Management of extra‐articular manifestations in spondyloarthritis

Abstract

Spondylarthritis (SpA) is a group of diseases with inflammatory arthritis consisting of ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondylarthritis. AS is a disease with inflammatory low back pain that typically occurs in adults between 20–40 years of age with a male–female ratio of 3:1.1 Influence on the patient's life quality and treatment decisions increases the importance of extra-articular manifestations.2 Extra-articular manifestations (EAM) are easily neglected in patients with SpA, including involvement of eyes, skin, gastrointestinal tract, bone, heart, lung, and kidney.3 An epidemiological study of AS revealed a higher prevalence of EAM in patients with AS compared to non-AS.4 Furthermore, the incidence of different EAM, including acute anterior uveitis, psoriasis, and inflammatory bowel disease, is 11.4%, 4.4%, and 3.7% respectively.4 Another study to review the prevalence of uveitis in AS and non-radiographic axial SpA showed 23% in AS, and 15.9% in non-radiographic axial SpA.5, 6 Acute anterior uveitis accounts for the main role of EAM. Acute anterior uveitis is always a concern in patients with AS, even if the duration of the disease is more than 10 years; however, the risk of psoriasis and inflammatory bowel disease decreased with a longer duration of the disease.4 It is also noted that AS plays a key role in the etiology of acute anterior uveitis, and uveitis can occur before the diagnosis of AS.7 In addition, heart conduction disturbances and aortic insufficiency are rare but important EAM of AS.4 According to a report, AS is highly related to dysbiosis.8 The pathogenesis of AS is related to human leukocyte antigen (HLA)-B27 and can affect gastrointestinal microbiota.9 HLA-B*27 promotes unfolded protein responses (UPR) by inducing the endoplasmic reticulum stress response; moreover, induction of UPR results in the production of interleukin (IL)-17, IL-23, tumor necrosis factor (TNF)-alpha.9 The subclinical inflammation of the gut found in half of the patients with SpA leads to the hypothesis of the gut-joint axis.10 Less than 10% of patients with inflammatory bowel disease are reported to have AS at the same time.3 On the other hand, around 5%–10% of AS patients are diagnosed with ulcerative colitis or Crohn's disease.3 Additionally, a previous study showed that younger age is a risk factor for the development of inflammatory bowel disease in AS patients.11 Psoriasis is a common skin-related extra-articular manifestation in patients with AS and leads to inflammation of the peripheral joints.12 These patients with AS and concomitant psoriasis would have a poorer outcome, such as back pain, compared to patients without psoriasis.13 Osteoporosis affects the daily life of patients with AS a lot and may lead to vertebral fractures in the long run. A previous observation study revealed lower bone mineral density in patients with AS.3 A higher risk of fragility fracture in patients with AS should be a concern in treatment. Compared to the average population, patients with AS have a higher chance of valvular heart diseases,14, 15 conduction disturbances, and cardiomyopathies.16 The mortality rate for AS patients with cardiovascular disease is estimated to be 2 times higher than that for the normal population.3 Concerning EAM of the lung and recent advances in high-resolution computerized tomography, patients with AS are likely to develop emphysema, upper lobe fibrosis, and some nonspecific interstitial changes like pleural thickening and parenchymal band.3 Nonsteroidal anti-inflammatory drugs (NSAIDs) should be used with caution, especially in patients with AS with gastrointestinal or cardiovascular complications. The fundamental strategy to treat whole SpA patients is lifestyle modification and non-pharmacological therapies. SpA patients need to keep a healthy lifestyle, including quitting smoking, avoiding trauma, healthy dietary habits, regular exercise, and physical therapy. These non-pharmacological therapies have been proven to be efficacious in many previous studies.17-19 Uveitis is the most common extra-articular manifestation. Without prompt medical treatment, uveitis will lead to glaucoma and even blindness.2 Steroids are the first step in the treatment of uveitis, including topical, intraocular, periocular, and systemic. However, steroid-sparing agents are necessary to prevent adverse effects of long-term steroid treatment. Currently, steroid-sparing agents in the treatment of uveitis include methotrexate, azathioprine, mycophenolate mofetil (MMF), and the TNF-alpha inhibitor.20 A series of randomized controlled trials of adalimumab in the treatment of noninfectious uveitis revealed promising results.21-23 According to the results of a meta-analysis,24 anti-TNF therapy can prevent the start of uveitis or flares in patients with AS. It can also be an alternative method for the treatment of uveitis. Regarding the adverse events or inefficiency of TNF inhibitors, around 30% of patients would switch to different kinds of TNF-alpha inhibitors or even stop using them every year; in addition, golimumab has a lower discontinuation rate than etanercept after a 3-year follow-up.25 Different therapies will be considered due to different kinds of EAM (Table 1). Pharmaceutical treatments such as symptomatic control medications, corticosteroids, antibiotics, immunosuppressive drugs, and biologics are often used to treat inflammatory bowel disease.26 Biologics for inflammatory bowel disease include the TNF-alpha inhibitors, ustekinumab, vedolizumab, and natalizumab; in addition to tofacitinib, a Janus kinase inhibitor (JAKi).27 Recently, risankizumab was approved in the treatment of moderately to severely active Crohn's disease. Turning now to the evidence on IL-17 inhibitors, recent studies revealed unfavorable results; however, no gastrointestinal adverse effects were found in the treatment of AS patients.28 The tactic to treat psoriasis is different and based on the severity. Evidence showed that topical corticosteroids, vitamin D analogs, phosphodiesterase 4 inhibitors, methotrexate, and topical or systemic calcineurin inhibitors are used in patients with mild psoriasis; additionally, TNF-alpha inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-23 inhibitors, and JAKi will be considered for patients with severe psoriasis.29, 30 Caution of NSAIDs Multidisciplinary discussion EAM can be found in different organs and may lead to a poorer outcome for patients with SpA. Personalized medicine should be kept in mind when treating SpA patients. The more precise treatment of patients with SpA with EAM and complications, the better the outcome these patients might get. Through the collaboration of physicians of multiple specialties, multidisciplinary guidelines are warranted to optimize the assessment and management of EAM in SpA. Our corresponding author James Cheng-Chung Wei is the editor-in-chief of the journal, so he was excluded from the peer-review process and all editorial decisions related to the acceptance. Publication of this article, and peer-review was handled independently by other editors to minimize bias.

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