Efficacy of TNF inhibitors in advanced ankylosing spondylitis with total spinal fusion: case report and review of literature

Introduction

Ankylosing spondylitis (AS) is a progressive immunomediated disorder characterized by inflammation and new bone formation, predominantly in the axial skeleton, although peripheral joint involvement, enthesitis, and extra-articular manifestations can also be observed to varying degrees. The spinal inflammation promotes formation of intervertebral syndesmophytes and osseous fusion, which can lead to both structural and functional impairments and decreased quality of life (QOL).¹ There is a strong association of AS with HLA-B27 genetic background.² The most common symptom is inflammatory back pain.³ Despite reported prevalence of AS between 0.2%–0.5% in the United States, AS accounts for only a minority of cases of chronic low-back pain.⁴ Delay in diagnosis of AS by many years is common, which may be in part due to failure of recognition by non-rheumatologists.⁵ Not initiating treatment in a timely manner in turn can result in worse long-term outcomes, due to irreversible new bone formation in the axial skeleton, pain, loss of spinal function, and diminished QOL.⁶ Although there is currently no cure for AS, treatment with TNF inhibitors (TNFis) has significantly improved symptoms, signs, and QOL in patients with AS.⁷ Biologic therapy is recommended when disease activity is high despite treatment with at least two NSAIDs and physiotherapy.⁸ Unfortunately, there are only limited data available regarding the efficacy of TNFis in patients with advanced AS, because most randomized clinical trials have excluded this subgroup.

Case report

The patient was a 45-year-old male with past medical history significant for obesity and hypertension who presented to the clinic with chronic and progressive low-back pain and neck pain for over 10 years. Written informed consent was provided by the patient to have the case details and any accompanying images published. Institutional approval was not required to publish the case details. The pain was severe and constant, which he rated 8 out of 10 on a pain scale. The pain was worse during the second half of the night, and awakened him intermittently. It was also severe in the morning, with associated stiffness lasting approximately 2 hours. The pain was aggravated by prolonged rest and alleviated with activity. In recent years, he had also noticed substantial limitation of movement in the neck and lower back. He had undergone physical therapy and taken maximum doses of several NSAIDs, which were only minimally efficacious. He denied history of uveitis, psoriasis, peripheral joint pain, or gastrointestinal symptoms suggestive of active inflammatory bowel disease.

Physical examination revealed limited movement of the cervical spine, with occiput-to-wall distance of 5 cm. He also had reduced chest expansion of only 2 cm and strikingly reduced range of motion at the lumbar spine, with abnormal modified Schober’s test of 12 cm from 10 cm upon forward flexion. He had tenderness over the bilateral sacroiliac joints and the lumbar spine. However, he did not exhibit any inflammatory-appearing rashes, abnormal nail changes, or active synovitis, enthesitis, or dactylitis in the peripheral joints. Blood work showed positive HLA-B27, elevated erythrocyte-sedimentation rate (ESR) of 50 and elevated CRP of 1.8 mg/dL (normal defined as <0.8 mg/dL). Plain radiographic imaging studies were notable for the fusion at the sacroiliac iliac joint bilaterally (Figure 1), bamboo spine at the lumbar spine (Figure 2), and ankyloses of the cervical spine (Figure 3). Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was 5.7, patient global assessment of disease 8, total back pain 8, Bath Ankylosing Spondylitis Functional Index (BASFI) score 6.3, and inflammation (mean of BASDAI questions 5 and 6 for morning stiffness) score 7.

Figure 1 The sacroiliac joints are fused.

Figure 2 Bridging syndesmophytes at multiple levels of the lumbar spine along the anterior fibers, consistent with a bamboo spine.

Figure 3 Mature ankylosis of the cervical spine with straightening.

