Molecular analysis of enthesopathy in a mouse model of hypophosphatemic rickets.

The bone tendon attachment site known as the enthesis comprises a transitional zone between bone and tendon, and plays an important role in enabling movement at this site. X-linked hypophosphatemia (XLH) is characterized by impaired activation of vitamin D, elevated serum FGF23 levels and low serum phosphate levels, which impair bone mineralization. Paradoxically, an important complication of XLH is mineralization of the enthesis (enthesopathy). Studies were undertaken to identify the cellular and molecular pathways important for normal post-natal enthesis maturation and to examine their role during the development of enthesopathy in mice with XLH (Hyp). The Achilles tendon entheses of Hyp mice demonstrate an expansion of hypertrophic-appearing chondrogenic cells by P14. Post-natally, cells in wild-type and Hyp entheses similarly descend from scleraxis- and Sox9-expressing progenitors; however, Hyp entheses exhibit an expansion of Sox9-expressing cells, and enhanced BMP and IHH signaling. These results support a role for enhanced BMP and IHH signaling in the development of enthesopathy in XLH.

Focal Synovial Inflammation Versus Enthesitis Theory in Distal Psoriatic Arthritis: A Pioneer Histopathologic Study.

ABSTRACT: The aim of this analysis was to re-examine the classical concept of distal interphalangeal joint (DIP) psoriatic arthritis (PsA) as an entheseal-driven disease. Two cadaveric fingers with severe psoriatic arthritis were analyzed. Our results demonstrate that inflammation of DIP PsA is multifocal without interconnection between entheses and articular cartilage of the DIP. We found a clear association between synovitis and focal loss of articular cartilage at the head of the intermediate phalanx. By contrast, the articular cartilage adjacent to the zone of severe enthesitis did not show notable damage. Fibrocartilaginous destructions of enthesis were characterized by either a multifocal lymphocytic inflammation, accompanied by osteoclastic resorption, beginning on the interface between the uncalcified and calcified fibrocartilage and then extending into the bone or a subchondral bone inflammation which insidiously destroyed first the bone and then the fibrocartilage. Some sections well showed an inflammation either mild or prominent starting at the level of vascular foramina of flexor enthesis, with secondary invading into the interface between bone and enthesis. The different anatomic sites examined showed a slight predominance of CD8+ T cells over CD4+ T cells: 52% up to 63% for CD8+ T cells vs. to 36% up to 48% for CD4+ T cells. Sparse interspersed CD1a+cells and PS100+cells were also seen with a predominance of PS100+ cells on CD1a+ cells. CD20+ B cells, plasmocytes, neutrophils, and mastocytes were absent or rare. CD123 positive cells were not observed. In DIP PsA, 3 findings predominate: (1) cartilage invasion by the thin pannus offers a more rational explanation for the focal joint destruction than does inflammation of the enthesis which is independent from articular cartilage, (2) the thick ventral plate and to a lesser extend the thin dorsal plate constitute a barrier between the inflamed entheses and the articular cartilage, and (3) an unusual form of minute vascular foramen contributes to the early stage of enthesitis. This small study suggests that DIP PsA is a complex disease. It affects anatomical micro sites which, although close, are in fact relatively independent of each other. Further studies are needed to test this hypothesis.

The effect of gender on disease activity and clinical characteristics in patients with axial psoriatic arthritis.

