Comorbidities in Patients with Spondyloarthritis




Chronic inflammatory spondyloarthritis involves axial symptoms of the spine and sacroiliac joints, or peripheral arthritis. Many patients suffer from extra-articular manifestations. With acute anterior uveitis, rapid treatment prevents synechiae. Other organs can be involved. Treatment includes exercise, nonsteroidal antiinflammatory drugs (if insufficient response, tumor necrosis factor blockers), and (with peripheral arthritis) sulfasalazine. Patients with ankylosing spondylitis have comorbidities and increased cardiovascular risk. For uveitis or inflammatory bowel disease, patients should be referred to an ophthalmologist or gastroenterologist. Cardiovascular risk may originate from atherosclerotic disease and cardiac manifestations. Epidemiological studies should be conducted before echocardiogram screening and cardiovascular risk management.








  • Extra-articular manifestations (EAMs) contribute significantly to the burden of disease in ankylosing spondylitis (AS).



  • The manifestation of EAMs has consequences for the choice of treatment.



  • Patients with AS have an approximately doubled risk for cardiovascular (CV) disease.



  • AS is a new, independent, CV risk factor.



  • The inflammatory process contributes significantly to the increased CV risk.



  • CV risk management is necessary and should focus on traditional CV risk factors and tight disease control.



Key Points


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, or by peripheral arthritis, which is classified as peripheral SpA. Axial SpA is subdivided in two types: (1) AS, which requires radiographic changes of the sacroiliac joints (according to the Modified New York Criteria), 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.


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).


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 criteria 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.


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. Evaluation of the enthesitis lesions can be performed with the Maastricht AS Enthesis Score (MASES) or the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index.


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. 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, 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. Renal involvement was encountered in severe AS in the past (amyloidosis), but seem to be less common in the current SpA population.


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. 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. but other biologicals are not very effective in SpA so far. Next to clinical improvement, a decrease of inflammation was observed on MRI of the sacroiliac joints and vertebral spine. 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.




EAMs of SpA


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.


The occurrence of acute anterior uveitis is increased in the HLA-B27 positive population, with a lifetime cumulative incidence of 0.2% in the general population compared with 1% in the HLA-B27 positive population.


The attacks of uveitis are usually recurrent and unilateral. The symptoms are sudden ocular pain with redness and photophobia. Inflammation can lead to debris, which accumulates in the anterior chamber and may cause papillary and lens dysfunction with blurring of vision. In some cases, glaucoma and severe visual impairment occurs if adequate treatment is delayed, but usually the uveitis subsides spontaneously within 3 months.


In patients with SpA who have sudden symptoms of a painful red eye it is recommended to refer the patient to the ophthalmologist as soon as possible. In most cases, acute uveitis can be treated successfully by the ophthalmologist with local corticosteroids and mydriatics. Sometimes an intraocular injection with corticosteroids or a high oral dosage of prednisone (up to 60 mg daily) is necessary to treat the inflammation. In most cases there is no residual visual impairment.


NSAIDs seem to show efficacy for uveitis. There is some evidence that the use of sulfasalazine reduces the recurrence rate of uveitis. Other immunosuppressive drugs used by the ophthalmologists to treat refractory uveitis, such as azathioprine and methotrexate, do not have much efficacy on the disease activity of SpA.


Some TNF-blocking agents can be used for indications of and active SpA disease, as well as refractory uveitis. Infliximab, an adequate treatment of SpA, decreases the recurrence rate of uveitis and is effective in refractory uveitis. The efficacy of etanercept on uveitis is uncertain because etanercept does not seem to prevent a relapse in combination with methotrexate and it was suggested that etanercept might even trigger an attack of uveitis. However, a comparison of three randomized studies with etanercept in AS showed a lower number of cases with uveitis in subjects treated with etanercept compared with placebo, indicating that etanercept inhibits the recurrence of uveitis.


An analysis of four placebo-controlled studies and three open-label studies with TNF agents in AS showed a frequency of flares of anterior uveitis in the placebo-group of 15.6 per 100 patient-years, compared with 7.9 per 100 patient-years in etanercept group and 3.4 per 100 patient-years in the subjects treated with infliximab. The attacks of uveitis during these studies were reported by the subjects and no follow-up studies or ophthalmologic controls were performed.


Reports on the efficacy of adalimumab on uveitis are mainly based on retrospective analysis of placebo-controlled trials, which show beneficial results. In a prospective study, subjects with AS were treated with adalimumab because of their high disease activity and screened by an ophthalmologist on uveitis. This study demonstrates a significant decrease (73%) of the recurrence rate of uveitis during adalimumab treatment.


