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02 June 2024: Articles  Brazil

Guillain-Barré Syndrome in a Patient Receiving Anti-Tumor Necrosis Factor for Crohn Disease: Coincidence or Consequence?

Challenging differential diagnosis, Unusual or unexpected effect of treatment, Adverse events of drug therapy

Sandro da Costa Ferreira ORCID logo1ACDEF*, Juarez Roberto de Oliveira Vasconcelos ORCID logo1ABCDEFG, Rosamar Eulira Fontes Rezende ORCID logo1B, Lilian Rose Otoboni Aprile ORCID logo1B, Luiz Ernesto de Almeida Troncon ORCID logo1DEFG

DOI: 10.12659/AJCR.943709

Am J Case Rep 2024; 25:e943709

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Abstract

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BACKGROUND: Antibodies against tumor necrosis factor alpha (anti-TNF-α) are currently widely used in the treatment of inflammatory bowel diseases (IBD), despite a number of reported adverse effects. Diverse neurologic syndromes, including the Guillain-Barré syndrome (GBS), an immune-mediated disease characterized by evolving ascending limb weakness, sensory loss, and areflexia, have been described in association with anti-TNF-α therapy.

CASE REPORT: A 45-year-old White woman was in follow-up with fistulizing ileocolonic Crohn disease using combination therapy (infliximab plus azathioprine) as CD maintenance therapy. After 3 years of this immunosuppressive therapy, she presented with symmetrical and ascending paresis in the lower limbs, and later in the upper limbs, in addition to reduced reflexes in the knees, 1 day after an infliximab infusion. The patient was hospitalized and treatment for CD was suspended. Neurophysiology studies demonstrated a pattern compatible with acute inflammatory demyelinating polyradiculopathy, with predominantly motor involvement, consistent with Guillain-Barré syndrome (GBS). Clinical, laboratory, and imaging exams were unremarkable. She was treated with intravenous immunoglobulins, with a progressive and complete resolution of neurological symptoms. After 1-year follow-up, she presented with active Crohn disease, and we opted for treating her with vedolizumab, with which she achieved clinical and endoscopic remission.

CONCLUSIONS: Patients receiving biological therapy with anti-TNF-α agents should be monitored for central or peripheral neurological signs and symptoms. The development of GBS can be secondary to anti-TNF-α treatment. The positive temporal relationship with TNF-α therapy and onset of neurological symptoms reinforces this possibility.

Keywords: Inflammatory Bowel Diseases, infliximab, Paralysis

Introduction

Biologic therapy using monoclonal antibodies against tumor necrosis factor alpha (anti-TNF-α) and using drugs such as infliximab, adalimumab, certolizumab pegol, and golimumab has significantly impacted the treatment of inflammatory bowel disease (IBD) in recent decades [1]. While these drugs’ effectiveness is proven, there are ongoing concerns regarding their safety profile [2,3]. Some of the most notable adverse effects linked to anti-TNF-α include an elevated risk of serious infections like tuberculosis, other chronic bacterial infections, and the potential development of neoplasms. Additionally, they can reactivate latent viral infections, provoke hypersensitivity reactions, and lead to dermatological, neurological, cardiovascular, and hepatic complications [3].

Guillain-Barré syndrome (GBS) is an immune-related disease marked by a symmetric weakening of the lower limbs that gradually extends to the upper limbs. Patients often also experience reduced osteotendinous reflexes, numbness in the limbs, physical weakness, sensory loss, and a lack of reflex responses [4,5]. Notably, two-thirds of GBS cases occur following infections or other immune triggers that lead to an abnormal autoimmune response [6].

Patients with conditions like IBD are frequently advised about the heightened risk of triggering or advancing demyelinating diseases, such as multiple sclerosis, due to anti-TNF drug use [2]. However, it is worth noting that anti-TNF therapy has also been linked to GBS, which is a lesser-known, but potentially incapacitating, immune-mediated neurological disorder [7–9].

We report a case of GBS in a patient with Crohn disease treated with infliximab and azathioprine.

