Guillain-Barré syndrome after treatment with anti-tumour necrosis factor α (etanercept) in a rheumatoid arthritis patient: Case report and literature review

Abstract

Rheumatoid arthritis (RA) is often treated with anti-tumor necrosis factor α (anti-TNF-α) medications. While these drugs can cause common side effects such as injection-site and infusion reactions, rare cases of Guillain-Barré syndrome (GBS) have been reported. It's a potentially life-threatening condition characterized by progressive, ascending weakness of the extremities and areflexia, with an incidence of about 1.5 cases per 100,000 annually and a mortality rate of around 5%. It has been linked to various triggers, including infections, vaccinations, and medications like TNF inhibitors. Anti-TNF-α treatments may induce GBS by activating latent infections, increasing susceptibility, triggering autoimmune responses, or disrupting the balance of TNF-α in the peripheral nervous system. We report a 39-year-old female with a 26-year history of RA, initially treated with methotrexate until it was discontinued due to myelosuppression. She was then prescribed etanercept. A few weeks later, she developed numbness and burning pain in her limbs. GBS was suspected based on her symptoms, and nerve conduction studies confirmed the diagnosis. She was successfully treated with plasmapheresis.

Introduction

Rheumatoid arthritis (RA) is commonly treated with anti-tumor necrosis factor α (anti-TNF-α) medications, such as etanercept. ¹ Adverse effects include injection-site and infusion reactions. ² However, anti-TNF-α therapy has also been associated with Guillain-Barré syndrome (GBS). ³ GBS is characterized by acute limb weakness and diminished reflexes and is diagnosed through cerebrospinal fluid analysis and electrophysiological studies. ⁴ Approximately 5% of cases result in death, and up to 30% may progress to respiratory failure. ⁵ We report a novel case of GBS developing during etanercept treatment for severe RA, which was successfully managed with immunoglobulin therapy and a switch to rituximab.

Case presentation

We present the case of a 39-year-old female diagnosed with rheumatoid arthritis at age 13. She initially experienced morning stiffness, arthralgia, and bone aches in her hands. Methotrexate (7.5 mg/week), prednisone (5 mg/day), and diclofenac sodium were prescribed for pain management.

During follow-up, she is positive for both rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) antibodies. Her complete blood count (CBC) showed low platelet and white blood cell (WBC) counts, necessitating the discontinuation of methotrexate due to drug-induced myelosuppression. She was then treated with etanercept (50 mg/mL), an anti-TNF medication, and reported improvement in her symptoms and daily functioning.

After four doses of etanercept, she developed numbness and burning pain in one lower limb, which progressed to both limbs. Neurological examination revealed dysesthesias and a loss of cutaneous sensation in the lower limbs. Guillain-Barré syndrome was suspected, and nerve conduction studies showed prolonged distal latency in the left tibial nerve and reduced conduction velocity in sensory nerves, supporting the diagnosis.

The patient underwent a thorough workup to exclude other conditions before a final diagnosis was made. Peripheral nerve-related disorders such as chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy were evaluated but ruled out by clinical findings and investigations. Central nervous system (CNS) diseases such as multiple sclerosis and transverse myelitis were excluded with the aid of imaging and neurological examinations. Electrolyte and vitamin disturbance and other metabolic disorders were also looked out for, but laboratory investigations revealed none. Muscle diseases and other infections, including HIV and Lyme disease, were also investigated and ruled out. All in all, these evaluations supported the diagnosis of this patient being Guillain-Barre syndrome.

Upon hospitalization in March 2023 at Hebron Hospital, laboratory tests revealed a low WBC count (3.287/µL), low platelets (108.9 × 10³/µL), low folic acid (2.2 ng/mL), and elevated C-reactive protein (16.7 mg/L). The autoimmune panel was positive only for rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (Anti-CCP Abs). Serum electrolytes, kidney, and liver functions were normal. Cerebrospinal fluid (CSF) analysis showed no albuminocytologic dissociation, and CSF culture was negative.

