Extra-articular Manifestations

Introduction

Mild constitutional symptoms, such as anorexia, malaise, weight loss and low-grade fever, may occur in early stages in some patients, especially with severe disease; these are more common among patients with juvenile-onset ankylosing spondylitis (AS), especially in developing countries. In many patients, daytime fatigue and getting tired easily is a common symptom and the burden of fatigue among patients with non-radiographic axial spondyloarthritis (nr-axSpA) is similar to that seen in AS. While biologics are effective in ankylosing spondylitis/ axial spondyloarthritis (AS/axSpA), fatigue remains unresponsive to tumor necrosis factor (TNF) inhibitors in many patients. Some may complain of lack of adequate uninterrupted sleep because of back pain and stiffness that is worse at night.

Acute Anterior Uveitis

AS is associated with many extra-articular manifestations (EAM) (Figure 7-1). The most common clinically apparent association is the occurrence of one or more episodes of non-infectious acute anterior uveitis (AAU). It occurs in 25% to 40% of patients with AS during the course of their disease, and sometimes this can be the presenting manifestation that should trigger a further rheumatologic diagnostic evaluation. AAU classically presents with a red, painful eye, photophobia and blurring of the vision. The eye acutely becomes painful and inflamed; there is circumcorneal congestion, the pupil is small and the iris is edematous and may appear slightly discolored compared to the contralateral side (Figure 7-2).

Slit-lamp examination of the eye shows copious exudate in the anterior chamber of the eye; and the inflammation is defined as non-granulomatous; that is, the inflammatory cells adhering to the endothelial lining cells of the cornea form aggregates called keratitic precipitates, which are small, in contrast to what is usually seen in “granulomatous uveitis” of sarcoidosis and some other diseases. Occurrence of AAU episodes in AS has a 1- to 2-day prodrome with eye pain or discomfort before cells in the anterior chamber can be detected by slit lamp examination. This inflammation can sometimes be intense and result in hypopyon (settling down of the inflammatory cells at the bottom of the anterior chamber of the eye) and fibrin exudation.

The individual attack of acute uveitis usually subsides within a few weeks, but residual visual impairment may occur if treatment is inadequate or delayed. The pupil may become irregular if the iritis is not properly treated because the inflamed iris can becomes attached posteriorly to the lens, causing posterior synechiae formation, or anteriorly to the cornea causing anterior synechiae. Such complications can lead to secondary glaucoma and cataract in the long run. Rarely, the posterior chamber may also become inflamed, resulting in macular edema and further visual blurring.

The uveitis episodes in patients with AS are unilateral in about 50% of the cases, “flip-flop” in about 45% (meaning that both eyes are involved but not simultaneously), and rarely bilateral (5% ). It can also occur among patients with psoriasis, PsA, inflammatory bowel disease and enteropathic spondyloarthritis (SpA). But the association is not as strong as with AS, and the clinical presentation of uveitis is more diverse. For example, uveitis in patients with psoriatic arthritis (PsA) or enteropathic SpA is more likely to be insidious in onset, persistent, posterior and active bilaterally. Moreover, whereas AAU in association with AS is more frequent in males (65%), but close to 90% of AAU patients with enteropathic SpA are females, and they may have insidious rather than abrupt onset of their uveitis.

As with AS, AAU itself also shows strong association with HLA-B27. Occurrence of AAU is significantly more common among AS patients who possess HLA-B27 gene. Patients seen by ophthalmologists for AAU, especially those who are HLA-B27 positive, should be questioned about inflammatory low back pain and also evaluated for other clinical features of SpA because AAU is an important clue to the diagnosis of AS/SpA. Since a prolonged delay in diagnosis is common among SpA patients and occurrence of AAU may be the reason for their first interaction with medical care, occurrence of AAU presents a unique opportunity for identifying such undiagnosed SpA patients.

A novel evidence-based algorithm called Dublin Uveitis Evaluation Tool (DUET) has been proposed to guide ophthalmologists and primary care physicians to refer appropriate AAU patients to rheumatologists. Although AAU can also occur due to other causes (e.g., infectious and neoplastic), most cases are presumed to be immune in origin. However, there are similarities as well as distinct differences in the patterns of uveitis in the various regions of the world because of geographical, environmental and genetic differences, AS and SpA in association with psoriasis and IBD are the most common systemic diseases associated with AAU in Europe, Australia and North America. Standardization of Uveitis Nomenclature (SUN) Working Group has just published their classification criteria for SpA/HLA-B27-associated anterior uveitis.

