The transition from enthesis physiological responses in health to aberrant responses that underpin spondyloarthritis mechanisms.

PURPOSE OF REVIEW: Despite immunology and translational therapeutics advances in inflammatory arthritis over the past two decades, the enthesis, which is the epicentric of the spondyloarthritis family pathological process, retains many mysteries because of tissue inaccessibility that hampers direct immune study. As entheses are subject to almost continuous mechanical stress and spondyloarthritis is linked to microdamage or injury and joint stress, it is cardinal to understand the physiological changes occurring within the entheses not only to be able to differentiate disease from health but also to understand the transition normal physiology break down and its merges into spondyloarthritis-related disease. RECENT FINDINGS: Imaging has played a major role in understanding the enthesis in human. Remarkable insights from enthesis functioning and microdamage in normal and with ageing including those linked to body mass index is emerging. The impact of mechanical stress and degenerative conditions on the development of the secondary entheseal vascular changes is not understood. Of note, ultrasound studies in psoriasis have shown higher power Doppler changes compared to controls pointing towards a role for vascular changes in the development of enthesitis in psoriatic arthritis. SUMMARY: The literature pertaining to normal entheses changes with age, microdamage and vascular changes in health is providing a roadmap for understanding of the enthesis and its potential role in evolution of spondyloarthritis including psoriatic arthritis.

Role of ultrasound for assessment of psoriatic arthritis patients with fibromyalgia.

OBJECTIVE: To investigate whether ultrasonography (US), as an objective imaging modality, can optimise the evaluation of disease activity in psoriatic arthritis (PsA) patients with concomitant fibromyalgia syndrome (FMS). METHODS: The study population included 156 consecutive PsA patients who were recruited prospectively and fulfilled the ClASsification criteria for Psoriatic ARthritis criteria. The patients underwent complete clinical evaluation including assessment of fulfilment of the 2016 fibromyalgia classification criteria. All of the patients underwent US evaluation including 52 joints, 40 tendons and 14 entheses. The US score was based on the summation of a semiquantitative score (including synovitis, tenosynovitis and enthesitis). Scoring was performed by a sonographer blinded to the clinical data. Spearman's correlation coefficient and multivariate linear regression models were used to examine the association of FMS with clinical and the US scores. RESULTS: Forty-two patients (26.9%) with coexisting PsA and FMS were compared with 114 (73.1%) PsA patients without FMS. Patients with PsA and FMS had significantly increased scores for clinical composite indices, including non-Minimal Disease Activity, Composite Psoriatic Disease Activity Index (CPDAI), Disease Activity for Psoriatic Arthritis (DAPSA) and Psoriatic Arthritis Disease Activity Score (PASDAS) (p<0.001). In contrast, the total US score and its subcategories were similar for those with and without FMS. The total US score significantly correlated with CPDAI, DAPSA and PASDAS (p<0.001) in the PsA without FMS but not in the PsA with FMS group. FMS was significantly associated with higher clinical scores (p<0.001) but not with the US score (multivariable linear regression models). CONCLUSIONS: US has significantly greater value than composite clinical scores in the assessment of disease activity in PsA patients with FMS.

Enthesitis in psoriatic arthritis (Part 1): pathophysiology.

Enthesitis is a key manifestation of PsA and current knowledge supports the concept that it may be among the primary events in the development of this disease, as well as other forms of SpA. Patients with PsA seem to have a different threshold to mechanical stress, which may be genetically determined. Hence patients with psoriatic disease respond pathologically with inflammation after being exposed to physiological mechanical stress. Activation of pro-inflammatory mediators such as IL-17 and TNF-α as well as the influx of innate immune cells are key events in the development of enthesitis in PsA. Chronic entheseal inflammation is accompanied by new bone formation, leading to bony spurs in peripheral (entheseophytes) and axial (syndesmophytes) structures. This article reviews the current knowledge on the mechanisms involved in the development of enthesitis in patients with PsA.

Enthesitis and its relationship with disease activity, functional status, and quality of life in psoriatic arthritis: a multi-center study.