The patient denied recent upper respiratory or gastrointestinal infections, recent surgeries, and vaccinations. Her medical history was otherwise unremarkable, with no history of lymphoma, systemic lupus erythematosus (SLE), or Sjögren's syndrome, and no family history of demyelinating disorders. Tests for HIV, Epstein-Barr virus (EBV), cytomegalovirus (CMV), syphilis, mycoplasma, and Campylobacter jejuni were negative. Imaging studies, including cerebral, thoraco-abdominal-pelvic CT scans, and cervical-lumbar spine MRI, were normal.

The patient underwent serial measurements of pulmonary function tests, including vital capacity, maximal inspiratory pressure, and maximal expiratory pressure, all of which were within normal limits. Additionally, she was closely monitored for clinical evidence of fatigue, bulbar dysfunction, and dysautonomia, none of which she exhibited. As a result, she remained stable and was not required to initiate mechanical ventilation.

She underwent five sessions of plasmapheresis and discharge on day twelve of hospitalization, resulting in partial resolution of neurological symptoms over the following months. Rituximab was prescribed as a replacement for etanercept, and her disease remains in remission.

Discussion

Guillain-Barré syndrome (GBS) is a potentially life-threatening condition characterized by rapidly progressive, ascending, symmetrical weakness of the extremities. ⁶ With an annual incidence of approximately 1.5 cases per 100,000 and a mortality rate of around 5%, about 10% of patients face severe disability one year post-onset. ⁷ It is an immune-mediated polyradiculoneuropathy that manifests through various clinical subtypes and mechanisms, leading to axonal, demyelinating, or mixed findings on electrodiagnostic studies. Factors such as antecedent infections, pathogenic cross-reactive antibodies via molecular mimicry, and the location of target gangliosides influence the severity and subtype of the disease.^3,8

GBS is associated with various triggers, including infections, vaccinations, and medications. ⁹ The most well-established association is with preceding infections, particularly viral and bacterial infections like Campylobacter jejuni, Epstein-Barr virus, cytomegalovirus, and influenza virus.^10,11 These infections are believed to initiate an autoimmune response that results in the demyelination and nerve damage characteristic of the disease. Some vaccinations, notably the influenza vaccine and certain tetanus-containing vaccines, have been linked to a slight increase in the risk. ¹² Additionally, immunomodulatory agents like tumor necrosis factor (TNF) inhibitors, including infliximab, adalimumab, and etanercept, have rarely been associated with GBS.^7,13 Recognizing these associations is essential for prompt diagnosis and management of at-risk patients.

Tumor necrosis factor α (TNFα) plays a significant pro-inflammatory role in rheumatoid arthritis (RA). Anti-TNFα therapies are effective in managing RA and are widely used. ¹² Despite their benefits, these therapies are associated with side effects, including infections, congestive heart failure, malignancies, drug-induced lupus, demyelinating disorders, and skin reactions. ¹⁴

Guillain-Barré syndrome related to TNF-α inhibitors is uncommon, with most cases occurring within the first year of treatment. Few cases develop after nearly 10 years of therapy. The proposed mechanisms include the activation of latent infections or increased susceptibility to infections due to TNF-α inhibition, leading to autoimmune responses. ¹⁵ Alternatively, these therapies might increase activated peripheral T cells or disrupt the balance of TNF-α and its receptors in the peripheral nervous system in susceptible individuals. ¹⁶

Overall adverse event rates associated with anti-TNF-α drugs have been reported to be approximately 53%. ¹⁷ Most case reports and studies suggest a frequency ranging from 0.02% to 0.2% among patients treated with anti-TNF-α drugs who develop demyelinating disorders including optic neuritis, multiple sclerosis (including exacerbation of underlying multiple sclerosis), myelitis, encephalitis, Guillain-Barre syndrome, transverse myelitis, and chronic inflammatory demyelinating polyneuropathy. ¹⁴

Through the review, only a handful of cases of anti-TNF-α-associated Guillain-Barré syndrome have been reported to date [Table 1], with a predominance of 9 cases out of 16 developing after administration of adalimumab and a lesser number of 4 cases after infliximab. Etanercept, which was reported in two cases to develop GBS, was used to treat ankylosing spondylitis patients [Psarelis et al., 2017; Shobha et al., 2019]. However, rheumatoid arthritis patients treated with etanercept have developed other adverse events, including aseptic meningitis ¹⁸ and dermatomyositis. ¹⁹

Table 1.

