To the editor,
Inflammatory tissue damage plays a role in chronic autoimmune diseases (ADs): leaky intestinal barrier and gut dysbiosis contribute to disease onset, progression and exacerbation in diabetes, arthritis, ankylosing spondylitis, autoimmune hepatitis (AIH) and systemic lupus erythematosus (1).
AIH is a chronic immune-mediated inflammatory liver disease; the underlying pathogenetic mechanisms remain unclear, although it is known that both genetic and environmental factors are involved (2).
The continuous exposure of the liver to gut-derived antigens have an influence on both innate and adaptive immune responses. Moreover, the intestinal barrier disruption can trigger bacteria and bacterial products translocation with the activation of immune cells and the release of proinflammatory cytokines in the liver (3).
We describe the case of a 61-year-old woman with severe asthma in treatment with high doses of inhaled corticosteroids (ICS) and long-acting beta agonist (LABA), nasal polyposis, and chronic follicular gastritis who was admitted to our hospital because of acute abdominal pain 7 years ago.
Laboratory data revealed increased liver enzymes (ALT 465 UI/L), blood hypereosinophilia (3,320 cells/mmc), positive titer of antinuclear antibodies (ANA, 1:160) and anti-Liver-Kidney Microsomial antibodies (anti-LKM, 1:40); anti-neutrophil cytoplasmic antibodies (ANCA) were negative.
FIP1L1-PDGFRA fusion transcript was not found and parasitological infections were excluded.
The patient underwent liver biopsy which showed portal/periportal predominantly lymphohistiocytic infiltrate with associated Multiple Myeloma antigen 1 (MUM1) positive plasma cells, especially at the interface, with moderate eosinophilic granulocytosis, diffuse lymphocytic cholangitis, lobular hepatocytic pycnosis and necro-inflammatory foci (Fig.1).
Based on clinical, laboratory and histopathological data, the patient was diagnosed with type I autoimmune liver disease.
Immunosuppressive therapy with oral corticosteroid (OCS) prednisone 37.5 mg/day was started and, when biochemical response was obtained, therapy with azathioprine 100 mg/day was added. OCS therapy was tapered until discontinuation, and azathioprine was progressively reduced to 50 mg/day in the absence of episodes of biochemical reactivation. However, during the course of immunosuppressive therapy, the patient reported several episodes per year of abdominal pain.
In February 2021 the patient presented an episode of chest pain, so she was hospitalized and diagnosed with acute pericarditis. Infectious or autoimmune etiologies were excluded and the patient was successfully treated with non-steroidal anti-inflammatory drugs (NSAIDs).
The administration of NSAIDs to treat pericarditis worsened asthma symptoms, so OCS therapy was restarted (prednisone 25 mg/day) and the patient needed more OCS pulses per year to reach the asthma symptoms control.
Taking into account the high rate of circulating and tissue eosinophils and the frequent asthma exacerbations which required OCS therapy, treatment with the monoclonal anti-interleukin-5 receptor (IL-5R) antibody benralizumab was started in September 2021 according to asthma schedule. Benralizumab is an IL-5R alpha-directed cytolytic monoclonal antibody which inhibits the maturation, activation, and survival of eosinophils, promoting eosinophil apoptosis. Benralizumab is indicated for the treatment of severe eosinophilic asthma uncontrolled with high doses of ICS/LABA, requiring OCS in add-on.
No consensus exists on how to reduce OCS after the initiation of biologics in severe asthma. The reduction of OCS dosages by 5 mg every 4 weeks, maintaining asthma control and adrenal function status, is suggested by recent evidence (4). A similar scheme was used in this case.
One year after starting benralizumab both respiratory and gastrointestinal symptoms were still well controlled.
In particular, from the first month of therapy, the patient presented improvement in dyspnea and reduction in wheezing episodes; no new asthma exacerbations occurred, no OCS therapy was required during the one-year period and the patient also reduced inhalation therapy without any worsening of asthma. Moreover, during the period of treatment with benralizumab, no new episodes of abdominal pain occurred. As expected, blood eosinophils were not detectable already after three months of therapy.
Forced expiratory volume in the first second (FEV1) value improved from 56% (pre-therapy) to 102% in September 2022; the fractional exhaled nitric oxide (FeNO) value was 18 ppb versus 47 ppb pre-therapy.
In October 2022 a new liver biopsy showed improvement in chronic AIH, compared to the previous biopsy. Although moderate lymphocytic inflammatory infiltrate in the portal spaces and focal interface hepatitis with mild fibrosis were present, no eosinophilic granulocytes and granulomas were detected (Fig.2).
Blood eosinophils were persistently undetectable and liver enzymes were in the normal range during periodic monitoring blood tests.
Therapy with benralizumab allowed the complete withdrawal of azathioprine with good control of autoimmune liver disease, which is currently in biochemical and histological remission.
No further episodes of pericarditis were reported.
Eosinophils have multiple homeostatic functions but they also can contribute to the tissue damage in ADs through different cellular mechanisms (5), playing a central role in the pathogenesis of asthma, allergic rhinitis, chronic rhinosinusitis with nasal polyps (CRSwNP), eosinophilic esophagitis, atopic dermatitis, eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES). More of these diseases are characterized by epithelial barrier damage: eosinophils secrete several cationic proteins that induce a decrease in the number of desmosomes and a loss of epithelial cells (6).
Although the benralizumab is extensively employed in eosinophilic asthma, this is, to our knowledge, the first case of AIH which has shown improvement after benralizumab treatment. The inhibition of the IL-5R allows the decrease of both circulating and tissue eosinophils, for this reason, in this case, benralizumab was our therapeutic choice.
Currently, few cases of AIH presenting with peripheral blood eosinophilia isolated (7) or associated with other AD, such as EGPA (8), are reported.
The presence of inflammatory eosinophilic liver infiltrate associate with peripheral blood eosinophilia is described in sporadic cases of both acute and chronic hepatitis (9) and only in one other case of AIH (10).
In our case, the anti IL-5R therapy proved to reduce liver inflammation, with both clinical and histological improvement, in a patient with a poor clinical response to conventional immunosuppressants, confirming that eosinophils could have a central role in some cases of AIH.
The link between eosinophilic inflammation, barrier damage and development, or evolution, of chronic ADs is suggested by increasing clinical evidence and should be considered in clinical practice. In this context, the employment of anti-eosinophilic drugs could improve the clinical management and outcome of non-canonical type 2 diseases.