Overview of Spondyloarthropathies: Difference between revisions

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<div class="editorbox"> '''Original Editor '''- [[User:Jess Bell|Jess Bell]] '''Top Contributors''' - {{Special:Contributors/{{FULLPAGENAME}}}}</div>
== Introduction ==
== Introduction ==
Spondyloarthropathy (or Spondyloarthritis) is an umbrella term for a group of inflammatory rheumatic diseases.<ref name=":0">Martey C. Overview of Spondyloarthropathies Course. Physioplus, 2020. </ref><ref name=":1">Ehrenfeld M, Infection and spondyloarthropathies. In: Shoenfeld Y, Agmon-Levin N, Rose NR editors. Infection and autoimmunity. Elsevier B.V. 2015. p745-57.</ref> Spondyloarthropathies are progressive and painful. They often involve the axial skeleton (i.e. the spine and the sacroiliac joints), but can also affect the peripheral skeleton.<ref name=":0" /> They are associated with enthesitis (inflammation of the site where tendons / ligaments insert into bone<ref>Schett G, Lories R, D'Agostino M, Elewaut D, Krikham B, Soriano ER et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 2017; 13: 731–741.</ref>) and dactylitis (i.e. diffuse swelling of the fingers<ref>McGonagle D, Tan AL, Watad A, Helliwell P. Pathophysiology, assessment and treatment of psoriatic dactylitis. Nat Rev Rheumatol. 2019; 15: 113–122. </ref>). Other areas affected include the heart, eyes, lungs, skin, gut and genitourinary tract.<ref name=":1" />
Spondyloarthropathy (or spondyloarthritis) is an umbrella term for a group of inflammatory rheumatic diseases.<ref name=":0">Martey C. Overview of Spondyloarthropathies Course. Plus, 2020. </ref><ref name=":1">Ehrenfeld M, Infection and spondyloarthropathies. In: Shoenfeld Y, Agmon-Levin N, Rose NR editors. Infection and autoimmunity. Elsevier B.V. 2015. p745-57.</ref> It is considered a common condition, but there is significant variation in the reported prevalence rates of spondyloarthropathy and its subgroups.<ref>Stolwijk C, van Onna M, Boonen A, van Tubergen A. [https://acrjournals.onlinelibrary.wiley.com/doi/abs/10.1002/acr.22831 Global prevalence of spondyloarthritis: a systematic review and meta-regression analysis]. Arthritis Care Res (Hoboken). 2016 Sep;68(9):1320-31.</ref>


There are five types of Spondyloarthritis:<ref name=":0" />
Spondyloarthropathies are progressive and painful. They often involve the axial skeleton (i.e. the spine and the sacroiliac joints), but they can also affect the peripheral skeleton.<ref name=":0" /> They are associated with enthesitis (inflammation of the site where tendons / ligaments insert into bone<ref>Schett G, Lories R, D'Agostino M, Elewaut D, Krikham B, Soriano ER et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 2017; 13: 731–741.</ref>) and dactylitis (i.e. diffuse swelling of the digits<ref>Girolimetto N, Giovannini I, Crepaldi G, De Marco G, Tinazzi I, Possemato N, Macchioni P, McConnell R, McGonagle D, Iagnocco A, Zabotti A. [https://www.mdpi.com/2077-0383/10/12/2604/htm Psoriatic Dactylitis: Current perspectives and new insights in ultrasonography and magnetic resonance imaging.] Journal of Clinical Medicine. 2021 Jun 12;10(12):2604.</ref>). Other areas affected include the [[Anatomy of the Human Heart|heart]], eyes, [[Lung Anatomy|lung]]<nowiki/>s, [[skin]], gut and genitourinary tract.<ref name=":1" />
* Ankylosing Spondylitis (also known as Bechterew's disease or Marie-Strumpell disease)
 
* Psoriatic Arthritis
There are five types of spondyloarthritis:<ref name=":0" />
* Reactive Arthritis (formerly called Reiter's syndrome)
* Axial spondyloarthritis (axSpA) - also known as [[Ankylosing Spondylitis (Axial Spondyloarthritis)|ankylosing spondylitis]] <ref>Fragoulis GE, Siebert S. [https://academic.oup.com/rheumatology/article/59/Supplement_4/iv79/5923433 Treatment strategies in axial spondyloarthritis: what, when and how?]. Rheumatology. 2020 Oct;59(Supplement_4):iv79-89.</ref>
* Enteropathic Arthritis
* [[Psoriatic Arthritis|Psoriatic arthritis]] - also known as peripheral spondyloarthritis <ref>Ogdie A, Coates LC, Gladman DD. [https://academic.oup.com/rheumatology/article/59/Supplement_1/i37/5802853 Treatment guidelines in psoriatic arthritis]. Rheumatology. 2020 Mar 1;59(Supplement_1):i37-46.</ref>
* Undifferentiated spondyloarthropathy
* [[Reactive Arthritis|Reactive arthritis]] - formerly called Reiter's syndrome<ref>Bentaleb I, Abdelghani KB, Rostom S, Amine B, Laatar A, Bahiri R. [https://link.springer.com/content/pdf/10.1007/s40588-020-00152-6.pdf Reactive arthritis: update. Current clinical microbiology reports]. 2020 Dec;7(4):124-32.</ref>
* [[Enteropathic Spondylitis|Enteropathic arthritis]]
* Undifferentiated spondyloarthritis (uSpA)