OBJECTIVES: In this study, we aimed to evaluate the effect of gender on clinical findings, disease activity, functional status and quality of life in patients with axial involvement in Turkey. METHODS: Patients with PsA who met the CASPAR classification criteria were enrolled consequently in this cohort. Turkish League Against Rheumatism (TLAR)-Network was formed with the participation of 25 centres. The demographic variables, fatigue, diagnostic delay, the beginning of peripheral arthritis, enthesitis, dactylitis and spine involvement, inflammatory low back pain, BASFI, HAQ, HAQ-s, visual analogue scale-pain (VAS-pain), anxiety, depression and disease activity parameters (ESR, DAS28, BASDAI) were recorded. Axial involvement was assessed according to clinical and radiological data according to modified New York (MNYC) or Assessment of SpondyloArthritis international Society (ASAS) criteria. RESULTS: A total of 1018 patients with PsA were included in this study. Of the 373 patients with axial involvement, 150 were male (40.2%) and 223 (59.8%) were female. Spondylitis was detected in 14,7% of men and 21,9% of women in all patients. Pain score (VAS) (p < .002), fatigue (p < .001), ESR (p < .001), DAS28 (p < .001), BASDAI score (p < .001), PsAQoL (p < .001), HAQ score (p < ,01), HAQ-S score (p < .001), anxiety (p < .001), depression (p < .024), FACIT (p < .001) and FiRST (p < .001) scores were statistically significantly worse in women than males with axial PsA. However, quality of life was better (p < .001) and PASI score (p < .005) were statistically worse in male patients than in female patients with axial involvement. CONCLUSION: This study has shown that the burden of disease in axial PsA has significant difference between genders. Disease activity, physical disability, functional limitation, depression and anxiety scores were higher in female patients, while quality of life were better and PASI score were higher in male patients. Therefore, we suggest that new strategies should be developed for more effective treatment of axial PsA in female patients.

Enthesitis in psoriatic arthritis (Part 3): clinical assessment and management.

Enthesitis is a common clinical feature of PsA, which is characterized by inflammation at the site of insertion of tendons, ligaments and joint capsule fibres into bone. Enthesitis is relatively unique to the spondyloarthritides, setting this group of diseases apart from other rheumatological conditions. The pathophysiological underpinnings of this clinical domain, and the imaging assessment of it, are described in accompanying articles in this supplement. The focus of this article is on the assessment of enthesitis by physical examination, the impact of enthesitis on function and quality of life, the impact of concomitant FM on clinical assessment, and the evidence for therapy of enthesitis garnered in trials of biologic and targeted synthetic DMARDs. Several physical examination measures of enthesitis have been developed and have proved reliable in assessment of enthesitis. Enthesitis has a significant deleterious impact on function and quality of life. The presence of concomitant FM in ≤20% of patients may result in artefactual worsening of assessment of disease severity and hinder achievement of the goal of low disease activity or remission. Several targeted therapies, which, for example, target the TNF, IL-17, IL-23, phosphodiesterase 4 or Janus kinase pathways, have shown significant efficacy in the treatment of enthesitis, resulting in improvement of function and quality of life for patients with PsA.

Updating the use of the Madrid Sonographic Enthesis Index (MASEI): a systematic review of the literature.

OBJECTIVE: To perform a systematic review of the literature to evaluate the use of the enthesis ultrasound Madrid Sonographic Entesis Index (MASEI) from its publication. METHODS: A systematic search of MEDLINE, EMBASE, and Cochrane Central Register databases was performed. The search strategy was constructed to identify publications containing terms related to enthesis and ultrasound. The only applied filter was studies conducted in humans. One reviewer systematically screened the search. A second reviewer verified the selection. The data extraction was focused on study characteristics, including population and components of the OMERACT filter. RESULTS: Sixty-eight of the 1581 identified studies had used MASEI, including 41 (60%) abstracts and 27 (40%) articles. Of the 27 articles, MASEI was mainly used for spondyloarthritis and related diseases in 12 (44%) articles, followed by both psoriatic arthritis and rheumatoid arthritis in five (19%) articles; however, it was also used in diseases such as Behçet disease, FM, familiar Mediterranean fever, SS, crystal arthropathies and systemic sclerosis. The feasibility of MASEI was reported in three (11%) articles, and the reliability in 12 (44%) with good to excellent values. No article evaluated the responsiveness to treatment. The construct validity of MASEI was assessed using biomarkers in seven (26%) articles, clinical examination in 13 (48%) and imaging procedures (only X-rays) in two (7%). The discriminative validity was assessed in 16 (59%) articles, not only in SpAs. CONCLUSION: MASEI is a feasible, reliable and valid ultrasound score for the study of enthesis in spondyloarthritis, psoriatic arthritis and other diseases.