Psoriatic arthritis (PsA) is an inflammatory arthritis with distinct phenotypic subtypes. Enthesitis is assigned as a hallmark of the disease, given its significant relations to disease activity and quality of life. Our objective is to evaluate the prevalence of enthesitis and its association with some clinical parameters, particularly quality of life, using data from a national registry. Patients with PsA meeting ClASsification criteria for Psoriatic Arthritis (CASPAR) were enrolled by means of a multi-centre Turkish League Against Rheumatism (TLAR) Network Project. The following information was recorded in web-based case report forms: demographic, clinical and radiographic data; physical examination findings, including tender and swollen joint counts (TJC and SJC); nail and skin involvement; Disease Activity Score-28 for Rheumatoid Arthritis with Erythrocyte Sedimentation Rate (DAS 28-ESR); Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); Maastricht Ankylosing Spondylitis Enthesitis Score (MASES); Psoriasis Area Severity Index (PASI); Bath Ankylosing Spondylitis Radiology Index for the spine (BASRI-s); Health Assessment Questionnaire (HAQ); Bath Ankylosing Spondylitis Functional Index (BASFI); Health Assessment Questionnaire for the spondyloarthropathies (HAQ-s); Psoriatic arthritis quality of Life scale (PsAQoL); Short Form 36 (SF-36); Hospital Anxiety Depression Scale (HADS); Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F); and Fibromyalgia Rapid Screening Tool (FiRST) scores. The patients were divided into two groups, namely with and without enthesitis, based on the triple Likert-type physician-reported statement of 'active enthesitis', 'history of enthesitis' or 'none' in the case report forms. Patients with active enthesitis were compared to others in terms of these clinical parameters. A total of 1130 patients were enrolled in this observational study. Of these patients, 251 (22.2%) had active enthesitis according to the clinical assessment. TJC, HAQ-s, BASDAI, FiRST and PsAQoL were significantly higher whereas the SF-36 scores were lower in patients with enthesitis (p < 0.05). Chronic back pain, dactylitis, and tenosynovitis were more frequent in the enthesopathy group (59.4%/39%, 13.1%/6.5% and 24.7%/3.4%, respectively). Significant positive correlations between the MASES score and the TJC, HAQ, DAS 28-ESR, BASDAI, FiRST and PsAQoL scores, and a negative correlation with the SF-36 score were found. When linear regression analysis was performed, the SF-36 MCS and PCS scores decreased by - 9.740 and - 11.795 units, and the FiRST scores increased by 1.223 units in patients with enthesitis. Enthesitis is an important involvement of PsA with significant relations to quality of life determined with PsAQoL and SF-36 scores. Our study found higher frequency of dactylitis and chronic back pain, and worse quality of life determined with SF-36 and PsAQoL scores in patients with enthesitis.

Enthesopathy-An Underappreciated Role in Osteoarthritis?

Osteoarthritis (OA) continues to be a debilitating disease worldwide, to date, no therapies have been definitely proven to modify disease progression or moderate symptom relief long term other than joint replacement. A contributing factor may be the lack of attention to the potential role of the periarticular enthesis and development and progression of OA. The enthesis is the site of attachment for a tendon, ligament, or joint capsule to the bony skeleton, thereby allowing centralized transmission and dissipation of mechanical loads. Because of this design, the enthesis is a site of stress concentration subject to inflammation during sports-related activities or spondyloarthropathies, which may lead to long-term degeneration. Our hypothesis is that functional incompetence of the enthesis resulting from either degenerative or inflammatory changes could be an initiating factor for OA and may thus provide a novel basis for the development of future disease management in this phenotype of patients.

Methotrexate achieves major cDAPSA response, and improvement in dactylitis and functional status in psoriatic arthritis.

