14 Saner B, Fankhaiiser S. Ultratard HIM, ein ncues Humaninsulin. \'orieilgegeniiber den bisherigen Priparaten?e Sdhizez Me'd Wolchcnschr 1986;116:116-9.

15 Francis AJ, Hanining I, Alberti KGMNIM. Human uiltralentc insulin:a comparison with porcine lente instulin as a twice-daily insuilin ininsulin-dependent diabetic patients with fasting hyperglyvcaemia. D)iabitesRes 1986;3:263-8.

16 Markussen J, Diers I, Hougaard P, et al. Soluble, prolonged-acting insulinderivatives. III. Degree of protraction, cystallizability and chemical stabilityof insulins substituted in positions A21, B13, B23, B27 and B330. PiroticEnginzeering 1988;2:157-66.

17 Andersen I, Hannibal S. Analytical and economical optimization of a glucosemethod with immobilized enzymes. journal of .Autornated Cht,instir 1983;5:188-92.

18 Jorgensen KH, larseti UD. Homogeneous mono- '-I itisulins. Preparationand characterization of mono- 'I-(Tyr A14)- and mono-'2I-(Tvr A19)-insulin. I)tabetoliuga 1980;19:546-54.

19 Frid A, Linde B. W'here do lean diabetics iniject thcir insulin? A studv usingcomptuted tomography. BrMVfed,7 1986;292:1638.

20 Frid A, (Gtunnarsson R, Ga,nter P, Linde 13. Effects of accidental intramuscularinjection onl inisLilini absorption in Il)l)M . Diabetes Care 1988;11:41-5.

21 Moore LW, Mitchell ML, Chalmers TlC. Variability in absorption ofinsulin-I" in normal and diabetic stubjects after stubctutaneous andintramusculair injcction. ] COlin Invest 1959;38: 1222-7.

22 Shahshahani IN, Kitabchi AE. lilucosc-lowering effect of insulin by differentroutes tn ohese and lean nonketotic diabetic patients. 7 Clin EndocrinolMetab 1978;47:34-40.

23 Owens DR, Haves TM, Alberti KGMNIM, et al. Comparative study ofsubcutancotus, ititramuLscuLlar, atid itntravenous admittistration of humanitisulin. L.aneet 1981 ;ii: 118-21.

24 Nora JJ, Smith D)W, Camcron JR. 'Ihc rotitc of insulin administratioti in themanagement of diabctes incilitus.] IPediatr 1964;64:547-51.

25 Hougaard 1, PIlum A, Ribel t. Kernel functioti smoothing of insulinahsorptiotu kitctics. Bliomntritcs ,in prcss).

A4ceepted 10J.1aY' 1989

Lupus Arthritis ResearchUnit,Rayne Institute,St Thomas's Hospital,London SEI 7EHD P D'Cruz, MRCP, registrarE Baguley, MRCP, seniorregistrarR A Asherson, MD, honoraryconsultant physicianG R V Hughes, MD, head ofLUpus Arthritis Research Unit

Correspondence to: DrHughes.

BrAled_7 1989;299:419-22

Ear, nose, and throat symptoms in subacute Wegener'sgranulomatosis

D P D'Cruz, E Baguley, R A Asherson, G R V Hughes

AbstractThe standard description of Wegener's granuloma-tosis emphasises renal failure and thus a distortedimpression may be given. Subacute and even chroniccases occur, and in these patients the presentation isvaried and often insidious, leading to delay indiagnosis. Twenty two such patients (13 women andnine men) with a mean age of 44 years were seen inour connective tissue disease clinic. The meanduration ofsymptoms before diagnosis was 3-6 yearsand the mean duration of disease 5.9 years (19 yearsin one patient). All patients had malaise and ear,nose, and throat symptoms, and most had jointpains. Impaired renal function was seen in sevenpatients only. Tissue biopsy was diagnostic inhalf of the patients, and appreciably high titres ofantineutrophil cytoplasmic antibodies were detectedin only nine of 18 patients in whom these weremeasured. The most useful investigations wereneutrophil counts, chest radiographs, and computedtomography of the sinuses and orbits. The mosteffective treatment was with intravenous pulses ofcyclophosphamide. No deaths occurred. At the timeof writing two patients were in remission and nolonger being treated and 18 patients were in partialremission on continued treatment.

