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Acta Oto-Laryngologica, 2005; 125: 1105 /1110

ORIGINAL ARTICLE

, 2005; 125: 1105 / 1110 ORIGINAL ARTICLE Wegener’s granulomatosis: A challenging disease for

Wegener’s granulomatosis: A challenging disease for otorhinolaryngologists

GABRIELLA CADONI 1 , DALIA PRELAJADE 2 , ELENA CAMPOBASSO 3 , LEA CALO 1 ,

STEFANIA AGOSTINO 1 , RAFFAELE MANNA 3 & GAETANO PALUDETTI 1

˘

Departments of Otorhinolaryngology, 1 Catholic University of the Sacred Heart, Rome, Italy, 2 Kaunas Medical University, Kaunas, Lithuania and 3 Department of Medicine, Catholic University of the Sacred Heart, Rome, Italy

Abstract Conclusions. Diagnosis of Wegener’s granulomatosis (WG) can be delayed because of its aspecific presenting symptoms. Detection of serum circulating antineutrophil cytoplasm antibodies (c-ANCAs), in combination with histology, permits one to identify WG at an early stage and to implement stage-adapted therapy. c-ANCA levels may also help to evaluate the response to medical therapy. Recently, the quality of life of WG patients has been improved by administering cotrimoxazole in order to prevent infections and recurrent diseases during the remission period. Objective. WG is of special significance to the otorhinolaryngologist because it is often initially limited to the upper respiratory tract before becoming systemic. The aim of this paper was to describe a series of WG patients and underline the difficulties involved in diagnosing and treating this challenging disease. Material and methods. This was a prospective study in 23 consecutive patients with head and neck manifestations of WG (17 systemic, 6 limited). Diagnosis was performed by means of both c-ANCAs detection using indirect immunofluorescence and histology in biopsy specimens. Treatment consisted of daily cyclophosphamide (CYC; 2 mg/kg/day) and glucocorticoids (prednisone; 1 mg/kg/day). If an improvement or toxic events occurred, CYC was discontinued and methotrexate was started. If, during remission of the disease, low serum c-ANCAs levels were detected, CYC was suspended and cotrimoxazole (1 g/day) was introduced. Results. Serum c-ANCAs detection was positive for all patients. Biopsy was diagnostic from the beginning in 19/23 cases. The six patients with limited WG did not show a progression to systemic disease. Only 3 patients with a diagnosis of delayed systemic WG died, whereas 19/23 patients were alive with good control of relapses.

Keywords: Circulating antineutrophil cytoplasm antibodies, cotrimoxazole, cyclophosphamide, methotrexate, tumor necrosis factor inhibitors, Wegener’s granulomatosis

Introduction

Wegener’s granulomatosis (WG) is a systemic dis- ease characterized by necrotizing granulomas and vasculitis of small vessels. It has been over half a century since Wegener [1,2] first described a group of patients who presented with upper airways disease and died of renal failure. In 1954, Godman and Churg [3] delineated three criteria for WG: necro- tizing granulomatous lesions of the upper airways, vasculitis and glomerulonephritis. WG is a relatively rare disease, with an incidence that varies from 5 to 15 cases per million people. Higher incidences have been reported in northern

compared to southern Europe [4]. The average age at initial diagnosis is 20 /40 years; no gender predominance has been reported [5 /7]. The etiology is unknown, although certain drugs, infections, environmental toxins and also genetic factors have been implicated. Some drugs, such as propylthiouracil [8] and monocycline [9], are clearly associated with vasculitis. Infectious agents have frequently been implicated as initiators of vasculitis, and nasal carriage of Staphylococcus aureus has been documented in WG [10,11]. As far as environ- mental factors are concerned, silica has repeatedly been mentioned as an etiologic agent in small-vessel vasculitis [12].