Munoz-Fernandez and associates evaluated presence of enthesis lesions in patients with idiopathic recurrent AAU without features of AS/SpA, and noted that a high percentage of patients with HLA-B27 showed evidence of enthesis lesions similar to those observed in patients with SpA. Rheumatologic evaluation of 175 consecutive patients with AAU revealed that 136 patients (77.7%) had an HLA-B27–associated extraocular disorder (46.3% with associated AS, 9.7% presumed AS, and 12% undifferentiated SpA). The male-to-female ratio was 1.3 to 1 and the median age at the time of the first attack of uveitis was 31 years. Among 117 of these 136 patients (66.9%) had more than one episode of AAU, the same eye was affected in 41%. The median frequency of active episodes of uveitis was 0.8 (SD ± 0.6) per year, and it decreased as the duration of the disease lengthened.

Some AS/axSpA patients develop dry eyes due to associated sicca/Sjogren’s syndrome.

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Inflammatory Bowel Disease

Apart from the well-known association of inflammatory bowel disease (IBD) with AS, clinically silent (asymptomatic) enteric mucosal inflammatory lesions, both macroscopic and microscopic, have been detected in the terminal ileum and proximal colon on ileocolonoscopic studies in >60% of AS patients with no gastrointestinal symptoms. This supports the existence of a pathogenic link between gut inflammation and AS, and it is independent of HLA-B27.

Follow-up studies of such patients indicate that 6% of them will develop IBD, and among those with histologically “chronic” inflammatory gut lesions 15% to 25% will develop clinically obvious CD, suggesting that the latter group of patients had initially a subclinical form of CD when they presented with arthritis. The appearance of SpA in patients with IBD is not related to the extent of the bowel disease. Recent genetic studies indicate that AS and IBD share many disease predisposing genes, as discussed earlier in Etiology and Pathogenesis. Anywhere between 5% and 10% of patients with AS develop IBD, in particular Crohn’s disease (CD); and conversely up to 30% of patients with IBD develop AS/SpA.

Psoriasis

Psoriasis is a relatively common skin disease with a variable prevalence in the general population that is generally considered to range between 1% to 3% worldwide, and PsA affects up to 30% of them. Among patients with AS, 5% to 16% develop psoriasis of variable degrees of severity. Some of these patients may just have co-occurrence by chance of two relatively common diseases. Patient with isolated AS and psoriasis may be considered to have either AS with psoriasis or as axial PsA. Axial disease alone is observed in 2% to 4% of patients with PsA. Conversely, >10% (range, 5% to 42%) of patients with psoriasis have associated inflammatory arthritis, and 25% to 70% of patients with PsA have axial involvement, depending on the definition used. PsA patients with axial disease at presentation are more likely to possess HLA-B27, have elevated ESR and radiographic evidence of damage to peripheral joints, and less likely to have a family history of PsA.

Cardiovascular Morbidity

Increased cardiovascular morbidity and mortality have been observed in AS because of accelerated atherosclerosis as a result of chronic inflammation, physical inactivity, hypertension and nonsteroidal anti-inflammatory drug (NSAID)-induced risks. In addition, increased incidence of diastolic left ventricular dysfunction has been known for a long time and it probably serves as a precursor to chronic heart failure and may cause morbidity and mortality.

Some of the relatively less common but quite characteristic extraskeletal features include aortic insufficiency and cardiac conduction disturbances, usually those with long-standing disease. Inflammation at the aortic root (aortitis) can lead to fibrosis that is often hemodynamically insignificant, but some patients can develop aortic incompetence due to a dilated aortic ring and changes in the aortic valve. Extension of the inflammation and fibrosis to the atrioventricular conduction system can cause a variable degrees of heart block in approximately 3% of patients, and may need a cardiac pacemaker.

Other Comorbidities

Pulmonary, renal and neurologic comorbidities in AS patients have recently been reviewed. Limitation of chest expansion can impair pulmonary function, but lung involvement in the form of a slowly progressive bilateral apical pulmonary fibrobullous disease or cavitations (with rare fungal infection) is a rare and late manifestation of AS in 1% to 2% of patients. However, the use of newer imaging modalities, such as high-resolution computed tomography (HRCT), suggest a higher incidence of interstitial lung disease than previously thought. In addition to ventilatory restriction from reduced chest wall movement, there is increased occurrence of obstructive sleep apnea in patients with advanced disease with ankylosis and forward-stooping cervical spine.

