The above case demonstrates the challenges in managing enteropathic arthritis given that the therapeutic options for patients with the more severe form have been rather limited. Commonly, oligoarthritis associated with IBD is associated with disease activity; however, in 10% of cases, it evolves into chronic arthritis [4
] as in this case. Even though sulfasalazine seems to be promising in IBD-related arthropathy [8
], our patient did not show a good response with the treatment, indicating the need for biologic therapy.
Although biologic treatment is a promising treatment option, the trials of this agent involved mainly other spondyloarthropathies, particularly ankylosing spondylitis (AS) and psoriatic arthritis [9
]. No randomized controlled trials have investigated therapeutic options in IBD-related arthropathy. The treatment is based almost entirely on extrapolation from treatment of other forms of spondyloarthropathies since they shared the same pathogenesis, which involves significant expression of TNF-α in the joint spaces as the major inflammatory mediators.
Among the biologic agents, infliximab, which is a chimeric anti-TNF-α monoclonal IgGI antibody, is the most widely used and has been proven in many studies to control the primary IBD and associated arthritis [12
]. For etanercept, only one small study by Marzo-Ortega and colleagues [14
] showed its efficacy in various spondyloarthritides, including IBD. In that study, the authors reported a significant increase in mean bone mineral density at the hip and spine in all patients who were treated with a six-month course of 25 mg of subcutaneous etanercept biweekly [14
]. Etanercept may improve joint symptoms, but studies do not show any benefit for the bowel inflammation as the treatment progresses [15
]. It has been proposed that the differential effects of infliximab and etanercept in IBD are due to the inability of the etanercept to bind directly to the cell surface of macrophages causing different signal was transmitted into the cell via transmembrane TNF. These signals do not induce mononuclear cells apoptosis within the bowel mucosa, which is the key pathogenesis in IBD [15
]. Although adalimumab has also been shown to be effective for the treatment of AS [16
], no trials have specifically examined the efficacy of adalimumab for patients with concomitant IBD and arthritis. Table [17
] summarizes the previous studies of anti-TNF in enteropathic arthritis.
Case series and studies of biologics in enteropathic arthritis
Although etanercept is not effective for bowel symptoms in IBD, it was started in this patient because she preferred to administer the subcutaneous medications herself at home and because her underlying colitis was in remission. Although there has been a concern of a potential flare of underlying IBD with etanercept, [22
] our patient had no relapse of colitis after 12 months of treatment and the underlying arthritis remained in remission.
Despite all of the potential benefits of the biologics, we still have an unresolved issue pertaining to the duration of the treatment. In other spondyloarthritis such as AS and psoariatic arthritis, a sustained response of up to two years was reported [14
]. Unfortunately, most of these patients relapse after a few weeks of withdrawal of the treatment. The relapse rate is high, ranging from 75% to 100%, and the mean time to relapse was reported to be as early as six to 17.5 weeks. However, retreatment is safe and still effective, resulting in similar clinical improvement [24
]. Therefore, the optimum duration of the treatment is not known, and most likely our patient will require lifelong and extremely expensive treatment.
In Malaysia, the cost and feasibility of biologics are indeed the major concern, and the treatment is available only in large tertiary centers. To date, only a few studies have looked into the cost-effectiveness of etanercept among patients with other groups of seronegative arthritis such as AS and psoariatic arthritis. The primary outcome measure used was quality-adjusted life years (QALYs), which was derived from utility values estimated as function disability measured by the British ankylosing spondylitis disease activity index (BASDAI), British ankylosing spondylitis functional index (BASFI), and EQ-5D scores. The results were rather conflicting and inconclusive as different populations were involved with different criteria of each patient, the time the TNF blocker was started was not the same, and no randomized control trials directly compared various anti-TNF-α inhibitors. A study by Ara and colleagues [25
] demonstrated the potential cost-effectiveness of etanercept plus NSAIDs compared with NSAIDs alone in patients who had severe unremitting AS and who failed two optimum NSAIDs in the UK, and the majority of costs were below £25,000 per QALY at five years. Etanercept is the only biologic within the range of cost-effectiveness estimates considered by the National Institute for Health and Clinical Excellence to represent a good value for money in the National Health Service [25
]. On the other hand, the incremental cost-utility ratios in The Netherlands vary between £43,000 and £124,000 per QALY for etanercept compared with usual care and £67,000 to £237,000 for infliximab [26
]. Thus, this model suggests that the high drug costs restrict efficient use in all patients who have a BASDAI of more than 4. Bravo and colleagues [27
] demonstrated, among patients with psoariatic arthritis, that, at a 10-year time horizon, etanercept was more cost-effective than infliximab. The incremental cost-effectiveness ratio was significantly higher at £26,000 per QALY to £31,000 per QALY for etanercept compared to £165,000 to 205,000 per QALY in infliximab with no superiority effectiveness. However, this study was not a head-to-head comparison.
Even though biologic treatment has demonstrated marked clinical and radiological improvement in both synovitis and enthesitis, thus preventing ankylosis in the short term, it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiologic progression and ankylosis can be stopped totally. A study by Baraliakos and colleagues [28
] showed that, after two years of treatment, magnetic resonance imaging revealed that minor spinal inflammation was still present in 64% of the patients. Therefore, long-term treatment may not guarantee the prevention of ankylosis, but at least it can delay the process and, hopefully with longitudinal studies of early disease, will be able to answer the question of whether these therapies constitute true long-term disease modifiers in spondyloarthropathies.