== Epidemiology / Aetiology ==
== Epidemiology / Aetiology ==
Symptoms associated with spondyloarthropathy typically start before the age of 45.<ref name=":0" /> They affect men slightly more than women with a 1,1:1 ratio and men are younger at diagnosis than women.<ref>Alzate M, Vargas F, Ramirez F, et alSAT0414 Differences in clinical presentation by gender in colombian patients with spondyloarthropathies. Annals of the Rheumatic Diseases 2017;76(2): 928.</ref> Unlike other rheumatic diseases like [[Rheumatoid Arthritis]], spondyloarthropathies are seronegative for rheumatoid factor.<ref>Navallas M, Ares J, Beltrán B, Lisbona MP, Maymó J, Solano A. Sacroiliitis associated with axial spondyloarthropathy: new concepts and latest trends. Radiographics. 2013 Jul-Aug;33(4):933-56.</ref>
Symptoms associated with spondyloarthropathy typically start before the age of 45.<ref name=":0" /> They affect men and women almost equally, with a 1.1:1 (male: female) ratio, although men tend to be younger at diagnosis than women.<ref name=":0" /><ref>Alzate M, Vargas F, Ramirez F, et al. SAT0414 Differences in a clinical presentation by gender in Colombian patients with spondyloarthropathies. Annals of the Rheumatic Diseases 2017;76(2): 928.</ref> With a prevalence rate of 0.5-1.9 percent, they are one of the most common rheumatic diseases - as common as [[Rheumatoid Arthritis|rheumatoid arthritis]].<ref>Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How to diagnose axial spondyloarthritis early. Annals of the Rheumatic Diseases. 2004; 63: 535-543.</ref> However, unlike other rheumatic diseases, spondyloarthropathies are seronegative for rheumatoid factors.<ref>Navallas M, Ares J, Beltrán B, Lisbona MP, Maymó J, Solano A. Sacroiliitis associated with axial spondyloarthropathy: new concepts and latest trends. Radiographics. 2013 Jul-Aug;33(4):933-56.</ref><blockquote>"So, unlike other rheumatic diseases, such as rheumatoid arthritis, the spondyloarthropathies are often negative for acute-phase inflammatory markers, such as C-reactive protein. They may be mildly raised, but certainly aren't often raised as much as would be in some other rheumatic diseases."<ref name=":0" /> -- Christopher Martey</blockquote>The aetiology and pathogenesis of spondyloarthropathies are complex and not fully understood. An initial systemic inflammatory response to a known or unknown source causes local tissue changes. These changes can be long-lasting in the local joint environment, and the persistent inflammation causes a cycle of unbalanced bone remodelling and axial [[bone]] loss.<ref name=":10">Lassiter W, Allam AE. Inflammatory Back Pain. [Updated 2020 Jun 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK539753/</nowiki></ref>
 
While the cause of spondyloarthropathy is not known, research suggests that there are environmental and genetic triggers.<ref name=":1" /> In particular, spondyloarthropathies have been found to share genetic links with the HLA-B27 gene.<ref name=":0" /><ref>Braun, J., Sieper, J. Early diagnosis of spondyloarthritis. ''Nat Rev Rheumatol.'' 2006; 2: 536-45.</ref> 90 percent of patients with axial spondyloarthritis have this gene. However, having this gene is not, in itself, diagnostic of spondyloarthropathy, as five to ten percent of patients who carry the HLA-B27 gene do not go on to develop these conditions.<ref name=":0" />


The etiology and pathogenesis of spondyloarthropathies have not been determined, but the research suggests that there are various environmental triggers, as well as a significant genetic component.<ref name=":1" />
This optional video provides a general overview of spondyloarthropathy.  


In particular, spondyloarthropathies have been found to share genetic links with the HLA-B27 gene.<ref name=":0" /><ref>Braun, J., Sieper, J. Early diagnosis of spondyloarthritis. ''Nat Rev Rheumatol.'' 2006; 2: 536-45.</ref> 90 percent of patients presenting with axial spondyloarthritis have this gene. However, it is important to note that having this gene is not, in itself, diagnostic of spondyloarthropathy as five to ten percent of patients who are HLA-B27+ do not go on to develop these conditions.<ref name=":0" />
{{#ev:youtube|https://www.youtube.com/watch?v=1Fgi7whO7NQ|width}}<ref>USME Spondyloarthropathy Available from: https://www.youtube.com/watch?v=1Fgi7whO7NQ (last accessed 8.11.2020) </ref>  


== Characteristics / Clinical Presentation ==
== Characteristics / Clinical Presentation ==
The symptoms of spondyloarthropathies are varied and as many individuals present with back pain, it is important to be able to distinguish between mechanical and inflammatory back pain. The specific features of each type of spondyloarthropathy are discussed below.
[[Low Back Pain|Back pain]] is extremely prevalent. <ref name=":4">Poddubnyy D. [https://academic.oup.com/rheumatology/article/59/Supplement_4/iv6/5923432 Classification vs diagnostic criteria: the challenge of diagnosing axial spondyloarthritis]. Rheumatology. 2020 Oct;59(Supplement_4):iv6-17.</ref> The occurrence of back pain lasting for three months or longer and back pain onset before 45 years of age is a starting point for the diagnosis of spondyloarthritis.<ref name=":4" /> It is important to be able to differentiate between different types of back pain (i.e. [[Differentiating Inflammatory and Mechanical Back Pain|mechanical or inflammatory back pain]]), and the different types of spondyloarthropathy. The specific features of each type of spondyloarthropathy are discussed below.
 
== Axial Spondyloarthritis ==
Axial spondyloarthritis is the prototypic form of spondyloarthropathy.<ref>Martey C. Diagnosis and Classification of Spondyloarthropathies Course. Plus, 2020.</ref> Patients with axial spondyloarthritis (axSpA) can have either non-radiographic or radiographic axial spondyloarthritis. Radiographic axial spondyloarthritis (r-axSpA) is also called [[Ankylosing Spondylitis (Axial Spondyloarthritis)|ankylosing spondylitis]].<ref name=":3">Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017 Jul 1;390(10089):73-84. </ref> While non-radiographic axial spondyloarthritis (nr-axSpA) does not show on x-ray, changes are evident on MRI.<ref name=":0" />
 
Axial spondyloarthritis tends to start when patients are aged in their 20s. There is a male-to-female ratio of 2:1 for radiographic axial spondyloarthritis and 1:1 for non-radiographic axial spondyloarthritis.<ref name=":3" />
 
Axial spondyloarthritis predominantly affects the spine, with inflammatory changes causing pain, stiffness and a loss of motion in the back.<ref name=":0" /><ref name=":2">Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2022 Apr 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/</ref> Patients will often present with impaired spinal movement, abnormal [[posture]], buttock and hip pain, peripheral arthritis, enthesitis and dactylitis.<ref name=":2" /><blockquote>"The inflammatory changes that occur don't just cause pain, but also ongoing stiffness and a loss of range of motion throughout the spine. This can lead to progressive deformity and the change in posture. Not only that, these painful conditions affect one's sleep and also have a huge impact on fatigue. This affects their livelihood, also how they interact with their loved ones and also their work productivity."<ref name=":0" /> -- Christopher Martey</blockquote>The following optional video provides a short summary of the main features of axial spondyloarthritis.  


