Enthesitis: Much More Than Focal Insertion Point Inflammation

Enthesitis: Much More Than Focal Insertion Point Inflammation Purpose of Review Recognition of the importance of enthesitis as the pivotal pathological process underpinning spondyloarthropathies (SpA) has increased in recent years. Thus, we summarized the current knowledge on the pathogenic role of enthesitis on SpA shown by both animal models and human studies in vivo. Recent Findings Experimental models have shown several SpA-like diseases that commence at entheses and are linked to nail disease as well as dactylitis, two important entheseal-associated conditions in humans. Frequently, enthesitis is not the primary outcome measure in studies of peripheral PsA and SpA although arguably it is the key parameter being indirectly assessed in spinal disease in ankylosing spondylitis. The use of different agents including JAK, IL-17, and IL-23 inhibitors contributes significantly to our understanding of enthesitis in terms of involved immune pathways. Summary Enthesitis and enthesis organ inflammation may be the primary pathological process underlying SpA associated skeletal inflammation. Emergent studies are beginning to elucidate the molecular basis for this type of joint inflammatory response. . . . . . Keywords Enthesitis Entheses IL-17 IL-23 IL-12 JAKi Introduction Enthesis Microanatomy In the last decades, great advances have occurred in the The enthesis organ, defined as a group of tissues including etiopathogenetic understanding of the spondyloarthropathies fibrocartilages, bursa, fat pad, adjacent trabecular bone net- (SpA) which was paralleled by the introduction of the TNFi works, deeper fascia, and enthesis, functions collectively to therapies resulted in better clinical outcomes. A pivotal com- carry out a common task, namely anchorage and stress resis- ponent of these advances was the recognition that enthesitis, tance [3, 4]. The recognition that the enthesis is an organ helps defined as inflammation of tendon, ligament, and joint capsule to conceptualize why entheseal inflammation may be associ- insertions to the bones, is the cardinal pathological process in ated with diffuse extracapsular swelling in addition to synovi- the SpA group of diseases [1, 2]. In this article, we focus on tis and osteitis. An especially important component of the recent aspects of enthesis biology in experimental studies and enthesis organ is the synovio-entheseal complex where bursal in man and update the reader on new therapy developments and other synovial cavity resident macrophages provide lubri- for enthesitis. cation, nourishment, and metabolic requirements as well as micro-debris waste disposal in health [5]. However, these res- ident macrophages have also been suggested to trigger severe This article is part of the Topical Collection on Spondyloarthritis joint swelling in disease [3, 6–8]. The functional anatomy of the enthesis and how fibrocartilage-lined joints, some of * Dennis McGonagle which wrap around tendons, function like entheses and the D.G.McGonagle@leeds.ac.uk unifying mechanical explanation for disease that stems from these concepts has been well covered previously [4, 6]. Given Department of Medicine ‘B’, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel the fact that both the nail and the flexor tendons are respec- tively anchored to the skeleton via the distal interphalangeal Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel joint tendon or accessory pulleys, creating an enthesis-like Section of Musculoskeletal Disease, Leeds Institute of Molecular structure provides further support for the key importance of Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital, Leeds, UK the enthesis in SpA-related skin and joint manifestations [9]. 41 Page 2 of 8 Curr Rheumatol Rep (2018) 20:41 The Primacy of Enthesitis in Animal Models experiments showed that development of arthritis was depen- dent on TNF receptor I (TNFRI) expression [21]. Indeed, it Recently, several animal model studies have demonstrated the was shown that TNFRI expression in mesenchymal cells re- essential role of enthesitis in pathogenesis of the SpA group of sulted in a SpA and intestinal phenotype, demonstrating that diseases [10] and shed light on the importance of specific mesenchymal cells are primary targets in this model [19]. A inflammatory pathways and various cytokines in acting local- confirmation of these findings is well given in the study by ly such as IL-23 [8], IL-17, and IL-22 as key pro- Milia et al. [22], who studied transgenic rats with high expres- inflammatory cytokine in SpA potentially secreted by sion of HLA-B27 and human β (2)-microglobulin (B27TR), entheseal resident cells [8, 11]. Indeed, as result of better un- randomly assigned to TNFi treatment. Early and late admin- derstanding of the immune pathways involved in enthesitis, istration of anti-TNFα antibodies prevented and improved we are witnessing novel treatment advances that offer new inflammation and joint remodeling, respectively, preserving opportunities to improve clinical entheseal disease including the enthesis organization [22]. Interestingly, SMAD1/5/8 sig- IL-23 and IL-17 blockers as biological agents, and small mol- naling, a marker of bone remodeling, was not inhibited by late ecules such as PDE4 inhibitors and JAK inhibition [12–14]. anti-TNFα treatment [22]. These animal models kindled con- However, the basis for the reported PDE4 inhibition effi- siderable interest in the theory that enthesitis therapy might be cacy for enthesitis, but not synovitis in RA, is not understood associated with irreversible new bone formation lesions fol- at this time. lowing biological agent therapy. At the present time, the con- In the last few years, several experimental animal models sensus is that the earlier that biological therapy is used in man, of SpA-like disease have helped elucidate the role of enthesitis then the lower the likelihood of entheseal new bone formation as the primary pathological process in SpA, identifying vari- occurrence in the spine [23]. ous entheseal T cell subtypes and new immune pathways Furthermore, enthesitis, or more specifically synovio- (Table 1). Systemic overexpression of IL-23 using hydrody- entheseal complex disease, has been reported as an early feature namic injection of IL-23 minicircle DNA activated IL-23R+, of paw inflammation in mice with a myeloid cell-specific A20 ROR-γt+ CD3+ CD4− CD8−, stem cell antigen 1 (Sca1)+ (TNFα-induced protein 3) deficiency [24]. These mice are entheseal resident T cell lymphocytes inducing the transcript characterized by high levels of inflammatory cytokines, leading expression of IL-6, IL-17, and IL-22 as well as of CXCL1 to consistent NF-κB activation and significant production of genes [8]. The same technology induced arthritis and TNF, IL-1, and IL-6 by macrophages [25]. Nevertheless, in osteoblast-mediated bone remodeling and resulted in SpA- the myeloid A20 knockout mice, SpA-type arthropathy is inde- like bone formation manifestation of SpA with IL-22 but not pendent of TNF but dependent on IL-1 and IL-6 [25]. In the IL-17A DNA minicircles [8]. However, in the aforementioned early phase of arthritis of these mice, Achilles tendon region model, enthesitis was IL-17A dependent and this is consistent swelling was noted, and hematoxylin-eosin staining showed with the SKG mouse model of enthesitis [8, 15]. inflammation of the synovio-entheseal complex (SEC) [24]. In 2016, it was shown that the majority of IL-23R- Disease was blocked by the tofacitinib administration which responsive cells in the normal murine entheses were γδ Tcells provided pre-clinical support for JAKi in PsA and SpA. expressing the RAR-related orphan receptor γt(ROR-γt) The importance of the IL-23/17 axis has been further sup- transcription factor, as well as the IL-23 and CCR6 receptors, ported by other experimental studies where disease also com- and are capable of IL-17A production [16]. More specifically, mences at the enthesis and is associated with other SpA man- Reinhardt et al. analyzed entheseal lymphocytes from C57BL/ ifestations including nail disease and dactylitis [15, 26, 27]. 