Comorbidities in Patients with Spondyloarthritis
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
References (105)
Extra-articular manifestations of ankylosing spondylitis: prevalence, characteristics and therapeutic implications
Eur J Intern Med
(2011)- et al.
Lack of efficacy of abatacept in axial spondylarthropathies refractory to tumor-necrosis-factor inhibition
Joint Bone Spine
(2012) - et al.
Effect of tumor necrosis factor alpha inhibition on bone density and turnover markers in patients with rheumatoid arthritis and spondyloarthropathy
Semin Arthritis Rheum
(2009) - et al.
Ophthalmic findings and frequency of extraocular manifestations in patients with HLA-B27 uveitis: a study of 175 cases
Ophthalmology
(2004) - et al.
Anti-tumor necrosis factor-alpha therapy with infliximab as an alternative to corticosteroids in the treatment of human leukocyte antigen B27-associated acute anterior uveitis
Ophthalmology
(2002) - et al.
Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study
Clin Gastroenterol Hepatol
(2006) - et al.
Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial
Lancet
(2002) - et al.
Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial
Gastroenterology
(2001) - et al.
The pathogenesis of atherosclerosis in autoimmune rheumatic diseases: roles of inflammation and dyslipidemia
J Autoimmun
(2007) - et al.
Cardiovascular risk profile of patients with spondylarthropathies, particularly ankylosing spondylitis and psoriatic arthritis
Semin Arthritis Rheum
(2004)
Aortitis and periaortitis in ankylosing spondylitis
Joint Bone Spine
Impaired coronary microvascular and left ventricular diastolic functions in patients with ankylosing spondylitis
Atherosclerosis
Left ventricular wall function abnormalities in patients with ankylosing spondylitis evaluated by gated myocardial perfusion scintigraphy
Rev Esp Med Nucl
The development of assessment of spondyloarthritis international society classification criteria for axial spondyloarthritis (part II): validation and final selection
Ann Rheum Dis
The assessment of Spondyloarthritis International Society Classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general
Ann Rheum Dis
Evaluation of the diagnostic criteria for ankylosing spondylitis; a proposal for the modification of the New York criteria
Arthritis Rheum
Prevalence of spondylarthropathies in HLA-B27 positive and negative blood donors
Arthritis Rheum
Enthesitis in ankylosing spondylitis and related spondylarthropathies
Curr Opin Rheumatol
Assessment of enthesitis in ankylosing spondylitis
Ann Rheum Dis
Development and validation of the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index
Ann Rheum Dis
High prevalence of low bone mineral density in patients within 10 years of onset of ankylosing spondylitis: a systematic review
Clin Rheumatol
High frequency of vertebral fractures in early spondylarthropathies
Osteoporos Int
Efficacy of celecoxib, a cycloogynase-2-specific inhibitor, in the treatment of ankylosing spondylitis
Arthritis Rheum
Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results of a fifty-two-week, randomized, controlled study
Arthritis Rheum
Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial
Arthritis Rheum
Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German spondyloarthritis inception cohort
Ann Rheum Dis
Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis
Ann Rheum Dis
Clinical efficacy and safety of etanercept versus sulfasalazine in patients with ankylosing spondylitis: a randomized, double-blind trial
Arthritis Rheum
Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial
Ann Rheum Dis
Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT)
Arthritis Rheum
Once-weekly 50-mg dosing of etanercept (Enbrel(R)) is as effective as 25-mg twice-weekly dosing in patients with ankylosing spondylitis
Ann Rheum Dis
Efficacy and safety of adalimumab in patients with ankylosing spondylitis. Results of a multicenter, randomized, double-blind, placebo-controlled trial
Arthritis Rheum
Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial
Arthritis Rheum
Successful short term treatment of patients with severe undifferentiated spondyloarthritis with the anti-tumor necrosis factor-alpha fusion receptor protein etanercept
J Rheumatol
Clinical response to discontinuation of anti-TNF therapy in patients with ankylosing spondylitis after 3 years of continuous treatment with infliximab
Arthritis Res Ther
Open label trial of anakinra in active ankylosing spondylitis over 24 weeks
Ann Rheum Dis
Efficacy of anakinra in active ankylosing spondylitis: a clinical and magnetic resonance imaging study
Ann Rheum Dis
Different response to rituximab in tumor necrosis factor blocker-naive patients with active ankylosing spondylitis and in patients in whom tumor necrosis factor blockers have failed: a twenty-four-week clinical trial
Arthritis Rheum
Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study
Ann Rheum Dis
Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: results of a multicenter, randomized, double-blind, placebo-controlled magnetic resonance imaging study
Arthritis Rheum
Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor alpha receptor fusion protein etanercept
Arthritis Rheum
Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: a multicenter randomized, double-blind, placebo-controlled study
Arthritis Rheum
Golimumab reduces spinal inflammation in ankylosing spondylitis: MRI results of the randomised, placebo-controlled GO-RAISE study
Ann Rheum Dis
Effectiveness, safety, and predictors of good clinical response in 1250 patients treated with adalimumab for active ankylosing spondylitis
J Rheumatol
Predicting the outcome of ankylosing spondylitis therapy
Ann Rheum Dis
Efficacy of adalimumab in the treatment of axial spondyloarthritis without radiographically defined sacroiliitis
Arthritis Rheum
Clinical and imaging efficacy of infliximab in HLA-B27-Positive patients with magnetic resonance imaging-determined early sacroiliitis
Arthritis Rheum
Prevalence of the spondyloarthritides in patients with uveitis
J Rheumatol
Undiagnosed spondyloarthropathy in patients presenting with anterior uveitis
J Rheumatol
The lifetime cumulative incidence of acute anterior uveitis in a normal population and its relation to ankylosing spondylitis and histocompatibility antigen HLA-B27
Invest Ophthalmol Vis Sci
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2022, Pharmacological ResearchCitation Excerpt :Rheumatic disorders are characterized by systemic inflammation that may involve extra-articular systems leading to significant morbidity and eventually also a reduced life span [10,11]. The SpA group of disorders is associated with several comorbidities, including uveitis, gastrointestinal, skin cardiovascular, pulmonary, renal, and neurological complications that contribute significantly to the morbidity of the disease and represent a real challenge for clinicians [6,12,13]. There is very little knowledge regarding the neurological morbidity in AS patients, although the latter has been reported to suffer from neurological complications either due to compression of neural tissues caused by joint damage or as a consequence of vasculitis neuropathy [14].
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