Nephrol Dial Transplant (1994) 9: 1219-1225

Editorial Comments

NephrologyDialysis

Transplantation

Treatment of Wegener's granulomatosis: the view from twonon-nephrologists

W. L. Gross1 and N. Rasmussen2

'Poliklinik far Rheumatologie der Medizinischen Universitat zu LObeck und Innere Medizin und klinische Immunologie derRheumaklinik Bad Bramstedt GmbH, Bad Bramstedt; 2Otopathological Laboratory, Department of Otolaryngology, Headand Neck Surgery, Rigshospitalet, Copenhagen, Denmark

IntroductionTreatment of Wegener's granulomatosis (WG) remainsproblematic: the drugs used in the 'standard proto-col'—daily low-dose cyclophosphamide (CP) and gluc-ocorticoids (GC)—are toxic, sometimes ineffective,and non-curing.

The introduction of CP and GC therapy 30 yearsago improved the prognosis in WG patients from amean survival of 5 months (based on 56 cases cited inthe literature [1]) to a rate of 93% chance of remission[2], with successful recovery even in dialysis-dependentcases. Nevertheless, an updated analysis [3] by thelatter group now presents less favourable data on boththe efficacy of the protocol (remission rate 75%) andthe attendant side-effects (serious infectious complica-tions, 46%; CP-induced haemorrhagic cystitis, 43%;bladder cancer, 2.8%; myelodysplasia, 2%; etc.). Theauthors now emphasize the variability of the clinicalcourse in WG. The diagnosis of WG was made within3 months after onset of symptoms in only 42% of theirpatients with a median of 4.7 and a mean of 15 monthsfor all patients. In many cases, particularly in thosewithout renal manifestations, WG followed an indolentcourse for up to 16 years before a definitive diagnosiscould be established and 'specific' treatment given. Asimilar experience was reported in a British series of265 WG patients: the mean times from onset of symp-toms to presentation and from presentation to dia-gnosis were both approximately 7 months. A correctdiagnosis was often missed for many years (< 1-188months). The mean survival time of 4.2 years inpatients receiving no drug treatment (10%) indicatesthe existence of very mild variants [4].

Importance of disease stagingSuch results are surprising but not new. Walton con-cludes in his now classic paper that 'the natural history(of WG) clearly has two phases'. Beginning with

Correspondence and offprint requests to: Prof. W. L. Gross,Abt. f. Rheumatologie, Rheumaklinik Bad Bramstedt Med.Krankenhausabt., Ratzeburger Allee 160 23538 Lubeck.

symptoms of chronic nasal or pulmonary infection, itcontinues with evidence of widespread inflammation[1]. Later clinical and histopathological studies haveconfirmed that WG follows a two-phase course [5]. Inmost patients the upper and/or lower respiratory tractis primarily affected (initial phase). In a number ofthese cases non-specific chronic inflammation of thesinuses or ears may be present for months to yearsbefore the diagnosis of WG is made. So the diseasegradually evolves into a locoregionally restricted dis-ease with more specific signs such as nasal crustingwith epistaxis, antral pain, oral ulceration, or subglottisstenosis. Biopsy [6] may show granulomatous inflam-mation, necrosis (microabcesses; collagen necrosis) andvasculitis (mostly: < 50% in nasal specimens) but thereare no clinical signs of generalized vasculitis. Thisrestricted form can then turn into the classic general-ized vasculitic disease (generalized phase) ultimatelyleading to a life-threatening course dominated by nec-rotizing glomerulonephritis, pulmonary capillaritis etc.The knowledge that WG follows a two-phase course,together with the increasing identification of casesduring the initial phase due to the diagnostic use ofantineutrophil cytoplasmic autoantibodies (ANCA),provide a rationale for a stage adapted treatmentofWG.

Alternative treatment modalities

Trimethoprim-sulphamethoxazole (Bactrim, (T/S)

While T/S may have the capacity to induce remissionin the initial phase of WG [7], the question of whetherit may actually prolong the initial phase is currentlybeing investigated in double-blind controlled studies.Recent experience does not indicate that T/S canprevent relapse of generalized WG in remission andthus it does not appear suited for treatment of renalWG [8].

