Анти-ТНФ-Альфа Ассоциированная Центральная Нервозность Демиэлизация. Производимое наркотиками обезвоживание или многоразовый склероз? Серия дел.

Abbreviations

Acute Disseminated Encephalomyelitis

Central Nervous System

Intravenous Methylprednisolone

lumbar puncture

Magnetic Resonance Imaging

Multiple Sclerosis

Oligoclonal Bands

plasma exchange

Tumefactive Demyelinating Lesions

Tumor Necrosis Factor‐alpha

Introduction

Tumor necrosis factor alpha (TNF‐alpha) is an inflammatory cytokine that plays a role in regulating inflammatory responses in the immune system [ 1 ]. In general, TNF‐α functions include activating a series of molecules and inflammatory factors, such as cytokines and chemokines [ 2 ]. In the central nervous system (CNS), it plays a part in neurogenesis and myelination of neural cells [ 3 ]. Additionally, TNF‐α has a pivotal role in the pathogenesis of Multiple Sclerosis (MS) through its two types of receptors: TNFR1 (TNF receptor 1), which signals neuroinflammatory processes, and TNFR2 (TNF receptor 2), which is engaged in cell survival, neuroprotection, and sustains homeostatic processes [ 4 ].

The pro‐inflammatory properties of TNF‐alpha have led to the development of agents that target its activity, commonly referred to as anti‐TNF‐alpha agents. Well‐known examples include adalimumab [ 5 ]. Currently, TNF‐alpha inhibitors are used for a wide range of autoimmune diseases [ 2 ]. However, their immunomodulatory effects raise concerns about potential adverse neurological events, particularly demyelination of the central nervous system (CNS). In rare cases, these drugs can trigger demyelination in patients with a predisposition or pre‐existing lesions [ 6 , 7 ].

This study describes two cases of central nervous system demyelination in patients who received adalimumab. Both patients were being treated with adalimumab for a diagnosis of inflammatory uveitis and presented with neurological symptoms. Additionally, this study tries to differentiate between MS triggers and demyelination and also emphasizes the necessity of careful consideration before prescribing the medication.

Case Presentation

Case 1

Case History/Examination

An 18‐year‐old man presented with subacute lower‐limb paresis over the past month. Neurological examination showed left lower‐limb paresis, paresthesia, and left‐sided hyperreflexia, with bilateral positive Babinski signs. Other neurological examinations were completely normal. There are no systemic symptoms such as arthralgia or skin rash.

The patient's past medical history was significant for recurrent inflammatory uveitis diagnosed 8 years earlier, for which he had been treated with adalimumab, which was initially administered weekly. Still, the dosage was subsequently reduced to once a month over the past year. There was no history of any neurological symptoms or other diseases other than uveitis. At the first visit in our clinic, at the age of seventeen, brain and cervical Magnetic Resonance Imaging (MRI) was done to rule out silent CNS demyelination lesions because of a positive familial history of MS in his mother and treatment with adalimumab, which were completely normal.

The patient initially received intravenous methylprednisolone (IVMP) at a dose of 1 g/day for 5 days, resulting in a significant improvement in his paresis. However, approximately 1 week later, he returned to our clinic with recurrence of left lower limb paresis and new‐onset visual symptoms in the form of acute right homonymous hemianopia.

Differential Diagnosis, Investigations, and Treatment

The first MRI showed periventricular and spinal cord demyelinating lesions, as well as ill‐defined tumefactive demyelinating lesions (TDLs). The second MRI, after symptom recurrence, showed improvement in prior lesions and the emergence of two new lesions (Figure 1 ).

Considering the patient's medical history of anti‐TNF‐α therapy, family history, clinical examination, and MRI findings, the differential diagnoses included inflammatory demyelinating disease such as multiple sclerosis. Other differential diagnoses included a brain tumor, but the lack of vasogenic edema and the existence of a cervical cord lesion were not in favor of a brain tumor. Lab tests, including rheumatological tests including ANA, anti‐dsDNA, PANCA, CANCA, beta‐2 glycoprotein IgG& IgM, Anticardiolipin antibodies IgG& IgM, Anti‐RO/SSA, Anti‐La/SSB, C3, C4, were normal, and Anti‐MOG and anti‐NMO antibodies were also negative. Lumbar puncture for cerebrospinal fluid (CSF) analysis with evaluation of oligoclonal bands (OCBs) was proposed, but the patient and his parents did not permit it in the acute phase, as they were so anxious at the time. We needed their permission to perform the LP (lumbar puncture) based on local legal and ethical rules of medical practice.