Data on the efficacy of golimumab on the recurrence rate of anterior uveitis are lacking. It can be concluded that, in most cases, attacks of anterior uveitis respond very well to (local) treatment by the ophthalmologist. In cases with refractory uveitis or a high uveitis recurrence rate, treatment with TNF-blocking agents can be successful, especially if the treatment is indicated for high disease activity of SpA. Adalimumab and infliximab seem to be more effective in lowering the recurrence rate of uveitis compared with etanercept.


Psoriasis


Psoriasis is a common skin disease with plaque lesions and nail deformities. Psoriatic arthritis occurs in 5% to 20% of people with psoriasis and can present as a symmetric polyarthritis, resembling rheumatoid arthritis, but with additional involvement of the distal interphalangeal joints. Axial disease occurs in about 5% of patients with psoriasis, asymmetrical sacroiliitis occurs in one-third of the cases, and spondylitis without sacroiliitis occurs in the rest. Enthesitis and dactylitis are common, especially in the oligoarticular form of the disease. In SpA, patients with psoriatic arthritis excluded, psoriasis occurs in approximately 5% to10%.


In case of scaling skin lesions or nail changes suspicious for psoriasis in SpA it is recommended to refer the patient to a dermatologist. Skin manifestations of psoriasis respond to local corticosteroids or psoralen plus ultraviolet A (PUVA) therapy.


In case of psoriatic arthritis, NSAIDs and intra-articular injections with corticosteroid are effective in monoarthritis or oligoarthritis. Methotrexate and leflunomide are effective in both psoriasis and peripheral arthritis, but show efficacy for the axial manifestations of SpA, whereas TNF-α blockers, such as infliximab, etanercept, adalimumab, and golimumab, are efficacious on psoriasis as well as the axial manifestations of SpA. In some cases, treatment of SpA with TNF-blocking agents can result in controversial reactions, including as new manifestations of psoriasis such as palmoplantar pustulosis.


IBD


IBD includes Crohn disease and ulcerative colitis. Approximately 10% of patients with IBD develop SpA. On the other hand, the chance of patients with SpA developing IBD is 5% to10%. Asymptomatic IBD is described in a high percentage (60%) of patients with SpA and can be detected by endoscopy of the colon and terminal ileum. During follow-up studies, it seemed that up to 6% of subjects with SpA who had chronic gut inflammation eventually developed Crohn disease.


Another indication that diseases such as SpA and IBD show some overlap is a study on serologic markers of IBD. In this study, a high percentage (55%) of subjects with AS without abdominal complaints had positive tests for perinuclear antineutrophil cytoplasmic autoantibody (pANCA), ANCA, or outer membrane porin C Saccharomyces cerevisiae IgG and IgA (Omp-C ASCA).


In case of persistent or frequently recurring diarrhea and/or blood or mucus production with the stools, it is advised to refer the patient with SpA to a gastroenterologist to perform a colonoscopy.


Treatment of IBD by a gastroenterologist is based on immunosuppressive drugs and anti-TNF. The use of NSAIDs can worsen the colitis manifestation; therefore it is advised to minimize the use of these drugs by patients with SpA who have IBD, except for celecoxib, which does not seem to increase the risk at exacerbation of the IBD. The use of sulfasalazine can be beneficial for SpA and IBD. In most cases, the efficacy of other immunosuppressive drugs used in IBD has no proven efficacy in SpA. Among the TNF-blocking agents, only infliximab and adalimumab are effective in SpA and IBD. Golimumab is effective in SpA, but not yet registered for IBD. Etanercept works well for spinal symptoms in SpA but not on IBD and, even worse, new manifestations of IBD might occur during etanercept treatment.


Therefore, in patients with SpA who have IBD, the use of NSAIDs should be minimized except for celecoxib, sulfasalazine might be beneficial for both indications, and the first choice of anti-TNF is infliximab or adalimumab.




EAMs of SpA


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.


The occurrence of acute anterior uveitis is increased in the HLA-B27 positive population, with a lifetime cumulative incidence of 0.2% in the general population compared with 1% in the HLA-B27 positive population.


The attacks of uveitis are usually recurrent and unilateral. The symptoms are sudden ocular pain with redness and photophobia. Inflammation can lead to debris, which accumulates in the anterior chamber and may cause papillary and lens dysfunction with blurring of vision. In some cases, glaucoma and severe visual impairment occurs if adequate treatment is delayed, but usually the uveitis subsides spontaneously within 3 months.


