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Abstract

Spondyloarthritis (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). Next to these spinal and articular symptoms, many patients with SpA also have extra-articular manifestations (EAMs). EAMs associated with SpA include anterior uveitis (25–30%), psoriasis (10–25%) or inflammatory bowel disease (IBD) (5–10%) and cardiovascular manifestations. Peripheral arthritis occurs in approximately 30% of patients, especially in large joints, and shows an asymmetrical, oligoarticular pattern. Other common joint complaints are due to enthesitis, which manifest as extra-articular bony tenderness in areas such as the Achilles tendon. Acute anterior uveitis presents with acute pain, loss of vision and redness in one eye that usually subsides spontaneously after several weeks. Rapid treatment by an ophthalmologist is required to prevent synechiae formation which could ultimately result in glaucoma and blindness. Although less common, organ involvement in SpA can also be located in the heart, lungs or kidneys. The risk of cardiovascular events is increased in SpA. Cardiac manifestations can involve the aortic valve (1–10%) or the atrioventricular node and the risk of atherosclerotic events is increased in this group. Treatment of SpA includes physical exercise and nonsteroidal anti-inflammatory drugs (NSAIDs), and in case of peripheral arthritis, sulphasalazine can be added. When there is insufficient response to NSAIDs, tumor necrosis factor blockers, especially infliximab, etanercept, adalimumab and golimumab, are very effective in treating axial manifestations, arthritis, enthesitis and psoriasis. Anterior uveitis in SpA can be treated adequately by the ophthalmologist and in the case of refractory uveitis, treatment with adalimumab and infliximab seems to be more effective compared with etanercept. When IBD occurs with SpA, the use of NSAIDs should be minimized, except for celecoxib, and infliximab or adalimumab are preferred to etanercept. The incidence of atherosclerotic events or SpA-specific cardiac manifestations may be decreased by cardiovascular risk management or effective antirheumatic treatment. Overall it is important to realize that extra-articular manifestations frequently occur in patients with SpA and should be taken into account in the choice of treatment.

Keywords

Ankylosing spondylitis anterior uveitis arthritis cardiac manifestations enthesitis IBD psoriasis spondyloarthritis

Introduction

Spondyloarthritis (SpA) is a group of rheumatic diseases which includes ankylosing spondylitis (AS) and patients with inflammatory back pain or asymmetrical synovitis, such as psoriatic arthritis, arthritis accompanying inflammatory bowel disease (IBD, e.g. Crohn’s disease and ulcerative colitis) and reactive arthritis.

SpA can be dominated by spinal symptoms, which can be classified as axial SpA [Rudwaleit et al. 2009b] or by peripheral arthritis, which is classified as peripheral SpA [Rudwaleit et al. 2011]. Axial SpA is subdivided into two types, AS, which requires radiographic changes of the sacroiliac joints (according to the Modified New York Criteria) [Van Der Linden et al. 1984], and 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 magnetic resonance imaging. Nonradiographic axial SpA can progress towards AS within a couple of years. The clinical symptoms of axial SpA include inflammatory back pain for at least 3 months with an age at onset under 45 years and at least one of the other ‘SpA features’: arthritis, enthesitis (heel), uveitis, dactylitis, psoriasis, Crohn’s disease/ulcerative colitis, good response to nonsteroidal anti-inflammatory drugs (NSAIDs), family history of SpA and elevated C-reactive protein (CRP) [Rudwaleit et al. 2009b].

Peripheral SpA requires peripheral arthritis compatible with SpA (usually asymmetric or predominant involvement of the lower limb), enthesitis or dactylitis and at least one of the other SpA features, as mentioned before [Rudwaleit et al. 2011].

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 (SI) 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, like 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 men, with a male:female ratio of 3:1. The diagnosis of AS is defined by the Modified New York Criteria [Van Der Linden et al. 1984] and depends, among other things, on the presence of sacroiliitis on the X-ray. The prevalence of SpA, including AS, is estimated at 0.9% in the white population, which equals the prevalence of rheumatoid arthritis [Braun et al. 1998].

Osteoporosis of the spine frequently occurs and can lead to vertebral fractures at a young age [Van Der Weijden et al. 2012a]. Owing to 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 scanning can help to detect these fractures [Van Der Weijden et al. 2012b], which may be missed with conventional radiography.

Peripheral arthritis occurs in 30% of patients and on onset shows a predominately asymmetrical and oligoarticular pattern, involving large joints of the lower limbs (knees, hips, ankles), shoulders, or smaller joints (dactylitis). Symmetrical 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 very common manifestation in SpA and occurs in 25–40% of 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 [McGonagle and Emery, 2000]. Evaluation of the enthesitis lesions can be performed with the Maastricht Ankylosing Spondylitis Enthesis Score (MASES) [Heuft-Dorenbosch et al. 2003] or the Spondyloarthritis Research Consortium of Canada enthesitis index [Maksymowych et al. 2009].