6, Tcrd-H2BeGFP, Rorc-GFP, and IL-23R-eGFP murine There is evidence for local IL-23 production in the gut [28] models, after performing hydrodynamic injection of IL-23 and it has been proposed that systemic circulation of IL-23 minicircle DNA [16]. Activated Vγ6+CD27− γ/δ T cells con- could then trigger SpA at the entheses [8]. IL-23 activating stituted the largest T cell subset [16]. Of particular relevance to resident Tcells within the enthesis promotes inflammation and the SpA concept was γδ T cells in the murine ciliary body, bone remodeling mediated by IL-17 and osteoproliferation thus offering a micro anatomical and immunological link be- mediated by IL-22 [29]. Thus far, there is little data on the tween the enthesis and the eye [17]. source of IL-23/17 axis cytokines driving human arthritis and TNF plays a key role in the pathogenesis of IBD, in which questions relating to whether IL-23 in particular is locally or enthesitis is also a typical manifestation when the disease also systemically produced remain to be elucidated. involves extra-intestinal structures [18]. Another animal mod- el demonstrating the involvement of entheses is the TNF over- expression model that was reported by Armaka et al. [19]who Human Studies of the Enthesis ΔARE/+ used a TNF transgenic model known as the TNF mu- tant mice, characterized by the development of Crohn’s-like The description of an IL-23-responsive population of T cells IBD and SpA-like disease [20]. Bone marrow-grafting [8], along with the description of a group of cytokine-dependent Curr Rheumatol Rep (2018) 20:41 Page 3 of 8 41 Table 1 Selected murine enthesitis models Reference Species Strain Intervention Characteristics Reihardt et al. [16] Mice Tcrd-H2BeGFP mice crossed Hydrodynamic injection Activated Vγ6+CD27− γ/δ Tcells were with mice of the susceptible of IL-23 minicircle DNA found in uninflamed entheseal tissue B10.RIII background and constituted the largest resident T cell subset. Armaka et al. [59� ] Mice TNF-overexpressing mouse Spondyloarthritis with a CD-like pathology ΔARE/+ model (TNF ) localized primarily in the small intestine. Additionally, the development of arthritis was dependent on TNF receptor I (TNFRI) expression with mesenchymal cells being primary responders. myelKO De wilde et al. [24]Mice A20 mice A20 knockout Enthesitis was found to be an early myelKO inflammatory lesion in A20 mice. A20 negatively modulated STAT1-dependent gene transcription in myeloid cells which was JAK/STAT dependent. Benham et al. [15] Mice BALB/c ZAP-70(W163C)- β-1,3-Glucan injected In curdlan-treated SKG mice, arthritis, enthesitis, mutant (SKG) mice intraperitoneally and ileitis were IL-23 dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-17A was pathogenic, while IL-22 was protective against ileitis. Sherlock et al. [8] Mice B10.RIII mice Immunization with type IL-23 is essential in enthesitis and acts on II collagen previously unidentified IL-23 receptor (IL-23R)+, RAR-related orphan receptor gt (ROR-gt)+CD3+CD4–CD8–, stem cell antigen 1 (Sca1)+ entheseal resident T cells which led to the induction of IL-6, IL-17, and IL-22 as well as of CXCL1 secretion leading to osteoblast remodeling which is characteristic of enthesitis. innate lymphoid cells (ILCs) [30], ledtoasearch forinnate Evaluating Enthesitis immune cells at the normal human enthesis. We selected small normal interspinous process entheses from donors with no sys- Unfortunately, in humans, enthesitis remains stubbornly diffi- temic inflammatory disease to explore the presence of type 3 cult to assess [33]. The complete avascularity of entheses at ILC populations. [31�� ]. The small interspinous process bone attachment sites and the low vessel density in adjacent entheses have advantages over large attachment sites like the ligaments and tendons as well as the lack of adaptive hyper- Achilles tendon where thick juxta-articular fibrocartilaginous plasia that is normally seen in synovitis make assessment of tissue that is completely devoid of immune cells precludes im- these sites particularly challenging [33]. Moreover, despite the mune cell subset evaluation. We showed that the normal human existence of various clinical measures for enthesitis, there is enthesis did indeed harbor a rare population of IL-23R- no sound consensus concerning their validity in PsA, since expressing type 3 ILCs [31 ]. We were also able to demon- gold standard validation has not been performed. Therefore, strate the presence of a comparatively abundant population of it is necessary to rely on imaging rather than clinical exam- γδ T cells. In health, entheseal cells were present in both the ination in order to detect non-accessible sites of entheses. enthesis soft tissue and the peri-entheseal bone [31�� ]. Indeed, numerous studies have shown that ultrasound (US) Furthermore, there was little evidence for expression of IL- could detect a subclinical enthesitis in PsA patients 17A transcripts in health, but of note, the IL-23R+ type 3 [34–36]. ILCs expressed TNFα transcript [31 ]. Following stimulation Typically, enthesitis is associated with diffuse peri- of human entheseal tissue with IL-23 and IL-1β,wedemon- entheseal soft tissue edema on magnetic resonance imaging strated upregulation of IL-17A and evidence for upregulation of (MRI) with this adjacent reaction being usually more conspic- IL-17F and IL-22 (Fig. 1). The inducible expression of IL-22 uous than inflammation within the insertion which reflects the on these entheseal resident immunocytes and the recognition greater vascularity of the peri-entheseal tissues (Fig. 2). Both that IL-22 drives human MSC osteogenesis [32� ] fit into a entheses and sacroiliac fibrocartilaginous joints have promi- model whereby inflammation at the entheses may later drive nent fibrocartilages and disease of both structures may be new bone formation (Fig. 1). associated with an adjacent severe osteitis that likely reflects �� �� 41 Page 4 of 8 Curr Rheumatol Rep (2018) 20:41 Fig. 1 Lymphocyte populations defined at the human enthesis. Thus far, two lymphocyte populations have been defined at the human enthesis. Innate lymphoid cells are part of the IL- 23-responsive T cells which are residents of the healthy enthesis. Gamma delta T cells are also resident at the enthesis. The activation of resident T cells within the enthesis by IL-23 may promote inflammation, osteogenesis, and bone loss and remodeling. These lymphocyte populations may release different cytokines including IL-17 and IL- 22 and TNF-α the excellent vascularity of the marrow (Fig. 3). However, immunological knowledge about human enthesis and the di- neither MRI nor US excludes the presence of enthesitis, and verse immune pathways that are involved in disease [42]. the role of imaging remains controversial since the use of Moreover, the use of enthesitis as an important manifestation power Doppler (PD) which is typical of RA-related synovitis of PsA, and its evaluation in drug trials, and clinical practice as activity is generally much less conspicuous at insertions [37, well, has increased dramatically with enthesitis now a univer- 38]. Studies comparing clinical enthesitis with imaging sal secondary outcome measure in trials [43]. The treatment of enthesitis in SpA show virtually no correlations [34]. enthesitis remains a challenge. Conventional DMARDs such Furthermore, where suspected pathology is seen, it is uncom- mon to get tissue to confirm the diagnosis. Therefore, the assessment criteria remain subjective. The exact histopatho- logical basis for the subclinical entheseal abnormalities pres- ent in PsA and other forms of SpA is poorly understood. However, a recent US study reported in abstract form has shown that subclinical enthesopathy in psoriasis cases re- gresses following anti-IL-12/23 therapy, suggesting an inflam- matory component [39]. Among the diverse clinical measures for enthesitis, the Leeds Enthesitis Index (LEI) uses the medial collateral liga- ment (MCL) origin in both knees as a site of enthesitis [40]. This anatomic structure forms an elaborate synovio-entheseal complex that might be inflamed as a result of events taking place elsewhere within the synovial cavity; thus, it is hard to interpret exactly what tenderness at this location means and whether it could be linked to synovitis. It might be that these difficulties and complexities in recognizing and measuring enthesitis contributed to the GRAPPA-OMERACT for PsA standardization unwittingly dropped enthesitis from core domain assessments [41]. The move towards trials in early PsA makes the need to address enthesitis an urgent one since early disease may might be strongly linked. Recent Clinical Developments Fig. 2 Magnetic resonance imaging (MRI) of the sacroiliac joints (SIJ) showing bilateral ischial tuberosity enthesitis in a patient with newonset The response of human enthesitis to various therapeutic agents PsA. The site of soft tissue entheseal inflammation is depicted by goes some way to improve the rudimentary state of arrowheads. In this case, there is sparing of the bony attachment. Curr Rheumatol Rep (2018) 20:41 Page 5 of 8 41 Fig. 3 Magnetic resonance imaging (MRI) of the sacroiliac joints (SIJ) showing bilateral sacral joint bone marrow edema on in a patient with early psoriatic arthritis. The Bone marrow edema is more florid at the anterior part of the joint adjacent to the capsular enthesis. It remains to be determined whether the patterns of inflammation at entheses in soft tissue or in the bone may influence responses to therapy as sulfasalazine and methotrexate are not significantly effective However, the two biggest classes of drugs used to treat PsA for enthesitis management, yet NSAIDs remain the first-line ther- and AS, namely TNF and IL-17 inhibitors, do not signal di- apy [43] although corticosteroid therapy including injection, rectly through the JAK pathway [52]. Nevertheless, IL-23 where appropriate or feasible, is also an option. TNF blockade signals via tyrosine kinase 2 (Tyk2) blockers for psoriasis is the standard of care for enthesitis and severe axial disease in support the idea of a therapy effect via IL-23 alone [51�� , 53]. those patients with partial response to conventional DMARDs An unexpected finding in this field is the apparent non- [44]. However, in recent years, many efforts were made to assess