Patients with subacute forms of Wegener's granu-

lomatosis present with a variety of clinical featuresand the insidious presentation often leads to delayin diagnosis. A history of ear, nose, and throatsymptoms was universal in our patients.

IntroductionThe classical presentation of Wegener's granuloma-

tosis with vasculitis of the upper and lower respiratorytracts together with fulminant glomerulonephritis andsystemic vasculitis is well recognised.' 2 By contrast,some patients present to rheumatology departmentswith features that are less dramatic, and the diagnosis isoften delayed. We studied 22 patients who presentedover the past three years at our connective tissuedisease clinic with subacute and chronic Wegener'sgranulomatosis.

Patients, methods, and resultsOf the 22 patients, 14 had been referred by other

centres in the United Kingdom, five were from ourhealth region, and three had been referred fromother countries. All were initially assessed as eitherinpatients or outpatients by standard clinical andlaboratory methods. The diagnosis of Wegener'sgranulomatosis was based on the clinical findings and

TABLE I- Clinicalfeatures and results oflaboratory tests in 22 patients with Wegener's granulomatosis

Ear, nose, Radiographv Antineutrophil High ervthrocyteCase and throat of ear, nose, Pulmonary Pulmonary Eve Rcnal Systemic cytoplasmic sedimentationNo Sex symptoms and throat symptoms radiography symptoms disease features Histology antibodv Neutrophilia rate

1 + + + + + + Insufficient tissue Negative* - +2 M ++ - -+ + Masal positive Positive* + +3 F + + + - + + Nasal:non-specific nccrosis Positive* + +4 F + ++ ++ + Lung positive Negative* + +5 F + + - + + + Nasal+ renal positivc Negative - +6 F + + - - - + Nasal positive Negative7 F + + + + + Recordsmissing - -8 F + - - - + + Negative Notdone + +9 MNi + t + + + + Nasal positive Positive* + +10 F + + + + + + Nasal positive Positive* + +11 F + + + + - + Lung positive Not done + +12 M + + + + + + Lung positive Positive + +13 F + ++ ± ± + Nasal positive Positive + +14 F + + + + + + Lung, nose, skin positive Positive stronig + +15 M + + + - + + + Ear and renal positive Not done + +16 F + + + - + + Non-diagnostic giant cclls Positive + +17 F + + - + + + Skin positive Negative + +18 INI + + + - + + Not done Negative + +19 F + + + - + + Nasal positive Negative - +20 M + Not done + + - + + Renal positive Negative* + +21 M + -- + + - + + Skin and renal positivle Positivc strong + +22 24 + - + + + + Sternal mass positive Negative* - +

+ =present; - =not present. *Antineutrophil cytoplasmic antibody assay carried out after treatmcit was started.

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TABLE II-Clinicalfeatures in22 patients at presentation

No ofSymptoms patients

Malaise, weight loss 22Ear, nose, and throat 22Pulmonary 1 7Joint 16Ocular 16Renal 6

TABLE III-Eye symptoms

No ofSymptoms patients

Conjunctivitis 9Iritis/episcleritis 9Retinal vasculitis 4Anterior uveitis 2Obstruction of

nasolacrimal duct 2Optic nerve compression 1Enucleation I

the careful exclusion of other diseases. Supportiveevidence came from laboratory investigations andhistological specimens (table I).There were 13 women and 9 men whose mean age

was 44 years (range 29-73 years). The mean duration ofsymptoms before diagnosis was 3-6 years (range 0-2-19years), and the mean total duration of disease was 5*9years (range 0-3-19 years).

