Comorbidities in Patients with Spondyloarthritis

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Introduction

Spondyloarthritis (SpA) is a group of rheumatic diseases that includes ankylosing spondylitis (AS), inflammatory back pain, asymmetrical synovitis (eg, psoriatic arthritis), arthritis accompanying inflammatory bowel disease (IBD) (eg, Crohn disease and ulcerative colitis), and reactive arthritis.

SpA can be dominated by spinal symptoms, which can be classified as axial SpA,1 or by peripheral arthritis, which is classified as peripheral SpA.2 Axial SpA is subdivided in two types: (1) AS, which requires radiographic changes of the sacroiliac joints (according to the Modified New York Criteria),3 and (2) the nonradiographic axial SpA, which is mainly based on a combination of clinical symptoms, the presence of HLA-B27 antigen, and signs of sacroiliitis on MRI. The nonradiographic axial SpA can progress toward AS within a couple of years. The clinical symptoms of axial SpA include inflammatory back pain during at least 3 months with onset before 45 years of age and at least one of the other SpA-features: arthritis, enthesitis (heel), uveitis, dactylitis, psoriasis, Crohn disease or ulcerative colitis, good response to nonsteroidal antiinflammatory drugs (NSAIDs), family history of SpA, and elevated C-reactive protein.1

Peripheral SpA requires peripheral arthritis compatible with SpA (usually asymmetric and/or predominant involvement of the lower limb), enthesitis or dactylitis, and at least one of the other SpA features (see above).2

AS is the most common type of SpA and presents with low-back pain and morning stiffness, due to a chronic inflammation of the sacroiliac joints and vertebral spine. This inflammatory process can result in calcification of the spinal ligaments, additional bone formation (syndesmophytes), and destruction of the vertebral spine leading to postural deformities, such as ankylosis of the cervical spine and kyphosis of the thoracic spine. AS is associated with the HLA-B27 antigen, starts at a relatively young age (15–40 years), and predominantly occurs in males, with a male/female ratio of 3:1. The diagnosis of AS is defined by the modified New York criteria3 and depends, among other factors, on the presence of sacroiliitis on the radiograph. The prevalence of SpA, including AS, is estimated at 0.9% in the white population, which equals the prevalence of rheumatoid arthritis.4

Peripheral arthritis occurs in 30% of patients with SpA and, at onset, shows a predominately asymmetrical and oligoarticular pattern involving large joints of the lower limbs (ie, knees, hips, and ankles), shoulders, or smaller joints (dactylitis). Symmetric polyarthritis may develop later during the disease. Arthritis might result in joint destruction that sometimes necessitates joint replacement of the hip or knee. Enthesitis is a common manifestation in SpA that occurs in 25% to 40% of the patients and is caused by a local inflammatory reaction at the bony adherence of the tendon. The sites most often involved are the Achilles tendons, plantar fascia, costosternal junctions, spinous processes, iliac crests, great trochanters, ischial tuberosities, and tibial tubercles.5 Evaluation of the enthesitis lesions can be performed with the Maastricht AS Enthesis Score (MASES)6 or the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index.7

Next to the spinal symptoms and peripheral arthritis, several extra-articular manifestations (EAMs) often occur in SpA, such as uveitis, psoriasis, and IBD, as well as comorbidities, such as osteoporosis and cardiovascular (CV) disease.

Acute anterior uveitis, previously called iridocyclitis, occurs in 25% to 30% of patients with AS and can be the first presenting symptom of the disease. Psoriasis develops in 10% to 25% of patients with SpA and IBD develops in only 5% to 10%.

Osteoporosis of the spine frequently occurs and can lead to vertebral fractures at a young age.8 Because of the rigidity of the ankylosed spine, minor trauma can also cause vertebral fractures and should be considered if the pattern of pain and mobility are changed after an accident. The use of CT scan can help to detect these fractures,9 which may be missed with conventional radiography. The changes in bone formation in SpA will be discussed in more detail in elsewhere in this issue.

CV manifestations, particularly conduction disturbances and aortic insufficiency, occur in 1% to 10% of patients with long-standing disease and the risk of atherosclerotic events is approximately doubled. Pulmonary complications are infrequent and can be caused by rigidity of the chest wall and apical pulmonary fibrosis.10 Renal involvement was encountered in severe AS in the past (amyloidosis), but seem to be less common in the current SpA population.10

It is important to realize the impact and prevalence of these EAMs and comorbidities because they might interfere with the efficacy of the commonly used drugs in SpA or, worse, some can be a contraindication for these drugs.

NSAIDs, as well as selective cyclooxygenase-2 (COX-2)–inhibitors (eg, celecoxib and etoricoxib), are very effective in reducing pain and morning stiffness, and for the treatment of arthritis and enthesitis.11, 12, 13, 14, 15 However, the presence of IBD or severe CV disease can be a relative contraindication for these drugs.