efficacy for ustekinumab for spinal enthesitis of AS despite the efficacy of several therapeutic agents in enthesitis. its efficacy in the peripheral skeleton (data not published). The Recent phase 3 studies have shown efficacy of PDE4 most obvious avenues for exploration are that the immune blockers for PsA but with lower ACR 20 responses compared system at the immunobiology peripheral and axial entheses to the biologic class of drugs. A favorable effect of the PDE4 may be fundamentally different and that higher doses of blocker, apremilast, on enthesitis has been reported [45, 46]. anti-IL-23 pathway cytokine are needed for axial disease. Given that the PDE4 blockers are ineffective in RA and do not One obvious difference is the relative absence of the block autoantibody production but suppress the neutrophil synovio-entheseal complex in the spine and where pathology influx to sites of tissue inflammation [47], it is likely that these is often located at entheseal bone anchorage points [33]. agents are working predominantly on innate immunity. This However, this intriguing observation around IL-12/23 block- supports the idea of what we termed MHC-1-opathy [48], ade apparent non-efficacy awaits further study including data whereby in the SpA group of diseases, initial site-specific on the IL-23 pathway antagonism with specific p19 blockers. innate immune activation drives adaptive immune activation The IL-17 blockers have also been evaluated for their effect via CD8+ T cells, which in turn drive IL-17-related neutro- on enthesitis. Secukinumab a IL-17A blocker has shown effi- philic tissue inflammation exacerbation of these diseases [48]. cacy for enthesitis in several trials [54, 55]. Ixekizumab, a Two recent studies have evaluated Janus kinase (JAK) inhibi- second IL-17A blocker with a 50-fold higher affinity, showed tion with tofacitinib, a pan JAK inhibitor for the treatment of efficacy for enthesitis in the P-SPIRIT-1 study [56]. However, PsA [49� , 50]. In biologic naïve cases, tofacitinib was com- in the P-SPIRIT 2 study with the same molecule in PsA cases pared to adalimumab, where enthesitis was assessed as a sec- that failed to respond to prior TNF blockade, there was no ondary outcome, reporting a favorable response [50]. significant effect on enthesitis at the pre-specified 24-week However, in the second study, the pre-specified statistical hi- assessment, but there was evidence for efficacy at earlier time erarchical model used precluded an evaluation of enthesitis points [57]. A third molecule, brodalumab, an IL-17RA [49� ]. It is likely that JAK inhibition will represent a new blocker, was also evaluated for its effect on enthesitis and no option in the treatment of PsA and enthesitis. The precise significant effect was found in those patients who had scores mechanism of action of JAK inhibition is unclear since over of more than 0 for enthesitis at week 12 between the group 50 different cytokines including interleukins, CSFs, and hor- receiving 140 mg of brodalumab and the group receiving mones that share various signaling pathways are mediated by 280 mg of brodalumab, as compared with the placebo group [58]. However, although not statistically significant, there was JAKs [51�� ]. 41 Page 6 of 8 Curr Rheumatol Rep (2018) 20:41 4. Shaw HM, Vazquez OT, McGonagle D, Bydder G, Santer RM, a greater numerical improvement in enthesitis in subjects on Benjamin M. Development of the human Achilles tendon enthesis higher dose of brodalumab. Given all the genetic and patho- organ. J Anat. 2008;213(6):718–24. logical data and the existing studies, it seems that these agents 5. McGonagle D, Aydin SZ, Tan AL. The synovio-entheseal complex will be effective for the therapy of enthesitis. and its role in tendon and capsular associated inflammation. J Rheumatol Suppl. 2012;89:11–4. 6. Benjamin M, Moriggl B, Brenner E, Emery P, McGonagle D, Redman S. The “enthesis organ” concept: why enthesopathies may not present as focal insertional disorders. Arthritis Rheum. Conclusions 2004;50(10):3306–13. 7. Apostolakos J, Durant TJS, Dwyer CR, Russell RP, Weinreb JH, Enthesitis is much more than local inflammation; indeed, it is Alaee F, et al. The enthesis: a review of the tendon-to-bone inser- considered as the primary pathological process underling tion. Muscles Ligaments Tendons J. 2014;4(3):333–42. SpA. This has been shown by investigating the enthesis in 8. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR- both animal models and human studies in vivo. Enthesitis gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. management is still a challenging matter for rheumatologists 2012;18(7):1069–76. and various new agents were evaluated for their effect on 9. Benjamin M, Kaiser E, Milz S. Structure-function relationships in enthesitis reporting different findings. The use of different tendons: a review. J Anat. 2008;212(3):211–28. 10. McGonagle D, Tan AL. The enthesis in psoriatic arthritis. Clin Exp agents including JAK, IL-17, and IL-23 inhibitors have con- Rheumatol. 2015;33(5 Suppl 93):S36–9. tributed significantly to our understanding of enthesitis in 11. Ahlfors H, Morrison PJ, Duarte JH, Li Y, Biro J, Tolaini M, et al. IL- terms of involved immune pathways. Nevertheless, there is 22 fate reporter reveals origin and control of IL-22 production in an unmet need for further studies to improve our understand- homeostasis and infection. J Immunol. 2014;193(9):4602–13. ing about enthesopathy seeking a better detection, and there- 12. Kavanaugh A, Puig L, Gottlieb AB, Ritchlin C, Li S, Wang Y, et al. Maintenance of clinical efficacy and radiographic benefit through fore management. two years of ustekinumab therapy in patients with active psoriatic arthritis: results from a randomized, placebo-controlled phase III Compliance with Ethical Standards trial. Arthritis Care Res (Hoboken). 2015;67(12):1739–49. 13. Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Conflict of Interest The authors declare that they have no conflict of Wollenhaupt J, Gladman DD, et al. Treatment of psoriatic arthritis interest. in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73(6): 1020–6. Human and Animal Rights and Informed Consent This article does not 14. Ebihara S, Date F, Dong Y, Ono M. Interleukin-17 is a critical target contain any studies with human or animal subjects performed by any of for the treatment of ankylosing enthesitis and psoriasis-like derma- the authors. titis in mice. Autoimmunity. 2015;48(4):259–66. Open Access This article is distributed under the terms of the Creative 15. Benham H, Rehaume LM, Hasnain SZ, Velasco J, Baillet AC, Commons Attribution 4.0 International License (http:// Ruutu M, et al. Interleukin-23 mediates the intestinal response to creativecommons.org/licenses/by/4.0/), which permits unrestricted use, microbial beta-1,3-glucan and the development of spondyloarthritis distribution, and reproduction in any medium, provided you give appro- pathology in SKG mice. Arthritis Rheumatol. 2014;66(7):1755–67. priate credit to the original author(s) and the source, provide a link to the 16. Reinhardt A, Yevsa T, Worbs T, Lienenklaus S, Sandrock I, Creative Commons license, and indicate if changes were made. Oberdorfer L, et al. Interleukin-23-dependent gamma/delta T cells produce interleukin-17 and accumulate in the enthesis, aortic valve, and ciliary body in mice. Arthritis Rheumatol. 2016;68(10):2476–86. 17. McGonagle D, Stockwin L, Isaacs J, Emery P. An enthesitis based model for the pathogenesis of spondyloarthropathy. Additive ef- fects of microbial adjuvant and biomechanical factors at disease References sites. J Rheumatol. 2001;28(10):2155–9. 18. Horton DB, Sherry DD, Baldassano RN, Weiss PF. Enthesitis is an Papers of particular interest, published recently, have been extraintestinal manifestation of pediatric inflammatory bowel dis- ease. Ann Paediatr Rheumatol. 2012;1(4):214. https://doi.org/10. highlighted as: 5455/apr.102920121510. � Of importance 19. Armaka M, Apostolaki M, Jacques P, Kontoyiannis DL, Elewaut D, �� Of major importance Kollias G. Mesenchymal cell targeting by TNF as a common path- ogenic principle in chronic inflammatory joint and intestinal dis- 1. McGonagle D, Gibbon W, O'Connor P, Green M, Pease C, Emery eases. J Exp Med. 2008;205(2):331–7. P. Characteristic magnetic resonance imaging entheseal changes of 20. Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. knee synovitis in spondylarthropathy. Arthritis Rheum. 1998;41(4): Impaired on/off regulation of TNF biosynthesis in mice lacking 694–700. TNF AU-rich elements: implications for joint and gut-associated 2. McGonagle D, Gibbon W, Emery P. Classification of inflammatory immunopathologies. Immunity. 1999;10(3):387–98. arthritis by enthesitis. Lancet. 1998;352(9134):1137–40. 21. Williams-Skipp C, Raman T, Valuck RJ, Watkins H, Palmer BE, 3. Benjamin M, McGonagle D. The enthesis organ concept and its Scheinman RI. Unmasking of a protective tumor necrosis factor relevance to the spondyloarthropathies. Adv Exp Med Biol. receptor I-mediated signal in the collagen-induced arthritis model. 2009;649:57–70. Arthritis Rheum. 