Enthesitis in psoriatic arthritis (Part 2): imaging.

Enthesitis is a hallmark finding in PsA and may predate the onset of synovitis. Clinical examination of enthesitis provides no structural information, relies on eliciting tenderness at entheseal sites and may not be sensitive or specific. Soft tissue imaging techniques such as musculoskeletal ultrasound and MRI can depict ultrastructural and inflammatory changes. Although these imaging techniques are complimentary, ultrasound can image superficial entheses with high fidelity and examine vascularity with the use of Doppler but cannot image subchondral bone. MRI depicts bone and can visualize bone marrow edema as well as soft tissue edema. However, due to short relaxation times, entheseal structures are not easily differentiated. There has been increasing recognition of biomechanical confounding, especially since the majority of the entheses examined are in the lower extremity. Imaging entheseal indices are being developed to minimize the effect of body weight and activity. In the following article, contemporary concepts of entheses in relation to imaging will be reviewed as well as important confounders in assessing entheseal alterations. The role and limitations of imaging techniques will be discussed.

Ultrasonography of enthesis in psoriatic arthritis: a descriptive and reliability analysis of elemental lesions and power Doppler subtypes.

Objective: To evaluate the reliability and prevalence of enthesis ultrasound (US) elemental lesions in patients with psoriatic arthritis (PsA), using the Madrid Sonographic Enthesis Index (MASEI) and Outcome Measures in Rheumatology (OMERACT) definitions.Methods: The study included 27 PsA patients with metacarpophalangeal joint swelling. An US rheumatologist performed the MASEI examination. Prevalence and reliability of the included elemental lesions [structure, thickness, erosion, enthesophytes, power Doppler (PD), and bursae] were evaluated. In addition, three other PD definitions were checked: PD OMERACT (≤ 2 mm to the bone profile), PD enthesis-tendon (> 2 mm from the bone profile), and PD bursa. Short (3-5 s) videos of US examinations were recorded for reliability assessment.Results: MASEI and all PD definitions showed good to excellent reliability. The best reliability values were found in erosions, bursae, and PD. When present, the PD signal always appeared in more than one location of the evaluated areas. Enthesis Doppler was present in 81.5% of patients. Abnormal tendon structure and enthesophytes were the most prevalent lesions.Conclusion: MASEI demonstrates to be a reliable tool in PsA. All enthesis US Doppler definitions demonstrate to be reliable for its use in PsA with minimal differences, being PD MASEI the most sensitive in active patients.

The effect of anti-IL-6 receptor antibody for the treatment of McH-lpr/lpr-RA1 mice that spontaneously developed destructive arthritis and enthesitis.

BACKGROUND: McH-lpr/lpr-RA1 mice are a new strain of mice which spontaneously develop destructive arthritis and enthesitis in the ankle. There is no published data that drug treatment has been trialed on these mice. This study examined the effect of the mouse anti-IL-6 receptor antibody, MR16-1, for the treatment of arthritis and enthesitis in McH-lpr/lpr-RA1 mice. METHODS: Male McH-lpr/lpr-RA1 mice were randomly divided into control and treatment groups. MR16-1 was administered from 10 weeks of age for the treatment group. Saline was applied for the control group. The drug was administered once a week, at an initial dose of 2 mg, then maintained at 0.5 mg once per week thereafter. The effects were evaluated by the histopathological synovitis score, in vivo imaging using indocyanine green liposomes, and analysis of the gene expression of inflammatory cytokines. RESULTS: Tissue analyses were carried out at 14, 17 and 20 weeks of age. The synovitis scores of treated groups were significantly lower compared with those of the control group at 14 and 17 weeks of age. The kappa coefficient was 0.77. However, progression of entheseal ossification persisted in the MR16-1 treated group. In vivo imaging using indocyanine green liposomes showed significant decreases in signal intensities of treated groups at week 14, but no significant differences were observed at week 18. Blood serum amyloid A levels in treated groups were significantly lower at 17 weeks of age. The gene expression levels of Tnf and Il17 were also significantly lower in MR16-1 treated groups. CONCLUSIONS: Administration of the anti-IL-6 receptor antibody is effective for the treatment of synovitis and bone destruction of McH-lpr/lpr-RA1 mice. McH-lpr/lpr-RA1 mice may be a suitable experimental model for the development of new treatments for destructive arthritis and enthesitis. IL-6 signal blockade could contribute to the treatment of destructive arthritis, and further studies should be carried out to confirm its potential in the prevention of enthesopathy developed to ossification.

