Editorial
Enthesitis, a clinical manifestation with many unknowns
Entesitis, una manifestación clínica con muchas incógnitas
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The term enthesopathy is used to describe any pathological change in the enthesis, while enthesitis indicates the presence of inflammatory changes. There are multiple causes of enthesopathy such as: metabolic diseases, some drugs (fluoroquinolones, retinoids and fluorinated agents) and rheumatic diseases.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We wrote this editorial about enthesitis, taking into account the great lack of knowledge of clinicians on the subject and calling the attention of the medical community to improve the understanding of this frequent manifestation of inflammatory diseases such as spondyloarthritis (SpA) and psoriatic arthritis (PsA). Although in recent years it has been possible to know more in detail some aspects that improve the diagnostic and therapeutic approach of enthesitis, the advances in the knowledge of some molecular, pathophysiological and therapeutic characteristics of this clinical manifestation are insufficient and still do not allow to impact totally on the deterioration of the quality of life that it generates.</p><p id="par0015" class="elsevierStylePara elsevierViewall">During our clinical practice, at some time, every one of us has evaluated and diagnosed a patient with “tennis elbow” or “golfer's elbow”, a typical example of isolated enthesitis that is triggered secondary to a sport activity due to repetitive mechanical overload, and which usually resolves spontaneously; however, the enthesitis pathognomonic of PsA and SpA, usually affects more than one enthesis and has a chronic behavior; but in this type of patients, it can be generated a speculative hypothesis that the inflammatory threshold is much lower, which would allow to develop an enthesitis even without any mechanical overload, secondary to an exaggerated body response to stress.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> This low threshold can be explained by genetic factors such as genes of the major histocompatibility complex class I and polymorphisms in the IL-23 receptor.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6,7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Mechanical stress is a central factor in the development of enthesitis, which explains why it occurs more frequently in the lower limbs. The innate immune response also seems to intervene as a trigger for its development, however, the precise molecular process is not known. The adequate response with non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of enthesitis suggests the production of local PGE2 as the early mediator that enables the response to mechanical overload, while the resident mesenchymal cells express cyclooxygenase 2. PGE2 produces vasodilation that widens the trans-cortical blood vessels, which facilitates the recruitment of neutrophils into the bone marrow of the entheseal compartment, and, in addition, PGE2 promotes the production of IL-17, facilitating the inflammatory response, which activates the IL-23/IL-17 pathway.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Studies in mice show that T cells expressing IL-23R reside in the enthesis and are phenotipically γ δ T cells, which represent the major source of IL-17 and TNF. IL-17 acts as an amplifier of the inflammatory process and induces the production of cytokines and mediators that trigger neutrophil migration. It has also been documented that the uncontrolled activation of myeloid cells or in the absence of A20 protein, signal transducers and activator of transcription 1 (STAT1) promote the release of cytokines that trigger enthesitis.