Tumor necrosis factor (TNF)-blocking agents made possible a substantial improvement of the treatment of SpA. Up to now, large placebo-controlled trials have demonstrated the efficacy of infliximab, etanercept, adalimumab, and golimumab in 60% to 70% of subjects with SpA.16, 17, 18, 19, 20, 21, 22, 23 but other biologicals are not very effective in SpA so far.24, 25, 26, 27, 28 Next to clinical improvement, a decrease of inflammation was observed on MRI of the sacroiliac joints and vertebral spine.29, 30, 31, 32, 33, 34, 35, 36 However, some of these TNF-blocking agents seem to be more effective in the treatment of EAMs, such as colitis, compared with other drugs of this group.

Interestingly, patients with SpA with comorbidities, such as osteoporosis, seem to show improvement of this manifestation because bone mineral density rises during anti-TNF treatment in most patients with SpA.37

Section snippets

Uveitis

Acute anterior uveitis is an acute attack with inflammation of the uvea and can be the first presenting symptom of the disease. In a study of 433 subjects with different types of uveitis, 44 cases (almost 10%) of SpA were detected, whereas other studies showed a percentage up to 50% of previously undiagnosed cases of SpA among subjects with uveitis.38, 39, 40

The occurrence of acute anterior uveitis is increased in the HLA-B27 positive population, with a lifetime cumulative incidence of 0.2% in

CV comorbidities—recent insights

It has been clearly established that patients with AS suffer from an increased CV risk in comparison with the general population. This increased risk is due to atherosclerotic diseases, such as myocardial and cerebral infarction, and the so-called AS-specific cardiac manifestations.

The traditional CV risk factors, as well as the underlying chronic inflammatory process, are important for the increased atherosclerotic risk in AS.67 In addition, inflammation also seems important for the

Preclinical atherosclerosis

Carotid artery intima media thickness (cIMT) is a valid instrument to assess preclinical, atherosclerosis and an important predictor for future CV disease. Thus far, several small scale studies demonstrated cIMT increases ranging from 0.07 mm and 0.12 mm, respectively.77, 78 This indicates only a 10% to 15% % increased CV risk and is much lower than the expected, approximately double, CV risk demonstrated in the studies mentioned above. This might indicate that, in AS, atherosclerotic plaques

AS-related cardiac manifestations

Several studies indicated that AS is also associated with non-atherosclerotic CV manifestations and it is hypothesized that inflammation affects different structures of the heart leading to these complications. Whereas aortitis was reported often in the older literature, now this complication is rare, and contemporary prevalence data are not available.

CV risk factors

Several large scale studies have demonstrated significantly higher, increased up to twofold, prevalence of hypertension75, 88, 89 and dyslipidemia.88 Dyslipidemia in AS is related to disease activity and, in active disease, characterized by lowered total and HDL-cholesterol concentrations.90, 91

There are also some indications that subjects with AS smoke much more than non–AS controls.91, 92

The effects of antirheumatic treatment

Because atherosclerosis is in essence an inflammation of the artery,93 one would expect that effective antirheumatic (ie, antiinflammatory), therapy would have a favorable impact on the CV risk in patients with AS. In rheumatoid arthritis there is increasing evidence from observational studies that TNF-blocking agents reduce the CV risk (albeit CV endpoint trials have not been conducted).

Because large-scale placebo-controlled CV endpoint studies with TNF blocking agents are not feasible

Undertreatment of CV comorbidity

Generally comorbidity is undertreated in patients with chronic diseases103; however, AS-specific data are lacking.

Particularly in AS, the identification of specific CV problems could be masked in patients with AS. For example, chest pain can be misinterpreted as musculoskeletal rather than originating from the heart.

CV risk management

AS should be regarded as a new, independent CV risk factor for which CV risk management should be considered. In 2009, the European League Against Rheumatism (EULAR) recommended CV risk management in patients with inflammatory arthritis, including AS,104 consisting of yearly CV risk screening (and treatment, if necessary) and effective treatment of the underlying inflammation. This was confirmed by the 2010 update of the Assessment of Spondyloarthritis International Society (ASAS)-EULAR

Summary

SpA is a chronic inflammatory disease with either predominantly axial symptoms of the spine and sacroiliac joints (axial SpA, including ankylosing spondylitis) or predominantly arthritis (peripheral SpA). Many patients with SpA also suffer from EAMs, including anterior uveitis, psoriasis or IBD, and cardiovascular manifestations. Peripheral arthritis occurs in approximately 30% of the patients, especially in large joints and shows an asymmetrical, oligoarticular pattern. Other common joint

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