HLA B27 Syndromes

Article Author:
Padmini Parameswaran
Article Editor:
Michael Lucke
Updated:
7/10/2020 10:50:29 AM
PubMed Link:
HLA B27 Syndromes

Introduction

The correlation between the presence of HLA-B27 and ankylosing spondylitis has been a known entity since the early 1970s.  Although common in the general population, this allele strongly contributes to the susceptibility of development of the linked family of inflammatory rheumatologic conditions collectively known as spondyloarthritis. Additional associated diseases, particularly acute anterior uveitis, are also highly correlated with possession of HLA-B27. Although associated with spondyloarthritis, the pathologic role of this allele in immune dysregulation remains under investigation. With lower frequency, the presence of the HLA-B27 allele has correlated with inflammatory bowel disease, psoriatic arthritis, and reactive arthritis.

Etiology

The human leukocyte antigens (HLA) are gene loci in the major histocompatibility complex class I of genes on chromosome 6, present on all nucleated cells.[1] Their function is to present endogenous antigens, such as peptides from viruses or intracellular pathogens, to cytotoxic T cells. High-density genome mapping in autoimmune diseases has shown that autoimmune diseases are usually polygenic and have a complex interplay involving both environmental and genetic factors; however, for most of them, the MHC region is associated with disease susceptibility. HLA-B27 allele is unique in that its presence alone can cause spondyloarthritis like disease in animal studies.[1] Although there are numerous studies into the HLA region and disease associations, the mechanism by which HLA-B27 predisposes individuals to develop spondyloarthritis remains unresolved.

Epidemiology

The presence of the HLA-B27 allele varies by geographic region, with more prevalence at northern latitudes. In the United States, the estimated prevalence is six to eight percent. The vast majority of patients with this allele will not develop an HLA-B27 associated syndrome. Over 100 subtypes or HLA-B27 have been characterized, with varying associations with spondyloarthritis.

The presence of the HLA-B27 allele is not essential for the development of spondyloarthropathy, but it is highly associated with the development of the disease. Research has identified more than forty other genetic loci in genome-wide mapping studies. HLA-B27 contributes to approximately thirty percent of the heritability of ankylosing spondylitis.[2] The incidence of acute anterior uveitis in HLA-B27 positive patients has shown on meta-analysis to vary from 40 to 82.5%. It can precede the onset of ankylosing spondylitis by approximately three years.[3] In contrast to the prevalence of roughly ninety percent of patients with ankylosing spondylitis, HLA-B27 is present in less than half of patients with psoriatic arthritis and inflammatory bowel disease (IBD).

Based on various studies, approximately 0.5 to 1% of the US population is affected by axial spondyloarthropathy.[4] Men have higher rates of radiographic evidence of axial spondyloarthritis, but recent advances in recognition of non-radiographic axial spondyloarthritis have challenged the traditional concept that males have a higher frequency of this disease.  Disease onset is typically between twenty and forty years of age.

Acute anterior uveitis is a common extra-articular manifestation and may affect more than twenty percent of patients with spondyloarthropathy.

Psoriatic arthritis occurs with an incidence rate of 6 per 100000 annually, with a prevalence rate of 1 to 2 per 1000 people, affecting men and women equally.[5] Psoriatic arthritis can be present before the onset of psoriasis in about 10 to 15% of patients. Approximately a third of patients with psoriasis will develop psoriatic arthritis. In patients with psoriasis, severe cutaneous involvement and obesity have correlated with increased risk for psoriatic arthritis. Patients with psoriatic scalp, intergluteal, and nail disease may also have an increased risk. 

Reactive arthritis, similar to psoriatic arthritis, affects men and women equally, and like ankylosing spondylitis, it is a disease of young adults. Enteric organisms, including Campylobacter, Shigella, Yersinia, Salmonella, Clostridium difficile, and urogenital organisms, particularly Chlamydia trachomatis, are common triggers of reactive arthritis.[6][7] Susceptibility to the development of reactive arthritis is markedly more significant in patients with positive HLA-B27 compared to the general population and may pose a risk to the development of more chronic arthritis. The correlation between HLA-B27 positivity is higher in Shigella-induced reactive arthritis than other enteropathic infections.[8] Prevalence estimates are 0.1% but may be underestimated as patients may have asymptomatic triggering infections.[8]

Pathophysiology

Although the mechanism by which HLAB-27 causes disease is unknown, several hypotheses have been postulated. According to the arthritogenic peptide hypothesis, when HLA-B27 forms a bond with a peptide from a microbial source, it triggers a CD8 T cell response to a self-peptide with a similar structure to the microbial peptideEvidence for this mechanism has surfaced in patients who develop reactive arthritis after salmonella or chlamydia infections, which trigger a specific HLA-B27 CD8 T cell response. The misfolding hypothesis suggests that HLA-B27 may misfold in the endoplasmic reticulum, causing functional alterations in dendritic cell populations and function, increased formation of osteoclasts, and also increased IL-23 production, which has been shown to have pathogenic effect in spondyloarthropathy.[2] Although researchers have studied the above in animal models, studies in humans are lacking and do not always support the above hypothesis.