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">9–12</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">This entheseal inflammation (enthesitis) is characterized by a pronounced tissue response, considered as an early characteristic of diseases such as PsA and SpA, which subsequently manifests itself with consequences such as enthesophytes, calcaneal spur and plantar fasciitis. These new bone formations are probably initiated by resident mesenchymal cells, which have the potential for proliferation and differentiation within the chondroblasts and the osteoblasts to form cartilage and bone. PGE2 is also an important activator of the differentiation of osteoblasts. On the other hand, it is known that the parathyroid hormone-related peptide is expressed in the enthesis and probably supports the recruitment or the activity of underlying bone cell populations. The bone morphogenetic proteins seem to promote the proliferation of mesenchymal precursors required to form hypertrophic chondrocytes. These cells build the structure for the apposition of new bone by osteoblasts, which forms the enthesophyte. Similarly, Wnt proteins together with their inhibitors, DKK1 and sclerostin, are effector molecules that promote the activity of osteoblasts for the apposition of new bone in the entheses.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">4,5,13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Enthesitis occurs more commonly in younger, obese patients and in those who have higher disease activity, leading this manifestation to further deterioration in quality of life. In some studies the prevalence of enthesitis in patients with PsA is approximately 35%, being the most frequently involved sites: the Achilles tendon, plantar fascia and lateral epicondyles.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> Several indexes have been described for its exploration, including: the Mander/Newcastle enthesitis index (MEI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), Spondyloarthritis Research Consortium of Canada (SPARCC) index, Berlin (Major) enthesitis index, Leeds enthesitis index (LEI), and University of California, San Francisco (UCSF) enthesitis index. The performance of the MASES, LEI, MEI, Berlin and SPARCC indexes was evaluated in patients with PsA, and the LEI index correlated more consistently with parameters of clinical disease activity; and in a study with patients with SpA, the UCSF index was the most sensitive among these 3 indexes (MASES, Berlin and UCSF).<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3–5,13</span></a> Its correct exploration in daily medical practice by the physical examination is limited since the findings are easily confused in those patients with primary or secondary fibromyalgia and in patients with pain amplification syndrome.</p><p id="par0045" class="elsevierStylePara elsevierViewall">Such limitations have led to find imaging techniques for the evaluation of enthesitis. Although there have been recent advances in magnetic resonance, ultrasound (US) seems to be the preferred method to detect enthesitis because it allows an accurate evaluation of the soft tissue components of the entheses and also of the formation of new bone. Hypoechogenicity, increased thickness of the tendon insertion, calcifications, enthesophytes, erosions and Doppler activity have been identified as the most important US characteristics in enthesitis.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">4,5,13</span></a> Instruments such as the Glasgow ultrasound enthesitis scoring system (GUESS) or the Spanish enthesitis index (SEI) have been developed to evaluate the presence and severity of enthesitis based on such morphological changes, although these findings are also commonly found in mechanical diseases. More recently, the high-resolution peripheral quantitative computed tomography (HR-pQCT) was introduced to define structural lesions of enthesitis, in particular the quantification of formation of new bone in PsA.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The limitation of knowledge on the enthesitis present in these inflammatory diseases is not only for the pathophysiological mechanisms and the diagnostic methods, but also in terms of the treatment since studies to evaluate the treatment of enthesitis have not been specifically designed; however, the observations about the apparent therapeutic efficacy significantly support the known pathophysiological concepts. In the treatment of this manifestation have been used NSAIDs and local steroids, which demonstrate greater efficacy in the acute stages; no disease modifying antirheumatic drug (DMARD) has been shown to be effective for enthesitis except apremilast (a phosphodiesterase 4 inhibitor). Tumor necrosis factor alpha (TNF-α) inhibitors have demonstrated efficacy on axial and peripheral manifestations associated with enthesitis both in PsA and SpA. In PsA they demonstrate to improve peri-entheseal osteitis detected by magnetic resonance and to increase the vascularization evaluated by Power Doppler US. Ustekinumab, an antibody against the P40 subunit common for IL-12 and IL-23, has also shown efficacy. More recently, medications such as secukinumab and ixekizumab have demonstrated improvement in the indexes for evaluation of enthesitis.