== Ankylosing Spondylitis ==
{{#ev:youtube|iN2EiKKKJss}}<ref>Novartis. More than just back pain, what is Axial Spondyloarthritis (axSpA)? Available from: https://www.youtube.com/watch?v=iN2EiKKKJss [last accessed 9/11/2020]</ref>
Ankylosing spondylitis (AS) is a seronegative spondyloarthritis of the spine and pelvis. AS affects the axial skeleton, as well as the peripheral joints, digits and entheses.<ref name=":2">Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2020 Jul 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK470173/</nowiki></ref>


It affects 0.1 to 1.4% of the population and is predominantly seen in males with a 3.4:1 (male:female) ratio.<ref name=":3">Dean LE, Jones GT, MacDonald AG, Downham C, Sturrock RD, Macfarlane GJ. Global prevalence of ankylosing spondylitis. Rheumatology (Oxford). 2014; 53(4): 650-7.</ref> The onset of symptoms usually occur in patients aged in their 20s and rarely after the age of 45.<ref name=":3" /> Less than 5% of cases will develop symptoms after the age of 45.<ref name=":3" /> AS is more prevalent within Europe (mean 23.8 per 10,000) and Asia (mean 16.7 per 10,000) than within Latin America (mean 10.2 per 10,000).<ref name=":3" />
It has been estimated that axial spondyloarthritis has a heritability of 90%, with the HLA-B27 gene being the most significant genetic factor.<ref name=":3" /><ref name=":2" /><ref>Ebrahimiadib N, Berijani S, Ghahari M, Pahlaviani FG. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358754/pdf/jovr-16-462.pdf Ankylosing Spondylitis]. J Ophthalmic Vis Res. 2021 Jul 29;16(3):462-469.</ref> The actual role of HLA-B27 in the pathogenesis of axial spondyloarthritis remains unclear, but evidence suggests that the [[cytokines]], tumour necrosis factor (TNF)-α and interleukin-17 are involved.<ref name=":3" />


The most common features of AS are chronic back pain and progressive stiffness.<ref name=":2" /> Patients will often present with impaired spinal movement, abnormal posture, buttock and hip pain, peripheral arthritis, enthesitis and dactylitis.<ref name=":2" /> The most common extra-articular manifestation of AS is inflammatory bowel disease, acute anterior uveitis and psoriasis.<ref name=":2" />
Radiographic axial spondyloarthritis has also been linked to an increased risk of cardiovascular disease due to the systemic inflammation associated with this condition. Because it results in diminished chest wall expansion and decreased spinal mobility, it can lead to a restrictive pulmonary pattern in individuals with this condition. These individuals are also more prone to vertebral [[Insufficiency Fracture|fragility fractures]], [[Atlantoaxial Osteoarthritis|atlantoaxial]] subluxation, [[Spinal Cord Injury|spinal cord injury]] and, occasionally, [[Cauda Equina Syndrome|cauda equina syndrome]].<ref name=":2" />


AS has been linked to an increased risk of cardiovascular disease, potentially due to the systemic inflammation associated with this condition. Because AS results in diminished chest wall expansion and decreased spinal mobility, it can lead to a restrictive pulmonary pattern in patients with AS. These individuals are also more prone to vertebral fragility fractures, atlantoaxial subluxation, spinal cord injury and, occasionally, cauda equina syndrome.<ref name=":2" />
The following optional video presents the key features of axial spondyloarthritis.


As with all spondyloarthropathies, the aetiology of AS is not fully understood, but research indicates that genetic background, microbial infection, endocrine abnormalities and immune reactions may be significant.<ref name=":4">Watad A, Bridgewood C, Russell T, Marzo-Ortega H, Cuthbert R, McGonagle D. The Early Phases of Ankylosing Spondylitis: Emerging Insights From Clinical and Basic Science. Front Immunol. 2018. 16;9: 2668-75.</ref> As discussed above, there is a correlation between AS and the HLA-B27 gene.<ref name=":0" /><ref name=":2" /><ref name=":4" />  
{{#ev:youtube|a23A3nAaO0E}}<ref>Zero To Finals. Ankylosing Spondylitis: Visual Explanation for Students. Available from https://www.youtube.com/watch?v=a23A3nAaO0E [last accessed: 8/11/2020]</ref>


For more information on AS, please [[Ankylosing Spondylitis|click here]].
For more information on axial spondyloarthritis, please [[Ankylosing Spondylitis (Axial Spondyloarthritis)|click here]].


== Psoriatic Arthritis ==
== Psoriatic Arthritis ==
Psoriatic Arthritis (PsA) is a chronic, immune-mediated inflammatory joint disease that is associated with psoriasis.<ref name=":5">Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis. Lancet. 2018; 391(10136): 2273-2284. </ref> Individuals present with joint and entheses inflammation in both the axial skeleton and peripheral joints. It affects multiple organs, including the skin and is associated with increased risk of mortality from cardiovascular disease.<ref name=":5" /><ref>Van den Bosch F, Coates L. Clinical management of psoriatic arthritis. Lancet. 2018; 391(10136): 2285-2294.</ref>  
Psoriatic Arthritis (PsA) is a chronic, immune-mediated inflammatory joint disease associated with psoriasis.<ref name=":5">Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis. Lancet. 2018; 391(10136): 2273-2284. </ref> It is also known as peripheral spondyloarthritis. Individuals present with joint and entheses inflammation in both the axial skeleton and peripheral joints. It affects multiple organs, including the skin and is associated with an increased risk of mortality from cardiovascular disease.<ref name=":5" /><ref>Van den Bosch F, Coates L. Clinical management of psoriatic arthritis. Lancet. 2018; 391(10136): 2285-2294.</ref>  


