Ankylosing Spondylitis (AS) is a chronic inflammatory disorder that primarily affects the spine and the sacroiliac joints, which connect the spine to the pelvis. AS belongs to the spondyloarthropathies, characterized by inflammation where tendons and ligaments attach to bone. The diagnosis of AS is strongly linked to the presence of the genetic marker Human Leukocyte Antigen B27 (HLA-B27), found in a large majority of patients. However, 10 to 20% of individuals who meet the clinical criteria for AS do not possess this marker. This seronegative variant confirms that the disease can exist without HLA-B27 and requires careful diagnostic consideration.
The Significance of the HLA-B27 Marker
The HLA-B27 gene is part of the major histocompatibility complex (MHC) class I system, coding for proteins on the cell surface. These proteins help the immune system differentiate between the body’s own cells and invading pathogens. The presence of the HLA-B27 allele is the strongest known genetic risk factor for developing AS.
Up to 95% of AS patients carry this gene, and people with HLA-B27 are about 60 times more likely to develop AS than those without it. Doctors routinely test for HLA-B27 because a positive result significantly increases the probability of an AS diagnosis. However, a positive test alone is not diagnostic, as most individuals with the gene never develop the disease, and its absence does not fully exclude the diagnosis.
Defining Seronegative Ankylosing Spondylitis
Seronegative AS represents a clear minority of all cases. Clinical studies show that these patients tend to have a later age of symptom onset compared to their seropositive counterparts. Seronegative patients frequently show a higher prevalence of peripheral arthritis (affecting joints in the limbs) and dactylitis (severe inflammation of an entire finger or toe). They also have an increased likelihood of experiencing extra-articular manifestations, such as psoriasis or Inflammatory Bowel Disease (IBD). Although spinal involvement is still present, the inflammatory burden and resulting functional disability have been reported to be slightly higher in some seronegative cohorts.
Confirming the Diagnosis Without Genetic Evidence
Since the genetic marker is absent, the diagnosis of seronegative AS relies heavily on objective evidence of inflammation and structural damage. The process begins with a detailed assessment of the patient’s symptoms, especially the characteristic inflammatory back pain. This type of pain typically begins before age 40, has a gradual onset, improves with exercise but not rest, and causes stiffness that is worst in the morning.
Imaging studies are the most powerful tool for confirming the disease in the absence of HLA-B27. Standard X-rays are used to look for sacroiliitis, which is inflammation and eventual bony fusion in the sacroiliac joints. Magnetic Resonance Imaging (MRI) is increasingly employed because it can detect active inflammation much earlier than X-rays. MRI reveals subtle inflammatory changes before permanent structural damage appears on conventional radiographs. The current classification criteria allow for a diagnosis based on imaging evidence of sacroiliitis plus at least one Spondyloarthritis feature, completely bypassing the need for genetic evidence.
Management Strategies and Disease Outlook
The general approach to managing HLA-B27 negative AS is similar to that for seropositive disease, focusing on reducing pain and inflammation while maintaining spinal mobility. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line pharmaceutical treatment and are often highly effective in controlling symptoms. Consistent physical therapy and exercise are also fundamental to the treatment plan, helping to preserve function and prevent progressive stiffness.
For patients whose symptoms are not adequately controlled by NSAIDs, biologic medications are used to target the underlying inflammatory process. These include TNF inhibitors and IL-17 inhibitors, which are highly effective in reducing disease activity in both HLA-B27 positive and negative patients. Because seronegative patients often have more peripheral joint involvement, disease-modifying antirheumatic drugs (DMARDs) may also be utilized to treat arthritis in the limbs.
The long-term prognosis for seronegative AS is variable but generally manageable with modern therapies. While some studies suggest a slightly higher burden of reported disease activity and peripheral symptoms, the absence of HLA-B27 does not appear to correlate with a significantly different degree of long-term structural damage to the spine. The primary goal of treatment remains consistent: to prevent spinal fusion and maintain the patient’s quality of life and functional independence.