A REVIEW OF WEGENER’S GRANULOMATOSIS –
A RARE GRANULOMATOUS DISEASE
Abstract:
Wegeners Granulomatosis is a rare multisystem autoimmune disease characterized by necrotizing granulomatous inflammation of the upper and lower respiratory tract, glomerulonephritis and vasculitis. The aetiology of WG remains unknown although a number of exogenous factors have been suggested to be of aetiological relevance. Most clinical characteristics of this disease are nonspecific, making the clinical diagnosis challenging. Histopathological examination of lesional tissue is not pathognomonic, but it remains an essential investigation to confirm the presence of disease and exclude other disorders. The present paper reviews the peculier aspects of this rare granulomatous disease with respect to diagnosis, laboratory features and treatment.
KEYWORDS:
Antineutrophil Cytoplasmic Antibodies , Autoimmune Disease, Gingival Hyperplasia, Granuloma, Glomerulonephritis
Introduction:
Wegener’s granulomatosis (WG) is a unique systemic inflammatory disease characterized by necrotizing granulomatous vasculitis of the upper and lower respiratory tract, pauci-immune segmental necrotizing glomerulonephritis, and small vessel vasculitis.1 WG was first reported by Friedreich Wegener in 1936, incorporating both clinical and histopathological criteria to describe what he believed represented a unique and distinctive syndrome.2 The cause of Wegener’s granulomatosis remains obscure, although progress has been made on understanding the interrelation between granulocytes, endothelium, and antineutrophil cytoplasmic antibodies. Environmental factors, such as silicates and nasal carriage with Staphylococcus aureus, might trigger the onset of the disease.The most common oral lesion is hyperplastic gingivitis (Strawberry Gingivitis) which is red to purple with many petechiae that may remain localized in the oral cavity for unusually long periods of time before multiorgan involvement occurs.3,4
The diagnosis of Wegener’s granulomatosis can be difficult, but is greatly helped by measurement of antineutrophil cytoplasmic antibodies with cytoplasmic staining (C-ANCA). For a proper diagnosis, histological evidence of granulomatous inflammation or small-vessel vasculitis, or both, in the appropriate clinical setting is needed, although a positive result for the C-ANCA test alone is not diagnostic.Management with appropriate therapy produces good response in most cases ,with occasional relapses.5 The present paper reviews the peculier aspects of this rare granulomatous disease with respect to diagnosis, laboratory features and treatment.
HISTORY OF FRIEDRICH WEGENER IN WEGENER’S GRANULOMATOSIS:
Friedrich Wegener was born on April 4, 1907, in Varel, a small town in northwestern Germany .Wegener began his medical studies in Munich in 1927, and completed his undergraduate training at the University of Kiel in 1932.6 By that time,Wegener had developed an interest in pathology, because of elective attachments with Karl August Borrmann (1870–1943), who is remembered for his classification of gastric carcinoma.
In June, 1934, Wegener did a post- mortem examination on a 38-year-old man who had died from uraemia after prolonged febrile illness. At autopsy, a saddle nose deformity was noted, and there was inflammation of nasal mucosa and cartilage with destruction of the nasal septum. Middle ear, larynx, pharynx, and trachea were similarly affected. Histological examination revealed granulomatous necrotising inflammation. The kidneys were large and swollen and showed histological evidence of necrotising glomerulonephritis.7
Wegener recognized the importance of his findings and it urged him to study the disorder in detail. Later he also encountered with many same disorder.Finally he said,“This disease was on the verge of being discovered. Somebody had to do it.”8
In 1936, Wegener examined his cases in great detail, excluded an infectious cause, and presented his findings at the meeting of the German Pathological Society in Breslau.In 1967, Wegener published an extensive review on his study cases as Wegener’s granulomatosis and also he witnessed the discovery of antineutrophil cytoplasmic antibodies as a marker of disease.9,10
AETIOLOGICAL FACTORS:
The specific aetiological factor for WG remains still unknown.Many clinical and experimental data suggested that microbial exogenous factors may highly prone to disease expression.