There is a wide variation in annual incidence of psoriatic arthritis, ranging from 0.1 to 23.1 cases per 100,000. Prevalence rates also vary between countries, as does the mean age at diagnosis (40.7 to 52.0 years).<ref name=":6">Kerschbaumer A, Fenzl KH, Erlacher L, Aletaha D. An overview of psoriatic arthritis - epidemiology, clinical features, pathophysiology and novel treatment targets. Wien Klin Wochenschr. 2016; 128(21-22): 791-795.</ref>
There is a wide variation in the annual incidence of PsA, ranging from 0.1 to 23.1 cases per 100,000. Prevalence rates also vary between countries, as does the mean age at diagnosis (40.7 to 52.0 years).<ref name=":6">Kerschbaumer A, Fenzl KH, Erlacher L, Aletaha D. An overview of psoriatic arthritis - epidemiology, clinical features, pathophysiology and novel treatment targets. Wien Klin Wochenschr. 2016; 128(21-22): 791-795.</ref>


Hallmark features of PsA are:<ref name=":6" />
Hallmark features of PsA are:<ref name=":6" />
* The presence of psoriasis
* the presence of psoriasis
* Inflammatory arthritis
* inflammatory arthritis
* Absence of serological tests for rheumatoid arthritis
* absence of [[Blood Tests|serological tests]] for rheumatoid arthritis
Between 60 and 70 percent of patients will develop psoriasis prior to PsA. However, in 15 to 20 percent of patients, symptoms of arthritis develop first. For some individuals (15 to 20 percent), psoriasis and arthritis will begin within a year of each other.<ref name=":6" />
Between 60 and 70 percent of patients will develop psoriasis before PsA. However, in 15 to 20 percent of patients, symptoms of arthritis develop first. For 15 to 20 percent of individuals, psoriasis and arthritis will begin within a year.<ref name=":6" />
 
For more information on PsA, please see [[Psoriatic Arthritis]]. The following optional video also provides a general overview of PsA. 


For more information on PsA, please [[Psoriatic Arthritis|click here]].
{{#ev:youtube|fQCU7rQbovk}}<ref>Zero To Finals. Psoriatic Arthritis. Available from: https://www.youtube.com/watch?v=fQCU7rQbovk [last accessed 8/11/2020]</ref>


== Enteropathic Arthritis ==
== Enteropathic Arthritis ==
Enteropathic Arthritis (EnA) is a spondyloarthropathy that occurs in patients who also have inflammatory bowel disease (IBD) and / or other gastrointestinal disease, such as ulcerative colitis and Crohn’s disease.<ref name=":7">Peluso R, Di Minno MN, Iervolino S, et al. Enteropathic spondyloarthritis: from diagnosis to treatment. Clin Dev Immunol. 2013; 2013: 631408. </ref>
Enteropathic Arthritis (EnA) is a spondyloarthropathy that occurs in patients who also have [[Irritable Bowel Syndrome|inflammatory bowel disease]] (IBD) and/or other gastrointestinal diseases, such as ulcerative colitis and [[Crohn's Disease|Crohn’s disease]].<ref name=":7">Peluso R, Di Minno MN, Iervolino S, et al. Enteropathic spondyloarthritis: from diagnosis to treatment. Clin Dev Immunol. 2013; 2013: 631408. </ref>


There is no gold standard test for EnA, so diagnosis generally relies on medical history and physical examination.<ref name=":7" /> Typically, patients who have IBD and then go on to develop inflammatory back pain and / or synovitis (predominantly in the lower limbs) are diagnosed as having spondyloarthropathy.<ref name=":7" /> Women are more likely to have peripheral joint involvement, whereas men are more likely to experience axial skeleton symptoms.<ref name=":7" />
There is no gold standard test for EnA, so diagnosis generally relies on medical history and physical examination.<ref name=":7" /> Typically, patients who have IBD and then go on to develop inflammatory back pain and/or synovitis (predominantly in the lower limbs) are diagnosed as having spondyloarthropathy.<ref name=":7" /> Women are more likely to have peripheral joint involvement, whereas men are more likely to experience axial skeleton symptoms.<ref name=":7" />


Between 17 and 39 percent of patients with IBD develop rheumatic manifestations. Between two and 16 percent of IBD patients develop EnA in the axial skeleton. The prevalence of sacroiliitis in this population is between 12 and 20 percent of patients.<ref name=":7" />
Between 17 and 39 percent of patients with IBD develop rheumatic manifestations. Between two and 16 percent of IBD patients develop EnA in the axial skeleton. The prevalence of sacroiliitis in this population is between 12 and 20 percent of patients.<ref name=":7" />


Like other spondyloarthropathies, there is an association with the HLA-B27 gene, ranging from 3.9 to 18.9 percent, but the pathogenesis is not fully understood.<ref name=":7" /> However, it has been observed that joint inflammation occurs in patients who are genetically predisposed and who have bacterial gut infections. This, therefore, suggests that there is some relationship between inflammation of the gut mucosa and arthritis.<ref name=":7" />
Like other spondyloarthropathies, there is an association with the HLA-B27 gene, ranging from 3.9 to 18.9 per cent, but the pathogenesis is not fully understood.<ref name=":7" /> However, it has been observed that joint inflammation occurs in patients who are genetically predisposed and who have bacterial gut infections. This, therefore, suggests that there is some relationship between inflammation of the gut mucosa and arthritis.<ref name=":7" />


For more information on EnA, please [[Enteropathic Spondylitis|click here]].
For more information on EnA, please [[Enteropathic Spondylitis|click here]].