Skin inflammation associated with arthritis, synovitis and enthesitis. Part 2: rheumatoid arthritis, reactive arthritis, Reiter's syndrome, Lyme borreliosis, dermatomyositis and lupus erythematosus.

Syndromes associated with concurrent skin and joint inflammation frequently pose a therapeutic challenge for both dermatologists and rheumatologists. In part 1 of this review, we discussed psoriatic arthritis as well as the autoinflammatory disorders SAPHO syndrome, Still's disease and Behçet's disease. Part 2 will address rheumatoid arthritis, reactive arthritis, Reiter's syndrome and Lyme borreliosis. In addition, we will discuss dermatomyositis and lupus erythematosus, two common autoimmune disorders that frequently present with both cutaneous and joint involvement. For each of the aforementioned disorders, we will highlight aspects of epidemiology, pathogenesis, clinical presentation, diagnosis and treatment.

A20 inhibition of STAT1 expression in myeloid cells: a novel endogenous regulatory mechanism preventing development of enthesitis.

OBJECTIVES: A20 is an important endogenous regulator of inflammation. Single nucleotide polymorphisms in A20 have been associated with various immune-mediated inflammatory diseases, and cell-specific deletion of A20 results in diverse inflammatory phenotypes. Our goal was to delineate the underlying mechanisms of joint inflammation in myeloid-specific A20-deficient mice (A20myelKO mice). METHODS: Inflammation in A20myelKO mice was assessed in a time-dependent manner. Western blot analysis and quantitative PCR analysis were performed on bone marrow-derived macrophages from A20myelKO and littermate control mice to study the effect of A20 on STAT1/STAT3 expression and STAT1/STAT3-dependent gene transcription in myeloid cells. The in vivo role of Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT) signalling in the development of enthesitis in A20myelKO mice was assessed following administration of a JAK inhibitor versus placebo control. RESULTS: Enthesitis was found to be an early inflammatory lesion in A20myelKO mice. A20 negatively modulated STAT1-dependent, but generally not STAT3-dependent gene transcription in myeloid cells by suppressing STAT1 but not STAT3 expression, both in unstimulated conditions and after interferon-γ or interleukin-6 stimulation. The increase in STAT1 gene transcription in the absence of A20 was shown to be JAK-STAT-dependent. Moreover, JAK inhibition in vivo resulted in significant reduction of enthesitis, both clinically and histopathologically. CONCLUSIONS: Our data reveal an important and novel interplay between myeloid cells and tissue resident cells at entheseal sites that is regulated by A20. In the absence of A20, STAT1 but not STAT3 expression is enhanced leading to STAT1-dependent inflammation. Therefore, A20 acts as a novel endogenous regulator of STAT1 that prevents onset of enthesitis.

Enthesopathic patterns of two South African female cadavers.

Enthesopathy is considered to be an osseous phenomenon, either disease-specific or bone-site specific, which occurs at the enthesis of bone. Upon routine cadaveric dissection of the glenohumeral region in two Caucasian females, enthesopathy of the right proximal humerus was observed unilaterally in both cases. Case 1 exhibited an inconsistent pattern of bony protuberances and crests dispersed across the lesser and greater tuberosities of the right humeral head. Varying degrees of ossification of the distal subscapularis muscle was also observed. Case 2 presented with a distinctively large enthesophyte that protruded supero-medially from the proximal right humerus. In addition, ossification of the distal-most aspect of the supraspinatus muscle was identified. Cases 1 and 2 were both reflective of osteophytic enthesopathy as proliferative change was clearly visible on the proximal aspect of each humerus. Whilst the presence of enthesopathies may be indicative of underlying pathology, it may prove beneficial to the field of bioarchaeology for the remodelling of lifestyles of ancient civilizations through the provision of current day variations as seen in these two case studies.