IVMP was administered again (1 g/day for 5 days), but due to lack of response, P/E (plasma exchange) for five sessions was started, which led to significant recovery. Rituximab was administered after P/E due to recurrence of symptoms and ongoing demyelinating disease, and adalimumab was discontinued.

Outcome and Follow‐Up

Following treatment of the acute phase, the patient's sensorimotor and visual symptoms showed significant improvement after 1 month (Figure 2 ). Follow‐up imaging also showed a reduction in both the number and size of the demyelinating lesions after 6 months, with stability at 15 months.

After 6 months, when our patient was clinically and paraclinically stable, we explained the importance of checking OCB for the diagnosis of MS to the patient and his parents again, and this led to their consent to undergo the LP to check for OCB, which was positive.

Although TDL and homonymous hemianopia are atypical for MS, overall, with ruling out other diseases and positive OCB, the diagnosis of MS was established based on the 2024 McDonald criteria. Dissemination in space was fulfilled by periventricular and cervical cord lesions (two of the five typical locations), and dissemination in time was completed with positive OCB [ 8 ].

Rituximab 1 g every 6 months was continued for maintenance therapy of multiple sclerosis as well as control of uveitis. Rituximab is used routinely as second‐line disease‐modifying therapy (DMT) in our country based on the MENACTRIMS guideline [ 9 ]. During the 15‐month follow‐up period, there is no evidence of relapse or MRI activity. Patients' disease and treatment timeline is presented in Table 1 .

Case 2

Case History/Examination

A 35‐year‐old woman presented with acute right hemiparesthesia and hemiparesis. The patient's past medical history included a history of recurrent inflammatory uveitis for the past 6 years, which was treated with several immunosuppressive drugs. During the 6 months preceding the onset of neurological symptoms, the patient had been treated with low‐dose prednisolone in combination with adalimumab. Also, before this presentation, the patient had no history of other neurological symptoms or diseases other than uveitis. On neurological examination, the patient demonstrated mild weakness with reduced muscle strength (4/5) accompanied by sensory disturbances on the right side of the body with bilateral positive hoffmann`s sing and right hyperreflexia and positive babinski. Other neurological assessments were within normal limits.

Differential Diagnosis, Investigations, and Treatment

Brain and spinal MRI were requested for further evaluation. Brain MRI demonstrated periventricular lesions with a “Dawson's fingers” morphology. In addition, spinal MRI revealed demyelinating lesions in the cervical spinal cord (Figure 3 ). Overall, the radiological findings were highly suggestive of multiple sclerosis. Based on the clinical presentation and MRI findings, the differential diagnoses included multiple sclerosis, other demyelination, and, less likely, other inflammatory diseases.

Rheumatological lab tests, including ANA, anti‐dsDNA, PANCA, CANCA, beta‐2 glycoprotein IgG & IgM, Anticardiolipin antibodies IgG & IgM, Anti‐RO/SSA, Anti‐La/SSB, C3, and C4, were normal. Given the typical MS lesions on brain MRI and the presence of a short‐segment peripheral lesion on spinal cord MRI, inflammatory disorders associated with longitudinally extensive transverse myelitis (LETM), such as neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD), were not considered, and the corresponding antibodies, including anti‐AQP4 and anti‐MOG antibodies, were not tested.

After the diagnosis was established, adalimumab was discontinued. The patient was subsequently treated with IVMP (1 g/day for 5 days), which resulted in significant improvement of neurological symptoms. Following rheumatology consultation, low‐dose prednisolone and azathioprine were initiated for simultaneous control of uveitis and demyelinating disease.

Outcome and Follow‐Up

Five months later, the patient re‐presented with new‐onset sensory disturbances. Repeat imaging was performed, and MRI of the cervical spinal cord revealed tow new lesions. The patient was again treated with IVMP. In addition, azathioprine was discontinued and replaced with Rituximab. Considering typical MS lesions and relapses with new cervical cord lesions, the diagnosis of MS was established based on the 2024 McDonald criteria. Dissemination in space was fulfilled by periventricular and cervical cord lesions (two of the five typical locations), and dissemination in time was completed with relapse and a new lesion [ 8 ]. We proposed to start rituximab for treatment of MS and uveitis concurrently and discontinued azathioprine. The patient did not return to the clinic afterward, and further follow‐up is not available. The patient's disease and treatment timeline is presented in Table 2 .

