The Disease-Modifying Therapies of Relapsing-Remitting Multiple Sclerosis and Liver Injury: A Narrative Review

Abstract

In this narrative review, we analyze pre-registration and post-marketing data concerning hepatotoxicity of all disease-modifying therapies (DMTs) available for the treatment of relapsing-remitting multiple sclerosis, including beta interferon, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, cladribine, natalizumab, alemtuzumab, and ocrelizumab. We review the proposed causal mechanisms described in the literature and we also address issues like use of DMTs in patients with viral hepatitis or liver cirrhosis. Most data emerged in the post-marketing phase by reports to national pharmacovigilance agencies and published case reports or case series. Serious liver adverse events are rare, but exact incidence is largely unknown, as are predictive factors. Unfortunately, none of the DMTs currently available for the treatment of multiple sclerosis is free of potential hepatic toxic effects. Cases of acute liver failure have been reported for beta-interferon, fingolimod, natalizumab, alemtuzumab, and ocrelizumab by different mechanisms (idiosyncratic reaction, autoimmune hepatitis, or viral reactivation). Patients with multiple sclerosis should be informed about possible hepatic side effects of their treatment. Most cases of liver injury are idiosyncratic and unpredictable. The specific monitoring schedule for each DMT has been reviewed and the clinician should be ready to recognize clinical symptoms suggestive for liver injury. Not all DMTs are indicated in cirrhotic patients. For some DMTs, screening for hepatitis B virus and hepatitis C virus is required before starting treatment and a monitoring or antiviral prophylaxis schedule has been established. Beta interferon, glatiramer acetate, natalizumab, and alemtuzumab are relatively contraindicated in autoimmune hepatitis due to the risk of disease exacerbation.

Treatment Challenges in Multiple Sclerosis – A Continued Role for Glatiramer Acetate?

“…Several DMTs are associated with a risk of liver injury (alemtuzumab, fingolimod, interferons, mitoxantrone, teriflunomide) (93). Autoimmune hepatitis and reactivation of chronic liver infections can also occur during DMT treatment (93,94). A retrospective Canadian study identified drug-induced liver injury in ∼2% of MS patients treated with interferon beta (95).…”

“…Glatiramer acetate has a favorable overall liver safety profile (94). Sporadic reports of rare adverse liver effects with glatiramer acetate have included cases of suspected drug-induced liver injury and autoimmune hepatitis (93,96), but no cases of hepatitis B virus or hepatitis C virus reactivation, or acute liver failure have been reported in patients treated with GA (94).…”

Therapeutic potential of mesenchymal stem cells in the treatment of acute liver failure

“…Transplantation of bio-artificial livers and hepatocytes could provide support of liver function temporarily and are therefore used as therapeutic approaches for the treatment of ALF[ 8 ]. Restored liver function and reduced incidence of extra hepatic complications were observed in ALF patients who underwent transplantation of hepatocytes[ 2 ].…”

“…However, short-term viability of engrafted hepatocytes and immune rejection against major histocompatibility complex (MHC) miss-matched transplanted hepatic cells significantly limited therapeutic efficacy of liver transplantation. Immunosuppressive therapy managed to temporarily improve survival of ALF patients who underwent liver transplantation[ 8 , 9 ]. Nevertheless, continuous and long-term use of immunosuppressive drugs may induce severe and life-threatening immunosuppression which may be fatal for ALF-treated patients[ 9 ].…”

Identification and Clinical Validation of Key Extracellular Proteins as the Potential Biomarkers in Relapsing-Remitting Multiple Sclerosis

“…They can trigger central nervous system inflammation, make immune cells (mainly T cells, B cells, and macrophages) move to the central nervous system, destruct oligodendrocytes or neurons with microglia, and cause demyelination and axonal damage eventually ( 3 ). Disease-modifying therapies have gradually been confirmed clinically to be effective in reducing the relapse of RRMS patients, implying that immune regulation plays an important role in RRMS ( 9 ). Up to now, subjected to the atypical clinical presentations, RRMS is still difficult to diagnose and lacks effective therapeutic targets.…”