PRESENTING FEATURES (TABLE II)

All 22 patients had systemic features of fever,malaise, and weight loss, and most had joint pains. Allhad ear, nose, and throat symptoms either at presenta-tion or later. These were often minor or the patientthought that they were not relevant until questionedabout them. Pulmonary and eye symptoms werecommon but appreciable renal disease was unusual.Nose-All 22 patients had nasal symptoms, the

commonest features being sinusitis (15) with nasaldischarge (15), nasal stuffiness (13), and facial pain(seven). Four patients had nasal crusting, suggestinginflammation of the nasal mucosa, and 12 had nose-bleeds, which were often heavy. Six patients had analtered sense of smell, six had pain at the nasal bridge,which suggested nasal chondritis, and in six the nasalbridge had collapsed, two of these patients needingreconstructive surgery.Ear-Fifteen patients had disease of the ear, the

commonest presenting features being conductive deaf-ness (13) and pain (11). Eight had a discharge, oftenpurulent, six had serous otitis media, and three hadotitis externa.

Throat-Twelve patients had throat symptoms, painbeing the commonest symptom in 10. Five werehoarse, and two developed stridor from laryngealobstruction, one of these requiring an emergencytracheostomy for subglottic stenosis. Another patientdeveloped a large cervical mass behind the tracheawhich responded poorly to treatment. Eleven patientshad mouth ulcers.Pulmonary symptoms- Seventeen patients had

pulmonary symptoms at presentation, cough anddypsnoea being the commonest features. Haemoptysiswas noted in half of the patients and one patient had alife threatening haemorrhage that responded to inten-sive treatment. Six patients had pleuritic pain; onedeveloped a sternal granulomatous mass and one hadupper lobe cavities that became infected with Asper-gillus fumigatus, causing abscesses which requiredsurgery.Eyes-There were various symptoms in the eye with

three definite patterns (table III)." The anteriorsegment was most commonly affected with conjuncti-vitis, iritis, and episcleritis, two patients had obstruc-tion of the nasolacrimal duct, and four had retinalvasculitis.

Jroints-Sixteen patients had joint symptoms, butonly three had clinical evidence of synovitis, andnone developed erosive damage. Joint pain was oftentransient and not commonly associated with active orpersistent synovitis.5 In the six patients with myalgiaall had normal muscle enzyme activity. One patienthad a widespread polychondritis of the ears, nose, andthroat.Skin-Twelve patients had evidence of vasculitis.

In three patients diagnostic skin biopsies showed aleucocytoclastic vasculitis, and two developed splinterhaemorrhages in association with the vasculitis. Otherpatients had nodules/papules (four), bruises (five),urticarial vasculitis (one), photosensitivity (one), andnecrotic vasculitis ulcers causing rupture of tendons(one).

Other organs-Five patients had peripheral neuro-pathy. One developed mononeuritis multiplex. Onepatient had arrhythmias.

Renal function-Five of the six patients with im-paired renal function had raised creatinine concentra-tions, five had significant proteinuria (>0-1-82 g/day),and four had microscopic haematuria. One patientrequired dialysis.

LABORATORY INVESTIGATIONS (TABLE IV)Most patients had negative or weakly positive

serology for antinuclear antibodies and antibodies toantideoxyribonucleic acid measured by Cnthidia andbinding assays. Seven patients had a positive rheuma-toid factor, the Rose-Waaler titre ranging from 1/4 to1/2560. None of these had evidence of renal disease.Five of 13 patients had high complement activity.Most patients had detectable concentrations ofimmune complexes by the polyethylene glycol precipi-tation method, and one patient had detectable concen-trations of cryoglobulins. Five patients had minornon-specific abnormalities of liver function: raisedserum alkaline phosphatase activity (five) and raisedserum alanine transaminase activity (three).

TABLE IV-Results oflaboratory tests in 22 patients

No ofInvestigation patients Result (mean)

Neutrophil leucocytosis 16 14 2x 10'/1(normal 2 0-8-0)

Anaemia 12 Women 92 g/lMen 101 g/l

Thrombocytosis 10 610x 10'/1(normal <400)

Eosinophilia 3 2-1 x 109/1(normal 0-04-0 4)

High erythrocyte sedimentation rate 20 77 mm in1st hour

Circulating immune complexes 14/15 68 mg IgG/l(normal <49)

High C reactive protein 11/15 112 mg/l(normal <10)

_ . . ..^11 v...