Next to these spinal and articular symptoms, many patients with SpA have extra-articular manifestations (EAMs), such as anterior uveitis, psoriasis, IBD and cardiovascular manifestations.

Acute anterior uveitis, previously called ‘iridocyclitis’, occurs in 25–30% of patients with AS and can be the first presenting symptom of the disease. Psoriasis develops in 10–25% of patients with SpA and IBD in only 5–10%. Cardiovascular manifestations, particularly conduction disturbances and aortic insufficiency, occur in 1–10% of patients with longstanding 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 [El Maghraoui, 2011]. Renal involvement was encountered in severe AS in the past (amyloidosis), but seems to be less common in the SpA population nowadays [El Maghraoui, 2011].

General treatment of spondyloarthritis

Exercises and physical therapy are very important in SpA to improve muscle strength and preserve spinal mobility. NSAID are effective in reducing pain, morning stiffness and for the treatment of arthritis and enthesitis. Selective cyclooxygenase 2 inhibitors are effective in SpA as well, such as celecoxib (dosage of 200–400 mg daily) and etoricoxib (90–120 mg daily) [Dougados et al. 2001; Van Der Heijde et al. 2005a]. Interestingly, there is some evidence that continuous usage of NSAIDs might delay the radiographic spinal progression compared with intermittent therapy [Wanders et al. 2005; Poddubnyy et al. 2012].

The efficacy of most disease-modifying antirheumatic drugs (DMARDs) in SpA is rather disappointing, especially compared with rheumatoid arthritis [Zochling et al. 2006]. Sulfasalazine is effective in peripheral SpA at a daily dosage of 2–3 g [Braun et al. 2011a] and shows some efficacy in treating spinal symptoms as well [Braun et al. 2011b] but not enthesitis [Song et al. 2011b].

The introduction of tumor necrosis factor (TNF) blocking agents made a substantial improvement in the treatment of SpA possible. Up to now, large placebo-controlled trials have demonstrated the efficacy of infliximab, etanercept, adalimumab and golimumab in 60–70% of patients with SpA [Van Der Heijde et al. 2005b, 2006a, 2006b; Inman et al. 2008]. Next to clinical improvement, a decrease in inflammation was observed on magnetic resonance imaging of the sacroiliac joints and vertebral spine [Baraliakos et al. 2005a; Braun et al. 2006, 2012; Lambert et al. 2007]. Treatment with anti-TNFs is most effective in young patients in cases of short disease duration, high functional level (low Bath Ankylosing Spondylitis Functional Index (BASFI)) and high CRP [Rudwaleit et al. 2009a; Vastesaeger et al. 2011]. However, improvement of disease activity with TNF blockers in cases with longstanding disease and ankylosis has also been described [Van Der Heijde et al. 2006b]. Anti-TNF therapy is indicated in cases of persistent high disease activity (BASDAI ≥ 4) and insufficient response to NSAIDs or sulfasalazine in cases of peripheral arthritis [Braun et al. 2011a]. Patients with nonradiographic axial SpA also seem to benefit from treatment with TNF blockers [Haibel et al. 2008; Barkham et al. 2009].

Next to the improvement in axial symptoms in patients with SpA, TNF blockers are very effective in the treatment of peripheral arthritis and enthesitis. Bone mineral density also rises during anti-TNF treatment in most patients with SpA [Barnabe and Hanley, 2009].

Clinical improvement in SpA drops relatively soon after cessation of anti-TNF treatment but returns after reintroduction of these drugs [Brandt et al. 2004, Baraliakos et al. 2005b]. One of the newer TNF-blocking agents, certolizumab pegol, has not been studied in patients with SpA. Other biological agents, such as interleukin-1 receptor antagonist (anakinra), rituximab, tocilizumab and abatacept, have only been studied in small groups of patients with SpA and did not show much efficacy [Tan et al. 2004; Haibel et al. 2005; Song et al. 2010, 2011a; Lekpa et al. 2012].

Treatment of extra-articular manifestations of spondyloarthritis

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 patients with different types of uveitis, 44 cases (almost 10%) of SpA were detected, whereas other studies showed up to 50% of previously undiagnosed cases of SpA among uveitis patients [Pato et al. 2000; Linder et al. 2004; Monnet et al. 2004].

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 [Linssen et al. 1991].

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 occur if adequate treatment is delayed, but most of the time the uveitis subsides spontaneously within 3 months.

In patients with SpA with sudden symptoms of a painful, red eye patients should be referred to an ophthalmologist as soon as possible.