Pulse CP

Inconsistent results were obtained in 12 patients withgeneralized WG treated with pulse CP [9], Similarly

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1220 W. L. Gross and N. Rasmussen

the NIH [10] reported only temporary benefit in 13 of a high cANCA titre [13]. In conclusion, in life-14 patients treated with the same pulse CP regimen; threatening situations and/or in cases of severe (multi-lack of response and failure to sustain improvement organ involvement) generalized WG the standardor to tolerate continued treatment was noted in 79% protocol appears to be superior to pulse CP plus GC.of patients. In contrast, two nephrological groups[11,12] reported the outcome after pulse CP therapy Mpthntrexatp

to be comparable with that of the standard protocol. memoirexaie

These differences may be ascribed to the fact that all Hoffman et al. recently used low-dose (20-the nephrological patients had renal involvement, 30 mg/weekly) MTX plus GC in 29 WG patientswhereas only 50% of the NIH patients and only 32% without 'immediately life-threatening disease',of the patients in LUbeck/Bad Bramstedt showed signs although 12 patients (41%) did have active glomerulo-of renal disease when starting treatment. In addition nephritis [14]. This produced a marked improvementthe group studied in Chapel-Hill [12] was heterogen- in 76% and remission in 69% of the patients! However,eous: only 19 of 37 WG patients had cANCA and a three of 29 (10%) suffered from Pneumocystis cariniimajority of the other patients had pANCA, suggesting pneumonia during the first month of treatment (includ-that cases of microscopic polyangiitis were included, ing prednisone 60 mg per day).Therefore, in order to find clinical and/orimmunological markers affecting the response to pulse c . • A (C A)CP, we studied its efficacy in 43 cANCA-positive and * P ' )biopsy-proven WG patients (Table 1). Fifty-eight per- Until now CsA has been used only as a back-upcent of the patients did not respond to pulse CP treatment in WG. In four patients with poor responsetreatment! Collectively, a poor response was seen in to (oral) CP or with intolerable side-effects, CsA waspatients with generalized disease involving more than able to control disease activity at dosages between 5four organ systems (mainly the heart, nervous system, and 10 (!) mg/kg per day [15]. Recently, Allen et al.

eyes, skin) with constitutional symptoms and with [16] presented data on patients with active WG under-

Table 1. Synopsis of clinical, laboratory and immunological findings in responders and non-responders to pulse cyclophosphamide treatment

(pulse-Cy)

Responder group Non-responder group P

Male/femaleMedian ageSympt. before diagn. was established (months)Daily Cy/Prd therapy prior to study entryDuration of therapy (months)Number of pulse-Cy given during the study

dosage of Cy (mg/m2)Oral Pd dosage during pulse-Cy therapy

daily dosage (mg)Disease extension score

at diagnosisstart of pulse-Cyend of pulse-Cy*

With only E and/or L at the start of pulse-CyMedian cANCA, titres

at diagnosis**start of pulse-Cy**end of pulse-Cy

cANCA, titre of 1:64 or higherat diagnosis**start of pulse-Cy"end of pulse-Cy

Median sIL-2R levels (U/ml) +start of pulse-Cy***end of pulse-Cy***

Median c-reactive protein (mg/dl.)##start of pulse-Cy#end of pulse-Cy#

5/1347(17-73)3(0-168)

13 (72%)10 (4-45)6(6-15)

637(412-833)13 (72%)4.5 (0-30)

9(2-11)4(0-11)0(0-5)7 (39%)

1:16(0-256)1:8 (0-128)

0(0-128)

5 (36%)1 (6%)1 (5%)

1126(415-2428)707 (321-3025)

1.1 (0-7.7)0.0(0-1.4)

15/1047 (23-68)6(0-168)

18 (72%)9(1-34)4(1-15)

689 (350-909)14 (56%)5.0 (0-20)

1 (3-15)4(0-11)6(2-11)2 (8%)

1:128 (0-512)1:16(0-512)1:64(0-2048)