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">4,5,14</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Enthesitis is undoubtedly a characteristic finding both of PsA and SpA, for this reason, in our daily practice we must improve our clinical skills to recognize this manifestation, and in case of suspicion and doubtful exploration is necessary to resort to imaging techniques such as US and magnetic resonance to document it, since their finding becomes a factor that negatively impacts the quality of life of patients with these diseases, therefore, it is imperative that the Colombian health system covers the cost of these imaging techniques carried out by qualified and trained personnel, both in rheumatology and in radiology of this type of musculoskeletal manifestations that are so specific of inflammatory diseases, that if are not controlled in a timely and adequate manner, they generate a high economic impact on the system and the society due to the generation of loss of productivity.</p><p id="par0060" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Note:</span> An interesting part of the preparation of this manuscript that I would like to share with the readers was the reading of an article published in <span class="elsevierStyleItalic">Medicina UPB</span> that guided me in the methodology for writing this editorial.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of interest</span><p id="par0065" class="elsevierStylePara elsevierViewall">The author declares that there is no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Edwin J. Entesitis, una manifestación clínica con muchas incógnitas. Rev Colomb Reumatol. 2018;25:221–223.</p>" ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Enthesopathy of rheumatoid and ankylosing spondylitis" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 3 | 1 | 4 |
| 2024 October | 75 | 10 | 85 |
| 2024 September | 150 | 7 | 157 |
| 2024 August | 85 | 7 | 92 |
| 2024 July | 68 | 9 | 77 |
| 2024 June | 64 | 6 | 70 |
| 2024 May | 73 | 15 | 88 |
| 2024 April | 65 | 17 | 82 |
| 2024 March | 68 | 15 | 83 |
| 2024 February | 60 | 5 | 65 |
| 2024 January | 94 | 4 | 98 |
| 2023 December | 87 | 6 | 93 |
| 2023 November | 90 | 11 | 101 |
| 2023 October | 98 | 12 | 110 |
| 2023 September | 49 | 2 | 51 |
| 2023 August | 53 | 18 | 71 |
| 2023 July | 65 | 13 | 78 |
| 2023 June | 108 | 10 | 118 |
| 2023 May | 115 | 12 | 127 |
| 2023 April | 94 | 2 | 96 |
| 2023 March | 77 | 5 | 82 |
| 2023 February | 57 | 9 | 66 |
| 2023 January | 52 | 2 | 54 |
| 2022 December | 38 | 4 | 42 |
| 2022 November | 46 | 4 | 50 |
| 2022 October | 31 | 13 | 44 |
| 2022 September | 47 | 22 | 69 |
| 2022 August | 35 | 9 | 44 |
| 2022 July | 39 | 22 | 61 |
| 2022 June | 34 | 15 | 49 |
| 2022 May | 38 | 8 | 46 |
| 2022 April | 45 | 10 | 55 |
| 2022 March | 49 | 11 | 60 |
| 2022 February | 39 | 3 | 42 |
| 2022 January | 69 | 7 | 76 |
| 2021 December | 37 | 11 | 48 |
| 2021 November | 54 | 8 | 62 |
| 2021 October | 82 | 15 | 97 |
| 2021 September | 53 | 10 | 63 |
| 2021 August | 66 | 16 | 82 |
| 2021 July | 42 | 12 | 54 |
| 2021 June | 46 | 8 | 54 |
| 2021 May | 65 | 11 | 76 |
| 2021 April | 174 | 15 | 189 |
| 2021 March | 126 | 19 | 145 |
| 2021 February | 114 | 11 | 125 |
| 2021 January | 74 | 16 | 90 |
| 2020 December | 82 | 15 | 97 |
| 2020 November | 89 | 6 | 95 |
| 2020 October | 69 | 11 | 80 |
| 2020 September | 101 | 20 | 121 |
| 2020 August | 183 | 12 | 195 |
| 2020 July | 144 | 11 | 155 |
| 2020 June | 114 | 13 | 127 |
| 2020 May | 127 | 15 | 142 |
| 2020 April | 142 | 6 | 148 |
| 2020 March | 164 | 14 | 178 |
| 2020 February | 168 | 18 | 186 |
| 2020 January | 118 | 10 | 128 |
| 2019 December | 97 | 10 | 107 |
| 2019 November | 77 | 6 | 83 |
| 2019 October | 82 | 7 | 89 |
| 2019 September | 21 | 4 | 25 |
| 2019 August | 11 | 5 | 16 |
| 2019 July | 8 | 9 | 17 |
| 2019 June | 18 | 31 | 49 |
| 2019 May | 22 | 20 | 42 |
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