OBJECTIVE: Despite the widespread clinical use of MTX in PsA, data from published randomized controlled studies suggest limited efficacy. The objective of the present study was to document the efficacy of MTX. METHODS: This was an open-label, prospective study of patients satisfying the ClASsification criteria for Psoriatic ARthritis study (CASPAR) criteria for PsA who received MTX in doses of ⩾15 mg/week throughout the follow-up period of 9 months. Disease activity was assessed across various domains by tender and swollen joint count, physician and patient global assessment, DAS-28 ESR, Clinical Disease Activity Index for PsA (cDAPSA), Leeds Dactylitis Instrument basic, Leeds Enthesitis Index (LEI), Psoriasis Area and Severity Index (PASI), Minimal Disease Activity and HAQ (CRD Pune version) at baseline and at 3, 6 and 9 months of follow-up. Response to therapy was assessed by EULAR DAS28 ESR, Disease Activity Index for PsA (cDAPSA) response, HAQ response and PASI75. MTX dose escalation and the use of combination DMARDS were dictated by disease activity. RESULTS: A total of 73 patients were included, with mean (s.d.) age 44 (9.7) years. The mean (s.d.) dose of MTX used was 17.5 (3.8) mg/week. Seven patients received additional DMARDS (LEF/SSZ). At the end of 9 months, significant improvement (P < 0.05) was noted in the tender joint count, swollen joint count, global activity, DAS-28ESR, cDAPSA, Leeds Dactylitis Index basic, LEI, PASI and HAQ. Major cDAPSA response was achieved in 58.9% of patients. EULAR DAS28 moderate and good response was achieved in 74% and 6.8% of patients, respectively. Minimal Disease Activity was achieved in 63% of patients. A PASI75 response and HAQ response was achieved in 67.9% and 65.8% of patients, respectively. CONCLUSION: MTX initiated at ⩾15 mg/week with targeted escalation resulted in significant improvement in the skin, joint, dactylitis, enthesitis and functional domains of PsA.

Musculoskeletal manifestations of Ebola virus.

The 2014 West African Ebola virus disease outbreak shocked the world as it swept through the region leaving Guinea, Liberia and Sierra Leone struggling to gain control. As the largest Ebola virus disease outbreak to date, there are more survivors in its wake than ever before, with a spectrum of health problems requiring management. Here we review various musculoskeletal manifestations of the virus that can occur both during and after the infection, and consider possible pathogenesis.

The problem in differentiation between psoriatic-related polyenthesitis and fibromyalgia.

The recognition of the primacy of enthesitis in animal models of spondyloarthritis and the prevalence of clinically occult enthesopathy in psoriatic subjects and of persistent joint pain in PsA subjects who have ostensibly good reduction of joint swelling under biological therapy has highlighted the potential impact of polyenthesitis in psoriatic disease. In daily practice, the formal demonstration of enthesitis is challenging for the following reasons: the relatively avascular nature of enthesis, often leading to the absence of overt clinical inflammatory signs; the frequent lack of elevation of inflammatory markers; and finally, the limitations of current imaging techniques to provide supportive evidence for inflammation in these areas. Consequently, enthesitis may present as widespread pain indistinguishable from FM or may emerge as the dominant feature after successful biological therapy for suppression of synovitis. The unmet needs in the differentiation between FM and enthesitis in psoriatic disease patients are highlighted and critically evaluated in this article.

Enthesitis detection by ultrasound: where are we now?

Over the last 25 years, ultrasound has been used to evaluate involvement at the entheses in spondyloarthritis (SpA) and psoriatic arthritis (PsA). Several studies have been reported indicating its value in detecting active inflammation at entheseal sites using both gray scale and Doppler findings. This review explores the recent literature and appraises the current knowledge and the unmet needs of enthesitis detection by ultrasound in the management of both SpA and PsA.

Construct validity and sensitivity to change of Belgrade Ultrasound Enthesitis Score in patients with spondyloarthritis: a pilot study.

The objective of this study was to determine the construct validity and sensitivity to change of Belgrade Ultrasound Enthesitis Score (BUSES) in spondyloarthritis patients. Seventy-six spondyloarthritis patients with enthesitis were included in this pilot, prospective, double-blinded ultrasound study. Thirty-four patients received biological and forty-two patients received non-biological therapy. BUSES was determined at the beginning, after 1, 3, and 6 months. Spearman's correlation coefficient was calculated between BUSES and baseline characteristics. Brunner-Langer mixed non-parametric ANOVA was used to examine sensitivity to change of BUSES and effect of biological therapy on BUSES. Effect of time on the presence of each of the ultrasound enthesitis signs (increased thickness, hypoehogenicity, Power Doppler, enthesophytes, and erosions) was assessed using Cochran Q test. There was a weak, positive correlation between BUSES and disease duration, clinical enthesitis score, BASFI, BASDAI, and ASDAS-ESR/CRP. BUSES was higher at the beginning than after 1 month (p = 0.004), after 3 months (p < 0.001) and after 6 months (p < 0.001), as well as BUSES was higher after 1 month than after 3 months (p < 0.001) and after 6 months (p = 0.002). There is no difference in efficiency between non-biological and biological therapies on BUSES. Increased thickness, hypoechogenicity, and Power Doppler have decreased on Achilles tendon's and plantar fascia's enthesis over time. BUSES has a certain degree of construct validity because of the weak, positive correlation with parameters referring to severity of spondyloarthritis. BUSES demonstrated sensitivity to change over time due to decreasing of ultrasound acute enthesitis signs in treated spondyloarthritis patients. BUSES could be useful for monitoring the progression of enthesitis and effectiveness of the treatment.