History and Physical

HLA-B27 associated syndromes frequently present in particular patterns that are critical to recognize in assessment for these diseases.

The cardinal feature of axial spondyloarthritis is inflammatory back pain. This condition may be differentiated from more common mechanical causes of back pain by the insidious onset of symptoms over three months at age under 45, prominent nocturnal pain in the second half of the night, morning stiffness with improvement with exercise, and lack of improvement with rest.[9] The presence of inflammatory back pain should prompt further evaluation for extra spinal features of spondyloarthritis. These features include uveitis, dactylitis, inflammatory bowel disease, psoriasis, and enthesitis, particularly when involving the heel.[9] Further history of a family history of spondyloarthritis and a good therapeutic response to non-steroidal anti-inflammatory treatments can heighten clinical suspicion for spondyloarthritis. Physical exam evaluation of axial spondyloarthritis may include Schober's test of lumbar flexion, occiput to wall distance, chest expansion, and sacroiliac pain with hip abduction and Gaenslen's maneuver.

Peripheral predominant presentations of spondyloarthritis share similar extra spinal features of the disease, including inflammatory arthritis, dactylitis, and enthesitis.[10] Some of these patients will fulfill the features of psoriatic arthritis. Cutaneous psoriasis predates psoriatic arthritis in most patients. Severe cutaneous involvement and nail pitting have correlated with the development of psoriatic arthritis.[11] Of note, links between a history of uveitis elevating the risk of psoriatic arthritis development in psoriasis have been reported, potentially associated with the HLA-B27 spectrum.[11][11] The presence of dactylitis on a physical exam is a specific feature suggestive of spondyloarthritis.

Patients with reactive arthritis typically present with a sudden onset of oligoarthritis. Identification of preceding genitourinary or enteric infection, typically in the preceding 1 to 4 weeks, may differentiate reactive arthritis from other forms of inflammatory arthritis.  Urethritis and uveitis may also be associated.

Acute anterior uveitis (AAU) has been strongly linked with HLA-B27 and is the most common cause of non-infectious uveitis. HLA-B27 associated uveitis is more common in younger patients with a typical age range of 20 to 40.[12] Young patients presenting with acute anterior uveitis should be evaluated for systemic symptoms of spondyloarthritis. A typical AAU presentation consists of acute onset of unilateral ocular pain and redness, with a variable degree of visual acuity loss. On ophthalmologic examination, leukocytes are present in the anterior chamber. Other complications may include posterior synechiae and hypopyon.

Inflammatory bowel disease may predate the onset of enteropathic arthritis or occur later in the disease course.  Attention is necessary to any changes in bowel habits and blood in the stool. Additionally, many patients may experience subclinical colonic inflammation.

Evaluation

There is no single diagnostic finding for spondyloarthritis and other HLA-B27 associated syndromes.  Evaluation of axial spondyloarthritis by plain radiographic imaging of the sacroiliac joints can detect characteristic changes, including erosions, sclerosis, and joint ankyloses. These changes may not be present in early disease. Additionally, patients may develop non-radiographic axial spondyloarthritis, with symptom severity equal to radiographically evident disease.  The presence of inflammatory features, including an elevated C reactive protein and abnormal MRI short tau inversion recovery (STIR) imaging, is used to detect inflammatory changes, particularly in patients with non-diagnostic plain film imaging.  Imaging results must be interpreted in correlation with the clinical context, as inflammatory changes on imaging, including bone marrow edema, is not specific and may be seen in athletes and healthy individuals. 

Lumbar spine imaging in axial spondyloarthritis may display squaring of the vertebral bodies as an early radiographic sign.  More specific later findings include syndesmophytes and facet joint ankyloses. A classic late presentation is a “bamboo” spine with advanced spinal fusion.

The presence of enthesitis may be further demonstrated by the use of power Doppler ultrasound, which can confirm inflammatory activity in the tendon and assess for erosive changes at sites of tendon insertion.

Arthrocentesis of involved peripheral joints yield synovial fluid findings typical for inflammatory arthritis with leukocyte counts over 2000 cells/mm3.  

HLA-B27 positivity increases the likelihood of spondyloarthritis in patients with a high pretest probability.  In patients with acute anterior uveitis, HLA-B27 requires testing. In patients with red-eye, which is concerning for uveitis, a prompt ophthalmology referral and slit lamp evaluation are indicated to confirm the diagnosis and exclude infectious processes.

All patients with reactive arthritis should be tested for HIV infection as well as undergo evaluation for triggering enteropathic and venereal disease.

