Current Rheumatology Reviews - Volume 5, Issue 3, 2009

Ankylosing spondylitis (AS) is a common rheumatic disorder in Chinese and other Asia populations. The prevalence of AS in Chinese is 0.2 to 0.3%, and the positive rate of B27 in AS is ranged from 90% to 97%. Undifferentiated spondloarthropathy (USpA) is classified as a form of SPA that does not meet the criteria for other SPA including AS, Reiter's syndrome, psoriatic arthritis (PsA) or inflammatory bowel disease related arthritis. For psoriasis, the lower incidence rate in Pacific Asian countries is due to the lower prevalence of HLA-CW6 within the population. Early diagnosis of AS is not possible by the previous classification criteria because radiologic changes of at least bilaterial class II sacroiliitis require 5 or more years to develop. The early diagnosis may need a new criteria which consists of clinical, laboratory (B27) and imaging findings (MRI). AS may develop acute and chronic inflammation at the different time. ESR and CRP are commonly used in rheumatoid arthritis (RA) but seems not working well to be used as a good disease activity biomarker in AS. In this issue, candidate biomarkers for the AS or for evaluation of response to the treatment will be discussed. Before the era of biologic agents, NSAIDs were only drugs proved to be useful in treating patients with SPA. However, approximately 20% are non-responder. From the serologic, synovial fluid and synovial pathology findings, TNF-α is highly associated with AS or other SPA. Early studies of anti-TNF-α therapy in SPA showed a very good efficacy for pain and inflammation as in RA. However, it is not certain for the biologic therapy to reduce the new bone formation in AS. This is still a treatment barrier but need to break through.

Many controlled studies have been conducted to prove the safety and efficacy of biologics in the treatment of psoriasis. However, only limited data are available in Asia-Pacific region. Open label studies of efalizumab and alefacept have been conducted in Taiwan. A placebo controlled trial of adalimumab had been done in Japan. For etanercept, the only published data in Asia-Pacific region was a retrospective study in South Korea. Two placebo-controlled studies were conducted for ustekinumab. The safety profile was in consistent with the results published in the pivotal studies but the therapeutic efficacy of the biologics seems to be somewhat less significant in Asia-Pacific region. A higher incidence of arthritis was observed during the efalizumab trial. Besides, a higher incidence of drug directed antibodies was found for efalizumab and infliximab. This review article will detail on the published data in Asia-Pacific region of the six biologics indicated for the treatment of psoriasis, namely alefacept (Amevive), efalizumab (Raptiva), etanercept (Enbrel), adalimumab (Humira), infliximab (Remicade) and ustekinumab (Stelara).

Spondyloarthropathy defines a group of diseases characterized by chronic inflammation of axial or peripheral joints with a variety of mucocutaneous, ophthalmic lesions. Evidence showed that these disorders are autoimmune in origin with T cells, B cells and monocytes/macrophages playing major roles. In addition, cytokines secreted by these immune cells also were considered indispensible to the triggering of these diseases. Before the era of biological agents, non-steroidal anti-inflammatory drugs (NSAIDS) were only drugs proved to be useful in treating patients with spondyloarthropathy. None of disease-modifying anti-rheumatic drugs (DMARDS) were considered effective in modification of disease course, especially in axial symptom. Thanks to the invention of biological agents, both clinical and radiological parameters were found to improve after targeting therapy. The efficacy of tumor necrosis factor blockage in patients with spondyloarthropathy is almost as effective as in patients with rheumatoid arthritis. New insight of pathogenesis uncovered novel molecules involved, which were potential targets in the future.