FIG 1-Multiple cavitating nodules in a patientgranulomatosis

with. Wegene

with Wegener's

RADIOLOGY

Thirteen patients had abnormal chest radiographs,and various abnormalities were seen with multiplepulmonary infiltrates, pleural effusions, and multiplenodules, some of which were cavitating (fig 1). Radio-graphs of the sinuses showed opacification or fluidlevels in 15 patients. Computed tomography of thesinuses and orbits delineated the extent of theabnormality in the sinus in 11 patients with erosion ofbone shown clearly. In three patients intraorbitalgranulomatous masses were found which had not beensuspected clinically, and in one patient a small granulo-matous mass at the orbital apex resulted in optic nervecompression (figs 2-4). The rapidly developing blind-ness, however, improved with treatment.

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HISTOLOGY

Diagnostic appearances of giant cell granulomas,vasculitis, and necrosis were seen in only eight patientsafter biopsy of the nasal mucosa, and two of the biopsyspecimens showed non-specific inflammation ornecrosis.

Four patients underwent renal biopsy and allshowed the histological findings of glomerulo-nephritis: proliferative glomerulonephritis (two),mesangiocapillary crescentic glomerulonephritis (one),and segmental necrotising glomerulonephritis (one).Four patients had lung biopsies (three ofwhich were

open lung biopsies), and only one had diagnosticappearances. Three skin biopsy specimens showed aleucocytoclastic vasculitis. One patient had severalbiopsies of a sternal mass, which showed non-specificnecrotic tissue.

ANTINEUTROPHIL CYTOPLASMIC ANTIBODY

Antineutrophil cytoplasmic antibody titres weremeasured in 18 patients using radioimmunoassay andimmunofluorescence. In eight of these patients theserum was assayed after treatment had begun. Positiveresults were seen in nine. Seven of the 18 patients werestrongly positive with high titres, while two werepositive with borderline raised titres. The other nineassayed were negative.

TREATMENT

All patients received oral prednisolone, and fivepatients also received intravenous pulses of methyl-

FIG 2-Computed tomography through the maxillary sinuses showinglarge granulomatous masses and destruwtion ofthe medial sinus walls

nography through the orbits showing a granulo-,ht orbit with erosion ofthe medial orbital wall

BMJ VOLUME 299 12 AUGUST 1989

FIG 4-Computed tomography: view of sagittal reconstruction alongthe left optic nerve showing a granulomatous mass at the orbital apexcausing compression of the optic nerve

prednisolone (1 g/pulse) in conjunction with immuno-suppressive treatment. Eleven patients receivedbetween one and three pulses of cyclophosphamide(500 mg/pulse) at weekly intervals followed by lowdoses of oral cyclophosphamide (1-2 mg/kg). Eightother patients were given oral cyclophosphamidedirectly. Thus 19 patients received cyclophosphamide.Six patients had been started initially on azathioprine,but four were later changed over to cyclophosphamidedue to failure of response.The most effective regimen for inducing remission

was intravenous pulses of cyclophosphamide(500-750 mg) at weekly intervals for three to fourweeks followed by low doses of oral cyclophosphamide(1-2 mg/kg). Intravenous pulses of methylpredniso-lone (0 5-1 g) were given when indicated and oralsteroids were given at a dose of 30-40 mg/day and thiswas reduced as the patient responded to treatment.Azathioprine was less effective in inducing or main-taining remission.

Complete remission was defined as the completeabsence of active disease. Partial remission was definedas clearly reduced disease activity and progress towardsimprovement; renal function and pulmonary infil-trates were stable or showing signs of resolution.

At the time of writing only two patients werein complete remission and receiving no treatment.Eighteen others were maintained in partial remissionwith continued treatment. Two patients showed a poorresponse despite intensive treatment, and one requiredrenal dialysis. No patient died.Most patients responded promptly to treatment,

showing a good response within two weeks. Althoughremission was maintained with treatment, there weredifficulties in controlling some symptoms. In par-ticular, symptoms in the ear, nose, throat, and eyewere the most difficult to manage effectively.To reduce the adverse effects of treatment the dose

of oral prednisolone was reduced rapidly to 10-15mg/day once the patient was clearly responding. Thedose of oral cyclophosphamide was maintained for atleast one year and gradually reduced while the patientwas monitored closely for evidence of relapse.