Treatment / Management

The HLA-B27 syndromes receive treatment with similar categories of drugs, but the first-line therapies and protocols are varied for each of them. 

For adults with active ankylosing spondylitis, the 2019 American College of Rheumatology guidelines recommended treatment with continuous NSAIDs over as needed NSAIDs as first-line therapy.[13] Studies have suggested that continuous treatment may decrease structural progression, but therapy is used primarily to control disease activity. If a patient has active ankylosing spondylitis despite the use of continuous NSAIDs, therapy with TNF inhibitors is indicated.  Non-biologic treatments such as sulfasalazine and methotrexate are ineffective for axial disease. No convincing data supports one TNF inhibitor over another unless another comorbidity such as tuberculosis, IBD, or recurrent uveitis is present. In a patient with tuberculosis, infliximab is less preferred compared to the other TNF inhibitors. TNF inhibitors, which are monoclonal antibodies, are preferred over Etanercept in the presence of IBD or uveitis. The IL-17 inhibitors secukinumab and ixekizumab have shown similar to efficacy to TNF inhibitors in the treatment of axial spondyloarthritis.  These agents may be considered when contraindications to TNF inhibitors such as congestive heart failure or demyelinating disease are present, or in patients who have not responded to initial treatment. Jak inhibitors have shown efficacy in the treatment of axial disease in clinical trials. Tofacitinib should be considered over the IL-17 inhibitors for use in IBD, due to the lack of efficacy of the latter in IBD. In patients with peripheral arthritis with a high risk of infections, sulfasalazine is a consideration.[13]

Assessing the various domains of disease activity in patients with psoriatic arthritis, including the presence of dactylitis, enthesitis, cutaneous psoriasis, and axial involvement, influence therapy choice. A TNF inhibitor is the recommended first-line treatment in patients with active psoriatic arthritis and enthesitis.[5] Oral small molecules such as methotrexate and apremilast may merit consideration in patients with more mild disease involvement or patients with higher concern for infection.  In patients with marked cutaneous involvement, IL-17, and IL-23 inhibition has shown greater benefit than TNF inhibitors in achieving psoriasis clearance. Trials dedicated to IL-23 inhibition in psoriatic arthritis have shown benefit. Biologics may be combined with oral small molecules for active psoriatic arthritis that does not respond to the biologic treatment or in the setting of persistent uveitis. Abatacept and tofacitinib decrease disease activity but are not presently in use as first-line therapies. All patients should receive counsel on the importance of smoking cessation, balanced diet, and low impact exercise like Tai-chi.[5]

Acute anterior uveitis initially gets treated with topical corticosteroids. Ophthalmologists may also choose to inject triamcinolone locally if the topical treatments fail. Oral corticosteroids are less frequently required, and use requires caution due to adverse effects.  In patients with refractory disease, mycophenolate mofetil, methotrexate, and azathioprine may be options as steroid-sparing agents. While TNF inhibitors are rarely useful when there is AAU without concomitant spondyloarthritis, infliximab and adalimumab have shown efficacy in the treatment of non-infectious anterior uveitis. Intra-ocular corticosteroid implants have been an option, as well.[14]

Treatment of reactive arthritis depends upon the underlying trigger and severity of the disease. In patients with a genitourinary infection, treatment with antibiotics is indicated to address the underlying cause of the infection. However, antibiotics are not recommended to treat arthritis as a stand-alone symptom. Acute reactive arthritis treatment uses maximum dose NSAIDs such as naproxen, diclofenac, or indomethacin. Systemic or intra-articular glucocorticoids at a low to moderate dose can be adjuncts when there is a lack of control of symptoms with NSAIDs. In patients with active disease, despite the use of two different NSAIDS over four weeks or with prolonged steroid use, Sulfasalazine is recommended. Methotrexate and TNF inhibitors may be options for patients with progress to a more chronic disease state. Treatment generally continues until achieving remission, after which discontinuation follows three to six months later.[15]

Differential Diagnosis

Peripheral arthritis is a common manifestation of numerous diseases. Exclusion of infections is paramount for any acutely inflamed joint. Lyme arthritis can mimic the onset of peripheral spondyloarthritis and may present similarly with inflammatory knee pain. Viral infections may frequently cause self-limited arthritis and should be an option in patients with less than six weeks of symptoms. Crystalline arthritis and rheumatoid arthritis may present similarly to peripheral spondyloarthritis but may often get excluded by synovial fluid analysis and serologic evaluation.

Non-inflammatory axial arthralgia, particularly osteoarthritis in the lower back or shoulder, hips, and knees, frequently cause pain and stiffness. However, degenerative arthritis presentations typically involve patients over age 40, are not usually associated with nocturnal pain in the second half of the night, and often worsen with exertion. Other differentials include malignancies, particularly multiple myeloma, central pain syndromes, hypothyroidism, and hypercalcemia. 