On the basis of the 1984 modified New York criteria,⁹ the patient was diagnosed with AS. Due to limited efficacy of prior treatments with NSAIDs and physiotherapy, the decision was made to start TNFis, specifically etanercept. Approximately 3 months into therapy, the patient reported marked improvement of his symptoms. His ESR and CRP had normalized to 10 and 0.4 mg/dL, respectively. In addition, BASDAI score also improved from 5.7 to 1.7, BASFI from 6.3 to 4.2, patient global assessment of disease from 8 to 2, total back pain from 8 to 2, and inflammation (mean of BASDAI questions 5 and 6 for morning stiffness) from 7 to 1. As such, he easily met the Assessment of Spondyloarthritis International Society 40 improvement criteria. After 4 years of ongoing treatment with etanercept, he continues to do well clinically without experiencing any adverse effects. He is also able to work and perform all his activities of daily living without any issues or problems.

Discussion

Compared to other types of spondyloarthritis, patients with AS are more likely to have symmetric sacroiliitis, stronger association with HLA-B27, and extensive spinal fusion.¹⁰ Needless to say, the functional disability, pain, and overall disease burden associated with AS are immense.¹¹ To make matters worse, the delay between the onset of associated symptoms and diagnosis of AS frequently takes longer than 10 years.¹² As such, it is not uncommon for patients to already have advanced disease at the time of diagnosis. In AS, some patients may achieve low disease activity over time, due to reaching a “burnout” state; however, other patients may still retain high disease activity despite being in the most advanced radiographic grading-system stage, i.e.,stage V, as proposed by Braun et al.¹³ Unfortunately, there is a paucity of data available in patients with advanced AS, because they are frequently excluded from clinical trials.

To my knowledge, there have been only a handful of studies that have reported the efficacy of TNFis in patients with advanced AS: two were observational studies without a control group for infliximab¹⁴ and adalimumab,¹⁵ one was a post hoc analysis of adalimumab in a phase III study, where eleven patients with total spinal ankylosis were evaluated,¹⁶ and another was a 12-week randomized double-blind placebo-controlled multicenter study of 82 advanced AS patients with etanercept.¹⁷ The results of these studies all suggested reduction of symptoms and signs of AS in patients with advanced but still active AS, similar to those in whom AS was not radiographically advanced. This was also the case for my patient, whose BASDAI score, BASFI score, severity of morning stiffness, ESR, and CRP all improved significantly upon treatment with etanercept. In addition, my patient is tolerating etanercept well without any unexpected adverse events, similarly to the patients in these studies who were treated with various TNFis.

To summarize, having advanced AS is not a contraindication to TNFi therapy as long as patients have active disease and have failed to respond adequately to at least two NSAIDs and physiotherapy. High baseline BASDAI score and CRP seem to be better predictors of clinical response to TNFis, since AS patients with varying degrees of ankylosis experience similar benefits from the treatment.^14–19 Several TNFis have been approved for AS, and their efficacy appears to be comparable, despite the lack of head-to-head comparisons.⁸ Etanercept was chosen for my patient due to his insurance company’s preference, although monoclonal antibodies, i.e., infliximab, adalimumab, certolizumab, and golimumab, would have been better choices had he had concomitant uveitis or inflammatory bowel disease.^20,21 However, more studies need to be performed to determine if or when biologics should be tapered in a patient like mine, who achieved sustained remission on chronic TNFi therapy. Furthermore, the current guidelines are not clear on whether patients should be switched to another TNFi or changed to anti-IL17 therapy if the ongoing TNFi therapy fails.

Key points

Having advanced AS and total spinal ankylosis is not a contraindication to TNFi if patients fail conventional treatment with NSAIDs and physiotherapy and disease is still active, i.e., elevated CRP, elevated BASDAI score, and active inflammation seen on magnetic resonance imaging. Improvement of symptoms, signs, and QOL of AS patients with advanced disease on TNFis are comparable to those in whom AS is not as radiographically advanced. Further studies need to be performed to determine whether switching to another TNFi or anti-IL17 therapy should be considered when ongoing TNFi therapy fails. Also, an ideal time to initiate a tapering regimen of biologics should be ascertained when patients achieve sustained remission on TNFis.