1106 G. Cadoni et al.

WG is associated with the presence of circulating antineutrophil cytoplasm antibodies (c-ANCAs), whose target autoantigens are primarily contained within azurophil granules. Recent findings [13 /15] demonstrate that c-ANCAs are best demonstrated in WG by using a combination of indirect immuno- fluorescence of normal peripheral blood neutrophils and an ELISA that detects ANCAs specific for proteinase 3 (PR3). The most widely accepted pathogenetic model suggests that c-ANCAs-acti- vated cytokine-primed neutrophils induce microvas- cular damage and a rapid escalation of inflammation with recruitment of mononuclear cells. Although all

studies on c-ANCAs target cells have concentrated on the neutrophils, there is evidence that monocytes also express PR3, and that c-ANCAs-induced monocyte activation can lead to release of mediators

[16].

In its ‘‘classic’’ form, WG involves three regions:

the head and neck; lung; and kidney. Some patients develop a disease restricted to only one or two of these target areas, the so-called ‘‘limited form’’ of WG. There is a high prevalence of head and neck

manifestations

Nasal obstruction, pain, ulceration, edema, dis- charge, an altered sense of smell, epistaxis and deformity are manifestations of nasosinusal involve- ment of WG. The commonest site of active nasal disease is the area of the Kiesselbacch locus, where one can see necrosis of the septal cartilage. The ‘‘typical’’ WG saddle nose deformity often ensues, but does not necessarily indicate the presence of an active disease. The remaining mucosa and turbinates are also frequently involved [18,21,22]. Otological symptoms can represent the onset of WG in 20 /25% of cases, whereas aural lesions may develop during the course of the disease in 14 /45% of cases [23 /28]. In the former situation, conductive or mixed uni- or bilateral hearing loss associated with other objective signs of otitis media with effusion can be the presenting features. Granuloma- tous obstruction of the Eustachian tube often con- stitutes the pathological basis of the disease. Sensorineural hearing loss due to vascular damage [29], deposits of immune complexes at the cochlear site or granulomatous involvement of the cochlear nerve [30] are less frequent. Facial palsy occurs in association with middle ear disease, but is extremely rare as a presenting sign [31]; it usually improves with cytotoxic therapy, but is often permanent when middle ear surgery has been incorrectly performed or treatment has been delayed. In a very few instances other cranial nerves, such as the IXth, Xth and XIth, are affected [32,33]. The peculiar gingival hyperplasia known as ‘‘strawberry gum’’ is pathognomic, but occasionally

(72.3 /99%) [5,17 /20].

presents in the early stages of WG [34]. Deep mucosal ulcers of the tongue, cheek, gingiva and palate are also rare but distinct signs. Occasionally, patients develop severe subglottic stenosis. According to the National Institutes of Health experience [35], subglottic stenosis was present in 16% of patients, half of whom needed a tracheostomy. Laryngeal symptoms of subglottic stenosis in WG patients are stridor, pain, dyspnea, wheezing and altered phonation [5,36,37].

Material and methods

A total of 23 patients affected by WG (14 females, 9 males; median age 48 years; male:female ratio 0.64) were included in our study between 1990 and 2001.

A total of 6/23 patients presented with limited WG

(Table I): 2 had a laryngeal localization, 3 had a nasosinusal involvement and 1 had unilateral facial palsy as the presenting symptom.

A total of 17/23 patients presented with systemic

WG (Table II). At the time of presentation, 16/17 showed renal involvement, with nephritis in only 4 cases; 10/17 had pulmonary lesions, 8 had ocular inflammation and there were 4 peripheral neuropa- thies. Three patients presented in an advanced stage of disease due to a delayed diagnosis. Diagnosis of WG was performed by serum c-ANCAs detection using an indirect immunofluor- escence technique and by histopathologic identifica- tion of granulomatous inflammation, multinucleated giant cells, necrosis and vasculitis in biopsy speci- mens. Biopsy was not performed in the one case of facial palsy. At our department the standard medical treatment for WG consists of daily cyclophosphamide (CYC) and glucocorticoids. In 22/23 patients, oral CYC was started at a dosage of 2 mg/kg/day, as a single dose given in the morning, together with oral prednisone at a dosage of 1 mg kg/day. If a sig- nificant improvement or toxic events occurred, CYC was discontinued, methotrexate (MTX) was started and prednisone was tapered. During the period of therapy, a blood cell count was obtained to evaluate toxic effects and the dosage of CYC was adjusted downward. Patients were followed up once a month from the

time of diagnosis; at each evaluation, a physical examination and a laboratory assessment (complete blood count, determination of the erythrocyte sedi- mentation rate, renal and hepatic function and c-ANCA, and urinalysis) were performed. One patient with limited WG (laryngeal) who refused CYC was treated with oral MTX at a dosage of 0.3 mg/kg, together with oral prednisone.