== Reactive Arthritis ==
== Reactive Arthritis ==
Reactive arthritis (ReA) is a seronegative spondyloarthritis, which occurs after an extra-articular infection, typically of the gastrointestinal or genitourinary tract.<ref>Courcoul A, Brinster A, Decullier E, Larbre JP, Piperno M, Pradat E et al. A bicentre retrospective study of features and outcomes of patients with reactive arthritis. Joint Bone Spine. 2018; 85(2): 201-205.</ref><ref name=":8">Selmi C, Gershwin ME. Diagnosis and classification of reactive arthritis. Autoimmun Rev. 2014; 13(4-5): 546-9. </ref> It is associated with inflammatory back pain, oligoarthritis (“a chronic inflammatory arthritis of unknown origin that begins before the age of 16 and lasts for at least 6 weeks”<ref>Petty RE, Cassidy JT. Oligoarthritis. In: Cassidy JT, Petty RE, Laxer RM, Lindsley CB editors. Textbook of Pediatric Rheumatology. Philadelphia: Saunders, 2011. p262-71.</ref>), and extra-articular symptoms.<ref name=":8" /> It tends to develop after at least one and at most three to six weeks after a urogenital or gastrointestinal infection.<ref name=":8" /><ref>Ono K, Kishimoto M, Shimasaki T, Uchida H, Kurai D, Deshpande GA et al. Reactive arthritis after COVID-19 infection. RMD Open 2020; 6: e001350.</ref>
Reactive arthritis (ReA) is a seronegative spondyloarthropathy, which occurs after an extra-articular [[Infectious Disease|infection]] (usually of the gastrointestinal or [[Urinary Tract Infection|genitourinary tract]]).<ref>Courcoul A, Brinster A, Decullier E, Larbre JP, Piperno M, Pradat E et al. A bicentre retrospective study of features and outcomes of patients with reactive arthritis. Joint Bone Spine. 2018; 85(2): 201-205.</ref><ref name=":8">Selmi C, Gershwin ME. Diagnosis and classification of reactive arthritis. Autoimmun Rev. 2014; 13(4-5): 546-9. </ref> It is associated with inflammatory back pain, oligoarthritis, and extra-articular symptoms.<ref name=":8" /> It tends to develop between one and six weeks after a urogenital or gastrointestinal infection.<ref name=":8" /><ref>Ono K, Kishimoto M, Shimasaki T, Uchida H, Kurai D, Deshpande GA et al. Reactive arthritis after COVID-19 infection. RMD Open 2020; 6: e001350.</ref>
 
A classic triad of symptoms has been identified:<ref name=":9">Wu IB, Schwartz RA. Reiter's syndrome: the classic triad and more. J Am Acad Dermatol. 2008; 59(1): 113-21.</ref>
* [[arthritis]]
* urethritis
* conjunctivitis
Dermatological manifestations (such as keratoderma blennorrhagicum, circinate balanitis, ulcerative vulvitis, changes in nails, and oral lesions) can occur.<ref name=":9" /> It can also affect the heart and eyes, although symptom severity is varied.<ref name=":8" />
 
ReA is more common in men<ref name=":9" /> and typically affects young adults.<ref name=":8" /> Its exact pathophysiology is not yet understood, but it appears likely that infectious and [[Immune System|immune]] factors are involved.<ref name=":9" /> Again, those affected are more likely to carry the HLA-B27 gene.<ref name=":8" />
 
The following optional video provides an overview of the characteristics of ReA.
 
{{#ev:youtube|snjGL2x6Eus}}<ref>Zero To Finals. Reactive Arthritis: Visual Explanation for Students. Available from: https://www.youtube.com/watch?v=snjGL2x6Eus [last accessed 8/11/2020]</ref>
 
Clinical symptoms can be distinguished from [[Septic (Infectious) Arthritis|septic arthritis]]. Key signs of [[Septic (Infectious) Arthritis|septic arthritis]] are:<ref name=":8" />
* fever
* systemic signs of infection
* monoarthritis
For more information on ReA, please see [[Reactive Arthritis]].


A classic triad of symptoms have been identified, which are:<ref name=":9">Wu IB, Schwartz RA. Reiter's syndrome: the classic triad and more. J Am Acad Dermatol. 2008; 59(1): 113-21.</ref>
== Undifferentiated Spondyloarthritis ==
* Arthritis
A diagnosis of undifferentiated spondyloarthropathy is given in cases where individuals exhibit features of spondyloarthropathy, but they do not fit into any of the conditions discussed above.<ref>Chou CT, Lin KC, Wei JCC, Tsai WC, Ho HH, Hwang CM et al. Study of undifferentiated spondyloarthropathy among first-degree relatives of ankylosing spondylitis probands. Rheumatology. 2005; 44(5): 662-5.</ref> It usually occurs in less than five joints and often involves the knee joint.<ref>Hauk L. Spondyloarthritis: NICE Releases Guidelines on Diagnosis and Treatment. Am Fam Physician. 2017; 96(10): 677-678.</ref>
* Urethritis
* Conjunctivitis
Dermatological manifestations (such as keratoderma blennorrhagicum, circinate balanitis, ulcerative vulvitis, nail changes, and oral lesions) can occur,<ref name=":9" /> and it can also affect the heart and eyes, although symptom severity is varied.<ref name=":8" />


ReA is more common in men<ref name=":9" /> and typically affects young adults.<ref name=":8" /> Its exact pathophysiology is not yet understood, but it appears likely that infectious and immune factors are involved.<ref name=":9" /> Again, those affected are more likely to carry the HLA-B27 gene.<ref name=":8" />
== Delay to Diagnosis ==
It is important to note that there is often a significant delay in diagnosing these conditions. Reasons for this delay may include:<ref name=":0" />


Clinical symptoms can be distinguished from septic arthritis. Key signs of septic arthritis are:<ref name=":8" />
* presenting at a young age
* Fever
* potentially being missed as a mechanical presentation (rather than inflammatory)
* Systemic signs of infection
* lack of healthcare professional and community awareness about these conditions
* Mnoarthritis
* lack of recognition
For more information, please [[Reactive Arthritis|click here]].
* lack of appropriate referrals


== Undifferentiated Spondyloarthropathy ==
On average, the delay to diagnosis is around 8.5 years.<ref name=":0" /> Delays are significant because early diagnosis results in better outcomes in terms of disease activity, function, spinal mobility and radiographic damage, as well as a better response to treatment.<ref>Seo MR, Baek HL, Yoon HH, Ryu HJ, Choi HJ, Baek HJ, Ko KP. Delayed diagnosis is linked to worse outcomes and unfavourable treatment responses in patients with axial spondyloarthritis. Clin Rheumatol. 2015; 34(8): 1397-405.</ref><blockquote>"Eight and a half years is too long. [...] But this delay to diagnosis is something that we, as clinicians can really work towards to cut down. If we identify the signs early, suspect spondyloarthritis and refer through to specialist, secondary care rheumatology, we might all be able to better change the management of these patients."<ref name=":0" /> -- Christopher Martey</blockquote>
The diagnosis undifferentiated spondyloarthropathy is used in cases where individuals exhibit features of spondyloarthropathy, but they do not fit into any of the conditions discussed above.<ref>Chou CT, Lin KC, Wei JCC, Tsai WC, Ho HH, Hwang CM et al. Study of undifferentiated spondyloarthropathy among first-degree relatives of ankylosing spondylitis probands. Rheumatology. 2005; 44(5): 662-5.</ref>


== Summary ==
== Summary ==
Spondyloarthropathy is an umbrella term that encompasses five inflammatory rheumatic diseases. These conditions can impact multiple areas of the body, as well as other organs.