In patients with SpA who have sudden symptoms of a painful red eye it is recommended to refer the patient to the ophthalmologist as soon as possible. In most cases, acute uveitis can be treated successfully by the ophthalmologist with local corticosteroids and mydriatics. Sometimes an intraocular injection with corticosteroids or a high oral dosage of prednisone (up to 60 mg daily) is necessary to treat the inflammation. In most cases there is no residual visual impairment.


NSAIDs seem to show efficacy for uveitis. There is some evidence that the use of sulfasalazine reduces the recurrence rate of uveitis. Other immunosuppressive drugs used by the ophthalmologists to treat refractory uveitis, such as azathioprine and methotrexate, do not have much efficacy on the disease activity of SpA.


Some TNF-blocking agents can be used for indications of and active SpA disease, as well as refractory uveitis. Infliximab, an adequate treatment of SpA, decreases the recurrence rate of uveitis and is effective in refractory uveitis. The efficacy of etanercept on uveitis is uncertain because etanercept does not seem to prevent a relapse in combination with methotrexate and it was suggested that etanercept might even trigger an attack of uveitis. However, a comparison of three randomized studies with etanercept in AS showed a lower number of cases with uveitis in subjects treated with etanercept compared with placebo, indicating that etanercept inhibits the recurrence of uveitis.


An analysis of four placebo-controlled studies and three open-label studies with TNF agents in AS showed a frequency of flares of anterior uveitis in the placebo-group of 15.6 per 100 patient-years, compared with 7.9 per 100 patient-years in etanercept group and 3.4 per 100 patient-years in the subjects treated with infliximab. The attacks of uveitis during these studies were reported by the subjects and no follow-up studies or ophthalmologic controls were performed.


Reports on the efficacy of adalimumab on uveitis are mainly based on retrospective analysis of placebo-controlled trials, which show beneficial results. In a prospective study, subjects with AS were treated with adalimumab because of their high disease activity and screened by an ophthalmologist on uveitis. This study demonstrates a significant decrease (73%) of the recurrence rate of uveitis during adalimumab treatment.


Data on the efficacy of golimumab on the recurrence rate of anterior uveitis are lacking. It can be concluded that, in most cases, attacks of anterior uveitis respond very well to (local) treatment by the ophthalmologist. In cases with refractory uveitis or a high uveitis recurrence rate, treatment with TNF-blocking agents can be successful, especially if the treatment is indicated for high disease activity of SpA. Adalimumab and infliximab seem to be more effective in lowering the recurrence rate of uveitis compared with etanercept.


Psoriasis


Psoriasis is a common skin disease with plaque lesions and nail deformities. Psoriatic arthritis occurs in 5% to 20% of people with psoriasis and can present as a symmetric polyarthritis, resembling rheumatoid arthritis, but with additional involvement of the distal interphalangeal joints. Axial disease occurs in about 5% of patients with psoriasis, asymmetrical sacroiliitis occurs in one-third of the cases, and spondylitis without sacroiliitis occurs in the rest. Enthesitis and dactylitis are common, especially in the oligoarticular form of the disease. In SpA, patients with psoriatic arthritis excluded, psoriasis occurs in approximately 5% to10%.


In case of scaling skin lesions or nail changes suspicious for psoriasis in SpA it is recommended to refer the patient to a dermatologist. Skin manifestations of psoriasis respond to local corticosteroids or psoralen plus ultraviolet A (PUVA) therapy.


In case of psoriatic arthritis, NSAIDs and intra-articular injections with corticosteroid are effective in monoarthritis or oligoarthritis. Methotrexate and leflunomide are effective in both psoriasis and peripheral arthritis, but show efficacy for the axial manifestations of SpA, whereas TNF-α blockers, such as infliximab, etanercept, adalimumab, and golimumab, are efficacious on psoriasis as well as the axial manifestations of SpA. In some cases, treatment of SpA with TNF-blocking agents can result in controversial reactions, including as new manifestations of psoriasis such as palmoplantar pustulosis.


IBD


IBD includes Crohn disease and ulcerative colitis. Approximately 10% of patients with IBD develop SpA. On the other hand, the chance of patients with SpA developing IBD is 5% to10%. Asymptomatic IBD is described in a high percentage (60%) of patients with SpA and can be detected by endoscopy of the colon and terminal ileum. During follow-up studies, it seemed that up to 6% of subjects with SpA who had chronic gut inflammation eventually developed Crohn disease.