Mineral tessellation in mouse enthesis fibrocartilage, Achilles tendon, and Hyp calcifying enthesopathy: A shared 3D mineralization pattern.

The hallmark of enthesis architecture is the 3D compositional and structural gradient encompassing four tissue zones - tendon/ligament, uncalcified fibrocartilage, calcified fibrocartilage and bone. This functional gradient accommodates the large stiffness differential between calcified bone and uncalcified tendon/ligament. Here we analyze in 3D the organization of the mouse Achilles enthesis and mineralizing Achilles tendon in comparison to lamellar bone. We use correlative, multiscale high-resolution volume imaging methods including µCT with submicrometer resolution and FIB-SEM tomography (both with deep learning-based image segmentation), and TEM and SEM imaging, to describe ultrastructural features of physiologic, age-related and aberrant mineral patterning. We applied these approaches to murine wildtype (WT) Achilles enthesis tissues to describe in normal calcifying fibrocartilage a crossfibrillar mineral tessellation pattern similar to that observed in lamellar bone, but with greater variance in mineral tesselle morphology and size. We also examined Achilles enthesis structure in Hyp mice, a murine model for the inherited osteomalacic disease X-linked hypophosphatemia (XLH) with calcifying enthesopathy. In Achilles enthesis fibrocartilage of Hyp mice, we show defective crossfibrillar mineral tessellation similar to that which occurs in Hyp lamellar bone. At the cellular level in fibrocartilage, unlike in bone where enlarged osteocyte mineral lacunae are found as peri-osteocytic lesions, mineral lacunar volumes for fibrochondrocytes did not differ between WT and Hyp mice. While both WT and Hyp aged mice demonstrate Achilles tendon midsubstance ectopic mineralization, a consistently defective mineralization pattern was observed in Hyp mice. Strong immunostaining for osteopontin was observed at all mineralization sites examined in both WT and Hyp mice. Taken together, this new 3D ultrastructural information describes details of common mineralization trajectories for enthesis, tendon and bone, which in Hyp/XLH are defective.

Ultrasonography of heel entheses in axial spondyloarthritis patients: frequency and assessment of associated factors.

PURPOSE: Foot entheses involvement is a common manifestation of spondyloarthritis. The superiority of ultrasonography examination in foot entheses damages detection has been reported. We aimed to compare the ultrasonography findings of foot entheses between spondyloarthritis patients. and healthy controls and to identify factors associated with enthesitic heel involvement. METHODS: We conducted a cross-sectional study including 37 patients with axial spondyloarthritis (G1) and 37 healthy subjects matched by age and gender (G0). The following pro-inflammatory cytokines were measured: Interleukin (IL-)1, IL-6, IL-17, and IL-23. A blind ultrasonography of foot entheses was performed to examine calcaneal tendon (CT) and plantar fascia (PF). RESULTS: The mean age was 44.62 ± 12.31 years. Non-steroidal anti-inflammatory drugs were taken in 92% of patients. Clinical heel enthesopathy was noted in 10 patients (27%) of G1. No participant has enthesitic pain in G0. Ultrasonography changes in CT and PF were more frequent in G1 than G0 (p = 0.001 and p = 10-3, respectively). In the PF, tendon thickening was significantly higher in G1 than G0 (p = 0.03). Power Doppler in both enthesitic sites was exclusively observed in G1 (p = 10-3). Regarding associated factors, CT enthesophytes were less frequent in patients taking non-steroidal anti-inflammatory drugs continuously or having regular physical activity. PF structural damages were associated with higher erythrocyte sedimentation rate (p = 0.02), higher IL-23 level (p = 0.01), and higher disease activity (p = 0.04). CONCLUSION: Ultrasonography lesions of heel entheses were frequent in spondyloarthritis. Disease activity and inflammatory markers were higher in patients with heel enthesitis. Non-steroidal anti-inflammatory drugs intake and regular physical activity may prevent enthesophytes' occurrence.