While the specific aetiology remains unknown, current research suggests a strong genetic component, as well as specific environmental triggers.
* Spondyloarthropathy is an umbrella term that encompasses five inflammatory rheumatic diseases:
** Axial spondyloarthritis
** Psoriatic arthritis
** Reactive arthritis
** Enteropathic arthritis
** Undifferentiated spondyloarthritis
* These conditions can impact multiple areas of the body, including joints and entheses, as well as other organs.
* While the specific aetiology remains unknown, current research suggests a strong [[Genetic Disorders|genetic]] component and specific environmental triggers.
* Understanding the signs of spondyloarthropathy is essential to help ensure appropriate referrals and better outcomes for these individuals


== References ==
== References ==
<references />
<references />
[[Category:Course Pages]]
[[Category:Course Pages]]
[[Category:Plus Content]]
[[Category:Rheumatology]]
[[Category:Musculoskeletal/Orthopaedics]]
[[Category:Differential Diagnosis]]

Latest revision as of 11:05, 24 October 2023

Original Editor - Jess Bell Top Contributors - Jess Bell, Kim Jackson, Ewa Jaraczewska, Tarina van der Stockt and Lucinda hampton

Introduction[edit | edit source]

Spondyloarthropathy (or spondyloarthritis) is an umbrella term for a group of inflammatory rheumatic diseases.[1][2] It is considered a common condition, but there is significant variation in the reported prevalence rates of spondyloarthropathy and its subgroups.[3]

Spondyloarthropathies are progressive and painful. They often involve the axial skeleton (i.e. the spine and the sacroiliac joints), but they can also affect the peripheral skeleton.[1] They are associated with enthesitis (inflammation of the site where tendons / ligaments insert into bone[4]) and dactylitis (i.e. diffuse swelling of the digits[5]). Other areas affected include the heart, eyes, lungs, skin, gut and genitourinary tract.[2]

There are five types of spondyloarthritis:[1]

Epidemiology / Aetiology[edit | edit source]

Symptoms associated with spondyloarthropathy typically start before the age of 45.[1] They affect men and women almost equally, with a 1.1:1 (male: female) ratio, although men tend to be younger at diagnosis than women.[1][9] With a prevalence rate of 0.5-1.9 percent, they are one of the most common rheumatic diseases - as common as rheumatoid arthritis.[10] However, unlike other rheumatic diseases, spondyloarthropathies are seronegative for rheumatoid factors.[11]

"So, unlike other rheumatic diseases, such as rheumatoid arthritis, the spondyloarthropathies are often negative for acute-phase inflammatory markers, such as C-reactive protein. They may be mildly raised, but certainly aren't often raised as much as would be in some other rheumatic diseases."[1] -- Christopher Martey

The aetiology and pathogenesis of spondyloarthropathies are complex and not fully understood. An initial systemic inflammatory response to a known or unknown source causes local tissue changes. These changes can be long-lasting in the local joint environment, and the persistent inflammation causes a cycle of unbalanced bone remodelling and axial bone loss.[12]

While the cause of spondyloarthropathy is not known, research suggests that there are environmental and genetic triggers.[2] In particular, spondyloarthropathies have been found to share genetic links with the HLA-B27 gene.[1][13] 90 percent of patients with axial spondyloarthritis have this gene. However, having this gene is not, in itself, diagnostic of spondyloarthropathy, as five to ten percent of patients who carry the HLA-B27 gene do not go on to develop these conditions.[1]

This optional video provides a general overview of spondyloarthropathy.

[14]

Characteristics / Clinical Presentation[edit | edit source]

Back pain is extremely prevalent. [15] The occurrence of back pain lasting for three months or longer and back pain onset before 45 years of age is a starting point for the diagnosis of spondyloarthritis.[15] It is important to be able to differentiate between different types of back pain (i.e. mechanical or inflammatory back pain), and the different types of spondyloarthropathy. The specific features of each type of spondyloarthropathy are discussed below.

Axial Spondyloarthritis[edit | edit source]

Axial spondyloarthritis is the prototypic form of spondyloarthropathy.[16] Patients with axial spondyloarthritis (axSpA) can have either non-radiographic or radiographic axial spondyloarthritis. Radiographic axial spondyloarthritis (r-axSpA) is also called ankylosing spondylitis.[17] While non-radiographic axial spondyloarthritis (nr-axSpA) does not show on x-ray, changes are evident on MRI.[1]

Axial spondyloarthritis tends to start when patients are aged in their 20s. There is a male-to-female ratio of 2:1 for radiographic axial spondyloarthritis and 1:1 for non-radiographic axial spondyloarthritis.[17]

Axial spondyloarthritis predominantly affects the spine, with inflammatory changes causing pain, stiffness and a loss of motion in the back.[1][18] Patients will often present with impaired spinal movement, abnormal posture, buttock and hip pain, peripheral arthritis, enthesitis and dactylitis.[18]

"The inflammatory changes that occur don't just cause pain, but also ongoing stiffness and a loss of range of motion throughout the spine. This can lead to progressive deformity and the change in posture. Not only that, these painful conditions affect one's sleep and also have a huge impact on fatigue. This affects their livelihood, also how they interact with their loved ones and also their work productivity."[1] -- Christopher Martey

The following optional video provides a short summary of the main features of axial spondyloarthritis.

[19]

It has been estimated that axial spondyloarthritis has a heritability of 90%, with the HLA-B27 gene being the most significant genetic factor.[17][18][20] The actual role of HLA-B27 in the pathogenesis of axial spondyloarthritis remains unclear, but evidence suggests that the cytokines, tumour necrosis factor (TNF)-α and interleukin-17 are involved.[17]

Radiographic axial spondyloarthritis has also been linked to an increased risk of cardiovascular disease due to the systemic inflammation associated with this condition. Because it results in diminished chest wall expansion and decreased spinal mobility, it can lead to a restrictive pulmonary pattern in individuals with this condition. These individuals are also more prone to vertebral fragility fractures, atlantoaxial subluxation, spinal cord injury and, occasionally, cauda equina syndrome.[18]

The following optional video presents the key features of axial spondyloarthritis.