In most cases acute uveitis can be successfully treated 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 for the inflammation to subside. 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 [Munoz-Fernandez et al. 2003; Wakefield et al. 2011]. Other immunosuppressive drugs used by the ophthalmologists to treat refractory uveitis, such as azathioprine and methotrexate, do not have much effect on the disease activity of SpA.

Some TNF-blocking agents can be used for active SpA as well as refractory uveitis. Infliximab is an adequate treatment for SpA, decreases the recurrence rate of uveitis and is effective in refractory uveitis [El-Shabrawi and Hermann, 2002; Braun et al. 2005]. The efficacy of etanercept on uveitis is doubted as etanercept does not seem to prevent a relapse in combination with methotrexate [Foster et al. 2003] and it was suggested that etanercept might even trigger an attack of uveitis [Rosenbaum, 2004]. However, a comparison of three randomized studies with etanercept in AS showed a lower number of cases with uveitis in the etanercept-treated patients compared with the placebo group [Sieper et al. 2010], 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 the etanercept group and 3.4 per 100 patient-years in the infliximab-treated group [Braun et al. 2005]. The attacks of uveitis during these studies were reported by the patients 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 [Rudwaleit et al. 2009c]. In a prospective study, patients with AS were treated with adalimumab because of high disease activity and they were also screened for uveitis by an ophthalmologist. This study demonstrated a significant decrease (73%) in the recurrence rate of uveitis during adalimumab treatment [Van Der Horst-Bruinsma et al. 2010].

Data on the efficacy of golimumab in preventing recurrence 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 5–20% of people with psoriasis and can present as a symmetrical polyarthritis, resembling rheumatoid arthritis, but with additional involvement of the distal interphalangeal joints [Khan, 2003]. Axial disease occurs in about 5% of patients with psoriasis with asymmetrical sacroiliitis in one-third of cases and spondylitis without sacroiliitis in the remainder. Enthesitis and dactylitis are common, especially in the oligoarticular form of the disease. In SpA, patients with psoriatic arthritis excluded, psoriasis occurs in approximately 5–10%. When scaling skin lesions or nail changes indicate psoriasis in SpA, it is recommended that patients are referred to a dermatologist.

Skin manifestations of psoriasis respond to local corticosteroids or psoralen combined with ultraviolet A therapy. In the case of psoriatic arthritis, NSAIDs and intra-articular injections with corticosteroids are effective in mono- or oligoarthritis [Gossec et al. 2012]. Methotrexate is proven to be effective in daily clinical practice for treating the skin and oligoarthritis and polyarthritis, despite the lack of randomized controlled trails to support this [Gossec et al. 2012]. Leflunomide is also effective in treating both psoriasis and peripheral arthritis, but not axial manifestations of SpA [Nash et al. 2006].

TNFα blockers, such as infliximab, etanercept, adalimumab and golimumab, are effective in treating skin and nail lesions of psoriasis [Nash et al. 2006]. In some cases treatment of SpA with TNF-blocking agents can result in new manifestations of psoriasis, such as palmoplantar pustulosis [Kary et al. 2006].

Inflammatory bowel disease

IBD includes Crohn’s disease and ulcerative colitis. Approximately 10% of patients with IBD develop SpA. However, the probability of patients with SpA developing IBD is 5–10%. Asymptomatic IBD is described in a high percentage of patients with SpA (60%) and can be detected by endoscopy of the colon and terminal ileum [Mielants et al. 1988]. During follow-up studies it appeared that up to 6% of patients with SpA and chronic gut inflammation eventually develop Crohn’s disease [Mielants et al. 1991].

Another indication that diseases such as SpA and IBD show some overlap is a study on serological markers of IBD. In one study, a high percentage (55%) of patients with AS without abdominal complaints had a positive test for pANCA, ANCA or Omp-C ASCA antibodies [De Vries et al. 2010].

When persistent or frequently recurring diarrhea or blood or mucus production with the stools occurs it is advised that the patient is referred to the gastroenterologist for a colonoscopy.

Treatment of IBD by the gastroenterologist is based on immunosuppressive drugs and anti-TNF. The use of NSAIDs can worsen colitis manifestations, therefore it is advised that the use of these drugs by patients with SpA and IBD is minimized, except for celecoxib, which does not seem to increase the risk of exacerbation of IBD [Sandborn et al. 2006]. The use of sulfasalazine can be beneficial for both SpA as well as IBD. However, the efficacy of other immunosuppressive drugs often used in IBD have in most cases not proven effective in SpA [Van Der Horst-Bruinsma et al. 2002]. Of the TNF-blocking agents only infliximab and adalimumab are effective in SpA and IBD, and golimumab is not yet registered for IBD [Hanauer et al. 2002; Rutgeerts et al. 2005; Braun et al. 2007; Sandborn et al. 2007a, 2007b]. Etanercept works well for spinal symptoms in patients with SpA but not on IBD and new manifestations of IBD might even occur during etanercept treatment [Sandborn et al. 2001; Song et al. 2008].