Treatment with pulses of cyclophosphamide waswell tolerated, although a few patients experiencednausea during the infusion. In five patients bonemarrow was suppressed with oral cyclophosphamide:two had neutropenia, two thrombocytopenia, and oneaplastic anaemia. All recovered when cyclophospha-

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mide was stopped. Three patients lost hair, two hadherpes infections (one herpes simplex and one herpeszoster). One developed Aspergillus fumigatus in a lungcavity, which was probably related to cyclophospha-mide. No haemorrhagic cystitis occurred, althoughpatients were closely monitored for this. In addition,no patient developed a malignancy associated withimmunosuppression, though they are being followedup.

DiscussionPatients with classical Wegener's granulomatosis are

often diagnosed rapidly because of prominent renaland pulmonary disease. But in our patients the presen-tation was insidious in 15, and the various changingsymptoms, especially in the absence of overt renaldisease, led to often considerable delay in making thediagnosis. In one case a patient suffered mild tomoderate ear, nose, throat, and pulmonary symptomsfor 19 years (and had been considered to have systemiclupus erythematosus and was treated with variabledoses of steroids) before Wegener's granulomatosiswas diagnosed.The clinical presentation was diverse with features

changing as the disease developed. Although allpatients had ear, nose, and throat symptoms, thesesymptoms often had to be elicited by direct question-ing as patients thought that they were irrelevant totheir current illness.

In previous studies of Wegener's granulomatosisnearly all patients had abnormal chest radiographs.6'9Only 13 of our 22 patients had abnormalities on chestradiography, however, and this lower figure probablyreflects the different spectrum of disease seen in ourseries of patients. None of our patients had symptomsof asthma and this, together with the few with eosino-philia and the rarity of cardiac disease, differs from ourclinical experience of Churg-Strauss syndrome.'0As in previous studies, the respiratory symptoms

responded rapidly to treatment but the changes seen onx ray films, especially the solitary or cavitating nodules,took several weeks or months to clear.The laboratory findings in our patients showed

the characteristic but non-specific features associatedwith vasculitis in Wegener's granulomatosis-thatis, neutrophil leucocytosis, anaemia, thrombocytosis,high erythrocyte sedimentation rate, and raised con-centrations of C reactive protein. Immune complexes,detected in moderate concentrations by the poly-ethylene glycol precipitation method, were seen in 20patients but were unhelpful diagnostically.Few biopsy specimens of nasal mucosa yielded

diagnostic findings, which almost certainly reflectsthe fact that it is difficult to obtain adequate amounts ofmaterial from biopsy of areas to which access isdifficult. With the more widespread use of sinusendoscopy and computed tomography to guide biopsythe yields may be greater.The antineutrophil cytoplasmic antibody assay was

found to be a specific and sensitive test for Wegener'sgranulomatosis in other studies.''4 We found a rela-tively low incidence of this antibody, and the resultswere confirmed by two other laboratories whichassayed the sera. There may be several explanationsfor this. For example, our patients had a differentspectrum of disease without renal failure, and the assaywas performed on serum taken from eight patients whohad already started treatment.

The treatment regimen was generally effective atinducing remission but less successful in maintainingit. There were no deaths, and most of the patientsresponded quickly. Our study lends further support tothe use of cyclophosphamide as the mainstay oftreatment in this disease.79 '5 Indeed the condition ofseveral of our patients had been deteriorating Withsteroid treatment alone before diagnosis. Azathioprineremains a useful alternative drug when cyclophospha-mide is not tolerated. We used no other immuno-suppressive drugs.