IgA nephropathy, observed in 1% to 2% of patients that had lacked response to TNF inhibitors and NSAID-related nephropathy can occur in some patients. Renal amyloidosis has become uncommon (0.3% to 1.2%), associated with disease duration and severity and also poor compliance with treatment. However, it is still relatively more common (4% to 7%) in some of the developing countries.

Psychiatric and mental health comorbidities are also common. In the International Map of Axial Spondyloarthritis (IMAS) survey, patients in the United States reported anxiety (43%) and depression (31%) as the most common comorbidities. Data from the survey also indicated that 57% of patients were at risk for psychological distress, especially patients with active axSpA, over 40 years of age and those who are physically inactive.

Spinal Fractures

Patients with AS have a 5-fold higher risk of clinical spine fracture (Figure 20-1) and a 35% increased risk of non-vertebral fracture, and neurologic manifestations can occur that are often related to post-traumatic spinal fractures, especially when associated with unstable and displaced fractures. The spinal fracture usually occurs in the cervical spine, and neurologic deficits are often subtle on initial presentation, resulting in the fracture being missed because of a low index of suspicion and poor visualization of lower cervical fractures on conventional radiographs (Figure 7-3). Extension of the ankylosed forward stooping cervical spine during conventional immobilization or for radiologic and MRI procedures can result in or worsen neurologic deficits in such patients. Aseptic spondylodiscitis can occur, mostly in the mid-thoracic spine, more commonly seen in patients with advanced disease. It is usually asymptomatic and can occur with minimal or no history of physical trauma.

The patients with AS are more likely to develop osteoporosis, and it can contribute to progressive spinal kyphosis that is worsened by non-traumatic vertebral compression fractures. Bone biopsies and assessment of biochemical markers of bone metabolism have shown that both diminished bone formation and enhanced bone resorption are involved. It is partly a result of ankylosis and lack of mobility but may also be related to a mineralization defect resulting from proinflammatory cytokines in patients with active disease. A marked reduction in bone mineral density of the lumbar spine and femoral neck has been observed on dual energy x-ray absorptiometry (DEXA) measurement in a group of relatively young patients with AS. One should also look for and treat any concomitant deficiency of vitamin D.

Cauda equina syndrome, characterized by dull pain in the lower back and upper buttock region, analgesia in the buttocks, genitalia, or thighs (saddle area), and a disturbance of bowel and bladder function, is a rare (0.5%) and characteristic but very late complication of AS. It probably results from chronic adhesive arachnoiditis, which results from fibrous entrapment and scarring of the sacral and lower lumbar nerve roots. Computed tomography (CT) and MRI examinations can show dural ectasia. dorsal arachnoid diverticuli causing scalloped erosions of the posterior vertebral elements, and adhesions of nerve roots of the cauda equina to the wall of the dural sac. Spontaneous atlantoaxial subluxation can rarely be seen in patients with AS, and even more rarely upward subluxation of axis may occur. There are a few case reports of co-occurrence of AS and demyelination, possibly multiple sclerosis, but a true link remains to be established.

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Fibromyalgia

The prevalence of fibromyalgia, among a total of 5,214 patients, was 16.4% (95% CI 12.3-20.5%). Prevalence varied with axSpA sub-classification: AS: 13.8% (9.1-18.6%); MRI positive nr-axSpA 20.3% (6.5-34.1%); and ‘clinical’ disease: 11.1% (6.0-16.2%). Overall, around one in six patients with axSpA also meet criteria for fibromyalgia.

It is a common disorder present in 2% to 8% adults in the general population, commonly develops between the ages of 25 and 55 and mainly affects women. People with a family history of fibromyalgia are eight times more likely to develop this condition. These patients are more sensitive to pain and report higher disease activity, poorer function and QoL, higher fatigue and moderate to severe level of emotional and mental distress (perceived stress, anxiety, depression, sleep disturbance and cognitive difficulties). They may continue to complain widespread pain even when the inflammation is completely resolved with effective medical management. Such patients pose a challenge and may require a team of healthcare professionals who specialize in management of fibromyalgia.