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.