Case Report

A 45-year-old White woman presented 6 months ago with abdominal pain, diarrhea, and significant weight loss of around 10 kg. After conducting an ileocolonoscopy (Figure 1A) and biopsies, she was diagnosed with Crohn disease (CD). Her initial treatment comprised a brief course of corticosteroids and 100-mg daily doses of azathioprine (1.5 mg/kg), to which she responded well. However, about 6 months following her CD diagnosis, she developed a perianal abscess and an enterocutaneous fistula. She underwent surgical abscess drainage and a course of antibiotics. Afterwards, we started administering infliximab therapy. This involved infusions of 5 mg/kg of infliximab in the 0th, 2nd, and 6th weeks (induction phase) and then every 8 weeks (maintenance phase) in combination with azathioprine (2 mg/kg). Her overall health has greatly improved under this regimen, and she has achieved clinical remission marked notably by weight gain and complete closure of the perianal fistula. After 6 months of combination therapy with infliximab and azathioprine, her ileocolonoscopy (Figure 1B) done 1 year after starting infliximab showed endoscopic healing.

The patient spent over 3 years receiving a combination of azathioprine (150 mg/day, 2.0 mg/kg) and infliximab (IFX) for maintenance therapy (5 mg/kg every 8 weeks) while in clinical remission and showing no signs of inflammatory activity, as evidenced by a C-reactive protein that was within normal ranges. After standard infliximab treatment at the hospital infusion center, she started displaying symptoms of symmetrical and ascending paresis in her lower limbs the following day, later extending to her upper limbs along with diminished knee reflexes, and she was subsequently admitted for examination. While in the hospital, her CD medication was temporarily stopped.

Exhaustive laboratory tests, including a complete blood count, electrolytes analysis, liver enzymes check, serologies for dengue, Zika virus, viral hepatitis, and Epstein-Barr virus (EBV), treponemal tests, and serum B12 and folate measurements found no anomalies. A computed tomography scan showed no structural changes, while a cerebrospinal fluid puncture uncovered just 3 lymphocytes and a protein concentration of 87 mg/dl, indicating a protein-cytological dissociation. An electroneuromyography study pointed to an acute inflammatory demyelinating polyradiculopathy with mainly motor involvement, which fits GBS.

To treat the condition, she received a course of intravenous gamma globulin infusions, which fully restored her muscle strength and reflex function within several weeks. Then, 2 weeks following her discharge, she was evaluated on an out-patient basis, and the use of infliximab was discontinued while the azathioprine therapy was resumed as part of her routine CD treatment. A subsequent cerebrospinal fluid puncture and electromyography, conducted 2 months later, both showed normal results.

At the 1-year follow-up, the patient was only using azathioprine as a monotherapy treatment for CD. However, she began experiencing abdominal pain, diarrhea, and asthenia. Ileocolonoscopy revealed aphthous ulcers in the terminal ileum, indicating active CD. Oral steroids were administered to regulate the CD, with fair results. However, using infliximab or another anti-TNF agent (Adalimumab and Certolizumab) was avoided due to their potential to trigger GBS. Instead, vedolizumab was introduced as a combined induction and maintenance therapy. This treatment led to the patient achieving clinical and endoscopic remission without experiencing any adverse events.

Discussion

GBS, prominently known to cause acute or subacute flaccid paralysis, is a diverse group of conditions characterized by differing clinical, electrophysiological, and pathological features triggered by an abnormal immune response affecting the myelin or axons of peripheral nerves [4,5]. It has an annual incidence rate of 1.5 cases per 100 000 people and a mortality rate of about 5%. One year after diagnosis, approximately 10% of patients remain severely disabled [4]. Generally, the clinical progression of this inflammatory polyradiculoneuropathy is typically monophasic [6].

GBS is usually set off by a preceding incident, often an infection, or following vaccination. Roughly two-thirds of GBS patients reportedly had an infection, commonly caused by pathogens such as cytomegalovirus, Epstein-Barr virus, varicella-zoster virus, Campylobacter jejuni, Hemophilus influenza, or Mycoplasma pneumoniae [4–6]]. Regarding post-vaccination GBS, epidemiological studies suggest the risk of GBS can be slightly elevated after receiving the influenza vaccine [10–12].

Therapy involving TNF-α antagonists has been linked to the onset of GBS [7,9]. TNF-α is a pro-inflammatory cytokine produced by macrophages in reaction to various stimuli. It plays a vital role in the immune system, stimulating the conversion of monocytes into macrophages, facilitating neutrophil recruitment, and forming granulomas. Hence, it is critical to fortify the host defense system against infectious diseases [13]. Moreover, TNF-α helps regulate the immune system by suppressing T cell reactivity to self-antigens [14].