Prevalence of Enthesopathies in Adults With X-linked Hypophosphatemia: Analysis of Risk Factors.

CONTEXT: Enthesopathies are the determinant of a poor quality of life in adults with X-linked hypophosphatemia (XLH). OBJECTIVE: To describe the prevalence of patients with enthesopathies and to identify the risk factors of having enthesopathies. METHODS: Retrospective study in the French Reference Center for Rare Diseases of the Calcium and Phosphate Metabolism between June 2011 and December 2020. Adult XLH patients with full body X-rays performed using the EOS® low-dose radiation system and clinical data collected from medical records. The main outcome measures were demographics, PHEX mutation, conventional treatment, and dental disease with the presence of enthesopathies. RESULTS: Of the 114 patients included (68% women, mean age 42.2 ± 14.3 years), PHEX mutation was found in 105 patients (94.6%), 86 (77.5%) had been treated during childhood. Enthesopathies (spine and/or pelvis) were present in 67% of the patients (n = 76). Patients with enthesopathies were significantly older (P = .001) and more frequently reported dental disease collected from medical records (P = .03). There was no correlation between the PHEX mutations and the presence of enthesopathies. Sixty-two patients had a radiographic dental examination in a reference center. Severe dental disease (number of missing teeth, number of teeth endodontically treated, alveolar bone loss, and proportion of patients with 5 abscesses or more) was significantly higher in patients with enthesopathies. CONCLUSION: Adult XLH patients have a high prevalence of enthesopathies in symptomatic adults patients with XLH seen in a reference center. Age and severe dental disease were significantly associated with the presence of enthesopathies.

Magnetic resonance imaging characteristics in patients with spondyloarthritis and clinical diagnosis of heel enthesitis: post hoc analysis from the phase 3 ACHILLES trial.

OBJECTIVE: To investigate the imaging characteristics and clinically assess heel enthesitis in spondyloarthritis (SpA) by applying in a post hoc analysis the Heel Enthesitis Magnetic Resonance Imaging Scoring system (HEMRIS) in blinded and centrally-read MRI data from the ACHILLES trial (NCT02771210). METHODS: ACHILLES included patients (≥18 years) with active psoriatic arthritis or axial SpA with clinical and MRI-positive heel enthesitis refractory to standard treatment. Patients were randomized to receive subcutaneous secukinumab 150/300 mg or placebo. At week 24, patients on placebo were switched to secukinumab treatment. MRI-positive heel enthesitis was confirmed in all patients by local investigators. MRIs were performed at 3 timepoints: screening and weeks 24 and 52. In the present analysis, all MRIs were re-evaluated by 2 blinded central readers in a consensus read fashion for a priori defined MRI parameters based on HEMRIS. RESULTS: At screening, 171/204 (83.8%) of patients presented with entheseal inflammation and/or structural damage, considering both the Achilles tendon and plantar fascia. Pathologies were more evident in the Achilles tendon area compared to the plantar aponeurosis. The most frequent pathologies were intra-tendon hypersignal and retrocalcaneal bursitis. The mean total entheseal inflammation score at screening in the Achilles tendon area was 2.99 (N=204) and the mean change (standard deviation [SD]) from screening to weeks 24 and 52 was - 0.91 (1.99) and - 0.83 (2.12) in the secukinumab group vs - 0.48 (1.86) and - 0.80 (1.98) in the placebo-secukinumab group, respectively. The mean total structural damage score at screening was 1.36 (N=204) and the mean change (SD) from screening to weeks 24 and 52 was 0.00 (0.65) and - 0.06 (0.56) in the secukinumab group vs 0.08 (0.48) and 0.04 (0.75) in the placebo-secukinumab group, respectively. CONCLUSIONS: Based on the newly developed HEMRIS, entheseal inflammation and/or structural damage was confirmed in 83.3% of ACHILLES patients. Pathologies were more evident in the Achilles tendon area compared to plantar fascia, with the inflammatory parameters being more responsive with secukinumab treatment compared to placebo. The present analysis, with detailed information on individual MRI parameters, contributes to the scientific debate on heel enthesitis. TRIAL REGISTRATION: ClinicalTrials.gov NCT02771210 .

