SERONEGATIVE SPONDYLOARTHROPATHIES

ABSTRACT: Spondyloarthropathies are often diagnosed late in the course of disease and treatment options have been limited, but new therapies are emerging with potential to offer significant relief and improve structural and functional outcomes.

CME OBJECTIVE: The reader will be aware of the clinical presentations of the seronegative spondyloarthropathies and available treatment options.
Anthony M. Turkiewicz, MD, no conflicts of interest.

The spondyloarthropathies (SpA) are a diverse group of chronic inflammatory conditions linked by distinctive clinical, radiographic, and genetic features. Inflammatory back pain and enthesitis (inflammation at sites where tendons and ligaments attach to bone) are hallmarks of this family of disorders that affect the spine and sacroiliac and peripheral joints. Extra-articular manifestations can include gut involvement, skin and mucosal lesions, uveitis, and cardiac abnormalities (including heart block and aortic regurgitation), says UAB clinical immunologist and rheumatologist Anthony M. Turkiewicz, MD.

"The spondyloarthropathies include ankylosing spondylitis (AS) — often regarded as the prototype; reactive arthritis (ReA); psoriatic arthritis (PsA); enteropathic spondyloarthropathy; and undifferentiated spondyloarthropathy," he says. "Because these disorders are not associated with rheumatoid factor, they are often labeled 'seronegative' spondyloarthropathies. Better understanding of involved pathological processes has led to new therapies that decrease disease activity and improve function."

A Genetic Link

Many individuals suffering from SpA carry the HLA-B27 gene. The strength of the association between HLA-B27 and disease susceptibility varies among various spondyloarthropathies, as well as ethnic and racial groups. "HLA-B27's precise molecular mechanism and its role in disease pathogenesis are not fully understood, but its presence seems to affect disease expression," Turkiewicz says.

Percentage of HLA-B27-positive Caucasian patients by disorder:

• AS - >90%
  
• ReA - 75% to 80%
  
• Enteropathic spondyloarthropathy - 45% to 65%
  
• PsA - 40%
  

Expanding Treatment Options

Recent research links AS to significant morbidity, including chronic pain, limited spinal mobility, and fatigue (Clin Exp Rheumatol. 2002;20[Suppl. 28]:S16-S22). "At least one third of patients with ankylosing spondylitis progress to severe disability," Turkiewicz says. "Because disease often begins in young individuals — mean age of onset is 26 — there is considerable lifetime socioeconomic impact for individuals and society."

Until recently, few therapeutic options for patients with SpA existed. Treatment was mainly supportive, limited to nonsteroidal anti-inflammatories (NSAIDs) and physical therapy. While these modalities can help control symptoms, they do not inhibit disease progression.

A number of disease-modifying antirheumatic drugs (DMARDS) for treatment of SpA have been evaluated in randomized controlled trials; the best studied is sulfasalazine. "Trials with sulfasalazine show modest improvement in peripheral disease, but none in axial symptoms," Turkiewicz says. "This efficacy was mostly restricted to early disease. Data from trials of other DMARDs, including methotrexate, hydroxychloroquine, and azathioprine and cyclosporine, show even less efficacy."

TNF inhibitors

Biologic response modifiers that suppress tumor necrosis factor-alpha (TNF-a) have emerged as important therapeutic options for SpA, he says. "Several observations provide rationale for investigating TNF inhibition of spondyloarthropathies. Transgenic mice overexpressing TNF-a develop enthesitis and arthritis resembling AS, and elevated TNF-a concentrations have been detected in synovial fluid and sacroiliac joints of patients with active disease."

Following randomized clinical trials of biological response modifiers in SpA, the Food and Drug Administration recently approved etanercept — a TNF-receptor fusion protein — for AS and PsA.

One study in AS patients found etanercept rapidly achieved significant sustained improvement in axial and peripheral disease; more than 80% of patients in the etanercept arm had a response, compared with 30% in the placebo group (N Engl J Med. 2002;346:1349-1356).

For the first time, significant improvement in axial symptoms and reduction in spinal inflammation have been reported in patients with SpA, he says. "Studies evaluating the TNF-a inhibitors infliximab and adalimumab have shown similar response rates. Sustained efficacy at stable dosing of infliximab in AS patients has been established 3 years from treatment initiation. Short-term data show these drugs are generally safe and well-tolerated, but long-term safety data are still needed," he says.

Another advantage of biologic response modifiers may be efficacy in late disease. At the 2004 Clinical Immunology Systemic Autoimmune Diseases Conference, Turkiewicz presented data from a SpA cohort treated with TNF inhibitors since 1998. "In our cohort consisting of 50 patients with all SpA subtypes, we observed improvement in symptoms and functional outcomes and decreases in serologic inflammatory markers, including a small number of patients with radiographically fused sacroiliac joints."

Earlier Detection, Treatment

Early diagnosis of SpA is largely based on history and physical examination. "SpA can have a much more insidious onset, compared with other inflammatory arthritides such as rheumatoid arthritis," Turkiewicz says. "Obstacles to early diagnosis include patients who delay seeking medical attention for what they interpret as common low-back pain and physician reliance on radiographic abnormalities."

An average 5- to 7-year delay exists between symptom onset and diagnosis. Radiographic changes may not be seen with conventional X-ray imaging for up to 8 years.

"New criteria have been proposed that emphasize clinical signs and symptoms rather than radiographic changes. In addition, other modalities are being investigated to detect structural changes earlier in disease. A validated scoring system for spinal MRI in spondylarthropathy has evolved, but as with all new therapies and diagnostics, benefits must be weighed against cost," he says.

Turkiewicz advises physicians to suspect SpA in younger patients with persistent low-back pain that improves with exercise.

"Concurrent skin or mucosal changes, as well as other associated extra-articular features, should also raise suspicion," he concludes. "These patients should be referred to a rheumatologist early for evaluation.

"We need to focus on shortening time to diagnosis. The earlier we begin treatment, the better our chances of relieving pain, improving function, and minimizing long-term effects of the disease."

For more information
Dr. Anthony Turkiewicz
1.800.UAB.MIST
mailto:mist@uabmc.edu