Repeatedly blocking TNF-α using TNF-α antagonists can reduce the apoptosis of auto-reactive T cells, increase autoimmune responses, and disturb the function of antigen-presenting cells. This should lead to the inability to reduce myelin-specific T cell reactivity and prolong the survival of activated T cells, thereby increasing the risk of developing or extending immune-mediated neuropathy [14–16]. These factors, either individually or combined, could theoretically trigger the manifestation of GBS in individuals who are immunogenetically susceptible to it [15].

All patients undergo screening for latent infections, such as tuberculosis and hepatitis B, before beginning biologic therapy. However, the increased risk of developing a viral or bacterial illness may be linked to the use of anti-TNF-α therapy [17]. It is often challenging to determine whether GBS is caused by anti-TNF-α therapy or merely is associated with it. This is because GBS incidents should result from this biological therapy or an unrelated triggering event, such as an antecedent or even a subclinical infection. That said, the existence of positive temporal relationships with anti-TNF-α therapy lends credibility to the potential causality of GBS in these cases [7,8].

Cases of GBS associated with anti-TNF-α therapy (specifically, Infliximab and Adalimumab) in patients with CD and ulcerative colitis have previously been reported [18–21], alongside those linked to rheumatological diseases [8,9]. The frequently observed temporal link could imply causality. This link is visible between the onset of symptoms and the timespan – from a few weeks up to 1 year – following treatment commencement. Equally noteworthy is the vast majority of patients who experienced symptom relief upon discontinuation of therapy.

Nevertheless, there have been no reported cases of a new exposure or repeated exposure to anti-TNF due to the reactivation of IBD after resolution of GBS [8,19,21].

In our case, the patient exhibited symmetrical and progressive weakness in both her lower and upper limbs, along with reduced knee reflexes, immediately after receiving a routine dose of infliximab. The diagnosis of GBS was confirmed via neurophysiology studies 2 days into her hospitalization, and infection screening tests, including laboratory and serological tests, showed no notable results. During this time and in the preceding weeks and months, no signs or symptoms indicative of an infectious process were present. This suggests a possible temporal connection between GBS and the use of anti-TNF-α.

After confirming the temporal connection between anti-TNF therapy and the onset of GBS, it seemed reasonable to stop the infliximab treatment and continue with azathioprine as the sole therapy.

A study on neurological complications after anti-TNF-α therapy shows an incidence of demyelinating diseases among patients taking these medications that is similar to the rates in the general public, as reported by Mohan et al [22]. However, Patwala et al noted the presence of GBS in 17 out of 19 cases evaluated after infliximab therapy. Notably, this condition improved after discontinuation, suggesting a potential cause-and-effect relationship between anti-TNF-α and demyelinating diseases [19]. For patients who have not had previous problems, the recommendation is to discontinue therapy if demyelination takes place. It would be more prudent to switch to an alternate therapy, like an anti-integrin or anti-interleukin, instead of opting for a different anti-TNF-α agent. In our opinion, the reintroduction of anti-TNF-α in patients who have had a demyelinating disease is not recommended, due to the risk of recurrence of the neurological condition. Therefore, in cases of relapses of inflammatory bowel disease, treatment must be carried out with other classes of immunobiologics.

One year after discontinuing infliximab, the patient experienced a worsening of IBD symptoms despite taking azathioprine. Following courses of steroids, we initiated treatment with vedolizumab, an anti-integrin agent that selectively targets the intestines. To the best of our knowledge, there’s only 1 case report that suggests a possible connection between vedolizumab and negative neurological adverse effects [23], which may be a result of its intestinal focus. In patients with IBD unresponsive to conventional treatment and experiencing demyelination when using anti-TNF treatments, vedolizumab has emerged as a preferred therapy. Besides its favorable safety profile, vedolizumab has proven effective in dealing with moderate-to-severe IBD.

Conclusions

This report highlights a case where a patient with CD developed GBS, a severe clinical condition, possibly associated with anti-TNF-α therapy.

While it is not possible to definitively link GBS to anti-TNF-α therapy, it may occur due to this treatment or independent triggers like prior infections. Therefore, clinicians should check for neurological signs and symptoms of demyelinating diseases in patients undergoing anti-TNF-α treatment and promptly initiate specific treatment if necessary.

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American Journal of Case Reports eISSN: 1941-5923
American Journal of Case Reports eISSN: 1941-5923