Introduction

Tumor necrosis factors (TNF) are a group of cytokines that can cause apoptosis, or programmed cell death. TNF is one of the first mediators (cytokine) that appears in the blood within minutes after stress or an injury occurs. It is an important molecule that acts as the body’s alarm and defense system. Other inflammatory mediators such as IL-1 and IL-6 show up later, and the evidence concludes that these mediators depend on the previously released TNF [1].

Monoclonal antibodies against TNF have been developed and are used in the treatment of various conditions including rheumatoid arthritis, and other inflammatory diseases such as Crohn’s disease and AS.

Nowadays, five anti-TNF-α inhibitors (originators) and several biosimilars are in use for the treatment of various rheumatic diseases. Although there are differences in their manufacturing process and modes of action, it seems that they share comparable efficacy and safety. As far as concerns regarding development of GBS, there are reports with almost all of them. The anti-TNF-α inhibitors of concern are adalibumab (Humira), etanercept (Enbrel), infliximab (Remicade), golimumab (Simponi), and certolizumab (Cimzia) [2]. As the patents for these drugs are running down or have expired, “biosimilars”—“a biological product that is highly similar to a reference product in terms of quality, safety, and efficacy and/or safety, purity, and potency demonstrated by rigorous comparability exercises” [3]—for infliximab (Inflectra, Remsima, and Flixabi) and etanercept (Benepali) have been developed, and licensed in Europe in the last 3 years [4].

Clinical case

A 50-year-old male presented to accident and emergency department with weakness in his upper and lower limbs that has been getting progressively worse in the last 24 h. There was no history of recent upper respiratory tract infection or gastrointestinal infection. However, he had taken a dose of etanercept (Enbrel®) 3 days previously. He had been diagnosed with AS 5 years ago and was on etanercept 50 mg per week for 5 years. Upon clinical examination the patient was apyrexic, hemodynamically stable, and fully oriented. His neurological exam results were normal cranial nerves, muscle power 4/5 biceps in both arms, 3/5 quadriceps in both legs, and no tendon reflexes. The rest of the clinical examination was without any significant abnormalities. The electromyogram showed a demyelination picture. The patient had done an MRI brain that was without any pathologies, and an MRI spine that showed a picture consistent with AS without myelopathy in the cervical and lumbar spine. A lumbar puncture was performed that showed albuminocytological dissociation consistent with GBS.

Etanercept was withdrawn, and the patient was immediately started on IVIG for 5 days, resulting in a small improvement in muscle weakness. He was then discharged from the hospital with physiotherapy instructions. The patient was re-admitted for a new cycle of IVIG 1 week later due to worsening of muscle weakness in follow-up. He also underwent a repeat MRI without any new findings. During his stay in the hospital, there was cessation of IVIG and 7 cycles of plasmapheresis were done with marked improvement in muscle weakness. The patient was discharged without medication and with instructions for physiotherapy. In the following months, there was complete resolution of neurological symptoms. The patient was taking NSAIDs with no good clinical response—Disease activity BASDAI 5,4. Two years later, the patient was started on secukinumab (when this drug became available in our country) and promptly responded with BASDAI 3,8. The patient continues secukinumab now for 8 months with no neurological findings. To our knowledge, there are no reports linking secukinumab and GBS until now. However, there is some evidence to suggest that IL-17 plays a role in GBS [5]. If this is the case, secukinumab may have a role in the therapy of GBS.

Discussion

After a thorough review of the available literature, it was found that several side effects are seen from anti-TNF-α treatment, one of the rarest being various demyelinating neuropathies.

There are several reports of peripheral neuropathies that are associated with anti-TNF-α treatment, including acute or chronic demyelinating neuropathies as well as vasculitic neuropathies. There is no clear mechanism of why or how anti-TNF-α treatment can induce a demyelinating event in a patient.

However, there are various proposed mechanisms behind this. Some of the most well-known ones include the induction of pro-inflammatory cytokines such as interferon gamma (IFN-γ), enhancement of the action of antigen-presenting cell (APC) towards myelin and a prolonged survival as well as a failed regression of myelin specific activated T-cells. This combination of increased cytokine production, altered and enhanced APC function and decreased in apoptosis of autoreactive- T cells is the most prominent theory behind why these medications induce various peripheral demyelinating diseases [6]. The serum levels of TNF-α seem to correlate with disease activity and severity in studies done so far. The disruption of the intrinsic balance of TNF-α and its receptors in the local compartment of the nervous system could also contribute in the development of GBS and other peripheral demyelinating diseases.

Another hypothesis has to do with the two different types of TNF-α receptors, TNFR1 and TNFR2, a transmembrane protein and a soluble cytokine respectively. TNFR1 has been seen to mediate demyelination and TNFR2 remyelination. Studies have shown that TNFR2 inhibition can alter the local repair of axonal injuries and myelin damage. This could be used, theoretically, in the future, as selective inhibition of soluble TNF-α through TNFR1 stimulation could become an alternative effective way of treating demyelinating diseases [7].

Although anti-TNF agents have been licensed in the treatment of the aforementioned diseases for almost two decades, reports suggest a causative link between their use and the “unmasking of demyelinating events” [8], and indeed the exacerbation of symptoms in patients with longstanding neurological disorders such as multiple sclerosis (MS) [8, 9].

There have been some studies that documented the re-initiation of either the same or a different anti-TNF agent and several reports exist in literature with conflicting results. In a total of 5 [10–14] studies where 84 patients were examined, 16 of them needed to re-initiate anti-TNF treatment due to impairment of daily activities from the underlying rheumatologic condition. Out of the 16 patients that re-started using anti-TNF agents, 4 had relapsing symptoms of the demyelinating polyneuropathy they were affected, while 16 had no relapse of the neuropathy or development of new symptoms.

While TNF-inhibitors remain the cornerstone of treatment for inflammatory diseases and spondyloarthropathies, there has been growing evidence for the involvement of IL-17 in patients with spondyloarthritis [15–18] and the efficacy of secukinumab, an anti-IL-17A monoclonal antibody, in the treatment of AS [19]. Indeed, in results of a phase 3 trial published earlier this year, it was found that 68.2% of patients given secukinumab 150 mg as a first line therapy for AS achieved ASAS20, and 50% of patients who are intolerant or had an inadequate response to anti-TNF therapy given secukinumab 150 mg achieved ASAS20 at week 16, compared to placebo. “Improvements at week 16 were sustained or continued to improve through week 52 in both anti-TNF subgroups.” [20] Ixekizumab, another anti-17A monoclonal antibody has been shown to be an effective IL17A inhibitor, and the preclinical data has been comprehensive [21]. It is currently in clinical trials for a number of different rheumatological disease such as ankylosing spondylitis and rheumatoid arthritis [22].

In conclusion, to our knowledge, there have been no reports of patients who, having taken an IL-17 inhibitor, developed GBS or other demyelinating events. Furthermore, we have found no other reports of IL-17 therapy being given to patients after they suffered GBS or other demyelinating events due to anti-TNF-α therapy. This makes our case report the first one regarding the use of secukinumab, an IL-17 inhibitor, for AS after anti-TNF-α induced GBS. The use of IL-17 inhibitor as a safer alternative in the management of AS is still in its infancy. As such, more data and long-term monitoring of these patients will be needed to confirm the safety of this treatment rationale, but to date our experiences and results have been positive.