2009;60(2):408–18. Curr Rheumatol Rep (2018) 20:41 Page 7 of 8 41 22. Milia AF, Ibba-Manneschi L, Manetti M, Benelli G, Generini S, 38. McGonagle D, Marzo-Ortega H, O’Connor P, Gibbon W, Pease C, Messerini L, et al. Evidence for the prevention of enthesitis in HLA- Reece R, et al. The role of biomechanical factors and HLA-B27 in B27/hbeta(2)m transgenic rats treated with a monoclonal antibody magnetic resonance imaging-determined bone changes in plantar against TNF-alpha. J Cell Mol Med. 2011;15(2):270–9. fascia enthesopathy. Arthritis Rheum. 2002;46(2):489–93. 23. Haroon N, Inman RD, Learch TJ, Weisman MH, Lee M, Rahbar 39. Laura Savage, Mark Goodfield, Elizabeth M.A. Hensor, Paul MH, et al. The impact of tumor necrosis factor alpha inhibitors on Emery, McGonagle D. Ultrasonographic improvement of peripher- radiographic progression in ankylosing spondylitis. Arthritis al subclinical enthesopathy in therapy-naive patients treated with Rheum. 2013;65(10):2645–54. ustekinumab for chronic plaque psoriasis: a 52-week, prospective, open label, controlled cohort study. Abstract ACR. 2016. 24. De Wilde K, Martens A, Lambrecht S, Jacques P, Drennan MB, Debusschere K, et al. A20 inhibition of STAT1 expression in my- 40. Healy PJ, Helliwell PS. Measuring clinical enthesitis in psoriatic eloid cells: a novel endogenous regulatory mechanism preventing arthritis: assessment of existing measures and development of an development of enthesitis. Ann Rheum Dis. 2017;76(3):585–92. instrument specific to psoriatic arthritis. Arthritis Rheum. 25. Matmati M, Jacques P, Maelfait J, Verheugen E, Kool M, Sze M, et 2008;59(5):686–91. al. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive 41. Orbai AM, Mease PJ, de Wit M, Kalyoncu U, Campbell W, Tillett polyarthritis resembling rheumatoid arthritis. Nat Genet. W, et al. Report of the GRAPPA-OMERACT Psoriatic Arthritis 2011;43(9):908–12. Working Group from the GRAPPA 2015 Annual Meeting. J Rheumatol. 2016;43(5):965–9. 26. Khmaladze I, Kelkka T, Guerard S, Wing K, Pizzolla A, Saxena A, et al. Mannan induces ROS-regulated, IL-17A–dependent psoriasis 42. Lubberts E. The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev arthritis-like disease in mice. Proc Natl Acad Sci U S A. Rheumatol. 2015;11(7):415–29. 2014;111(35):E3669–E78. 43. Sakkas LI, Alexiou I, Simopoulou T, Vlychou M. Enthesitis in 27. Sakkas LI, Bogdanos DP. Are psoriasis and psoriatic arthritis the psoriatic arthritis. Semin Arthritis Rheum. 2013;43(3):325–34. same disease? The IL-23/IL-17 axis data. Autoimmun Rev. 44. Coates LC, Kavanaugh A, Mease PJ, Soriano ER, Laura Acosta- 2017;16(1):10–5. Felquer M, Armstrong AW, et al. Group for research and assessment 28. Ciccia F, Accardo-Palumbo A, Rizzo A, Guggino G, Raimondo S, of psoriasis and psoriatic arthritis 2015 treatment recommendations Giardina A, et al. Evidence that autophagy, but not the unfolded for psoriatic arthritis. Arthritis Rheumatol. 2016;68(5):1060–71. protein response, regulates the expression of IL-23 in the gut of 45. Edwards CJ, Blanco FJ, Crowley J, Birbara CA, Jaworski J, Aelion patients with ankylosing spondylitis and subclinical gut inflamma- J, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients tion. Ann Rheum Dis. 2014;73(8):1566–74. with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis. 29. Kehl AS, Corr M, Weisman MH. Enthesitis: new insights into path- ogenesis, diagnostic modalities, and treatment. Arthritis Rheumatol 2016;75(6):1065–73. (Hoboken, NJ). 2016;68(2):312–22. 46. Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, 30. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Wollenhaupt J, Gladman DD, et al. Longterm (52-week) results et al. Innate lymphoid cells—a proposal for uniform nomenclature. of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol. 2015;42(3):479–88. Nat Rev Immunol. 2013;13(2):145–9. 31.�� Cuthbert RJ, Fragkakis EM, Dunsmuir R, Li Z, Coles M, Marzo- 47. Costa L, Del Puente A, Peluso R, Tasso M, Caso P, Chimenti MS, et al. Small molecule therapy for managing moderate to severe psori- Ortega H, et al. Brief report: group 3 innate lymphoid cells in human enthesis. Arthritis Rheumatol. 2017;69(9):1816–22. This atic arthritis. Expert Opin Pharmacother. 2017;18(15):1557–67. is a very important study that indicates the presence of resident 48. McGonagle D, Aydin SZ, Gul A, Mahr A, Direskeneli H. ‘MHC-I- innate lymphocytes in human entheses that may have a opathy’-unified concept for spondyloarthritis and Behcet disease. pathogrenic role in SpA. Nat Rev Rheumatol. 2015;11(12):731–40. 32.� El-Zayadi AA, Jones EA, Churchman SM, Baboolal TG, Cuthbert 49.� Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba RJ, El-Jawhari JJ, et al. Interleukin-22 drives the proliferation, mi- A, et al. Tofacitinib for psoriatic arthritis in patients with an inade- gration and osteogenic differentiation of mesenchymal stem cells: a quate response to TNF inhibitors. N Engl J Med. 2017;377(16): novel cytokine that could contribute to new bone formation in 1525–36. This is an important study to show the involvment spondyloarthropathies. Rheumatology (Oxford). 2017;56(3):488– of JAK signal pathways in PsA and the efficacy of JAKi in 93. This study shows the importance of IL-22 as a key pro- the treatment of PsA. inflammatory cytokine in the SpA group of diseases. 50. Mease P, Hall S, FitzGerald O, van der Heijde D, Merola JF, Avila- 33. Benjamin M, McGonagle D. The anatomical basis for disease Zapata F, et al. Tofacitinib or adalimumab versus placebo for pso- localisation in seronegative spondyloarthropathy at entheses and riatic arthritis. N Engl J Med. 2017;377(16):1537–50. related sites. J Anat. 2001;199(Pt 5):503–26. 51.�� Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea 34. Bandinelli F, Prignano F, Bonciani D, Bartoli F, Collaku L, JJ. JAK inhibition as a therapeutic strategy for immune and inflam- Candelieri A, et al. Ultrasound detects occult entheseal involvement matory diseases. Nat Rev Drug Discov. 2017;16(12):843–862. in early psoriatic arthritis independently of clinical features and This is a review paper that provides an elegant summary of psoriasis severity. Clin Exp Rheumatol. 2013;31(2):219–24. the role of JAK signal pathways in the diverse autoimmune diseases. 35. Freeston JE, Coates LC, Helliwell PS, Hensor EM, Wakefield RJ, Emery P, et al. Is there subclinical enthesitis in early psoriatic ar- 52. Eyerich S, Eyerich K, Cavani A, Schmidt-Weber C. IL-17 and IL- thritis? A clinical comparison with power doppler ultrasound. 22: siblings, not twins. Trends Immunol. 2010;31(9):354–61. Arthritis Care Res (Hoboken). 2012;64(10):1617–21. 53. Ritchlin C, Rahman P, Kavanaugh A, McInnes IB, Puig L, Li S, et 36. Hamdy M, Omar G, Elshereef RR, Ellaban AS, Amin M. Early al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal anti- detection of spondyloarthropathy in patients with psoriasis by using body, ustekinumab, in patients with active psoriatic arthritis despite the ultrasonography and magnetic resonance image. Eur J conventional non-biological and biological anti-tumour necrosis Rheumatol. 2015;2(1):10–5. factor therapy: 6-month and 1-year results of the phase 3, 37. Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Efficacy of multicentre, double-blind, placebo-controlled, randomised etanercept in the treatment of the entheseal pathology in resistant PSUMMIT 2 trial. Ann Rheum Dis. 2014;73(6):990–9. spondylarthropathy: a clinical and magnetic resonance imaging 54. Mease P, McInnes IB. Secukinumab: a new treatment option for study. Arthritis Rheum. 2001;44(9):2112–7. psoriatic arthritis. Rheumatol Ther. 2016;3(1):5–29. 41 Page 8 of 8 Curr Rheumatol Rep (2018) 20:41 55. McInnes IB, Mease PJ, Ritchlin CT, Rahman P, Gottlieb AB, psoriatic arthritis and an inadequate response to tumour necrosis Kirkham B, et al. Secukinumab sustains improvement in signs factor inhibitors: results from the 24-week randomised, double- and symptoms of psoriatic arthritis: 2 year results from the phase blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. 3 FUTURE 2 study. Rheumatology (Oxford). 2017;56(11):1993– Lancet. 2017;389(10086):2317–27. 58. Mease PJ, Genovese MC, Greenwald MW, Ritchlin CT, Beaulieu AD, 56. Mease PJ, van der Heijde D, Ritchlin CT, Okada M, Cuchacovich Deodhar A, et al. Brodalumab, an anti-IL17RA monoclonal antibody, RS, Shuler CL, et al. Ixekizumab, an interleukin-17A specific in psoriatic arthritis. N Engl J Med. 2014;370(24):2295–306. monoclonal antibody, for the treatment of biologic-naive patients 59.� Armaka M, Apostolaki M, Jacques P, Kontoyiannis DL, Elewaut with active psoriatic arthritis: results from the 24-week randomised, D, Kollias G. Mesenchymal cell targeting by TNF as a common double-blind, placebo-controlled and active (adalimumab)-con- pathogenic principle in chronic inflammatory joint and intestinal trolled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. diseases. J Exp Med. 2008;205(2):331–7. An important clinical 2017;76(1):79–87. study and one of the very few that includes enthesitis as an 57. Nash P, Kirkham B, Okada M, Rahman P, Combe B, Burmester outcome in the treatment of PsA. GR, et al. Ixekizumab for the treatment of patients with active http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Current Rheumatology Reports Springer Journals

Enthesitis: Much More Than Focal Insertion Point Inflammation