Published cases WHO developed peripheral neuropathies after treatment with different types of anti-TNF-α.

Authors (year)	Age/sex	Primary diagnosis	Anti-TNF-α used
Cisternas, Marcela et al. (2002)	N/A	Psoriasic arthritis	Infliximab
Shin, In-Sook J et al. (2006)	56 year old male	Rheumatoid arthritis	Infliximab
Silburn, S et al. (2008)	46-year-old woman	Rheumatoid arthritis	Infliximab
Kurmann, Patric Thierry et al. (2009)	N/A	Rheumatoid arthritis	Adalimumab
López Méndez, Pino et al. (2011)	31 year-old male	Rheumatoid arthritis	Adalimumab
Cesarini, Monica et al. (2011)	71-years-old	Crohn disease	Adalimumab
Soto-Cabrera, Elizabeth et al. (2012)	65 year old woman	Psoriasic arthritis	Adalimumab
Alvarez-Lario, Bonifacio et al. (2013)	50 year old female	Rheumatoid arthritis	Adalimumab
Ratnarajan, Gokulan et al. (2015)	43-year-old woman	Ulcerative colitis	Infliximab
Cançado GG, Vilela EG. (2017)	64-year-old	Crohn disease	Adalimumab
Psarelis, Savvas et al. (2017)	N/A	Ankylosing spondylitis	Etanercept
Natividade, Natallia Barreiros de et al. (2017)	45-year-old male	Psoriasis	Adalimumab
Patwala, Kurvi et al. (2017)	37-year-old man	Crohn disease	Adalimumab
Lee, Jong-Hak et al. (2018)	23-year-old male	Crohn disease	Adalimumab
Díez, Francisco Javier Domínguez. (2018)	58-year-old woman	Undifferentiated arthritis	Golimumab
Shobha, V et al. (2019)	24-year-old male	Ankylosing spondylitis	Etanercept

N/A: not available.

GBS was not reported to have developed after etanercept therapy for rheumatoid arthritis patients. An examination of large epidemiological databases will be necessary to determine the true incidence of etanercept-related GBS.

In treating Guillain-Barré syndrome linked to TNF-α antagonist therapy, discontinuation of the medication is recommended for suspected drug-induced neuropathy. ¹³ While intravenous methylprednisolone alone has limited efficacy, treatments like intravenous cyclophosphamide or immunoglobulin (IVIg) may improve outcomes, with reported responses varying from complete recovery to resistance after nine months. ¹⁶

The reporting of this study conforms to CARE guidelines. ²⁰

Conclusion

This case describes a rare but important relationship between the treatment of rheumatoid arthritis with etanercept and the occurrence of Guillain-Barré syndrome (GBS). The patient's history highlights the importance of monitoring for neurologic symptoms, among others, in the patients receiving anti-TNFα therapies after many months of treatment without side effects. While substantial evidence supports the efficacy of etanercept in the management of RA, its risk of severe side effects leaves many healthcare providers on the lookout. The successful treatment of this patient with plasmapheresis and later improvement after changing to rituximab explains the need to act with speed in the management of suspected drug neuropathy. As the pathogens of GBS become more elaborated, so will the development of new anti-TNF-α drugs that would explain the above-clinical effects. Clinicians should continually reassess the risks and benefits of such treatments and remain vigilant in administering appropriate care to ensure that patient safety is not compromised by the risks associated with these therapies.