IRH is recognized as a new type of drug-induced liver injury (DILI) because it is an indirect hepatotoxicity caused by the enhanced immune response induced by ICIs(17). IRH is a diagnosis of exclusion. Progression of liver metastases should be excluded firstly. Then we need to rule out viral hepatitis, alcohol-related liver disease, nonalcoholic fatty liver disease, thrombosis, ischemic hepatitis, septicemia, and autoimmune hepatitis (18). Myocarditis and myotis should also be excluded when AST is elevated while ALT or bilirubin is low or normal(19). IRH patients generally have no specific clinical manifestations, only fever, fatigue, appetite loss and other non-specific symptoms. Very few patients begin with acute liver failure (20). IRH can occur at any time after the administration of ICIs, usually within 3 months(21). It was reported that major feature of IRH cases was biliary injury(22). CT or MRI are important means to assess the progression of liver focus or the lesion of biliary tract. Liver biopsy has decisive role in the diagnosis of IRH. For patients have, with unknown etiology, severe liver injury, rapid disease progression, and poor therapeutic effect, liver tissue biopsy should be completed as soon as possible(23). The morphological features of IRH are acute hepatitis with lobular inflammation and acidophil bodies and centrilobular necrosis(3).
At present, the major guidelines on the treatment of steroid-sensitive IRH are in general accord(6, 7, 23, 24). Patients with grade 1 hepatic injury of CTCAE can continue treatment of ICIs but hepatic function should be monitored regularly. Patients with grade 2 hepatic injury of CTCAE should suspend ICIs therapy and monitoring should be done more frequently. If hepatic injury gets worse, prednisone (0.5-1mg/kg) should be considered. Patients with grade 3–4 hepatic injury of CTCAE should permanently stop ICIs and prednisone (1-2mg/kg) should be used. In general, patients with grade 3–4 IRH of CTCAE can recover quickly from high dose of steroid, but relapses are normal during the gradual reduction of steroid dosage(21). If there was no improvement after 3 days of steroid, immunosuppressants should be used. But there is no consensus on immunosuppressive treatment of steroid resistant IRH.
It should be emphasized that immunosuppressants should be used timely for steroid resistant IRH(25). In addition, plasma exchange, intravenous immunoglobulin and other supportive treatment are also helpful(23).
The patient in this report developed IRH after treatment of PD-1 inhibitor. Bilirubin and liver enzyme decreased to some extent after 3 days treatment of methylprednisolone. However, long term methylprednisolone at a dosage of 120mg/day may do harm to almost every organ. Side effects include infection, venous thrombotic events, hyperglycemia, mood swings, and insomnia(26). Several cases were reported to experience worsening of liver test in procession of corticosteroids discontinuation by taper(27). In order to avoid exposure to long time of large dose of steroid, we decided to try another drug, tofacitinib.
Many important cytokines including interleukin, interferon, granulocyte/macrophage colony-stimulating factor, erythropoietin and thrombopoietin are transmitted through the JAK-STAT signaling pathway(28) (Figure. 4). JAK family has four members: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2)(29). There are seven STATs: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6, which are highly homologous in several regions(30). Cytokines transfer information through different JAK pairs. JAK3 only expresses in hematopoietic stem cell and makes up a pair only with JAK1(31). Different JAK pairs have different biological functions.
JAK inhibitors can simultaneously block the signal transducing pathways of a variety of cytokines, thus playing an immunosuppressive role(32). Tofacitinib is the first small molecule non-receptor JAK to be approved for use in human autoimmune diseases. At present, tofacitinib is mainly used in the treatment of rheumatoid arthritis and psoriasis(33). It is currently the most approved JAK inhibitor for indications including rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis(34). Tofacitinib mainly inhibits JAK1 and JAK3 and slightly inhibits JAK2. Tofacitinib also plays a role in some diseases caused by immune disorders, such as inflammatory bowel disease(35) and alopecia universalis(36, 37).
It was reported that the pathological characteristics of IRH are similar to autoimmune hepatitis(14). JAK/STAT signaling pathway plays an important role in autoimmune hepatitis(38). Han Wang et al. established a mouse model of hepatitis using Concanavalin A (ConA) and found that tofacitinib could reduce transaminase levels in mice. The levels of several anti-inflammatory cytokines, such as interleukin-10(IL-10), were increased in mice treated with tofacitinib, while the levels of interferon -γ (IFN-γ) and tumor necrosis factor -α (TNF-α) were decreased, which indicates that tofacitinib attenuate immune-mediated liver injury(39).
Noticeable, a previous study proved JAK/STAT signaling pathway played a vital role in the tumorigenesis. Inhibition of JAK1/2 in combination with anti-PD-L1 therapy partially blocked anti-tumor immunologic responses. More than 3 months after only one cycle of PD-1 inhibitor, the major axis diameter of lesion to be assessed of the patient increased 38.1%, which seems to be not so significant progression. From this, we suppose tofacitinib may participated in anti-tumor progression of the patient.
In a retrospective analysis of steroid-resistant ICIs related myocarditis, tofacitinib was used in 11 steroid-resistant patients, with 7 patients recovered from myocarditis, indicating that tofacitinib may have impactful clinical benefits when being used early in steroid-resistant patients(16). We reported the first case of tofacitinib, a JAK inhibitor blocking a variety of cytokines, in treatment of IRH. This may provide a new option for treatment of IRH.
Though bilirubin decreased steadily after treatment of steroid and tofacitinib, transaminase and GGT increased gradually. We supposed that injury of bile ducts was improved, while injury of hepatic cells tended to get worse. Besides, elevated GGT was reported to be correlated with poor prognosis of patients treated with ICIs(40, 41). We all agreed that intensive therapy should be given to the patient. There were some reports of hemodialysis in treatment of ICIs related kidney injury(42, 43) and cytokine release syndrome(44), but no report of hemodialysis in IRH.
Considering that there was no unified standard of subsequent therapy, human immunoglobulin and artificial liver system were given to the patient. Subsequent treatments were proved to be effective by facts that bilirubin, transaminase and GGT all decreased.