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Medicine & Public Health; Rheumatology
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Abstract

Purpose of Review Recognition of the importance of enthesitis as the pivotal pathological process underpinning spondyloarthropathies (SpA) has increased in recent years. Thus, we summarized the current knowledge on the pathogenic role of enthesitis on SpA shown by both animal models and human studies in vivo. Recent Findings Experimental models have shown several SpA-like diseases that commence at entheses and are linked to nail disease as well as dactylitis, two important entheseal-associated conditions in humans. Frequently, enthesitis is not the primary outcome measure in studies of peripheral PsA and SpA although arguably it is the key parameter being indirectly assessed in spinal disease in ankylosing spondylitis. The use of different agents including JAK, IL-17, and IL-23 inhibitors contributes significantly to our understanding of enthesitis in terms of involved immune pathways. Summary Enthesitis and enthesis organ inflammation may be the primary pathological process underlying SpA associated skeletal inflammation. Emergent studies are beginning to elucidate the molecular basis for this type of joint inflammatory response. . . . . . Keywords Enthesitis Entheses IL-17 IL-23 IL-12 JAKi Introduction Enthesis Microanatomy In the last decades, great advances have occurred in the The enthesis organ, defined as a group of tissues including etiopathogenetic understanding of the spondyloarthropathies fibrocartilages, bursa, fat pad, adjacent trabecular bone net- (SpA) which was paralleled by the introduction of the TNFi works, deeper fascia, and enthesis, functions collectively to therapies resulted in better clinical outcomes. A pivotal com- carry out a common task, namely anchorage and stress resis- ponent of these advances was the recognition that enthesitis, tance [3, 4]. The recognition that the enthesis is an organ helps defined as inflammation of tendon, ligament, and joint capsule to conceptualize why entheseal inflammation may be associ- insertions to the bones, is the cardinal pathological process in ated with diffuse extracapsular swelling in addition to synovi- the SpA group of diseases [1, 2]. In this article, we focus on tis and osteitis. An especially important component of the recent aspects of enthesis biology in experimental studies and enthesis organ is the synovio-entheseal complex where bursal in man and update the reader on new therapy developments and other synovial cavity resident macrophages provide lubri- for enthesitis. cation, nourishment, and metabolic requirements as well as micro-debris waste disposal in health [5]. However, these res- ident macrophages have also been suggested to trigger severe This article is part of the Topical Collection on Spondyloarthritis joint swelling in disease [3, 6–8]. The functional anatomy of the enthesis and how fibrocartilage-lined joints, some of * Dennis McGonagle which wrap around tendons, function like entheses and the D.G.McGonagle@leeds.ac.uk unifying mechanical explanation for disease that stems from these concepts has been well covered previously [4, 6]. Given Department of Medicine ‘B’, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel the fact that both the nail and the flexor tendons are respec- tively anchored to the skeleton via the distal interphalangeal Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel joint tendon or accessory pulleys, creating an enthesis-like Section of Musculoskeletal Disease, Leeds Institute of Molecular structure provides further support for the key importance of Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital, Leeds, UK the enthesis in SpA-related skin and joint manifestations [9]. 41 Page 2 of 8 Curr Rheumatol Rep (2018) 20:41 The Primacy of Enthesitis in Animal Models experiments showed that development of arthritis was depen- dent on TNF receptor I (TNFRI) expression [21]. Indeed, it Recently, several animal model studies have demonstrated the was shown that TNFRI expression in mesenchymal cells re- essential role of enthesitis in pathogenesis of the SpA group of sulted in a SpA and intestinal phenotype, demonstrating that diseases [10] and shed light on the importance of specific mesenchymal cells are primary targets in this model [19]. A inflammatory pathways and various cytokines in acting local- confirmation of these findings is well given in the study by ly such as IL-23 [8], IL-17, and IL-22 as key pro- Milia et al. [22], who studied transgenic rats with high expres- inflammatory cytokine in SpA potentially secreted by sion of HLA-B27 and human β (2)-microglobulin (B27TR), entheseal resident cells [8, 11]. Indeed, as result of better un- randomly assigned to TNFi treatment. Early and late admin- derstanding of the immune pathways involved in enthesitis, istration of anti-TNFα antibodies prevented and improved we are witnessing novel treatment advances that offer new inflammation and joint remodeling, respectively, preserving opportunities to improve clinical entheseal disease including the enthesis organization [22]. Interestingly, SMAD1/5/8 sig- IL-23 and IL-17 blockers as biological agents, and small mol- naling, a marker of bone remodeling, was not inhibited by late ecules such as PDE4 inhibitors and JAK inhibition [12–14]. anti-TNFα treatment [22]. These animal models kindled con- However, the basis for the reported PDE4 inhibition effi- siderable interest in the theory that enthesitis therapy might be cacy for enthesitis, but not synovitis in RA, is not understood associated with irreversible new bone formation lesions fol- at this time. lowing biological agent therapy. At the present time, the con- In the last few years, several experimental animal models sensus is that the earlier that biological therapy is used in man, of SpA-like disease have helped elucidate the role of enthesitis then the lower the likelihood of entheseal new bone formation as the primary pathological process in SpA, identifying vari- occurrence in the spine [23]. ous entheseal T cell subtypes and new immune pathways Furthermore, enthesitis, or more specifically synovio- (Table 1). Systemic overexpression of IL-23 using hydrody- entheseal complex disease, has been reported as an early feature namic injection of IL-23 minicircle DNA activated IL-23R+, of paw inflammation in mice with a myeloid cell-specific A20 ROR-γt+ CD3+ CD4− CD8−, stem cell antigen 1 (Sca1)+ (TNFα-induced protein 3) deficiency [24]. These mice are entheseal resident T cell lymphocytes inducing the transcript characterized by high levels of inflammatory cytokines, leading expression of IL-6, IL-17, and IL-22 as well as of CXCL1 to consistent NF-κB activation and significant production of genes [8]. The same technology induced arthritis and TNF, IL-1, and IL-6 by macrophages [25]. Nevertheless, in osteoblast-mediated bone remodeling and resulted in SpA- the myeloid A20 knockout mice, SpA-type arthropathy is inde- like bone formation manifestation of SpA with IL-22 but not pendent of TNF but dependent on IL-1 and IL-6 [25]. In the IL-17A DNA minicircles [8]. However, in the aforementioned early phase of arthritis of these mice, Achilles tendon region model, enthesitis was IL-17A dependent and this is consistent swelling was noted, and hematoxylin-eosin staining showed with the SKG mouse model of enthesitis [8, 15]. inflammation of the synovio-entheseal complex (SEC) [24]. In 2016, it was shown that the majority of IL-23R- Disease was blocked by the tofacitinib administration which responsive cells in the normal murine entheses were γδ Tcells provided pre-clinical support for JAKi in PsA and SpA. expressing the RAR-related orphan receptor γt(ROR-γt) The importance of the IL-23/17 axis has been further sup- transcription factor, as well as the IL-23 and CCR6 receptors, ported by other experimental studies where disease also com- and are capable of IL-17A production [16]. More specifically, mences at the enthesis and is associated with other SpA man- Reinhardt et al. analyzed entheseal lymphocytes from C57BL/ ifestations including nail disease and dactylitis [15, 26, 27]. 