In contrast with the results of previous studies therewere no instances of haemorrhagic cystitis, althoughthe patients were carefully monitored for this. Theadverse effects were otherwise similar to those in otherstudies. The association of malignancy with long termcyclophosphamide use'6 has yet to be determined inour series of patients and must await longer follow up.Though the diagnosis and treatment of fulminant

Wegener's granulomatosis is usually clear cut, ourresults show that this is not true of the subacute forms,in which lesions may recur for over a decade.Cyclophosphamide remains the most effective treat-

ment, but the use of "standardised" regimens formanaging Wegener's granulomatosis may need re-considering in the light of experience with chronic andsubacute forms of the disease.

We thank Drs D A H Yates, J A Mathews, and N F Jonesfor permission to include three of the patients in this study.The antineutrophil cytoplasmic antibody assays were per-formed by Dr M Khamashta and Dr M Santiago in the lupusarthritis research laboratory. We thank Dr C M Lockwoodand Dr C Kallenberg for confirming the results, and Mrs JHarris for secretarial help.

1 Fahey JL, Leonard E, Churg J, Godman G. Wegener's granulomatosis.AmJMed 1954;17:168-79.

2 Wolff SM, Fauci AS, Horn RG, Dale DC. Wegener's granulomatosis. AnnIntern Med 1974;81:513-25.

3 Spalton DJ, Graham EM, Page NGR, Sanders MD. Ocular changes in limitedforms of Wegener's granulomatosis. Br] Ophthalmol 1981,65:553-63.

4 Coutu RE, Klein M, Lessell S, Friedman E, Snider GL. Limited form ofWegener's granulomatosis. Eye involvement as a major sign. JAM-I1975 ;233:868-7 1.

5 Noritake DT, Weiner SR, Bassett LW, Paulus HE, Weisbart R. Rheumaticmanifestations of Wegener's granulomatosis. J Rheumatol 1987;14:949-5 1.

6 Ridley MG, Wolfe CS, Asherson RA, Hughes GRV. Recurrent otitis mediaand pulmonary infiltrates as presenting features in Wegener's granuloma-tosis. BrMedJ7 1988;297:352-3.

7 Carrington CB, Liebow AA. Limited forms of angiitis and granulomatosis ofWegener's type. Am7Med 1966;41:497-527.

8 Pinching AJ, ILockwood CM, Pussell BA, et al. Wegener's granulomatosis:observations on 18 patients with severe renal disease. Q 7 Med 1983.Autumn;52(208):435-60.

9 Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener's grantilomatosis:prospective clinical and therapeutic experience with 85 patients for 21 years.Ann InternMed 1983;98:76-85.

10 Lanham JG, Elkon KB, Pusey CD, Hughes GRV. Systemic vasculitis withasthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome.Medicine 1984;63:65-81.

11 Lockwood CM, Bakes D, Jones S, Whitaker KB, Moss DW, Savage COS.Association of alkaline phosphatase with an autoantigen recognised bycirculating anti-neutrophil antibodies in systemic vasculitis. Lancet 1987;i:716-20.

12 Savage COS, Jones S, Winearls CG, Marshall PD, Lockwood CM. Prospectivestudy of radioimmunoassay for antibodies against neutrophil cytoplasm indiagnosis of systemic vasculitis. Lancet 1987;i: 1389-93.

13 Venning MC, Arfeen S, Bird AE. Antibodies to neutrophil cvtoplasmicantigen in systemic sasculitis. Lancet 1987;ii:85(0.

14 Luqmani RA, Beaman M, Shenot PM, Adu D, Michacl J, Bacon PA.Antineutrophil cytoplasmic antibodies (ANCA) in limited Wegener'sdisease. Brj Rheumatol 1988;27(suppl 1):33.

15 Reza MJ, Dornfeld L, Goldberg LS, Bluestone R, Pearson CM. Wegener'sgranulomatosis. Long term follow-up of patients treated with cyclo-phosphamide. Arthritis Rheum 1975;18:501-6.

16 Weiner SR, Paulus HE. Treatment of Wegener's granulomatosis withcyclophosphamide: an outcome analysis. Arthritis Rheum 1988;31(suppl):39.

(Accepted 12 April 1989)

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