[21]

For more information on axial spondyloarthritis, please click here.

Psoriatic Arthritis[edit | edit source]

Psoriatic Arthritis (PsA) is a chronic, immune-mediated inflammatory joint disease associated with psoriasis.[22] It is also known as peripheral spondyloarthritis. Individuals present with joint and entheses inflammation in both the axial skeleton and peripheral joints. It affects multiple organs, including the skin and is associated with an increased risk of mortality from cardiovascular disease.[22][23]

There is a wide variation in the annual incidence of PsA, ranging from 0.1 to 23.1 cases per 100,000. Prevalence rates also vary between countries, as does the mean age at diagnosis (40.7 to 52.0 years).[24]

Hallmark features of PsA are:[24]

  • the presence of psoriasis
  • inflammatory arthritis
  • absence of serological tests for rheumatoid arthritis

Between 60 and 70 percent of patients will develop psoriasis before PsA. However, in 15 to 20 percent of patients, symptoms of arthritis develop first. For 15 to 20 percent of individuals, psoriasis and arthritis will begin within a year.[24]

For more information on PsA, please see Psoriatic Arthritis. The following optional video also provides a general overview of PsA.

[25]

Enteropathic Arthritis[edit | edit source]

Enteropathic Arthritis (EnA) is a spondyloarthropathy that occurs in patients who also have inflammatory bowel disease (IBD) and/or other gastrointestinal diseases, such as ulcerative colitis and Crohn’s disease.[26]

There is no gold standard test for EnA, so diagnosis generally relies on medical history and physical examination.[26] Typically, patients who have IBD and then go on to develop inflammatory back pain and/or synovitis (predominantly in the lower limbs) are diagnosed as having spondyloarthropathy.[26] Women are more likely to have peripheral joint involvement, whereas men are more likely to experience axial skeleton symptoms.[26]

Between 17 and 39 percent of patients with IBD develop rheumatic manifestations. Between two and 16 percent of IBD patients develop EnA in the axial skeleton. The prevalence of sacroiliitis in this population is between 12 and 20 percent of patients.[26]

Like other spondyloarthropathies, there is an association with the HLA-B27 gene, ranging from 3.9 to 18.9 per cent, but the pathogenesis is not fully understood.[26] However, it has been observed that joint inflammation occurs in patients who are genetically predisposed and who have bacterial gut infections. This, therefore, suggests that there is some relationship between inflammation of the gut mucosa and arthritis.[26]

For more information on EnA, please click here.

Reactive Arthritis[edit | edit source]

Reactive arthritis (ReA) is a seronegative spondyloarthropathy, which occurs after an extra-articular infection (usually of the gastrointestinal or genitourinary tract).[27][28] It is associated with inflammatory back pain, oligoarthritis, and extra-articular symptoms.[28] It tends to develop between one and six weeks after a urogenital or gastrointestinal infection.[28][29]

A classic triad of symptoms has been identified:[30]

Dermatological manifestations (such as keratoderma blennorrhagicum, circinate balanitis, ulcerative vulvitis, changes in nails, and oral lesions) can occur.[30] It can also affect the heart and eyes, although symptom severity is varied.[28]

ReA is more common in men[30] and typically affects young adults.[28] Its exact pathophysiology is not yet understood, but it appears likely that infectious and immune factors are involved.[30] Again, those affected are more likely to carry the HLA-B27 gene.[28]

The following optional video provides an overview of the characteristics of ReA.

[31]

Clinical symptoms can be distinguished from septic arthritis. Key signs of septic arthritis are:[28]

  • fever
  • systemic signs of infection
  • monoarthritis

For more information on ReA, please see Reactive Arthritis.

Undifferentiated Spondyloarthritis[edit | edit source]

A diagnosis of undifferentiated spondyloarthropathy is given in cases where individuals exhibit features of spondyloarthropathy, but they do not fit into any of the conditions discussed above.[32] It usually occurs in less than five joints and often involves the knee joint.[33]

Delay to Diagnosis[edit | edit source]

It is important to note that there is often a significant delay in diagnosing these conditions. Reasons for this delay may include:[1]

  • presenting at a young age
  • potentially being missed as a mechanical presentation (rather than inflammatory)
  • lack of healthcare professional and community awareness about these conditions
  • lack of recognition
  • lack of appropriate referrals

On average, the delay to diagnosis is around 8.5 years.[1] Delays are significant because early diagnosis results in better outcomes in terms of disease activity, function, spinal mobility and radiographic damage, as well as a better response to treatment.[34]

"Eight and a half years is too long. [...] But this delay to diagnosis is something that we, as clinicians can really work towards to cut down. If we identify the signs early, suspect spondyloarthritis and refer through to specialist, secondary care rheumatology, we might all be able to better change the management of these patients."[1] -- Christopher Martey

Summary[edit | edit source]

  • Spondyloarthropathy is an umbrella term that encompasses five inflammatory rheumatic diseases:
    • Axial spondyloarthritis
    • Psoriatic arthritis
    • Reactive arthritis
    • Enteropathic arthritis
    • Undifferentiated spondyloarthritis
  • These conditions can impact multiple areas of the body, including joints and entheses, as well as other organs.
  • While the specific aetiology remains unknown, current research suggests a strong genetic component and specific environmental triggers.
  • Understanding the signs of spondyloarthropathy is essential to help ensure appropriate referrals and better outcomes for these individuals

References[edit | edit source]

