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Ankylosing Spondylitis: An Update From EULAR 2007



Ankylosing spondylitis (AS) is a chronic systemic inflammatory rheumatic disorder of uncertain etiology that primarily affects the axial skeleton. It usually starts in the late teens and early twenties and can lead to progressive bony fusion of the sacroiliac joints and the vertebral column; some patients may also show extra-articular manifestations.[1] This disease belongs to a group of rheumatic diseases known as the spondyloarthropathies (SpA), which show a strong association with a genetic marker called HLA-B27.[1,2] Its diagnosis at an early stage is not a simple task because there are no established criteria for early diagnosis, and many patients may have atypical presentations.[3-5] Magnetic resonance imaging (MRI) or computerized tomography (CT) can be used to help diagnose the disease at an earlier stage when pelvic radiograph does not show sacroiliitis. The burden of this illness has a tremendous impact on the individual patient and society at large, but this burden is largely underestimated.[6]

Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) and a life-long program of appropriate regular exercises have been the mainstay of symptom control for almost 6 decades. The traditional disease-modifying antirheumatic drugs (DMARDs) used for rheumatoid arthritis (RA) are ineffective in the typical AS patient with disease limited to the axial skeleton, which includes hip and shoulder joints.[7] Tumor necrosis factor (TNF) has been identified as an important mediator of chronic immunoinflammatory disease states, such as rheumatoid arthritis and AS. The inhibition of TNF through a biologically engineered receptor fusion protein (etanercept) or monoclonal antibodies (infliximab and adalimumab) has been shown to be remarkably effective in decreasing inflammatory activity in AS. To maintain their maximal functional ability, patients with AS need to be diagnosed earlier and educated on their disease and about the availability of this new treatment option.[7,8]

EULAR 2007 was a very successful meeting with more than 12,400 attendees, and progress in the field of AS and related SpA was very well highlighted. In fact, in the opening plenary session, Professor Joachim Sieper (Berlin, Germany) gave an outstanding presentation, entitled "Spondyloarthropathies -- At the Crossroads of Imaging, Pathology and Novel Therapeutics."[9]

TNF Antagonists and Their Effect on Syndesmophyte Formation

Sieper pointed out that TNF antagonists seem to be more effective in AS than RA.[10] However, unlike in RA, where treatment with TNF antagonists suppresses radiographic progression, such an effect has not been demonstrated in AS over a 2-year course of treatment with etanercept[11] or with infliximab.[12] However, he correctly pointed out that these studies used the Outcome in AS International Study (OASIS) cohort as a historical control, which is not an ideal control group to compare with, and that when a subgroup of OASIS patients who met the eligibility criteria for inclusion in the TNF-antagonist trials was used for comparison, a small nonsignificant retardation of radiographic progression was seen in both studies. Moreover, it is interesting that in a very recently published study of 33 AS patients on treatment with infliximab, radiographic progression in the first 2 years was noted in only 21% of the patients and in only 15% in the additional 2 years.[13] Radiographic progression was slowed down in comparison with published data from the OASIS cohort. However, AS patients with early disease need to be treated for a longer period of time in order to establish whether TNF antagonists indeed do or do not inhibit syndesmophyte formation. There is also a need for a better scoring method to assess structural damage in AS, because the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS) used in these studies focuses heavily on the formation of syndesmophytes and the occurrence of ankylosis (osteoproliferation), while erosive changes (osteolysis) have a minor influence on the total score.[11-16]

Differences in Inflammatory Bone Remodeling Between AS and RA

Histopathological findings suggest that the structural damage in AS happens in 3 steps. Inflammation is the first step, and it causes cartilage erosion and bone destruction. These lesions result in repair processes, such as fibrous tissue formation. Slowly this tissue then gets ossified, resulting in the formation of syndesmophytes.[9] In contrast, structural damage in RA occurs in only 2 steps: inflammation followed by erosive bone destruction. Georg Schett reported that the cytokines TNF, interleukin (IL)-1, and IL-17 are potent inducers of osteoclast formation, either by direct stimulation of these cells or by inducing the expression of RANKL (receptor activator of nuclear factor-kappaB ligand), which is a critical mediator for bone resorption in arthritis.[17,18] However, joints have a natural "response to stress" mechanism that can result in new bone formation, such as osteophytes. This reaction is abundant in AS and related SpA, but it is virtually absent in RA.[17,18]

Inflammation Inhibits Osteoproliferation

Georg Schett reported that his research team has recently discovered that Wingless (Wnt) signaling is a key inducer of osteophyte formation, and has identified a negative regulator of Wnt, called Dickkopf-1 (DKK-1), which is a master regulator of joint remodeling in arthritis.[19] Moreover, they have found that TNF is a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human RA. Thus, TNF can induce DKK-1, which in turn downregulates bone anabolic responses and prevents the formation of osteophytes.[20] These data suggest that the changes of joint architecture observed in various forms of arthritis are under a tight regulation of molecules critically involved in bone metabolism.[17]