6, Tcrd-H2BeGFP, Rorc-GFP, and IL-23R-eGFP murine There is evidence for local IL-23 production in the gut [28] models, after performing hydrodynamic injection of IL-23 and it has been proposed that systemic circulation of IL-23 minicircle DNA [16]. Activated Vγ6+CD27− γ/δ T cells con- could then trigger SpA at the entheses [8]. IL-23 activating stituted the largest T cell subset [16]. Of particular relevance to resident Tcells within the enthesis promotes inflammation and the SpA concept was γδ T cells in the murine ciliary body, bone remodeling mediated by IL-17 and osteoproliferation thus offering a micro anatomical and immunological link be- mediated by IL-22 [29]. Thus far, there is little data on the tween the enthesis and the eye [17]. source of IL-23/17 axis cytokines driving human arthritis and TNF plays a key role in the pathogenesis of IBD, in which questions relating to whether IL-23 in particular is locally or enthesitis is also a typical manifestation when the disease also systemically produced remain to be elucidated. involves extra-intestinal structures [18]. Another animal mod- el demonstrating the involvement of entheses is the TNF over- expression model that was reported by Armaka et al. [19]who Human Studies of the Enthesis ΔARE/+ used a TNF transgenic model known as the TNF mu- tant mice, characterized by the development of Crohn’s-like The description of an IL-23-responsive population of T cells IBD and SpA-like disease [20]. Bone marrow-grafting [8], along with the description of a group of cytokine-dependent Curr Rheumatol Rep (2018) 20:41 Page 3 of 8 41 Table 1 Selected murine enthesitis models Reference Species Strain Intervention Characteristics Reihardt et al. [16] Mice Tcrd-H2BeGFP mice crossed Hydrodynamic injection Activated Vγ6+CD27− γ/δ Tcells were with mice of the susceptible of IL-23 minicircle DNA found in uninflamed entheseal tissue B10.RIII background and constituted the largest resident T cell subset. Armaka et al. [59� ] Mice TNF-overexpressing mouse Spondyloarthritis with a CD-like pathology ΔARE/+ model (TNF ) localized primarily in the small intestine. Additionally, the development of arthritis was dependent on TNF receptor I (TNFRI) expression with mesenchymal cells being primary responders. myelKO De wilde et al. [24]Mice A20 mice A20 knockout Enthesitis was found to be an early myelKO inflammatory lesion in A20 mice. A20 negatively modulated STAT1-dependent gene transcription in myeloid cells which was JAK/STAT dependent. Benham et al. [15] Mice BALB/c ZAP-70(W163C)- β-1,3-Glucan injected In curdlan-treated SKG mice, arthritis, enthesitis, mutant (SKG) mice intraperitoneally and ileitis were IL-23 dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-17A was pathogenic, while IL-22 was protective against ileitis. Sherlock et al. [8] Mice B10.RIII mice Immunization with type IL-23 is essential in enthesitis and acts on II collagen previously unidentified IL-23 receptor (IL-23R)+, RAR-related orphan receptor gt (ROR-gt)+CD3+CD4–CD8–, stem cell antigen 1 (Sca1)+ entheseal resident T cells which led to the induction of IL-6, IL-17, and IL-22 as well as of CXCL1 secretion leading to osteoblast remodeling which is characteristic of enthesitis. innate lymphoid cells (ILCs) [30], ledtoasearch forinnate Evaluating Enthesitis immune cells at the normal human enthesis. We selected small normal interspinous process entheses from donors with no sys- Unfortunately, in humans, enthesitis remains stubbornly diffi- temic inflammatory disease to explore the presence of type 3 cult to assess [33]. The complete avascularity of entheses at ILC populations. [31�� ]. The small interspinous process bone attachment sites and the low vessel density in adjacent entheses have advantages over large attachment sites like the ligaments and tendons as well as the lack of adaptive hyper- Achilles tendon where thick juxta-articular fibrocartilaginous plasia that is normally seen in synovitis make assessment of tissue that is completely devoid of immune cells precludes im- these sites particularly challenging [33]. Moreover, despite the mune cell subset evaluation. We showed that the normal human existence of various clinical measures for enthesitis, there is enthesis did indeed harbor a rare population of IL-23R- no sound consensus concerning their validity in PsA, since expressing type 3 ILCs [31 ]. We were also able to demon- gold standard validation has not been performed. Therefore, strate the presence of a comparatively abundant population of it is necessary to rely on imaging rather than clinical exam- γδ T cells. In health, entheseal cells were present in both the ination in order to detect non-accessible sites of entheses. enthesis soft tissue and the peri-entheseal bone [31�� ]. Indeed, numerous studies have shown that ultrasound (US) Furthermore, there was little evidence for expression of IL- could detect a subclinical enthesitis in PsA patients 17A transcripts in health, but of note, the IL-23R+ type 3 [34–36]. ILCs expressed TNFα transcript [31 ]. Following stimulation Typically, enthesitis is associated with diffuse peri- of human entheseal tissue with IL-23 and IL-1β,wedemon- entheseal soft tissue edema on magnetic resonance imaging strated upregulation of IL-17A and evidence for upregulation of (MRI) with this adjacent reaction being usually more conspic- IL-17F and IL-22 (Fig. 1). The inducible expression of IL-22 uous than inflammation within the insertion which reflects the on these entheseal resident immunocytes and the recognition greater vascularity of the peri-entheseal tissues (Fig. 2). Both that IL-22 drives human MSC osteogenesis [32� ] fit into a entheses and sacroiliac fibrocartilaginous joints have promi- model whereby inflammation at the entheses may later drive nent fibrocartilages and disease of both structures may be new bone formation (Fig. 1). associated with an adjacent severe osteitis that likely reflects �� �� 41 Page 4 of 8 Curr Rheumatol Rep (2018) 20:41 Fig. 1 Lymphocyte populations defined at the human enthesis. Thus far, two lymphocyte populations have been defined at the human enthesis. Innate lymphoid cells are part of the IL- 23-responsive T cells which are residents of the healthy enthesis. Gamma delta T cells are also resident at the enthesis. The activation of resident T cells within the enthesis by IL-23 may promote inflammation, osteogenesis, and bone loss and remodeling. These lymphocyte populations may release different cytokines including IL-17 and IL- 22 and TNF-α the excellent vascularity of the marrow (Fig. 3). However, immunological knowledge about human enthesis and the di- neither MRI nor US excludes the presence of enthesitis, and verse immune pathways that are involved in disease [42]. the role of imaging remains controversial since the use of Moreover, the use of enthesitis as an important manifestation power Doppler (PD) which is typical of RA-related synovitis of PsA, and its evaluation in drug trials, and clinical practice as activity is generally much less conspicuous at insertions [37, well, has increased dramatically with enthesitis now a univer- 38]. Studies comparing clinical enthesitis with imaging sal secondary outcome measure in trials [43]. The treatment of enthesitis in SpA show virtually no correlations [34]. enthesitis remains a challenge. Conventional DMARDs such Furthermore, where suspected pathology is seen, it is uncom- mon to get tissue to confirm the diagnosis. Therefore, the assessment criteria remain subjective. The exact histopatho- logical basis for the subclinical entheseal abnormalities pres- ent in PsA and other forms of SpA is poorly understood. However, a recent US study reported in abstract form has shown that subclinical enthesopathy in psoriasis cases re- gresses following anti-IL-12/23 therapy, suggesting an inflam- matory component [39]. Among the diverse clinical measures for enthesitis, the Leeds Enthesitis Index (LEI) uses the medial collateral liga- ment (MCL) origin in both knees as a site of enthesitis [40]. This anatomic structure forms an elaborate synovio-entheseal complex that might be inflamed as a result of events taking place elsewhere within the synovial cavity; thus, it is hard to interpret exactly what tenderness at this location means and whether it could be linked to synovitis. It might be that these difficulties and complexities in recognizing and measuring enthesitis contributed to the GRAPPA-OMERACT for PsA standardization unwittingly dropped enthesitis from core domain assessments [41]. The move towards trials in early PsA makes the need to address enthesitis an urgent one since early disease may might be strongly linked. Recent Clinical Developments Fig. 2 Magnetic resonance imaging (MRI) of the sacroiliac joints (SIJ) showing bilateral ischial tuberosity enthesitis in a patient with newonset The response of human enthesitis to various therapeutic agents PsA. The site of soft tissue entheseal inflammation is depicted by goes some way to improve the rudimentary state of arrowheads. In this case, there is sparing of the bony attachment. Curr Rheumatol Rep (2018) 20:41 Page 5 of 8 41 Fig. 3 Magnetic resonance imaging (MRI) of the sacroiliac joints (SIJ) showing bilateral sacral joint bone marrow edema on in a patient with early psoriatic arthritis. The Bone marrow edema is more florid at the anterior part of the joint adjacent to the capsular enthesis. It remains to be determined whether the patterns of inflammation at entheses in soft tissue or in the bone may influence responses to therapy as sulfasalazine and methotrexate are not significantly effective However, the two biggest classes of drugs used to treat PsA for enthesitis management, yet NSAIDs remain the first-line ther- and AS, namely TNF and IL-17 inhibitors, do not signal di- apy [43] although corticosteroid therapy including injection, rectly through the JAK pathway [52]. Nevertheless, IL-23 where appropriate or feasible, is also an option. TNF blockade signals via tyrosine kinase 2 (Tyk2) blockers for psoriasis is the standard of care for enthesitis and severe axial disease in support the idea of a therapy effect via IL-23 alone [51�� , 53]. those patients with partial response to conventional DMARDs An unexpected finding in this field is the apparent non- [44]. However, in recent years, many efforts were