Neurological Side Effects of TNF-α Inhibitors Revisited: A Review of Case Reports

Abstract

Over the past two decades, the use of tumor necrosis factor alpha (TNF-α) inhibitors has significantly improved the treatment of patients with immune-mediated inflammatory diseases. Firstly, introduced for rheumatoid arthritis, these inhibitors are currently approved and used for a variety of conditions, including ankylosing spondylitis, Crohn's disease, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ulcerative colitis, and chronic uveitis. Despite their immense therapeutic efficacy, TNF-α inhibitors have been associated with neurological adverse effects that bring new clinical challenges. The present review collects data from multiple studies to evaluate the incidence and the relationship between TNF-α inhibitors and neurological side effects and to explore the potential underlying mechanisms of this association. Moreover, it highlights the importance of patient selection, particularly in the case of individuals with a history of demyelinating diseases, raises awareness for clinicians, and calls for ongoing research that will improve TNF-α targeting strategies and offer safer and more effective therapeutic options.

Keywords: TNF-α inhibitors; demyelination; neurological damage; neurological events; neurological side effects.

Figure 1

TNF-α mechanism of action. For details, see the text above. Created with biorender.com.

Figure 2

Percentage distribution of TNF-α inhibitors used in various diseases.

Figure 3

Diagnosed conditions after treatment with TNF-α inhibitors: autoimmune encephalitis (purple), CNS demyelination (light purple), inflammatory demyelination (pink), meningitis (yellow–green), MRS (cyan), multifocal motor neuropathy (red), myelopathy (light blue), non-demyelinating CNS inflammation (light green), peripheral demyelination (grey); neurodegenerative diseases (green); seizures (dark red); neurosarcoidosis (yellow); LSS (blue); Henoch–Schönlein purpura (dark yellow). INFL (infliximab), GOL (golimumab), ETA (etanercept), CZP (certolizumab), ADA (adalimumab).

Figure 4

Primary disease outcome after treatment with TNF-α inhibitor: mild improvement (purple), no improvement (light purple), not reported (pink), partial resolution (yellow–green), significant improvement (cyan), significant resolution (gray), worsening neurological symptoms (green). INFL (infliximab), GOL (golimumab), ETA (etanercept), CZP (certolizumab), ADA (adalimumab).

Figure 5

MS pathology. T cells, macrophages, and antigen-presenting cells (APCs) enter the central nervous system (CNS) and secrete cytokines that damage the oligodendrocytes, cells that produce myelin in the CNS. B cells can produce myelin-specific antibodies which will lead to complement cascade activation and membrane–attack complex formation that further damages the oligodendrocytes. A new hypothesis suggests that anti-myelin oligodendrocyte glycoprotein (anti-MOG) autoantibody will induce stress in the oligodendrocyte endoplasmic reticulum (ER). This event will induce morphological abnormalities in oligodendrocytes and demyelination in the broad sense. Moreover, oligodendrocytes secrete Kallikrein 6 (KLK6) and matrix metalloprotease (MMP)-9, which will damage the blood–brain barrier (BBB) and exacerbate the pathology of multiple sclerosis [156]. Created with biorender.com.

Figure 6

The role of TNF-α in PSO, RA, PsA, and uveitis. In RA, macrophage and Th1 cells secrete TNF-α, activating the synovial fibroblasts, which leads to excessive production of cathepsins and matrix metalloproteinases (MMPs). This overproduction will result in cartilage and bone destruction and consequently joint erosion. In PSO, the stressed keratinocytes secrete TNF-α, which activates dendritic cells (DCs), inducing the activation of Th1 cells and Th17 cells. The activated T cells secrete TNF-α and IL-17, which cause epidermal changes and keratinocyte hyperproliferation. Activation of DCs by TNF-α secreted by macrophages induces migration of T cells and inflammation responsible for uveitis. In PsA, macrophages secrete TNF-α, which activates in parallel the synovial fibroblasts and DCs. DC activation will further activate Th17, which will produce keratinocyte hyperproliferation and epidermal changes and activate osteoclasts. Created with biorender.com.