Uveitis has many causes; common infectious causes include herpes simplex, herpes zoster, CMV, and toxoplasmosis, as well as less common infections, including tuberculosis and syphilis. Behcet disease, Vogt-Koyanagi-Harada syndrome, relapsing polychondritis, Sjogren syndrome, sarcoidosis, and juvenile idiopathic arthritis cause uveitis as well.[14]

Prognosis

The development of targeted biologic therapies, ranging from TNF inhibitors to IL-17, IL-23, and JAK/STAT pathway inhibition has provided marked advances in the ability to manage the inflammatory complications of HLA-B27 related disease. Factors associated with poor prognosis in psoriatic arthritis include the presence of radiographic erosions, dactylitis, and elevated ESR and CRP.  Joint deformities affecting the function and highly active disease particularly impact the quality of life. Mild to moderate ankylosing spondylitis is associated with impairments in physical function. Complications of the disease include osteoporosis, cardiovascular disease, and vertebral fractures. Patients can develop severe hip involvement requiring total hip arthroplasty and severe flexion deformities of the cervical spine, restricting their range of motion. Hopefully, early identification and initiation of effective treatment may decrease the progression of radiographic disease and preserve physical function. Effective treatment limits the risk of radiographic joint disease in peripheral arthritis. Reactive arthritis usually affects patients for three to five months, and most patients will be disease-free within six to twelve months. Rarely, there is chronic arthritis, which may prompt evaluation for one of the other spondyloarthropathies.

Complications

Complications of ankylosing spondylitis include atlantoaxial subluxation and subsequent neurologic impairment, spinal fracture from low impact trauma, advanced hip osteoarthritis with increased rates of total hip arthroplasty, and perioperative complications from a rigid cervical spine or limited chest expansion. Aortic dissection, acute coronary syndromes, and conduction abnormalities may also occur in increased rates compared to the general population. Anterior uveitis is associated with glaucoma, posterior synechiae, band keratopathy, cystoid macular edema, and cataract formation. 

Similar to other inflammatory rheumatologic conditions, the risk of ischemic cardiovascular disease increases in patients with psoriasis, psoriatic arthritis, and ankylosing spondylitis. Increased rates of metabolic syndrome have explicitly been seen in psoriatic arthritis. Controlling disease activity may decrease this risk. Attention to modifiable risk factors is critical. Statin initiation has correlated with reduced mortality in ankylosing spondylitis.[16]

Deterrence and Patient Education

Physical therapy can help in the management of functional aspects of the disease. Aerobic exercise is a strong recommendation; low impact exercise may be preferable if depending on patient preference.  Maintenance of a healthy weight can help both with offloading the joints as well as with the efficacy of TNF inhibitors. Smoking cessation for all patients is essential.  

Enhancing Healthcare Team Outcomes

Patients with ankylosing spondylitis are often not diagnosed by rheumatologists upon onset of symptoms. Since lower back pain is a prevalent complaint, often they go undiagnosed for decades.[17] [Level 5] Patients often see several physicians and other health professionals, including primary care physicians, sports medicine practitioners, chiropractors, physical therapists, and orthopedic physicians, before evaluation by a rheumatologist. Collaboration within a hospital system between providers and the creation of algorithms that prompt an earlier rheumatology referral when a younger patient has inflammatory pattern back pain or other spondyloarthritis features can help to capture the patients earlier in the disease course.[18] [Level 2] 

In patients who have a diagnosis of spondyloarthropathies may see an impact on several aspects of daily life. Psoriatic arthritis can have significant effects on the patient’s physical, psychological, and sexual function.[19] [Level 3] Pharmacists should go over all medication options with the clinician and other members of the team, verifying optimal dosing and performing a medication reconciliation for drug interactions. Nursing should reinforce the counsel of the pharmacist and the prescriber by educating the patient on proper dosing and administration, as well as side effects that should prompt the patient to contact the clinician's office.

Similarly, ankylosing spondylitis may impair physical function, contributing to work absence and disability, career changes, and activity modification. Some evidence suggests that aquatic therapy may play an essential role in improving physical function, range of motion, and overall pain in patients with ankylosing spondylitis as compared to home-based self-guided exercises.[20] [Level 2] Resistance training has been shown to improve disease activity, including physical function and quality of life in some patients with psoriatic arthritis.[21] [Level 2] 

Ophthalmologist referrals are essential in the management of uveitis for differentiating between inflammatory and infectious triggers. 

Gastroenterologists may lead decisions in the management and diagnosis of IBD in patients with spondyloarthropathies. Subclinical gut inflammation is also common. The involvement of an interprofessional team, including physical therapists, behavioral health counselors, and pharmacists may be helpful in the management of the patient.[17][18] [Level 5]


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