Ankylosing spondylitis (AS) is the prototype of spondyloarthritides. The diagnosis of AS is often delayed until late stage with radiographic damage. The development of anti-TNFα therapy has been an important therapeutic advance in AS. The efficacy of anti-TNFα therapy is indubitable in short term and up to five years in published studies in both western countries and Asia. Whether anti-TNFα therapy in AS has disease modifying properties remain unclear. Latent tuberculosis (TB) infection and reactivation of hepatitis B virus infection (HBV) are the major concerns because both TB and HBV are endemic in Asia. Because of the high cost of anti-TNFα therapy, alternative regimens have been adopted in AS patients. Early diagnosis, identify predictive markers and aggressive treatment in early stage of disease in order to alter the disease progression of AS warrant further investigations.

Although the etiology of ankylosing spondylitis is unknown, it is necessary to develop tools for evaluating the patient response to the new therapeutic drugs. AS is mediated by chronic inflammation and characterized by bone destruction and formation. Recently, tumor necrosis factor-alpha (TNF-alpha) blockade has been widely used for treatment of AS, and the patient response is evaluated by examining the levels of various biomarkers such as matrix metalloproteinases (MMPs), interleukins (ILs), and vascular endothelial growth factor (VEGFs). This review discusses the recent studies suggesting candidate biomarkers for evaluation of the response to treatment and the joint remodeling markers.

Until a decade ago, treatment of ankylosing spondylitis (AS) used to be quite unsatisfactory. However, the advent of TNF blockers has brought about a dramatic change in clinical approach to this disease. The long diagnostic delay- typically 7 to 10 years in the past- is no longer considered acceptable. AS and axial uSpA are probably part of the same disease spectrum. There is great interest currently in making an early diagnosis of AS. The latter would require presence of a combination of several clinical (such as inflammatory back pain, enthesitis, uveitis, or asymmetrical lower extremity arthritis), laboratory (such as HLA-B27 or C-reactive protein), and imaging (X-Rays or MRI) parameters. Although MRI would provide the confirmatory evidence, it may not be necessary in a situation where the probability of axial SpA is already more than 90%. Lastly, it remains to be shown whether early intervention with anti-TNF agents alters the long-term outcome of AS.

Undifferentiated spondyloarthritis (USpA) include incomplete forms or early phases of definite seronegative spondyloarthritis (SpA) and cases of spondyloarthritis that remain undifferentiated. The treatment of SpA is more conditioned by the disease localization. Non-steroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs are the main therapeutic agents for the treatment of peripheral arthritis in USpA. Tumor necrosis factor-α (TNF-α) has been detected in sacroiliac joints of patients with SpA. Anti-TNF-α therapy has been shown efficacious in patients with active ankylosing spondylitis (AS) and psoriatic arthritis. Similar to these SpA subtypes, therapeutic options in USpA are also limited. In those cases in which severe symptoms persist despite these treatments or when there is a severe axial involvement, biologic therapy (such as anti-TNF-α agents) represent an effective choice. In these patients, anti-TNF-α treatment raises the important possibility of blocking a shift from USpA to differentiated forms of spondyloarthritis.

Full text available

An extensive histopathogical analysis of synovial tissues is a good method to understand how specific cellular or molecular events developed in spondyloarthropathy (SpA). Although it is difficult to take biopsy sampling (the axial skeleton, sacroiliac joint, the enthesis, etc.), some histologic studies of peripheral syovial specimen (knee, hip etc.) have demonstrated the specific cellular or molecular features in SpA. The immunohistologic findings in SpA synovial tissues showed increased vascularity, synovial hyperplasia, inflammatory cells infiltration (especially macrophage subset, CD163+) and matrix metalloproteinase (MMP) expression (especially MMP3). Numbers of CD163+ macrophage and polymorphonuclear cells was correlated to global disease activity in SpA. TNF-α blockade have been shown not only to significantly improve the signs and symptoms of SpA but also to improve functional status and quality of life. CD163+ macrophages and MMP3 are rapidly downregulated by effective treatment with TNF-α blockade, and they are valuable synovial biomarkers for response to treatment in SpA. In the future, more molecular or cellular studies still need to be explored to understand detailed pathogenesis of SpA.