Is ultrasonographic enthesitis evaluation helpful for diagnosis of non-radiographic axial spondyloarthritis?

The aim of this study is to evaluate the diagnostic utility of ultrasonographic enthesitis assessment in patients with non-radiographic axial spondyloarthritis (nr-axSpA) and to compare different sonographic scoring methods. Patients with nr-axSpA (n = 30) and mechanical back pain (MBP) (n = 30) were enrolled in the study with standardized clinical criteria. For both of the groups, a total of 18 entheses were evaluated in each patient with B mode ultrasound and power Doppler by a sonographer who is blinded to initial clinical and radiological assessments. Glasgow Ultrasound Enthesitis Scoring System (GUESS), Madrid Sonographic Enthesitis Index (MASEI) and D'Agostino grading system were performed. Intra-rater and inter-rater reliability analyses were evaluated with the intraclass correlation coefficient (ICC). There was at least one enthesitis in 96.7% of patients with nr-axSpA. Median values of the number of enthesitis were 5 in nr-axSpA and 0 in MBP. Mean GUESS total scores were 0.9 in MBP and 4.5 in nr-axSpA. Mean MASEI total scores were 2.3 and 10.5, respectively. The sensitivities were 96.7% and 93.3% for GUESS and MASEI while the detected specificities were 80% for both methods. For Intra-rater reliability analysis, ICC was calculated as 0.981 for GUESS and 0.975 for MASEI, while it was calculated as 0.964 and 0.962 for inter-rater reliability analysis. Thus, evaluation of enthesitis with ultrasound is a reliable, helpful tool for the distinction of patients with nr-axSpA from patients with MBP. We favored the use of MASEI because of assessing upper extremity, using power Doppler and having a correlation with disease activity.

The effect of foot position on Power Doppler Ultrasound grading of Achilles enthesitis.

The aim of this study was to determine whether foot position could modify power Doppler grading in evaluation of the Achilles enthesis. Eighteen patients with clinical Achilles enthesitis were studied with power Doppler ultrasound (PDUS) in five different positions of the foot: active and passive dorsiflexion, neutral position, active and passive plantar flexion. The Doppler signal was graded in any position and compared with the others. The Doppler signal was higher with the foot in plantar flexion and decreased gradually, sometimes till to disappear, while increasing dorsiflexion. The Doppler signal was always less during the active keeping of the position of the joint, than during the passive. The PDUS examination of the Achilles enthesis should be performed also with the foot in passive plantar flexion, in order not to underestimate the degree of vascularization.

Nail psoriasis as a predictor of the development of psoriatic arthritis.

Psoriatic arthritis is a psoriasis-related spondyloarthropathy that occurs in 20-30% of patients with psoriasis. Various imaging studies have demonstrated that there is a considerable proportion of undiagnosed psoriatic arthritis among patients with psoriasis. Since early detection and treatment of psoriatic arthritis could, ultimately, allow the prevention of clinical and radiologic progression of the disease, there is the need to establish clinical indicators to detect this risk. Nail psoriasis has been proposed as a predictor for the development of psoriatic arthritis. The inflammation involving the entheses, called enthesitis, is an early inflammatory change seen in psoriatic arthritis, and nail changes appear to result from the close relationship between the nail and the enthesis of the distal interphalangeal extensor tendon, one of the main entheseal compartments affected in psoriatic arthritis. As skin lesions precede articular symptoms in more than 75-80% of patients with psoriatic arthritis, dermatologists may play a key role in the early detection and management of psoriatic arthritis.