– Exposure to infectious agents such as Staphylococcus aureus,Mycobacterium avium- intra cellular or Parvovirus B19 and Fungi causes non specific activation of the immune system ,resulting in elevation of cytokine levels in the presence of ANCA and leading to cell destruction.11-14
– Environmental factors have also been implicated as a potential triggering factor for WG.It has been reported that ANCA associated Glomeruonephritis and Vasculitis can be associated with occupational exposure to crystalline silica or hydrocarbon, inhaled fumes and particulars – but the evidence is conflicting.15
– In WG inflammatory response is highly elucidated by pathergic reaction to certain foreign agent in which specific autoimmune response may occur.
CLINICAL PRESENTATION:
Wegener’s granulomatosis can affect a wide spectrum of systems, and causes diseases involving Ocular, Cardiac, Aural, Cutaneous, Neural and vascular system.The quintessential features are seen in upper respiratory system , Lungs and kidney .
UPPER RESPIRATORY SYSTEM:
Upper respiratory tract disease occurs in 95% of patients with WG .16 The Sinusitis, solitary and most common initial presentation seen in 73% of patients,although may be unrecognized by clinicians for several months until other manifestations of WG arise.17 Patients may also complain of nasal obstruction, and crusting, foul-smelling rhinorrhea, purulent nasal discharge, epistaxis, hyposomia (due to mucosal swelling) and epiphora (caused by involvement of both the naso-lacrimal duct and the lacrimal sac) .18
PULMONARY AIRWAY:
Necrotizing granulomatous pulmonary inflammation may give rise to a variety of symptoms such as cough (which is usually unproductive), pyrexia, haemoptysis, dyspnea, thoracic pain and post- obstructive infection. Nodular(70%) and cavitary disease(35–50%)of patients with WG of lung involvement is usually sub-pleural.19,20
RENAL DISEASE:
The renal disease is usually initially asymptomatic, although with time it can leads to potential complications. In WG, ≤20% to 80% of patients at the time of diagnosis is asymptomatic.During follow up 80% to 94% of patients invariably develop renal involvement, characteristic by the presence of focal, segmental, crescentic and necrotizing glomeruonephritis. The glomerulonephritis can lead to rupture of Bowman’s capsule.17,21
ORAL MANIFESTATION:
Oral lesions are reported to be occur in 6-13% of patients.17 The gingivae, particularly the upper anterior region are the usual oral site of involvement of WG. A strawberry- like gingivitis is suggested to be a one of the characteristic sign of WG .It is thought to be an early manifestation, if present, is characteristic sign of WG.This manifest as enlarged, interdental papillae with red to purple in colour, have petechiae on its surface with granular appearance. Other intraoral sites that are rarely affected include the tongue, palate and lips. Palatal mucosal ulceration and inflammatory destruction is uncommon, but can arise as a down ward extension of WG from the nose and nasal septum. 22-24
DIAGNOSTIC CRITERIA:
In 1990, American College of Rheumatology proposed diagnostic criteria for diagnosis of WG, which requires atleast two features of following four criteria .25
Criteria Description
Oral ulcer or Nasal discharge Development of painful or painless oral ulcers or Purulent or bloody nasal discharge
Abnormal chest radiograph Chest radiograph showing the presence of nodules, fixed infiltrates or cavities
Nephritic urinary sediment Microhaematuria ( ≥ 5 red blood cells per high power field) or red cell casts in urine
Biopsy Histological change showing granulomatous Inflammation within the wall of an artery or in the perivascular or extravascular area.
DIAGNOSTIC METHODS:
BIOCHEMICAL INVESTIGATION:
If WG was suspected from clinical history,systemic and oral examination, then biochemical investigations should be done to detect the clinical course of this disease.It should include complete blood count, ESR, C-Reactive Protein, Serum Creatinine,Blood Urea Nitrogen levels, 24hr Proteinuria,Urinalysis and ANCA serology test.Besides this, special stains are also required for detection of microbial organisms to rule out systemic infections.