Uncoupling of Inflammation and Ankylosis

The TNF antagonist etanercept targets sites of active inflammation but does not inhibit osteoproliferation in an animal model of joint ankylosis.[21] In a mouse model of inflammatory arthritis, the bone-destructive pattern could be reversed into a bone-forming pattern through blockade of either TNF-alpha or DKK-1.[19] Thus, successful blocking of inflammation in AS does not necessarily imply the arrest of radiographic progression, and it is possible that there may be uncoupling of inflammation and ankylosis. Therefore, it appears that inflammation has to disappear or has to be of a low degree before osteoproliferation can take place. It is even possible that increased osteoproliferation might occur as a consequence of TNF blockade, because suppression of inflammation seems to stimulate osteoproliferation.

TNF Blockade: Targeting the Molecular Pathways Driving Osteoproliferation

Sieper[9] suggested that controlling disease progression in AS may require the use of TNF antagonists as well as drugs that target the molecular pathways driving osteoproliferation, such as NSAIDs that seem to reduce appearance of osteoproliferation via inhibition of prostaglandins.[22,23] He proposed a head-to-head comparison between 3 groups of patients receiving either TNF antagonists as monotherapy, NSAID as monotherapy, or a combination therapy with TNF antagonists plus NSAID over at least a period of 2 years. There is also need to focus on strategies on how to diagnose the disease earlier and when to initiate early and more effective treatment.[9]

Genetics of AS

Despite recent advances in the treatment of AS, the etiology still remains elusive. There is substantive evidence that genetic factors play a pivotal role in susceptibility to AS, especially HLA-B27 and other genes within the major histocompatibility complex (MHC) region. Due to larger datasets of patients with AS, plus the recent advancements in genotyping, many non-MHC candidate genes are being uncovered. Proton Rahman reported studies of the loci for IL-1 gene cluster in Canadian and Korean patients with AS.[24,25] He explained that there are 2 structurally distinct forms of IL-1 cytokine (IL-1-alpha and IL-1-beta), and their biologic activities are initiated by binding with type 1 IL-1 receptor and inhibited by IL-1 receptor antagonist (IL-Ra). The genes of interest reside on chromosome 2q12-13, spanning a 360-kb region, and include IL-1-A, IL-1-B, as well as IL-1-F5 to IL-1-F10 and IL-1 receptor antagonist (IL-1RN) genes. This region has previously been linked to AS.[26] The most significant associations have been noted for markers in both IL-1-A and IL-1-B genes, although the association was more striking for IL-1-A.

Th17 T-Cell Subset Is Important in the Pathogenesis of AS

Rahman stated that recent studies in Crohn's disease and psoriasis have resulted in the finding that the gene on chromosome 1 for a receptor for a proinflammatory cytokine IL-23 is a major non-MHC candidate.[27] IL-23 receptor gene (IL-23R) is also associated with AS in 3 major cohorts (American, British, and Canadian). He then explained the importance of this finding. Traditionally, CD4+ cells are subdivided into Th1, Th2, and regulatory T cells. Another population of T cells has emerged (Th17) that is characterized by IL-17 production. Two additional cytokines are involved in the development to Th17 cells: IL-12 (which is important in the differentiation of naive T cells to Th1 cells) and IL-23 (which promotes the expansion of Th17 cells). These findings suggest that the Th17 T-cell subset may be important in the pathogenesis of AS, in addition to psoriasis and Crohn's disease. A recent report suggests that IL-22, a Th17 cytokine, mediates IL-23-induced dermal inflammation and hyperplasia of the epidermis (acanthosis).[28] Also, the human IL-12/23 monoclonal antibody is very effective as a treatment for psoriasis.[29] Thus, the elucidation of the genetic determinants is of utmost relevance because it can lead to a better understanding of disease pathogenesis and hopefully to potential new therapies.

Other Miscellaneous Reports

IL-23 is selectively overexpressed in subclinical intestinal inflammation sites in patients with AS at levels similar to those seen in patients with Crohn's disease.[30]

TNF-alpha blockade is effective in preventing the development of inflammation in the early phase of inflammatory bowel disease in HLA-B27 transgenic rats.[31]

Switching from a failed anti-TNF therapy to adalimumab was effective and well tolerated in patients with AS, psoriatic arthritis, or RA. Moreover, adalimumab is the first TNF antagonist to demonstrate clinical efficacy in a controlled study in patients with early preradiographic axial SpA (early AS). The substantial percentage of patients who achieved partial remission is especially encouraging and might indicate that TNF antagonists may be even more effective in early forms of axial SpA.[32]

Supported by an independent educational grant from Bristol-Myers Squibb



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