Enthesopathies - Mechanical, inflammatory or both?

Entheses have the challenging task of transferring biomechanical forces between tendon and bone, two tissues that differ greatly in composition and mechanical properties. Consequently, entheses are adapted to withstand these forces through continuous repair mechanisms. Locally specialized cells (mechanosensitive tenocytes) are crucial in the repair, physiologically triggering biochemical processes to maintain hemostasis. When repetitive forces cause "material fatigue," or trauma exceeds the entheses' repair capacity, structural changes occur, and patients become symptomatic. Clinical assessment of enthesopathies mainly depends on subjective reports by the patient and lacks specificity, especially in patients with central sensitization syndromes. Ultrasonography has been increasingly used to improve the diagnosis of enthesopathies. In this article, the literature on how biomechanical forces lead to entheseal inflammation, including factors contributing to differentiation into a "clinical enthesitis" state and the value of ultrasound to diagnose enthesopathies will be reviewed, as well as providing clues to overcome the pitfalls of imaging.

Adult rheumatologic features, treatment and complications of X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is a rare genetic phosphate disorder caused mainly by PHEX mutations. Unlike for children, knowledge of the disease's manifestations in adults is limited. Musculoskeletal symptoms are the main feature of the disease in young adults associated with a heavy burden on patients' life. They include fractures and pseudofractures, pain, joint stiffness, osteoarthritis, enthesopathies, and muscle weakness, eventually leading to impaired quality of life. Conventional treatment with phosphate supplements and vitamin D analogs is indicated in symptomatic patients. Appropriate rehabilitation is also a key to the management of the disease to improve physical function and decrease pain, stiffness, and fatigue. Regarding the incidence and consequences of musculoskeletal features in XLH, all patients should be assessed by a bone disease specialist and, if necessary, managed by a multidisciplinary team.

The Jumper's Knee - a New Look at Non-surgical Treatment. Pilot Study.

BACKGROUND: There are many opinions and views regarding the methods of treatment of patellar ligament enthesopathy. No gold standard of treatment exists. This paper presents our approach involving conservative treatment and an appropriate rehabilitation regime. Our aim was to assess the effectiveness of a combination of various conservative treatment techniques and the time needed to return to sport. MATERIAL AND METHODS: The study enrolled 14 patients treated in 2019 and 2020. Knee joint evaluation was based on clinical and radiological examination (sonography and MR). All patients were treated conservatively according to a specially prepared treatment protocol. Patients were evaluated at two-week intervals until the symptoms subsided completely. The KOOS, Kujala and SF36 questionnaires were used to evaluate the results. RESULTS: All of the patients returned to painless physical activity within 3-4 weeks from the start of treatment. In the group of professional athletes, 100% returned to sport. The return to sport took slightly longer for pa-tients with bilateral (5-6 weeks) in comparison to unilateral jumper's knee (3-4 weeks). The longest period of return to sport, in a patient who had severe pain at rest before starting treatment, was 7 weeks. Statistically significant improvement was noted in all of the questionnaires used and in all subdomains at 6 months after the beginning of the treatment. CONCLUSIONS: 1. The conservative approach proposed by us generated promising results in the treatment of the jumper's knee. 2. A 100% rate of return to sport was recorded among our patients.

Applying EMG technology in medial and lateral elbow enthesopathy treatment using Myo motion controller.

Electromyography (EMG) is a diagnostic technique allowing for the detection of signals generated by changes in electrical potentials of striated muscles. The application of this technology is becoming an increasingly popular subject of scientific research. With the appearance of new devices retrieving EMG data, novel methods of its processing for various purposes are being developed. One such device is the Myo movement controller, produced by Thalmic Labs (now North). The device has been used for the analysis of muscle activation levels in patients with "tennis elbow" and "golfer's elbow"-conditions of upper limbs which usually result from occupational injuries. The process of their rehabilitation is complex and requires a continuous monitoring of its progress. The data obtained by means of the Myo controller was used for pattern recognition of an injured hand with relation to the healthy one. The study involved examining ten subjects, including five controls. The results indicate that the muscle activation force is considerably lower in injured individuals. The arithmetic mean for the 6 analyzed motions in the injured group is 38.54% lower. The SmartEMG application ( https://www.smartemg.com ) enables the implementation of procedures performed during an examination as well as those involved in the management of the collected recordings. The study produced satisfactory results, which indicates the possibility of using the Myo controller in the treatment of elbow enthesopathy.

