Systemic autoimmune disease in asbestosis rapidly responding to anti-interleukin-1beta antibody canakinumab: a case report

Systemic autoimmune disease in patients with asbestosis has been reported in terms
of both autoantibody production and systemic autoimmune clinical manifestations. Investigations
on several cohorts of asbestos-exposed subjects have demonstrated either antinuclear
antibody positivity in 1.5 to 70 % and RF positivity in 1.4 to 35 % 7]. This rather wide range of reported autoantibody positivity may be in part explained
by the different types of inhaled asbestos dust, as demonstrated by experimental studies
in mice showing that amphibole, but not chrysotile, asbestos induces an autoimmune
response, although both fibers activate the NALP3 inflammasome 11]. The different immunogenicity of the two fibers seems to be related to distinct inflammatory
pathway activation by the amphibole and chrysotile fibers 11].

RA represents the most frequent systemic autoimmune disease associated with asbestos
exposure, and clinical findings of RA in patients with asbestosis were first described
more than 40 years ago 5], 12]. An increased risk of RA in asbestos-exposed subjects (Odds ratio [OR] 2.5 [95 %
CI, 1.0–6.8]) was reported in a Swedish study 13], and in a case-control study, the asbestos-exposed population of Libby, Montana,
was compared to the unexposed population of Missoula, Montana. A significantly increased
frequency of systemic autoimmune disease (OR 2.14 [95 % CI, 0.90–5.10]), and a higher
risk of RA (OR 3.23 [95 % CI, 1.31-7.96]) were observed in the exposed population
6]. In the same study, an association between asbestos exposure and SLE was found, in
keeping with the previously reported high frequency of ANA positivity in the Libby
population 4]. However, apart from single case reports 14], other population-based studies evaluating the risk of SLE in asbestos-exposed workers
are lacking.

Other systemic autoimmune diseases, including systemic sclerosis, ANCA-associated
vasculitis, and retroperitoneal fibrosis, have been reported sporadically in patients
with asbestosis 7].

As described, our patient had a history of occupational exposure and typical clinical
and radiological findings of asbestosis with associated persistent ANA positivity,
low grade fever, arthralgia, and episodes of mild arthritis without evidence of articular
erosions, and was negative for RF and anti-CCP antibody. Hence, he met the criteria
for UCTD 15] rather than RA, or, as proposed by other Authors 6], he had systemic autoimmune disease associated with asbestosis.

Over the last decades, experimental studies have shown the crucial role exerted by
IL-1 in pulmonary homeostasis and pathology 16], 17]. The IL-1 family is composed by IL-1alpha and IL-1beta, two major agonistic molecules,
and IL-1R antagonist (IL-1Ra) that bind to the same IL-1 receptor 18]. IL-1alpha precursor, which is present intracellularly in healthy tissues and during
hypoxic death (but not in apoptosis), is released from cells undergoing necrosis and
is biologically active, while IL-1beta precursor is produced be monocytes and macrophages,
and it is activated after cleavage by caspase 1 which in turn is activated by NALP3
inflammasome 18]. Regarding the lung, experimental studies have shown that in absence of inflammatory
stimuli, alveolar type II cells enhance the production of prostaglandin E2 which in
turn inhibits fibroblast proliferation through an IL-1 alpha mediated pathway 19]. Under inflammatory stimuli such as silica or asbestos inhalation, IL-1 beta seems
to play a pivotal role in the pathogenesis of fibrosis and mesothelioma 10]. Indeed, inhaled silica or asbestos are captured by macrophages with activation of
NALP3 inflammasome which induces the conversion of procaspase 1 in an active form
to cleave the IL-1 beta precursor in active IL-1beta with consequent fibrotic nodules
formation 10], 20]. IL-1beta is also involved in T-lymphocyte activation with subsequent dysregulated
autoimmunity and autoantibody production 3]. An increased release of IL-1beta by alveolar macrophages in patients with asbestosis
was reported around 20 years ago 16], and increased serum levels have been found in coal workers with pneumoconiosis and
in cement mason apprentices 21], 22].

Based on the consistent body of evidence of the pathogenic role of inflammasome-dependent
release of IL-1beta in patients with asbestosis and related systemic autoimmune disease,
we decided to treat our patient with canakinumab, a specifically targeted anti-IL-1beta
antibody, which has been licensed for the treatment of inflammasome-mediated autoinflammatory
syndromes 23]. The dramatic improvement of clinical features and acute phase reactants over 1 week
encouraged us to continue the treatment, and, at the 4-month visit, the patient achieved
clinical remission. Similar favorable results have been recently reported in a patient
with silicosis treated with anakinra, an IL-1 receptor antagonist acting on both IL1
alpha and Il-1 beta 24]. Differently from this report, given the central pathogenic role of IL-1 beta, we
decided to employ canakinumab due to its selective action directed against this cytokine,
and, according to patient’s preference, for its lower frequency of administration.