Head and neck manifestations of WG

1107

Table I. Details of patients with limited WG (c-ANCAs were detected in all patients).

Patient

Nasosinusal

Follow-up period

no.

localization

Larynx

Cranial nerves

Biopsy

(months)

1

Rhinitis

Inferior turbinate

108

2

Rhinosinusitis

Inferior turbinate

120

3

Saddle nose

Inferior turbinate

96

4

Hipoglottic

Laryngeal

60

5

Glottic

Laryngeal

0

6

VIIth cranial nerve palsy

120

Results

Head and neck localizations were present in all 17 systemic WG patients: 10 of them had a nasosinusal involvement, 11 had mixed hearing loss associated with serous otitis media in 9 cases and chronic hyperplastic otitis media in 2, and 1 had progressive bilateral sensorineural hearing loss. Of the six patients with limited WG, two had dysphonia and dyspnea with a subglottic laryngeal localization and one needed a tracheotomy for respiratory distress; three with nasosinusal involvement suffered with nasal obstruction, crusts and purulent secretions, bloody discharge and pain, and in one case a progressive saddle nose deformity occurred; one patient showed unilateral facial palsy as the present- ing symptom, in association with clinical features of bilateral serous otitis media. Serum c-ANCAs detection was positive for all 23 patients (Table II). C-ANCAs positivity as a unique finding was conclusive for an early diagnosis of WG for the patient with unilateral facial palsy as the presenting symptom. One patient with hyperplastic chronic mastoiditis underwent a tympanoplasty before c-ANCAs positivity and a kidney biopsy permitted us to make a definitive diagnosis of systemic WG. The first biopsy was diagnostic in 19/23 cases (Table II). Laryngeal and inferior turbinate biopsies were positive in two and three cases, respectively with limited WG. For patients with systemic symp- toms and serum c-ANCAs positivity, an inferior turbinate biopsy proved diagnostic in eight cases; three had a positive lung biopsy after negative kidney (n /2) and mastoid (n /1) biopsies; one other lung biopsy was positive; five kidney biopsies were positive. During the first month of follow-up, 7/22 patients stopped taking CYC due to toxicity and were administered steroids; 3 of them relapsed and MTX was added to the regimen. The six patients with limited WG did not show a progression to systemic involvement of the disease.

If, during remission of the disease, low serum c- ANCA levels were detected, CYC was suspended and cotrimoxazole (1 g/day) was introduced. The one patient who refused standard therapy was lost to follow-up (range 0 /132 months). Only 3 patients with a delayed diagnosis of systemic WG died, whereas 19/23 patients were alive with a good control of relapses with standard therapy.

Discussion

WG is an uncommon disease which is hard to identify. Since its first description in 1936 it has undergone significant changes in terms of its diag- nosis and treatment. It has special significance to the otorhinolaryngologist because the disease is initially limited to the upper respiratory tract before becom- ing systemic [23,25,27,38,39]. The systemic form of WG is more frequent than the localized one [40] but since determination of c- ANCAs was introduced as a diagnostic tool, in combination with histology, an increasing number of cases have been identified at an early stage [22]. Such early identification is of great importance in order to implement stage-adapted therapy. In our experience, diagnosis of some cases of WG can be delayed because of the aspecific presenting symptoms. The resistance of WG to traditional medical treatment, and the worsening of symptoms, encouraged us to perform new diagnostic immune tests and histology; sometimes, occasional histologi- cal findings of granulomatous inflammation induced us to consider WG in the differential diagnosis. In the literature, the specificity of c-ANCAs for diagnosing WG has been widely discussed. Negativ- ity of c-ANCA tests does not necessarily exclude the diagnosis of WG [41], as they can become positive during the course of the disease. The application of c-ANCAs testing as a clinical diagnostic tool is still regarded as controversial [15]. In our series, c- ANCAs positivity was the determining factor for diagnosis, even if histology was aspecific. Never- theless, for a correct diagnostic interpretation of

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G. Cadoni et al.

