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.