Discussion

Anti‐TNF‐alpha drugs are used to treat inflammatory diseases. In diseases such as non‐infectious uveitis, like the cases presented in this study, paradoxically, these drugs can trigger demyelination.

In the first case, although homonymous hemianopia and TDL are atypical for MS [ 6 ], positive OCB helped diagnose MS. OCB can be transiently positive in non‐MS demyelinating lesions such as acute disseminated encephalomyelitis (ADEM) [ 10 ] in the acute phase. Positive OCB 6 months after the acute phase suggests MS (a non‐monophasic demyelinating process) rather than monophasic demyelinating processes such as ADEM or drug‐induced demyelination. However, given the long‐term use of adalimumab, the dose reduction over the past year, and the persistence of disease activity after discontinuing the medication, this process appears independent of the drug. Although a positive family history of MS, it should be considered that initiating anti‐TNF‐alpha agents is not recommended in individuals with a positive family history of MS. These medications are better replaced with another drug.

In the second case, diagnosis of MS was established based on the patient's MRI that showed lesions typical of MS, and relapse after 5 months from discontinuation of the anti‐TNF‐α drug, but due to recent use of adalimumab, the drug may play a role in clinically triggering the disease, rather than causing it.

Uveitis can also occur in patients with MS and be a precursor to it [ 11 ]. MS‐related uveitis or demyelinating plaque‐associated uveitis is often characterized by bilateral intermediate uveitis with peripheral vascular leakage or panuveitis [ 12 ]. Patients with (any type of) uveitis are approximately three times more likely to develop MS during 15 years of follow‐up compared to a similar control group [ 13 ]. Given the above, it is recommended that, in cases of inflammatory uveitis without a specific rheumatologic cause, CNS demyelination be investigated with a CNS MRI. Based on recurrent neurological symptoms after discontinuation of the anti‐TNF‐α drug, the treatment of the patient was followed with Rituximab, which is effective for MS or demyelinating lesions and non‐infectious uveitis [ 14 ].

In vitro, studies have shown that TNF‐α induces mitochondrial dysfunction in oligodendrocyte progenitor cells, ultimately leading to impaired oligodendrocyte precursor differentiation and reduced axonal myelination [ 15 ]. However, trials of anti‐TNF agents for MS patients have shown that they are not only ineffective but also have adverse effects, including activation of the immune system and exacerbation of the disease [ 16 ]. Cases of MS being triggered following the use of TNF‐alpha inhibitors have been reported in the past. Also, in rare cases, the new onset of MS has occurred following the use of this drug.

In conclusion, it is also advisable to avoid the administration of anti‐TNF‐alpha agents to patients with MS and those with a positive family history if it is possible. For other patients, an MRI scan of the central nervous system to exclude subclinical demyelinating lesions can support more informed decisions about initiating TNF‐α inhibitor therapy and potentially prevent adverse effects. Anti‐TNFα should also be discontinued after CNS demyelination occurs. Ultimately, it is recommended that, in cases of inflammatory uveitis without a specific inflammatory cause, CNS demyelination be investigated with a CNS MRI.

Author Contributions

Marzie Abutorabi‐zarchi: conceptualization, supervision, writing – original draft, writing – review and editing, investigation, data curation. Amin Ziyaei: writing – original draft, writing – review and editing. Davoud Ghane: data curation, investigation.

Funding

The authors have nothing to report.

Ethics Statement

This study was approved by the Ethics Committee of Shahid Sadoughi University of Medical Sciences, Yazd, Iran (Approval code: IR.SSU.REC.1404.053).

Consent

Written informed consent from patients was obtained for publication of their clinical information and medical images. The patients' identifying information has been removed to ensure their privacy.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

We extend our sincere gratitude to the patients for their cooperation in preparing the study. We used AI agents to improve the text, focusing on grammatical accuracy and adherence to academic standards.

Data Availability Statement

The data of this study are available from the corresponding author upon reasonable request.

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Associated Data

Data Availability Statement

The data of this study are available from the corresponding author upon reasonable request.