Table II. Details of patients with systemic WG (c-ANCAs were detected in all patients).

Follow-up

Patient

Nasosinusal

period

no.

localization

Middle ear

Kidney

Lung

Eye

PNS

Biopsy

(months)

1

Serous otitis

Proteinuria

Parenchymal

Brachial

Inferior

102

 

lesion

palsy

turbinate

2

Rhinitis

SNHL

Glomerulonephritis Parenchymal lesion

Conjunctivitis

Kidney

8

3

Sinusitis,

Serous otitis

Nephrosis

Granuloma

Kidney,

48

saddle nose

inferior

 

turbinate

4

Rhinosinusitis

Proteinuria

Dacryoadenitis

Paresthesiae

Inferior

35

 

turbinate

5

Serous otitis

Episcleritis

91

6

Serous otitis

Proteinuria

Inferior

98

 

turbinate

7

Serous otitis

Proteinuria

Conjunctivitis

Neuropathy

Inferior

97

 

turbinate

8

Saddle nose

Chronic otitis

Proteinuria

Radiopaque

Lung,

103

 

area

mastoid

9

Sinusitis

Serous otitis

Microhematuria

Radiopaque

Inferior

51

 

area

turbinate

10

Sinusitis

Serous otitis

Hemoglobinuria

Parenchymal

Episcleritis

Inferior

90

 

lesion

turbinate

11

Chronic otitis

Hemoglobinuria

Kidney

71

12

Sinusitis

Serous otitis

Proteinuria

Conjunctivitis

Neuropathy

Inferior

91

 

turbinate

13

Proteinuria

Parenchymal

Lung

87

 

lesion

14

Sinusitis

Serous otitis

Nephrosis

Temporary

Kidney

57

 

blindness

15

Maxillary

Glomerulonephritis

Radiopaque

Kidney,

6

sinusitis

area

lung

16

Sinusitis

Serous otitis

Proteinuria

Radiopaque

Kidney,

3

 

area

lung

17

Proteinuria

Radiopaque

Episcleritis

Kidney

123

 

area

SNHL /sensorineural hearing loss; PNS /peripheral nervous system.

serological data it is necessary to carefully assess the clinical /pathological relationship. c-ANCA levels have been also used to evaluate the response to medical therapy; as in other reports, their levels were lower during the periods of remis- sion. The close relationship between antibody titer and the clinical course suggests a possible role of antibodies in the pathogenesis of the disease [38,42]. The poor prognosis of WG was marginally im- proved by the use of steroids and cytotoxic agents (CYC, MTX). Conventional treatment with CYC and glucocorticoids is limited by the occurrence of toxic events. The interruption of CYC administra- tion and its substitution by MTX is associated with a higher rates of recurrences, as was seen in 8/23 patients in our series. A less toxic treatment for systemic WG [43] can be considered for cases diagnosed early. Anti-in- flammatory doses of steroids can be used in localized WG, whereas cytotoxic drugs together with immu- nosuppressive doses of steroids can be administered

when WG becomes a systemic disease. Fever and joint pain can characterize the evolution of WG from a localized to a generalized disease. Recently, the quality of life of WG patients was improved by administering cotrimoxazole in order to prevent infections and recurrent diseases during the remission period [44]. Because of the apparent correlation between infection and WG activation, the management of infections, especially those caused by S. aureus, requires special attention, especially for the localized variant of WG, and cotrimoxazole is considered the drug of choice for the prevention of relapses [22]. Moreover, cotrimox- azole may be worth trying not only during the initial stage of WG but also for the generalized disease when the patient is not acutely ill [45]. In our series only three patients died, all of whom had delayed diagnosis and treatment. Plasmapheresis or plasma exchange has occasion- ally been used in rapidly progressive glomerulone- phritis [46], and hemodialysis with CYC and

steroids has been performed in WG complicated by pregnancy [47]. In a recent study [48], an improvement in refractory WG was achieved with two tumor necrosis factor inhibitors (infliximab and etanercept) and the immunosuppressant 15-deoxyspergualin.

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L,