study were participants in the INSPIRE study (19). Furthermore, as mentioned above, until a more accurate tool is validated and available, the clinical evaluation will continue to be the main way for enthesitis assessment. Another limitation is the inclusion of patients with relatively long disease duration (11.4 years). Considering the enthesitis primacy theory (11), earlier disease may appear differently, possibly with more active sites. In summary, clinical enthesitis is a common condition, lasting >6 months. Most patients have only a few sites affected simultaneously, involving the insertions of the Achilles tendons, plantar fascia, and lateral epicondyles most frequently. More active disease, more pain, and less damage are associated with enthesitis, while higher BMI, more active disease, and younger age are risk factors for developing this condition. Enthesitis resolves in most patients without changing treatment; however, a betterdesigned prospective, randomized controlled study that will evaluate the newer as well as the older classical DMARD therapeutic options is warranted. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. 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