An evaluation of the relationship between the degree of entheseal changes and the severity of osteodegenerative processes at fibrocartilaginous entheses.

An enthesis refers to the interface at which a tendon or a ligament integrates into the periosteum. Its morphology can be influenced by intrinsic factors such as sex, age, and extrinsic factors such as levels of activity, which will in turn impact on bone remodeling and lead to morphological changes. In bioarcheology, entheseal changes have had a long tradition of being used for the reconstruction of past activities. The literature has shown that in some cases of osteoarthritis, entheseal changes are associated with osteoarthritic manifestations. This work aims to evaluate the relationship between the degree of entheseal changes and the severity of osteodegenerative processes. The studied materials consisted of 30 humeri and 30 femora from the osteological collection at St George's University of London. Intensities of both entheseal changes and osteodegenerative processes were macroscopically assessed and scored. The difference in scores of entheseal changes between osteoarthritic groups and nonosteoarthritic groups is statistically significant at a confidence level of 95% (α = .05) for both the humeri and femora. Results show a positive correlation between the degree of entheseal changes and the severity of osteodegenerative processes in the femora, suggesting that enthesis may play a role in osteoarthritis. Findings from this work supports the proposed hypothesis that the degree of entheseal changes and the severity of osteoarthritic manifestation are related. This work contributes to current knowledge that osteoarthritis is a disease involving the whole joint; the enthesis could potentially be a target for the diagnosis of osteoarthritis.

A entese refere-se à interface por meio da qual um tendão ou um ligamento se integra ao periósteo. Sua morfologia pode ser influenciada por fatores intrínsecos como sexo, idade e fatores extrinsecos como niveis de atividade, que por sua vez impactam na remodelacção óssea e levam à alterações morfológicas. Em bioarqueologia, o uso das alterações das enteses tem uma longa tradição de reconstruir atividades passadas. A literatura evidencia que, em alguns casos de osteoartrite, as alterações das enteses estão associadas às manifestações osteoartríticas. Esta pesquisa tem como objetivo avaliar a relação entre o grau de alterações das enteses e a severidade de processo osteo-patológicos. O material estudado consiste em 30 úmeros e 30 fêmures provenientes da coleção osteologica da St George's University of London. A intensidade de ambos, alteraçoes das enteses e processo osteodegenerativo foram avaliados e classificados macroscopicamente. A diferença na intensidade das alterações das enteses entre os grupos com e sem osteoartrite é estatisiticamente significativa à um nivel de confiança de 95% (α = .05) para ambos, úmeros e fêmures. Os resultados mostram uma correlação positiva entre o grau de alteração das enteses e a severidade dos processos osteodegenerativos nos fêmures, sugerindo que as enteses podem desempenhar um papel na fisiopatologia da osteoartrite. Os achados dessa pesquisa apoiam a hipótese proposta de que o grau de alteração das enteses e a severidade das manifestações da osteoartrites estão relacionados. Esta investigação contribui para o conhecimento atual de que a osteoartrite é uma patologia que envolve toda a articulação e que as enteses podem ser potencialmente um alvo para o diagnóstico da ostaoartrite.

Osteoarthritis, entheses, and long bone cross-sectional geometry in the Andes: Usage, history, and future directions.

