DISCUSSION
Wegener granulomatosis or GPA is one of the rare components of a wide
spectrum of diseases named ANCA-associated vasculitides. This disease
was first described by Heinz Klinger and colleagues in 1931 those five
years later; Friedrich Wegener described a series of affected patients
and introduced it as a distinct form of vasculitis (7). From an
etiological point of view, the exact etiologies of GPA remain unknown,
however, the relationship between the pathophysiological changes of the
disease and ANCA has been fully confirmed. Now, it seems that a variety
of genetic and microbial factors involve in triggering disease and its
severity. It is now presumed that the inflammatory basis of GPA is
referred to as ANCA positivity (8). In pathological assessments, it has
been shown that immune response to some environmental insults may result
in hyper-secretion of some cytokines such as tumor necrosis factor,
interleukin 17, and interferon-gamma leading ultimately to the
development of granulomatous vascular lesions (9). Also, via interaction
between ANCA and proteinase-3 enzyme, the adhesion of neutrophils to
vascular endothelium can be triggered which leads to damage to
endothelial cells (10). Moreover, the over-expression of some genes has
been also described to be associated with GPA such as the CTLA-4 gene
(involves in T-cells activation), PRTN-3 (involves in activation of
proteinase-3), and HLA-DP gene (involves in activation of neutrophils
and monocytes) (11). Regarding the etiologic role of infections, some
evidence is available in the flaring role of hepatitis C virus,
Epstein-Barr virus, cytomegalovirus, parvovirus, and Covid-19 infections
and the appearance of GPA (12,13). Also, it is now suggested a close
link between the likelihood of GPA and some medications such as
phenytoin, hydralazine, allopurinol, and anti-thyroid drugs with unclear
etiological roles (14,15). Epidemiologically, the annual incidence of
GPA is estimated at 10 to 20 cases per one million directly dependent on
geographical characteristics, with a higher incidence in colder areas.
The disease is more prominent in older adults than in children whose age
peaks at 64 to 75 years old but with no gender predilection (16).
GPA is known as a multisystem syndrome with evidence of inflammatory
reactions in different organs such as the upper respiratory tract (as
rhinitis, sinusitis, otitis, or mastoiditis), vascular bed (as small
vessels damages, vasculitis), kidney system (as glomerulonephritis) and
respiratory system (as alveolar hemorrhage and lung nodules). In this
regard, appearing generalized systemic symptoms, especially non-specific
symptoms are expected in relation to GPA. Upper respiratory involvement
is predictable in more than 90% of patients, lower respiratory tract
involvement (as pulmonary infiltrations, pleural effusion, and nodules)
in about 15 to 50% of patients, renal involvement in 10 to 20% of
patients, eye defects (commonly as scleritis) in about 50%, skin
defects (as purpura, nodules, ulcers, and granulomas) in 50 to 60%,
nervous system (commonly as peripheral neuropathies) in 30 to 40%,
musculoskeletal system (as myalgia and/or arthralgia) in 70%, and even
cardiovascular system (as valvular lesions or pericarditis) in less than
10% of patients (17-20).
To evaluate patients suspected of GPA, all clinical and paraclinical
assessments should be considered including minute physical examination,
tracking laboratory parameters including blood count, electrolytes,
inflammatory markers, imaging, and tittering specific markers of
PR3-ANCA and histological assessments if required (21). Radiological
assessment according to the involved organs should be also proposed.
Such management can help to differentiate GPA from other misleading
conditions. With respect to therapeutic approaches, the treatment of
such patients is based on the combination of immunosuppressive drugs
such as glucocorticoids, cyclophosphamide, methotrexate, and rituximab
(22). In more severe cases, plasmapheresis may be also indicated. In
life-threatening conditions, a combination of glucocorticoids and
cyclophosphamide was found to be a very effective regimen (23). The
efficacy and safety of rituximab and according to the RAVE trial, it has
demonstrated the similarity of effectiveness and safety of this drug
compared to cyclophosphamide (24). In GPA with a milder state,
glucocorticoids combined with methotrexate are preferred. In those with
renal dysfunction or pulmonary hemorrhage complicated by respiratory
compromise, plasmapheresis should be considered (25).
GPA with salivary glands involvement has been reported rarely. In the
present case, despite the previous evidence of arthritis, the occurrence
of swelling and involvement of the parotid and submandibular glands
along with the observation of the pulmonary nodule raised the suspicion
of the occurrence of other autoimmune disorders. Based on this, the
general and specific evaluations indicated the positivity of the ANCA
marker in this patient, which, along with pulmonary nodular involvement,
strongly suggested GPA. Thus, the treatment with a combination of
methotrexate, prednisolone, and rituximab was selected leading to
improvement of clinical condition. In a similar study by Ryota Kikuchi
et al (26), the case described was an old man manifesting with low-grade
fever and painful enlargement of the right submandibular gland that led
to the definitive diagnosis of GPA based on the presence of multiple
organs involvement along with histopathologic evidence in a skin biopsy
sample of necrotizing granulomatous inflammation with vasculitis. He was
successfully treated with methylprednisone and cyclophosphamide with
gradual improvements in symptoms and radiologic findings. Alper Ceylan
et al (27) described a young woman with parotid gland swelling along
with cough, arthralgia, epistaxis, nasal obstruction, weight loss, and
resistance to antibiotic therapy. The prominent findings, in this case,
were to reveal diffuse enlargement and cutaneous fistulas on the
bilateral parotid glands and also positivity for c-ANCA that the
diagnosis was strongly in favor of the disease. In general, it should be
kept in mind that one of the diagnoses in case of symptoms of
inflammatory reaction in salivary glands along with involvement in other
vital organs such as lung nodular involvement should be this disease and
its treatment management should be based on the treatment protocols as
soon as possible.