Another indication that diseases such as SpA and IBD show some overlap is a study on serologic markers of IBD. In this study, a high percentage (55%) of subjects with AS without abdominal complaints had positive tests for perinuclear antineutrophil cytoplasmic autoantibody (pANCA), ANCA, or outer membrane porin C Saccharomyces cerevisiae IgG and IgA (Omp-C ASCA).


In case of persistent or frequently recurring diarrhea and/or blood or mucus production with the stools, it is advised to refer the patient with SpA to a gastroenterologist to perform a colonoscopy.


Treatment of IBD by a gastroenterologist is based on immunosuppressive drugs and anti-TNF. The use of NSAIDs can worsen the colitis manifestation; therefore it is advised to minimize the use of these drugs by patients with SpA who have IBD, except for celecoxib, which does not seem to increase the risk at exacerbation of the IBD. The use of sulfasalazine can be beneficial for SpA and IBD. In most cases, the efficacy of other immunosuppressive drugs used in IBD has no proven efficacy in SpA. Among the TNF-blocking agents, only infliximab and adalimumab are effective in SpA and IBD. Golimumab is effective in SpA, but not yet registered for IBD. Etanercept works well for spinal symptoms in SpA but not on IBD and, even worse, new manifestations of IBD might occur during etanercept treatment.


Therefore, in patients with SpA who have IBD, the use of NSAIDs should be minimized except for celecoxib, sulfasalazine might be beneficial for both indications, and the first choice of anti-TNF is infliximab or adalimumab.




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. In addition, inflammation also seems important for the development of AS-specific cardiac manifestations.


Mortality


Two recent mortality studies indicated a 60% to 90% increased mortality in comparison to the general population ( Table 1 ). Most important, the causes of death were circulatory (40%), malignancies (27%), and infections (23%) ; or were 17%, 17%, and 29%, respectively.



Table 1

Mortality in AS

























Study Study Design Comparison Group Number of Patients Time Period Findings
Bakland et al, 2011 Hospital-based General population 677 1977–2009 SMR a : 1.61 (1.29–1.93)
Mok et al, 2011 Hospital-based General population 2332 1999–2008 SMR: 1.87 (1.61–2.13)

a SMR: Standardized mortality ratio.



These figures are similar to the standardized mortality ratio in older studies, indicating that there was no decline of mortality during the last decades. Predictors of mortality may include increased C-reactive protein levels and infrequent or non-NSAID use.


CV Comorbidity


A population-based cohort investigation in almost 5400 men, demonstrated a 40% increased risk for myocardial infarction, that was age-dependent and peaked at age 60–64 (hazard ratio = 2.4; 95% CI: 1.3–4.5). The largest study comprised more than 8.600 subjects with AS and prevalence ratios ranged from 1.25 for cerebrovascular disease to 1.37 for ischemic heart disease, with the greater excess risk in younger subjects.


However, an almost threefold increased prevalence of myocardial infarction was reported in a questionnaire-based study of 400 subjects with AS, and a doubled prevalence of ischemic heart disease was reported in a Swedish population study ( Table 2 ).



Table 2

CV atherosclerotic comorbidities in AS








































Study Population Studied Study Design Number of AS Patients Outcome Measures and Findings
Symmons et al, 2004 UK Community-based AS cohort vs general population 5392 First myocardial infarction, hazard ratio: 1.4 (95% CI: 1.2–1.8)
Han et al, 2006 US PharMetrics Patient Centric database (US)
Cross-sectional vs 4 matched controls
1843


  • Prevalence ratio:



  • Ischemic heart disease: 1.2 (95% CI 1.0–1.5)



  • Peripheral vascular disease: 1.6 (95% CI 1.2–2.2)



  • Congestive heart failure 1.8 (95% CI 1.2–2.6)



  • Cerebrovascular disease: 1.7 (95% CI 1.3–2.3)

Peters et al, 2010 Netherlands Referral based two-center study vs general population 383 Odds ratio: 3.1 (95% CI 1.9–5.1)
Szabo et al, 2011 Canada Population-based cohort compared with general population 8616


  • Prevalence ratio:



  • Ischemic heart disease: 1.37 (95% CI 1.31–1.91)



  • Peripheral vascular disease: 1.6 (95% CI 1.2–2.2)



  • Cerebrovascular disease: 1.25 (95% CI 1.15–1.35)

Bremander et al, 2011 Sweden Population-based cohort study 935 Ischemic heart disease SMR a : 2.20 (95% CI 1.77–2.70)

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Comorbidities in Patients with Spondyloarthritis
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