Akin to approaches encouraged by Verano (1997) in the Andes, and Ortner (2011, 2012) for general paleopathological studies, this article focuses on accurate descriptions and definitions of osteoarthritis, entheses, and long bone cross-sectional geometry. By evaluating these conditions as part of biological responses to abnormal skeletal changes and biomechanical stress, this research discusses each condition's pathogenesis. Further, this article emphasizes a "small data" approach to evaluating these conditions in ancient culturally and biologically related human populations, where the study samples must have good skeletal preservation, where estimates of age and sex need to be included as major factors, and where abnormalities need to be described and evaluated. This article also discusses global clinical and osteological research on ways scholars are currently trying to establish industry-wide methods to evaluate osteoarthritis, entheses, and long bone cross-sectional geometry. Recent studies have focused on rigorous evaluation of methodological techniques, recording protocols, and inter- and intra-observer error problems. Additionally, scholars have focused on physical intensity of movement using biomechanics, evaluated burials of known occupation, and used complex statistical methods to help interpret skeletal changes associated with these conditions. This article also narrows to focus on these conditions within thematic "small data" areas throughout the Andes. This research concludes with describing future directions to understand skeletal changes, such as more multidisciplinary studies between osteologists and pathologists, collaborations with living people to collect CT, x-rays, or computer-aided motion capture, and a stronger focus on how these conditions correlate with intense biomechanical changes in younger individuals.

Impact of guselkumab, an interleukin-23 p19 subunit inhibitor, on enthesitis and dactylitis in patients with moderate to severe psoriatic arthritis: results from a randomised, placebo-controlled, phase II study.

OBJECTIVE: To evaluate the effect of guselkumab on enthesitis and dactylitis in a phase II trial of patients with active psoriatic arthritis (PsA). METHODS: This was a phase II, randomised, placebo-controlled, double-blind trial of adults with active PsA (≥3 swollen and ≥3 tender joints and C reactive protein ≥0.3 mg/dL) despite conventional synthetic disease-modifying anti-rheumatic drug, non-steroidal anti-inflammatory drug, and/or oral corticosteroid therapy. Patients were randomised to subcutaneous injections of guselkumab 100 mg or placebo at weeks 0, 4 and every 8 weeks, with placebo crossover to guselkumab at week 24. Dactylitis was scored on a scale of 0-3 on each digit; enthesitis was assessed using the Leeds Enthesitis Index (0-6). Other assessments included American College of Rheumatology (ACR) and Psoriasis Area and Severity Index responses. RESULTS: Of 149 randomised patients, 107 patients had enthesitis (mean score=2.7) and 81 patients had dactylitis (mean dactylitis score=5.7) at baseline. Mean improvements in enthesitis and dactylitis at week 24 were greater in the guselkumab group versus placebo and sustained through week 56. Similar results were observed for the proportions of patients with resolution of enthesitis and dactylitis. At week 56, mean improvements in enthesitis and dactylitis among patients who switched from placebo to guselkumab treatment were similar to those in the guselkumab group. In the guselkumab group, ACR20 responders had greater improvements in enthesitis and dactylitis versus non-responders (week 24). CONCLUSIONS: At week 24, the guselkumab group had greater mean improvements in enthesitis and dactylitis and greater proportions of patients with resolution of enthesitis and dactylitis versus placebo. ACR20 response was associated with improvements in enthesitis and dactylitis. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT02319759.URL: https://clinicaltrials.gov/ct2/show/NCT02319759; Registered 18 December 2014.

Imaging of diffuse idiopathic skeletal hyperostosis (DISH).

Diffuse idiopathic skeletal hyperostosis (DISH) is a condition characterised by calcification and ossification of ligaments and entheses. The condition usually affects the axial skeleton, in particular, at the thoracic segment, though also other portions of the spine are often involved. DISH often involves also peripheral tendinous and/or entheseal sites either alone, or in association with the involvement of peripheral joints. At times, new bone formation involves the bone itself, but sometimes it involves joints not usually affected by osteoarthritis (OA) which result in bony enlargement of the epiphysis, joints space narrowing and a reduced range of motion. Because of the entheseal involvement, DISH can be mistaken for seronegative spondyloarthropathies or for a "simple" OA. Furthermore, other implications for the recognition of DISH include spinal fractures, difficult intubation and upper endoscopies, decreased response rates in DISH with concomitant spondyloarthritides, and increased likelihood to be affected by metabolic syndrome and cardiovascular diseases. This Atlas is intended to show the imaging finding in DISH in patients diagnosed with the condition by the Resnick classification criteria.