Influence of Disease Manifestations on Health-related Quality of Life in Early Psoriatic Arthritis.

OBJECTIVE: Psoriatic arthritis (PsA) is a multifaceted disease. Affecting joints, skin, entheses, and dactylitis, its effect on health-related quality of life (HRQOL) could be substantial. We aim to assess HRQOL in patients newly diagnosed with PsA and analyze its associations with disease manifestations. METHODS: Data collected at time of diagnosis from patients with PsA included in the Dutch south-west Early Psoriatic Arthritis cohort (DEPAR) study were used. HRQOL was assessed using 8 domains of the Medical Outcomes Study Short Form-36 (SF-36) questionnaire. Patients were classified based on primary manifestation in arthritis subtypes (i.e., mono-, oligo-, or polyarthritis) and other subtypes (i.e., enthesitis, dactylitis, and axial disease). In all patients, presence of arthritis, enthesitis, dactylitis, psoriasis, and chronic inflammatory back pain was determined. Multivariable linear regression was used to determine associations of PsA manifestations with HRQOL. RESULTS: Of 405 patients, primary manifestation was peripheral arthritis in 320 (78 monoarthritis, 151 oligoarthritis, and 91 polyarthritis), enthesitis in 37, axial disease in 9, and dactylitis in 39. Mean scores of SF-36 domains were lower than the Dutch reference population and similar across arthritis subtypes. A higher number of enthesitis locations and tender joints, and presence of chronic back pain, were independently associated with worse SF-36 scores. Psoriasis and dactylitis were not associated with worse scores. CONCLUSION: HRQOL was diminished in PsA at time of diagnosis compared to the Dutch reference population, and tender joints, enthesitis at clinical examination, and back pain as indicators of pain affected HRQOL.

Enthesopathy in rheumatoid arthritis and spondyloarthritis: An ultrasound study.

OBJECTIVE: We aimed to compare the prevalence of enthesopathy seen on ultrasonography (US) in spondyloarthritis (SpA) and rheumatoid arthritis (RA) and compared it to healthy controls. METHODS: All included patients with RA (2010 ACR/EULAR criteria) and SpA (ASAS criteria) and healthy controls underwent clinical and US evaluation of enthesis at seven sites (quadriceps, proximal and distal patellar, Achilles and triceps tendons, plantar aponeurosis and lateral epicondyle enthesis). The Glasgow Ultrasound Enthesitis Scoring System (GUESS) and the Madrid Sonographic Enthesitis Index (MASEI) scores were determined by two sonographers blinded to clinical data. RESULTS: We included 30 patients with RA (mean age: 55.7±14.8 years, mean disease duration 10.5±7.9years); 41 with SpA (mean age: 45.3±15.4 years, mean disease duration 9.2±8.7years) and 26 healthy controls (HC) (mean age: 50.4±17.3years). Patients with SpA and RA had similar prevalence of painful enthesis of examined sites (17% vs. 14%, non-significant [ns]), but more than among in healthy controls (3%, P<0.05 for RA and SpA comparison). Comparison between SpA and RA patients revealed that at least one US enthesis abnormality was found with similar frequency (46% and 48% sites [ns]) but both rheumatic diseases had higher frequency of US enthesis abnormality than HC (31%, P<0.05 for RA and SpA comparison). The mean MASEI score was 8.5±7.3 for RA patients, 7.8±6.5 for SpA patients (ns) and 3.4±2.8 for healthy controls (P<0.05 for RA and SpA comparison). Overall, 6 RA (20%) and 4 SpA (10%) patients had a MASEI score≥18 (ns). None of the healthy controls had a MASEI score≥18 (P<0.05 for RA and SpA comparison). The mean GUESS score was 5.8±3.1 and 6.3±3.9 for RA and SpA patients (ns), and 4.0±3.1 for healthy controls (P<0.01 vs. SpA and <0.05 vs. RA). CONCLUSIONS: RA and SpA patients did not differ in entheseal abnormalities seen on US. Such US features may have low specificity in inflammatory conditions affecting joints and enthesis such as SpA and RA.