Therefore, in patients with SpA and 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.

Cardiovascular disease

During the past decade one European, hospital-based, mortality study with 667 AS patients has been published indicating a 60% increased mortality in comparison to the general population [Bakland et al. 2011]. Most major death causes were circulatory in origin (40%), and predictors of mortality were increased CRP levels and infrequent or non-NSAID use. Reduced (cardiovascular) mortality with (frequent) use of NSAIDs has also been observed in patients with inflammatory arthritis [Goodson et al. 2009], but in the general population their use approximately doubles cardiovascular risk [Trelle et al. 2011].

In a minority (1–10%) of patients with longstanding AS aortic valve incompetence occurs due to aortitis of the ascending aorta and conduction abnormalities, caused by involvement of the atrioventricular node [O’Neill and Bresnihan, 1992]. Conduction disturbances in AS are due to local inflammation and an effect on the atrioventricular node which sometimes require pacemaker implantation when complete heart block occurs [Bergfeldt, 1997]. The incidence of atrioventricular or bundle branch block is increased among the HLA-B27-positive population, independently of the diagnosis of AS [Bergfeldt, 1997]. In AS the variable degrees of atrioventricular or bundle branch block occur in approximately 5% of patients. Aortic insufficiency is reported in 1–10% of patients and increases with age, disease duration and the presence of peripheral arthritis [Peters et al. 2004].

In addition to these characteristic cardiovascular lesions associated with AS, myocardial involvement may also occur, particularly left ventricular dysfunction. Left ventricular dilatation, as well as a poorly contracting left ventricle, were reported in 5 of 28 patients with AS compared with healthy controls [Ribeiro et al. 1984]. These finding were confirmed at necropsy of the myocardium in another group of patients with AS [Brewerton et al. 1987].

Overall, there is an increased risk for the so-called AS-specific cardiac manifestations, such as aortic insufficiency, left ventricular dysfunction and conduction disturbances. However, the present literature does not allow final conclusions to be made about the extent of these AS-specific cardiac manifestations because most studies are based on a hospitalized patient population with severe disease.

Currently, it is estimated that the cardiovascular risk from atherosclerotic origin in patients with AS is twice as high compared with aged-matched controls [Peters et al. 2010b]. Traditional cardiovascular risk factors only partly explain the increased (atherosclerotic) cardiovascular risk in AS (with particularly an increased frequency of hypertension) [Han et al. 2006; Bremander et al. 2011] but inflammation seems to play an important role in atherosclerotic disease as well as the AS-specific cardiac manifestations. Anti-inflammatory therapy, including the use of TNF blockers, might decrease the AS-specific cardiac manifestations and atherosclerotic cardiovascular risk in AS, but there is no evidence to support this hypothesis. However, cardiovascular risk management, as recommended by the EULAR guidelines, might help to decrease the increased atherosclerotic risk in patients with SpA in the future [Peters et al. 2010a].

Conclusions

In patients with SpA, physical exercises and NSAIDs are the treatments of choice. In the case of peripheral arthritis, sulphasalazine can be added as a useful DMARD.

When there is insufficient response to NSAIDs, TNF blockers are very effective in treating SpA, especially infliximab, etanercept, adalimumab and golimumab. These drugs work very well on the axial manifestations and on arthritis, enthesitis and psoriasis.

For EAMs, anterior uveitis can be treated adequately by the ophthalmologist using local treatment. In refractory uveitis or when there is a high recurrence rate, treatment with adalimumab and infliximab seems to be more effective compared with etanercept.

When IBD occurs in patients with SpA, the use of NSAIDs should be minimized but celecoxib can be used if needed. The preferred anti-TNF therapy is infliximab and adalimumab instead of etanercept.

For atherosclerotic events or AS-specific cardiac manifestations there is no evidence in favor of treatment with TNF blockers, but cardiovascular risk management can be useful to prevent further events.

Overall, it is important to realize that in patients with SpA, EAMs frequently occur and should be taken into account in the choice of treatment.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

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Management and evaluation of extra-articular manifestations in spondyloarthritis

Abstract

Keywords

Introduction

General treatment of spondyloarthritis

Treatment of extra-articular manifestations of spondyloarthritis

Uveitis

Psoriasis

Inflammatory bowel disease

Cardiovascular disease

Conclusions

Footnotes

Funding

Conflict of interest statement

References