Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions

Mahmud Mahamid1,3, Reuven Mader4, Rifaat Safadi1,2 1Liver Unit, Holy Family Hospital, Nazareth, Israel; 2Hadassah Medical Center, Jerusalem, Israel; 3Shaare Zedek Medical Center, Jerusalem, Israel; 4Rheumatology Unit, Ha’emek Medical Center, Afula, Israel Background: Elevation of liver enzymes in rheumatoid arthritis patients treated with tocilizumab (Actemra®) or anakinra (Kineret®) is a well-documented phenomenon. However, characterization of liver histology has not been defined in most cases. Similarly, the factors involved in decisions regarding discontinuation of treatment and outcome have not been discussed in the literature to any significant extent. Cases: Two women with rheumatoid arthritis refractory to standard therapies are reported here. One was treated with tocilizumab and the other with anakinra, and both developed toxic liver effects. Liver biopsy in both cases showed focal necrosis of hepatocytes – a hallmark of drug toxicity – with steatosis and early fibrosis. Inflammatory infiltrates were prominent in the patient treated with anakinra but not in the tocilizumab-treated patient. However, FibroTest (Assistance publique – Hôpitaux de Paris, Paris, France) in the latter patient showed an inflammatory activity of A2 and was staged as F2, and the histology also showed hemorrhagic areas. Although both patients were overweight and both had been exposed to steroids, the steatosis and steatohepatitis were considered to be related to drug hepatotoxicity. Other possible etiologies for liver injury were excluded. Discontinuation of anakinra led to rapid normalization of liver enzymes. The patient receiving tocilizumab developed hepatosplenomegaly but had normal liver enzymes. In spite of the hepatosplenomegaly, the tocilizumab treatment was continued since the patient had not responded to other drugs. There was a good response to the tocilizumab treatment and the liver biopsy showed only insignificant, reversible liver injury. At follow-up at 6-months the patient remains stable. Conclusion: As cases showing tocilizumab or anakinra liver toxicity are appearing more frequently to the authors, a full assessment for liver injury is recommended in patients given those drugs, with careful consideration of the decision to continue or discontinue treatment. Further studies with long-term follow-up analysis are mandatory to guide appropriate management strategies. Keywords: anakinra, interleukin receptors, liver injury, rheumatoid arthritis, tocilizuma

Hepatotoxicity due to tocilizumab and anakinra in rheumatoid arthritis: two case reports

Elevation of liver enzymes in patients with rheumatoid arthritis treated with the biological agents, tocilizumab and anakinra, is now well documented. However, histological characterization of these effects and outcomes has not been defined. Here we report toxic liver effects in two women with rheumatoid arthritis, refractory to all nonbiological therapies, following treatment with anakinra and tocilizumab. Liver biopsy in both cases showed focal necrosis of hepatocytes as a hallmark of drug toxicity, along with steatosis and early fibrosis. In addition, the patient treated with anakinra demonstrated inflammatory changes. Tocilizumab was continued with no further deterioration in liver function. Withdrawal of anakinra led to rapid normalization of liver function. The biological agents, tocilizumab and anakinra, may result in significant histological hepatic changes, including necrosis, but despite this, the outcome appears to be good

Portal Vein Thrombosis and Thrombocytopenia in Eosinophilic Granulomatosis with Polyangiitis: A Paradox?

A 36-year-old woman with eosinophilic granulomatosis with polyangiitis (EGPA) presented with necrotic skin lesions and pulmonary infiltrates. There was eosinophilic vasculitis on skin biopsy, and substantial tissue eosinophilia in her bone marrow. She had unexplained worsening thrombocytopenia, which prompted a thrombophilia work-up. However, abnormalities in liver enzymes led to the extraordinary finding of portal vein thrombosis. Thrombocytopenia resolved with treatment with low molecular weight heparin. This case highlights the risk of hypercoagulability in eosinophilia specifically, and in EGPA. We suggest that thrombosis should be ruled out in all cases of EGPA

Diffuse idiopathic skeletal hyperostosis: a review

Coined in 1975 by Resnick et al., diffuse idiopathic skeletal hyperostosis describes a systemic condition that is mainly characterized by flowing ossification of the spine and, less frequently, peripheral entheses. Its overall incidence is 6-12%, but it is more frequently observed in males than in females and subjects aged >50 years, and its increased prevalence in people aged >70 years suggests that the course of the disease begins between the third and fifth decade of life but its clinical manifestations do not appear until later. Its pathogenesis and etiology remain unknown, but it has been reported to be associated with a number of genetic, metabolic, and constitutional factors. The aim of this review is to describe the main features of the disease and stimulate research into its pathogenesis, prevention, and treatment

Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A(3 )adenosine receptor expression

Methotrexate (MTX) exerts an anti-inflammatory effect via its metabolite adenosine, which activates adenosine receptors. The A(3 )adenosine receptor (A(3)AR) was found to be highly expressed in inflammatory tissues and peripheral blood mononuclear cells (PBMCs) of rats with adjuvant-induced arthritis (AIA). CF101 (IB-MECA), an A(3)AR agonist, was previously found to inhibit the clinical and pathological manifestations of AIA. The aim of the present study was to examine the effect of MTX on A(3)AR expression level and the efficacy of combined treatment with CF101 and MTX in AIA rats. AIA rats were treated with MTX, CF101, or both agents combined. A(3)AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis. A(3)AR level was tested in PBMC extracts from patients chronically treated with MTX and healthy individuals. The effect of CF101, MTX and combined treatment on A(3)AR expression level was also tested in PHA-stimulated PBMCs from healthy individuals and from MTX-treated patients with rheumatoid arthritis (RA). Combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect in AIA rats. MTX induced A(2A)AR and A(3)AR over-expression in paw cells from treated animals. Moreover, increased A(3)AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals. MTX also increased the protein expression level of PHA-stimulated PBMCs from healthy individuals. The increase in A(3)AR level was counteracted in vitro by adenosine deaminase and mimicked in vivo by dipyridamole, demonstrating that receptor over-expression was mediated by adenosine. In conclusion, the data presented here indicate that MTX induces increased A(3)AR expression and exhibition, thereby potentiating the inhibitory effect of CF101 and supporting combined use of these drugs to treat RA

Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A(3 )adenosine receptor expression

Methotrexate (MTX) exerts an anti-inflammatory effect via its metabolite adenosine, which activates adenosine receptors. The A(3 )adenosine receptor (A(3)AR) was found to be highly expressed in inflammatory tissues and peripheral blood mononuclear cells (PBMCs) of rats with adjuvant-induced arthritis (AIA). CF101 (IB-MECA), an A(3)AR agonist, was previously found to inhibit the clinical and pathological manifestations of AIA. The aim of the present study was to examine the effect of MTX on A(3)AR expression level and the efficacy of combined treatment with CF101 and MTX in AIA rats. AIA rats were treated with MTX, CF101, or both agents combined. A(3)AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis. A(3)AR level was tested in PBMC extracts from patients chronically treated with MTX and healthy individuals. The effect of CF101, MTX and combined treatment on A(3)AR expression level was also tested in PHA-stimulated PBMCs from healthy individuals and from MTX-treated patients with rheumatoid arthritis (RA). Combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect in AIA rats. MTX induced A(2A)AR and A(3)AR over-expression in paw cells from treated animals. Moreover, increased A(3)AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals. MTX also increased the protein expression level of PHA-stimulated PBMCs from healthy individuals. The increase in A(3)AR level was counteracted in vitro by adenosine deaminase and mimicked in vivo by dipyridamole, demonstrating that receptor over-expression was mediated by adenosine. In conclusion, the data presented here indicate that MTX induces increased A(3)AR expression and exhibition, thereby potentiating the inhibitory effect of CF101 and supporting combined use of these drugs to treat RA

A narrative review

Publisher Copyright: Copyright © 2022 Couto, Parreira, Power, Pinheiro, Madruga Dias, Novofastovski, Eshed, Sarzi-Puttini, Pappone, Atzeni, Verlaan, Kuperus, Bieber, Ambrosino, Kiefer, Khan, Mader, Baraliakos and Bruges-Armas.Diffuse Idiopathic Skeletal Hyperostosis (DISH) and Ossification of the Posterior Longitudinal Ligament (OPLL) are common disorders characterized by the ossification of spinal ligaments. The cause for this ossification is currently unknown but a genetic contribution has been hypothesized. Over the last decade, many studies on the genetics of ectopic calcification disorders have been performed, mainly on OPLL. Most of these studies were based on linkage analysis and case control association studies. Animal models have provided some clues but so far, the involvement of the identified genes has not been confirmed in human cases. In the last few years, many common variants in several genes have been associated with OPLL. However, these associations have not been at definitive levels of significance and evidence of functional significance is generally modest. The current evidence suggests a multifactorial aetiopathogenesis for DISH and OPLL with a subset of cases showing a stronger genetic component.publishersversionpublishe