made to assess efficacy for ustekinumab for spinal enthesitis of AS despite the efficacy of several therapeutic agents in enthesitis. its efficacy in the peripheral skeleton (data not published). The Recent phase 3 studies have shown efficacy of PDE4 most obvious avenues for exploration are that the immune blockers for PsA but with lower ACR 20 responses compared system at the immunobiology peripheral and axial entheses to the biologic class of drugs. A favorable effect of the PDE4 may be fundamentally different and that higher doses of blocker, apremilast, on enthesitis has been reported [45, 46]. anti-IL-23 pathway cytokine are needed for axial disease. Given that the PDE4 blockers are ineffective in RA and do not One obvious difference is the relative absence of the block autoantibody production but suppress the neutrophil synovio-entheseal complex in the spine and where pathology influx to sites of tissue inflammation [47], it is likely that these is often located at entheseal bone anchorage points [33]. agents are working predominantly on innate immunity. This However, this intriguing observation around IL-12/23 block- supports the idea of what we termed MHC-1-opathy [48], ade apparent non-efficacy awaits further study including data whereby in the SpA group of diseases, initial site-specific on the IL-23 pathway antagonism with specific p19 blockers. innate immune activation drives adaptive immune activation The IL-17 blockers have also been evaluated for their effect via CD8+ T cells, which in turn drive IL-17-related neutro- on enthesitis. Secukinumab a IL-17A blocker has shown effi- philic tissue inflammation exacerbation of these diseases [48]. cacy for enthesitis in several trials [54, 55]. Ixekizumab, a Two recent studies have evaluated Janus kinase (JAK) inhibi- second IL-17A blocker with a 50-fold higher affinity, showed tion with tofacitinib, a pan JAK inhibitor for the treatment of efficacy for enthesitis in the P-SPIRIT-1 study [56]. However, PsA [49� , 50]. In biologic naïve cases, tofacitinib was com- in the P-SPIRIT 2 study with the same molecule in PsA cases pared to adalimumab, where enthesitis was assessed as a sec- that failed to respond to prior TNF blockade, there was no ondary outcome, reporting a favorable response [50]. significant effect on enthesitis at the pre-specified 24-week However, in the second study, the pre-specified statistical hi- assessment, but there was evidence for efficacy at earlier time erarchical model used precluded an evaluation of enthesitis points [57]. A third molecule, brodalumab, an IL-17RA [49� ]. It is likely that JAK inhibition will represent a new blocker, was also evaluated for its effect on enthesitis and no option in the treatment of PsA and enthesitis. The precise significant effect was found in those patients who had scores mechanism of action of JAK inhibition is unclear since over of more than 0 for enthesitis at week 12 between the group 50 different cytokines including interleukins, CSFs, and hor- receiving 140 mg of brodalumab and the group receiving mones that share various signaling pathways are mediated by 280 mg of brodalumab, as compared with the placebo group [58]. However, although not statistically significant, there was JAKs [51�� ]. 41 Page 6 of 8 Curr Rheumatol Rep (2018) 20:41 4. Shaw HM, Vazquez OT, McGonagle D, Bydder G, Santer RM, a greater numerical improvement in enthesitis in subjects on Benjamin M. Development of the human Achilles tendon enthesis higher dose of brodalumab. Given all the genetic and patho- organ. J Anat. 2008;213(6):718–24. logical data and the existing studies, it seems that these agents 5. McGonagle D, Aydin SZ, Tan AL. The synovio-entheseal complex will be effective for the therapy of enthesitis. and its role in tendon and capsular associated inflammation. J Rheumatol Suppl. 2012;89:11–4. 6. Benjamin M, Moriggl B, Brenner E, Emery P, McGonagle D, Redman S. The “enthesis organ” concept: why enthesopathies may not present as focal insertional disorders. Arthritis Rheum. Conclusions 2004;50(10):3306–13. 7. Apostolakos J, Durant TJS, Dwyer CR, Russell RP, Weinreb JH, Enthesitis is much more than local inflammation; indeed, it is Alaee F, et al. The enthesis: a review of the tendon-to-bone inser- considered as the primary pathological process underling tion. Muscles Ligaments Tendons J. 2014;4(3):333–42. SpA. This has been shown by investigating the enthesis in 8. Sherlock JP, Joyce-Shaikh B, Turner SP, Chao CC, Sathe M, Grein J, et al. IL-23 induces spondyloarthropathy by acting on ROR- both animal models and human studies in vivo. Enthesitis gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. management is still a challenging matter for rheumatologists 2012;18(7):1069–76. and various new agents were evaluated for their effect on 9. Benjamin M, Kaiser E, Milz S. Structure-function relationships in enthesitis reporting different findings. The use of different tendons: a review. J Anat. 2008;212(3):211–28. 10. McGonagle D, Tan AL. The enthesis in psoriatic arthritis. Clin Exp agents including JAK, IL-17, and IL-23 inhibitors have con- Rheumatol. 2015;33(5 Suppl 93):S36–9. tributed significantly to our understanding of enthesitis in 11. Ahlfors H, Morrison PJ, Duarte JH, Li Y, Biro J, Tolaini M, et al. IL- terms of involved immune pathways. Nevertheless, there is 22 fate reporter reveals origin and control of IL-22 production in an unmet need for further studies to improve our understand- homeostasis and infection. J Immunol. 2014;193(9):4602–13. ing about enthesopathy seeking a better detection, and there- 12. Kavanaugh A, Puig L, Gottlieb AB, Ritchlin C, Li S, Wang Y, et al. Maintenance of clinical efficacy and radiographic benefit through fore management. two years of ustekinumab therapy in patients with active psoriatic arthritis: results from a randomized, placebo-controlled phase III Compliance with Ethical Standards trial. Arthritis Care Res (Hoboken). 2015;67(12):1739–49. 13. Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Conflict of Interest The authors declare that they have no conflict of Wollenhaupt J, Gladman DD, et al. Treatment of psoriatic arthritis interest. in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor. Ann Rheum Dis. 2014;73(6): 1020–6. Human and Animal Rights and Informed Consent This article does not 14. Ebihara S, Date F, Dong Y, Ono M. Interleukin-17 is a critical target contain any studies with human or animal subjects performed by any of for the treatment of ankylosing enthesitis and psoriasis-like derma- the authors. titis in mice. Autoimmunity. 2015;48(4):259–66. Open Access This article is distributed under the terms of the Creative 15. Benham H, Rehaume LM, Hasnain SZ, Velasco J, Baillet AC, Commons Attribution 4.0 International License (http:// Ruutu M, et al. Interleukin-23 mediates the intestinal response to creativecommons.org/licenses/by/4.0/), which permits unrestricted use, microbial beta-1,3-glucan and the development of spondyloarthritis distribution, and reproduction in any medium, provided you give appro- pathology in SKG mice. Arthritis Rheumatol. 2014;66(7):1755–67. priate credit to the original author(s) and the source, provide a link to the 16. Reinhardt A, Yevsa T, Worbs T, Lienenklaus S, Sandrock I, Creative Commons license, and indicate if changes were made. Oberdorfer L, et al. Interleukin-23-dependent gamma/delta T cells produce interleukin-17 and accumulate in the enthesis, aortic valve, and ciliary body in mice. Arthritis Rheumatol. 2016;68(10):2476–86. 17. McGonagle D, Stockwin L, Isaacs J, Emery P. An enthesitis based model for the pathogenesis of spondyloarthropathy. Additive ef- fects of microbial adjuvant and biomechanical factors at disease References sites. J Rheumatol. 2001;28(10):2155–9. 18. Horton DB, Sherry DD, Baldassano RN, Weiss PF. Enthesitis is an Papers of particular interest, published recently, have been extraintestinal manifestation of pediatric inflammatory bowel dis- ease. Ann Paediatr Rheumatol. 2012;1(4):214. https://doi.org/10. highlighted as: 5455/apr.102920121510. � Of importance 19. Armaka M, Apostolaki M, Jacques P, Kontoyiannis DL, Elewaut D, �� Of major importance Kollias G. Mesenchymal cell targeting by TNF as a common path- ogenic principle in chronic inflammatory joint and intestinal dis- 1. McGonagle D, Gibbon W, O'Connor P, Green M, Pease C, Emery eases. J Exp Med. 2008;205(2):331–7. P. Characteristic magnetic resonance imaging entheseal changes of 20. Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. knee synovitis in spondylarthropathy. Arthritis Rheum. 1998;41(4): Impaired on/off regulation of TNF biosynthesis in mice lacking 694–700. TNF AU-rich elements: implications for joint and gut-associated 2. McGonagle D, Gibbon W, Emery P. Classification of inflammatory immunopathologies. Immunity. 1999;10(3):387–98. arthritis by enthesitis. Lancet. 1998;352(9134):1137–40. 21. Williams-Skipp C, Raman T, Valuck RJ, Watkins H, Palmer BE, 3. Benjamin M, McGonagle D. The enthesis organ concept and its Scheinman RI. Unmasking of a protective tumor necrosis factor relevance to the spondyloarthropathies. Adv Exp Med Biol. receptor I-mediated signal in the collagen-induced arthritis model. 2009;649:57–70. Arthritis Rheum. 