Medicine – Seronegative Spondyloarthritides and Comparison with Seropositive Rheumatoid Arthritis

The seronegative spondyloarthritides, now commonly referred to collectively as spondyloarthritis, are a group of related inflammatory rheumatic diseases that share several clinical, genetic, and radiological characteristics. They are traditionally called seronegative because rheumatoid factor is usually absent. These disorders have an important association with HLA-B27 and frequently involve the sacroiliac joints, spine, peripheral joints, and entheses. Extra-articular manifestations involving the eyes, skin, gastrointestinal tract, cardiovascular system, and genitourinary tract may also occur.

Main Seronegative Spondyloarthritides

1. Ankylosing Spondylitis

Ankylosing spondylitis is the classic axial form of spondyloarthritis and predominantly affects the sacroiliac joints and spine. Patients typically develop inflammatory back pain, prolonged morning stiffness, and progressive restriction of spinal movement. Advanced disease may lead to ankylosis and the characteristic radiological appearance of a bamboo spine. Extra-articular manifestations include anterior uveitis, aortic regurgitation, conduction abnormalities, and, rarely, apical pulmonary fibrosis.

2. Psoriatic Arthritis

Psoriatic arthritis is an inflammatory arthritis associated with psoriasis. Its presentation is highly variable and may include asymmetrical oligoarthritis, symmetrical polyarthritis, distal interphalangeal joint disease, spondylitis, or the severe destructive form known as arthritis mutilans. Dactylitis, enthesitis, and psoriatic nail changes are particularly characteristic and can help distinguish the disease from rheumatoid arthritis.

3. Enteropathic Arthritis

Enteropathic arthritis refers to inflammatory arthritis associated with inflammatory bowel disease, particularly Crohn’s disease and ulcerative colitis. Patients may develop peripheral arthritis affecting predominantly the lower limbs or axial disease involving the sacroiliac joints and spine. The severity of peripheral arthritis may sometimes parallel intestinal disease activity, whereas axial disease can progress relatively independently of bowel inflammation.

4. Reactive Arthritis

Reactive arthritis, formerly called Reiter’s syndrome, develops after an infection elsewhere in the body, particularly a gastrointestinal or genitourinary infection. It classically presents with the combination of arthritis, conjunctivitis, and urethritis, although the complete triad is not present in every patient. Other manifestations include enthesitis, sacroiliitis, oral ulceration, circinate balanitis, and keratoderma blennorrhagicum.

Comparison with Seropositive Rheumatoid Arthritis

1. Pattern of Peripheral Arthritis

Peripheral arthritis in the seronegative spondyloarthritides is commonly asymmetrical, often presenting as an oligoarthritis predominantly involving the lower limbs. By contrast, seropositive rheumatoid arthritis typically causes a symmetrical inflammatory polyarthritis, particularly affecting the small joints of the hands and feet.

2. Spinal Involvement

Spinal disease is characteristic of the spondyloarthritis group. Chronic inflammation may cause sacroiliitis, spondylitis, syndesmophyte formation, and eventually ankylosis. Rheumatoid arthritis generally does not produce this pattern of axial ankylosis. When the spine is involved in rheumatoid arthritis, the cervical spine is particularly important, with atlantoaxial instability or subluxation being a recognised complication.

3. Sacroiliac and Cartilaginous Joints

The sacroiliac joints are commonly affected in spondyloarthritis, and sacroiliitis is one of the characteristic features of axial disease. Progressive inflammation can lead to erosions, sclerosis, narrowing, and eventually fusion. Significant sacroiliac involvement is much less characteristic of rheumatoid arthritis.

4. Genetic Associations

The major genetic association of the seronegative spondyloarthritides is HLA-B27, particularly in ankylosing spondylitis and axial spondyloarthritis. In comparison, rheumatoid arthritis has important associations with certain HLA-DRB1 alleles, historically described in simplified teaching tables as an association with HLA-DR4.

5. Eye Manifestations

Ocular inflammation may occur in both groups but tends to take different forms. Acute anterior uveitis is particularly characteristic of spondyloarthritis and presents with a painful red eye, photophobia, and blurred vision. Conjunctivitis is especially associated with reactive arthritis. Rheumatoid arthritis, in contrast, can produce scleritis or episcleritis, with scleritis representing the more serious inflammatory manifestation.

6. Skin and Mucosal Manifestations

The spondyloarthritis group has several characteristic mucocutaneous manifestations depending on the particular disease. These include psoriasis in psoriatic arthritis, keratoderma blennorrhagicum and mucosal ulceration in reactive arthritis, and erythema nodosum in association with inflammatory bowel disease.

Seropositive rheumatoid arthritis may instead produce rheumatoid nodules, particularly in patients with longstanding seropositive disease. More severe systemic rheumatoid arthritis can also be associated with cutaneous vasculitis.

7. Cardiovascular Manifestations

Cardiovascular involvement in spondyloarthritis, particularly longstanding ankylosing spondylitis, may include aortitis, aortic regurgitation, and cardiac conduction abnormalities. These complications result from inflammation and fibrosis involving the aortic root and nearby cardiac structures.

In rheumatoid arthritis, pericarditis is a recognised extra-articular cardiac manifestation. Patients with rheumatoid arthritis also have an increased long-term risk of cardiovascular disease related to chronic systemic inflammation.

8. Pulmonary Manifestations

Advanced ankylosing spondylitis may cause restriction of chest wall movement because of ankylosis of the thoracic and costovertebral joints. Apical pulmonary fibrosis is another recognised but uncommon complication.

Rheumatoid arthritis can produce several pulmonary abnormalities, including rheumatoid lung nodules, pleural effusions, and interstitial lung disease with pulmonary fibrosis. Lung involvement can therefore represent an important extra-articular complication of rheumatoid disease.

9. Gastrointestinal Manifestations

Gastrointestinal disease has a particularly strong relationship with the spondyloarthritis group because Crohn’s disease and ulcerative colitis are associated with enteropathic arthritis. Intestinal ulceration and inflammation may therefore coexist directly with the musculoskeletal manifestations.

Gastrointestinal problems in rheumatoid arthritis are less characteristic of the disease itself and may instead arise from medications, including NSAIDs, corticosteroids, and other antirheumatic treatments.

10. Genitourinary Manifestations

Genitourinary involvement is particularly relevant to reactive arthritis, in which urethritis may occur following a sexually acquired infection. Genital mucosal lesions, including circinate balanitis, may also develop.

These manifestations are not characteristic features of uncomplicated rheumatoid arthritis and therefore may provide useful clues when distinguishing reactive arthritis from rheumatoid disease.

Key Differences

The seronegative spondyloarthritides can be distinguished from seropositive rheumatoid arthritis by their tendency toward asymmetrical peripheral arthritis, sacroiliitis, axial inflammation, enthesitis, and HLA-B27 association. They are also associated with characteristic extra-articular manifestations such as anterior uveitis, psoriasis, inflammatory bowel disease, and urethritis. In contrast, rheumatoid arthritis more typically produces symmetrical peripheral polyarthritis, is associated with rheumatoid factor and anti-CCP antibodies, and may cause complications such as rheumatoid nodules, cervical spine instability, scleritis, pericarditis, and rheumatoid lung disease.