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 Martey C. Overview of Spondyloarthropathies Course. Plus, 2020.
  2. ↑ 2.0 2.1 2.2 Ehrenfeld M, Infection and spondyloarthropathies. In: Shoenfeld Y, Agmon-Levin N, Rose NR editors. Infection and autoimmunity. Elsevier B.V. 2015. p745-57.
  3. ↑ Stolwijk C, van Onna M, Boonen A, van Tubergen A. Global prevalence of spondyloarthritis: a systematic review and meta-regression analysis. Arthritis Care Res (Hoboken). 2016 Sep;68(9):1320-31.
  4. ↑ Schett G, Lories R, D'Agostino M, Elewaut D, Krikham B, Soriano ER et al. Enthesitis: from pathophysiology to treatment. Nat Rev Rheumatol. 2017; 13: 731–741.
  5. ↑ Girolimetto N, Giovannini I, Crepaldi G, De Marco G, Tinazzi I, Possemato N, Macchioni P, McConnell R, McGonagle D, Iagnocco A, Zabotti A. Psoriatic Dactylitis: Current perspectives and new insights in ultrasonography and magnetic resonance imaging. Journal of Clinical Medicine. 2021 Jun 12;10(12):2604.
  6. ↑ Fragoulis GE, Siebert S. Treatment strategies in axial spondyloarthritis: what, when and how?. Rheumatology. 2020 Oct;59(Supplement_4):iv79-89.
  7. ↑ Ogdie A, Coates LC, Gladman DD. Treatment guidelines in psoriatic arthritis. Rheumatology. 2020 Mar 1;59(Supplement_1):i37-46.
  8. ↑ Bentaleb I, Abdelghani KB, Rostom S, Amine B, Laatar A, Bahiri R. Reactive arthritis: update. Current clinical microbiology reports. 2020 Dec;7(4):124-32.
  9. ↑ Alzate M, Vargas F, Ramirez F, et al. SAT0414 Differences in a clinical presentation by gender in Colombian patients with spondyloarthropathies. Annals of the Rheumatic Diseases 2017;76(2): 928.
  10. ↑ Rudwaleit M, van der Heijde D, Khan MA, Braun J, Sieper J. How to diagnose axial spondyloarthritis early. Annals of the Rheumatic Diseases. 2004; 63: 535-543.
  11. ↑ Navallas M, Ares J, Beltrán B, Lisbona MP, Maymó J, Solano A. Sacroiliitis associated with axial spondyloarthropathy: new concepts and latest trends. Radiographics. 2013 Jul-Aug;33(4):933-56.
  12. ↑ Lassiter W, Allam AE. Inflammatory Back Pain. [Updated 2020 Jun 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK539753/
  13. ↑ Braun, J., Sieper, J. Early diagnosis of spondyloarthritis. Nat Rev Rheumatol. 2006; 2: 536-45.
  14. ↑ USME Spondyloarthropathy Available from: https://www.youtube.com/watch?v=1Fgi7whO7NQ (last accessed 8.11.2020)
  15. ↑ 15.0 15.1 Poddubnyy D. Classification vs diagnostic criteria: the challenge of diagnosing axial spondyloarthritis. Rheumatology. 2020 Oct;59(Supplement_4):iv6-17.
  16. ↑ Martey C. Diagnosis and Classification of Spondyloarthropathies Course. Plus, 2020.
  17. ↑ 17.0 17.1 17.2 17.3 Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017 Jul 1;390(10089):73-84. 
  18. ↑ 18.0 18.1 18.2 18.3 Wenker KJ, Quint JM. Ankylosing Spondylitis. [Updated 2022 Apr 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470173/
  19. ↑ Novartis. More than just back pain, what is Axial Spondyloarthritis (axSpA)? Available from: https://www.youtube.com/watch?v=iN2EiKKKJss [last accessed 9/11/2020]
  20. ↑ Ebrahimiadib N, Berijani S, Ghahari M, Pahlaviani FG. Ankylosing Spondylitis. J Ophthalmic Vis Res. 2021 Jul 29;16(3):462-469.
  21. ↑ Zero To Finals. Ankylosing Spondylitis: Visual Explanation for Students. Available from https://www.youtube.com/watch?v=a23A3nAaO0E [last accessed: 8/11/2020]
  22. ↑ 22.0 22.1 Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis. Lancet. 2018; 391(10136): 2273-2284.
  23. ↑ Van den Bosch F, Coates L. Clinical management of psoriatic arthritis. Lancet. 2018; 391(10136): 2285-2294.
  24. ↑ 24.0 24.1 24.2 Kerschbaumer A, Fenzl KH, Erlacher L, Aletaha D. An overview of psoriatic arthritis - epidemiology, clinical features, pathophysiology and novel treatment targets. Wien Klin Wochenschr. 2016; 128(21-22): 791-795.
  25. ↑ Zero To Finals. Psoriatic Arthritis. Available from: https://www.youtube.com/watch?v=fQCU7rQbovk [last accessed 8/11/2020]
  26. ↑ 26.0 26.1 26.2 26.3 26.4 26.5 26.6 Peluso R, Di Minno MN, Iervolino S, et al. Enteropathic spondyloarthritis: from diagnosis to treatment. Clin Dev Immunol. 2013; 2013: 631408.
  27. ↑ Courcoul A, Brinster A, Decullier E, Larbre JP, Piperno M, Pradat E et al. A bicentre retrospective study of features and outcomes of patients with reactive arthritis. Joint Bone Spine. 2018; 85(2): 201-205.
  28. ↑ 28.0 28.1 28.2 28.3 28.4 28.5 28.6 Selmi C, Gershwin ME. Diagnosis and classification of reactive arthritis. Autoimmun Rev. 2014; 13(4-5): 546-9. 
  29. ↑ Ono K, Kishimoto M, Shimasaki T, Uchida H, Kurai D, Deshpande GA et al. Reactive arthritis after COVID-19 infection. RMD Open 2020; 6: e001350.
  30. ↑ 30.0 30.1 30.2 30.3 Wu IB, Schwartz RA. Reiter's syndrome: the classic triad and more. J Am Acad Dermatol. 2008; 59(1): 113-21.
  31. ↑ Zero To Finals. Reactive Arthritis: Visual Explanation for Students. Available from: https://www.youtube.com/watch?v=snjGL2x6Eus [last accessed 8/11/2020]
  32. ↑ Chou CT, Lin KC, Wei JCC, Tsai WC, Ho HH, Hwang CM et al. Study of undifferentiated spondyloarthropathy among first-degree relatives of ankylosing spondylitis probands. Rheumatology. 2005; 44(5): 662-5.
  33. ↑ Hauk L. Spondyloarthritis: NICE Releases Guidelines on Diagnosis and Treatment. Am Fam Physician. 2017; 96(10): 677-678.
  34. ↑ Seo MR, Baek HL, Yoon HH, Ryu HJ, Choi HJ, Baek HJ, Ko KP. Delayed diagnosis is linked to worse outcomes and unfavourable treatment responses in patients with axial spondyloarthritis. Clin Rheumatol. 2015; 34(8): 1397-405.
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