2009;60(2):408–18. Curr Rheumatol Rep (2018) 20:41 Page 7 of 8 41 22. Milia AF, Ibba-Manneschi L, Manetti M, Benelli G, Generini S, 38. McGonagle D, Marzo-Ortega H, O’Connor P, Gibbon W, Pease C, Messerini L, et al. Evidence for the prevention of enthesitis in HLA- Reece R, et al. The role of biomechanical factors and HLA-B27 in B27/hbeta(2)m transgenic rats treated with a monoclonal antibody magnetic resonance imaging-determined bone changes in plantar against TNF-alpha. J Cell Mol Med. 2011;15(2):270–9. fascia enthesopathy. Arthritis Rheum. 2002;46(2):489–93. 23. Haroon N, Inman RD, Learch TJ, Weisman MH, Lee M, Rahbar 39. Laura Savage, Mark Goodfield, Elizabeth M.A. Hensor, Paul MH, et al. The impact of tumor necrosis factor alpha inhibitors on Emery, McGonagle D. Ultrasonographic improvement of peripher- radiographic progression in ankylosing spondylitis. Arthritis al subclinical enthesopathy in therapy-naive patients treated with Rheum. 2013;65(10):2645–54. ustekinumab for chronic plaque psoriasis: a 52-week, prospective, open label, controlled cohort study. Abstract ACR. 2016. 24. De Wilde K, Martens A, Lambrecht S, Jacques P, Drennan MB, Debusschere K, et al. A20 inhibition of STAT1 expression in my- 40. Healy PJ, Helliwell PS. Measuring clinical enthesitis in psoriatic eloid cells: a novel endogenous regulatory mechanism preventing arthritis: assessment of existing measures and development of an development of enthesitis. Ann Rheum Dis. 2017;76(3):585–92. instrument specific to psoriatic arthritis. Arthritis Rheum. 25. Matmati M, Jacques P, Maelfait J, Verheugen E, Kool M, Sze M, et 2008;59(5):686–91. al. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive 41. Orbai AM, Mease PJ, de Wit M, Kalyoncu U, Campbell W, Tillett polyarthritis resembling rheumatoid arthritis. Nat Genet. W, et al. Report of the GRAPPA-OMERACT Psoriatic Arthritis 2011;43(9):908–12. Working Group from the GRAPPA 2015 Annual Meeting. J Rheumatol. 2016;43(5):965–9. 26. Khmaladze I, Kelkka T, Guerard S, Wing K, Pizzolla A, Saxena A, et al. Mannan induces ROS-regulated, IL-17A–dependent psoriasis 42. Lubberts E. The IL-23-IL-17 axis in inflammatory arthritis. Nat Rev arthritis-like disease in mice. Proc Natl Acad Sci U S A. Rheumatol. 2015;11(7):415–29. 2014;111(35):E3669–E78. 43. Sakkas LI, Alexiou I, Simopoulou T, Vlychou M. Enthesitis in 27. Sakkas LI, Bogdanos DP. Are psoriasis and psoriatic arthritis the psoriatic arthritis. Semin Arthritis Rheum. 2013;43(3):325–34. same disease? The IL-23/IL-17 axis data. Autoimmun Rev. 44. Coates LC, Kavanaugh A, Mease PJ, Soriano ER, Laura Acosta- 2017;16(1):10–5. Felquer M, Armstrong AW, et al. Group for research and assessment 28. Ciccia F, Accardo-Palumbo A, Rizzo A, Guggino G, Raimondo S, of psoriasis and psoriatic arthritis 2015 treatment recommendations Giardina A, et al. Evidence that autophagy, but not the unfolded for psoriatic arthritis. Arthritis Rheumatol. 2016;68(5):1060–71. protein response, regulates the expression of IL-23 in the gut of 45. Edwards CJ, Blanco FJ, Crowley J, Birbara CA, Jaworski J, Aelion patients with ankylosing spondylitis and subclinical gut inflamma- J, et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients tion. Ann Rheum Dis. 2014;73(8):1566–74. with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann Rheum Dis. 29. Kehl AS, Corr M, Weisman MH. Enthesitis: new insights into path- ogenesis, diagnostic modalities, and treatment. Arthritis Rheumatol 2016;75(6):1065–73. (Hoboken, NJ). 2016;68(2):312–22. 46. Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, 30. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Wollenhaupt J, Gladman DD, et al. Longterm (52-week) results et al. Innate lymphoid cells—a proposal for uniform nomenclature. of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol. 2015;42(3):479–88. Nat Rev Immunol. 2013;13(2):145–9. 31.�� Cuthbert RJ, Fragkakis EM, Dunsmuir R, Li Z, Coles M, Marzo- 47. Costa L, Del Puente A, Peluso R, Tasso M, Caso P, Chimenti MS, et al. Small molecule therapy for managing moderate to severe psori- Ortega H, et al. Brief report: group 3 innate lymphoid cells in human enthesis. Arthritis Rheumatol. 2017;69(9):1816–22. This atic arthritis. Expert Opin Pharmacother. 2017;18(15):1557–67. is a very important study that indicates the presence of resident 48. McGonagle D, Aydin SZ, Gul A, Mahr A, Direskeneli H. ‘MHC-I- innate lymphocytes in human entheses that may have a opathy’-unified concept for spondyloarthritis and Behcet disease. pathogrenic role in SpA. Nat Rev Rheumatol. 2015;11(12):731–40. 32.� El-Zayadi AA, Jones EA, Churchman SM, Baboolal TG, Cuthbert 49.� Gladman D, Rigby W, Azevedo VF, Behrens F, Blanco R, Kaszuba RJ, El-Jawhari JJ, et al. Interleukin-22 drives the proliferation, mi- A, et al. Tofacitinib for psoriatic arthritis in patients with an inade- gration and osteogenic differentiation of mesenchymal stem cells: a quate response to TNF inhibitors. N Engl J Med. 2017;377(16): novel cytokine that could contribute to new bone formation in 1525–36. This is an important study to show the involvment spondyloarthropathies. Rheumatology (Oxford). 2017;56(3):488– of JAK signal pathways in PsA and the efficacy of JAKi in 93. This study shows the importance of IL-22 as a key pro- the treatment of PsA. inflammatory cytokine in the SpA group of diseases. 50. Mease P, Hall S, FitzGerald O, van der Heijde D, Merola JF, Avila- 33. Benjamin M, McGonagle D. The anatomical basis for disease Zapata F, et al. Tofacitinib or adalimumab versus placebo for pso- localisation in seronegative spondyloarthropathy at entheses and riatic arthritis. N Engl J Med. 2017;377(16):1537–50. related sites. J Anat. 2001;199(Pt 5):503–26. 51.�� Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea 34. Bandinelli F, Prignano F, Bonciani D, Bartoli F, Collaku L, JJ. JAK inhibition as a therapeutic strategy for immune and inflam- Candelieri A, et al. Ultrasound detects occult entheseal involvement matory diseases. Nat Rev Drug Discov. 2017;16(12):843–862. in early psoriatic arthritis independently of clinical features and This is a review paper that provides an elegant summary of psoriasis severity. Clin Exp Rheumatol. 2013;31(2):219–24. the role of JAK signal pathways in the diverse autoimmune diseases. 35. Freeston JE, Coates LC, Helliwell PS, Hensor EM, Wakefield RJ, Emery P, et al. Is there subclinical enthesitis in early psoriatic ar- 52. Eyerich S, Eyerich K, Cavani A, Schmidt-Weber C. IL-17 and IL- thritis? A clinical comparison with power doppler ultrasound. 22: siblings, not twins. Trends Immunol. 2010;31(9):354–61. Arthritis Care Res (Hoboken). 2012;64(10):1617–21. 53. Ritchlin C, Rahman P, Kavanaugh A, McInnes IB, Puig L, Li S, et 36. Hamdy M, Omar G, Elshereef RR, Ellaban AS, Amin M. Early al. Efficacy and safety of the anti-IL-12/23 p40 monoclonal anti- detection of spondyloarthropathy in patients with psoriasis by using body, ustekinumab, in patients with active psoriatic arthritis despite the ultrasonography and magnetic resonance image. Eur J conventional non-biological and biological anti-tumour necrosis Rheumatol. 2015;2(1):10–5. factor therapy: 6-month and 1-year results of the phase 3, 37. Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Efficacy of multicentre, double-blind, placebo-controlled, randomised etanercept in the treatment of the entheseal pathology in resistant PSUMMIT 2 trial. Ann Rheum Dis. 2014;73(6):990–9. spondylarthropathy: a clinical and magnetic resonance imaging 54. Mease P, McInnes IB. Secukinumab: a new treatment option for study. Arthritis Rheum. 2001;44(9):2112–7. psoriatic arthritis. Rheumatol Ther. 2016;3(1):5–29. 41 Page 8 of 8 Curr Rheumatol Rep (2018) 20:41 55. McInnes IB, Mease PJ, Ritchlin CT, Rahman P, Gottlieb AB, psoriatic arthritis and an inadequate response to tumour necrosis Kirkham B, et al. Secukinumab sustains improvement in signs factor inhibitors: results from the 24-week randomised, double- and symptoms of psoriatic arthritis: 2 year results from the phase blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. 3 FUTURE 2 study. Rheumatology (Oxford). 2017;56(11):1993– Lancet. 2017;389(10086):2317–27. 58. Mease PJ, Genovese MC, Greenwald MW, Ritchlin CT, Beaulieu AD, 56. Mease PJ, van der Heijde D, Ritchlin CT, Okada M, Cuchacovich Deodhar A, et al. Brodalumab, an anti-IL17RA monoclonal antibody, RS, Shuler CL, et al. Ixekizumab, an interleukin-17A specific in psoriatic arthritis. N Engl J Med. 2014;370(24):2295–306. monoclonal antibody, for the treatment of biologic-naive patients 59.� Armaka M, Apostolaki M, Jacques P, Kontoyiannis DL, Elewaut with active psoriatic arthritis: results from the 24-week randomised, D, Kollias G. Mesenchymal cell targeting by TNF as a common double-blind, placebo-controlled and active (adalimumab)-con- pathogenic principle in chronic inflammatory joint and intestinal trolled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. diseases. J Exp Med. 2008;205(2):331–7. An important clinical 2017;76(1):79–87. study and one of the very few that includes enthesitis as an 57. Nash P, Kirkham B, Okada M, Rahman P, Combe B, Burmester outcome in the treatment of PsA. GR, et al. Ixekizumab for the treatment of patients with active

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