ANCA SEROLOGY TEST:
The current recommendation for a mandatory ANCA testing for WG is essential when there is a strong clinical evidence of signs and symptoms.The association between WG and ANCA was first confirmed by Vanderwoude et al in 1985.26Initial screening of all sera by Indirect Immunofluorescent on ethanol fixed Neutrophils should be done to discriminate 2 main pattern of ANCA: Cytoplasmicpattern(C-ANCA) and a Perinuclear pattern(P-ANCA).27Myeloperoxidase and Proteinase 3 are the major target antigen for P-ANCA and C-ANCA which is present in the granules of neutrophils and lysosomes of Monocytes .C-ANCA is considered to be a sensitive and specific marker for multisystem WG and may be helpful in tracking disease activity and possible relapse.The detection of ANCA levels also plays an important role in the monitoring of patients response to treatment.28
RADIOGRAPHIC INVESTIGATION:
Chest radiographs and Computerized Tomography scan are mainly required to detect the specific characterized features of WG in Pulmonary system. The most common feature of pulmonary involvement is the radiological presence of single or multiple (usually less than 10) cavitary nodules of 5 to 100 mm diameter at cortical and sub-pleural sites.29
PATHOLOGY:
Biopsy is mandatory to confirm the disease, to rule out and differentiate it from other granulomatous diseases.Wegeners Granulomatosis has three specific pathological features and it serves as an element in diagnostic criteria:Necrosis, Granulomatous Inflammation,Multinucleated Giant cells and Vasculitis.30 The granulomatous inflammation is characterized by collections of loose macrophages, multinucleated giant cells, acute or chronic inflammatory cells, and the cellular composition of the granulomatous lesions of WG are composed of CD4+ T-cells, CD8+ T-cells, histiocytes, CD20+ B-lymphocytes, neutrophil granulocytes, CD68+ macrophages and CD68+ multinucleated giant cells that envelop the central area of necrosis.31,32
The central necrosis can be distinct and shows a serpiginous pattern of necrosis, Polymorphonuclear leucocytes and epithelioid histiocytes which may get arranged around the necrotic foci, occasionally. And the vasculitis of WG typically show fibrinoid necrosis affecting the walls of small to medium- sized arteries and veins, the affected vessel wall has acute/or chronic inflammatory infiltrate and occasionally accompanied by granulomatous inflammation within the vessel wall. At the same time, most of the case reports with Gingival biopsy of WG shows pseudoepitheliomatous hyperplasia, Polymorph microabscess and giant cells .30,33..
TREATMENT
The choice of therapeutic agents for WG depends on severity of disease. If correct therapeutic decision is taken, most of the patient responds immediately to treatment within a week.Therapy is mainly aimed at inducing remission with oral prednisolone 1mg/kg and cyclophosphamide 2-3 mg /kg. Once remission is achieved prednisolone is usually tapered gradually to alternate days at 3 months and then discontinued, whereas cyclophosphamide is continued for atleast a year after remission induction.34 Resolution of oral lesions, clearing of pulmonary infiltrates with evidence of stable scarring and no further evidence of active renal sediment signifies complete remission. However, remission in some cases may soon be followed by relapse which usually coincides with tapering of immunosuppressive therapy.At present combination of Azathioprine and low dose prednisolone are mainly used as maintenance therapy.Because of high morbidity associated with standard therapy, intermittent intravenous treatment with cyclophosphamide has been introduced with the intention of reducing treatment related morbidity.35,36,37.
Conclusion
Wegener’s granulomatosis is a multisystem disorder associated with significant morbidity and mortality. ANCA and other immunological analysis are relevant to its diagnosis but histopathological confirmation is vital.The oral health care provider’s role is vital to the diagnosis of Wegener’s Granulomatosis as “Strawberry Gingivitis” could be an early presenting symptom.Appropriate referral and relevant management of the oral lesions would be under the purview of the oral physician thereby ensuring early diagnosis and better outcome.