13 (68%)10 (42%)14 (56%)

812(241-2699)891 (355-2804)

0.0(0-11.3)2.1 (0-26)

<0.05<0.05

<0.05

<0.05<0.05

<0.05

•Data on organ involvement at the end of pulse-Cy in one non-responder missing. " c A N C A titres were determined at diagnosis in 33/43,at the start of pulse-Cy in 41/43 patients. ***Serum levels of sIL-2R were measured prior to pulse-Cy in 41/43 patients. #Serum levels ofc-reactive protein were measured at the start and end of pulse-Cy in 41/43 patients. + median value of healthy blood donors: 556 U/ml.##normal: <0.8mg/dl.Reinhold-Keller et al. 1993, with permission.

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Wegener's granulomatosis

going combined CsA and low-dose GC therapy. CsAwas effective at initial doses of up to 5 mg/kg/day, butmild flare-ups occurred when this was lowered to2 mg/kg/day.

Schmitt et al. [17] reported on 20 patients whoreceived renal transplants between 1982 and 1993.Treatment before transplant consisted of oral CP andGC in 18 patients, and of pulse CP and GC orazathioprine plus GC in one patient each. At the timeof transplant, six patients showed symptoms of activedisease. Nevertheless, 18 patients are still alive withfunctioning grafts (mean creatinine: 1.7 mg/%) and 16are in complete remission. These data demonstratethat the rate of survival and graft function in patientswith WG is comparable to that of other transplantrecipients, so patients with still active WG need not beexcluded from transplantation. Frequencies of relapseafter transplant are given in Figure 1. One patient (onCsA + GC) died 46 months after transplant during asevere relapse involving the lungs and the gut, but notthe kidneys; all other patients suffering less severerelapses were treated successfully by adding CP orincreasing the dosage of GC or azathioprine. Thesedata indicate that immunosuppressive therapy aftertransplantation must not necessarily include CP andthat CsA is effective under such circumstances.

High-dose intravenous administered invnunoglobulin(1VIG)

The ability of FVTG to diminish vasculitic features wasdescribed recently [18,19]. IVIG was given to 26patients (WG, 14; microscopic polyangiitis, 11; rheum-atoid vasculitis, 1), mostly refractory to or intolerantof GC and cytotoxic drugs, in whom it was necessaryto escalate therapy. They received Sandoglobulin2 g/kg over 5 days. All appeared to improve afterFVIG, with 13 of 26 achieving full remission. Thebenefit was sustained in 18 of 26 at 12 months.Allowing for changes in other medications, 19 of 26were in full remission after 1 year, six in partialremission while one had died of septic complications.In another study FVTG was given to eight patients withWG and one with systemic pANCA-associated vascul-itis, none of whom had reached complete remission

Fig. 1.

1221

under standard therapy [20]. The response was meas-ured by blind interdisciplinary clinical assessment(ENT, etc.), MRI of the head, and immunodiagnosticanalyses. All nine patients were treated withVenimmune (0.4 g/kg/day for 5 days). Sixty percentof the patients responded to therapy by showingimprovement of single disease manifestations but com-plete remission was not experienced in any of thepatients. FVTG may thus play a role as an adjuvant toconventional therapy in patients with progressivedisease.

Monoclonal-antibody therapy

This was introduced for treatment of vasculitis in 1990[21]; a case of severe vasculitis treated several timeswith an anti-CDw52 antibody (Campath 1H)responded with significant but only transient improve-ment. Remission lasting for more than 2 years, how-ever, was achieved by following anti-CDw52 withinjection of an anti-CD4 antibody. The same groupnow reports on four patients with primary and second-ary vasculitides (microscopic polyangiitis, Sjogren'ssyndrome, Behcet's disease) who were unresponsive toimmunosuppressive drugs but who received 'substan-tial and sustained benefit' from Campath 1H andhIgGlCD4 [22]. Similar results have been obtained ina few patients with systemic WG (C. M. Lockwood,personal communication). Two other groups havereported on the successful treatment of two severe anduntractable cases of relapsing polychondritis with vas-culitis using a mouse and chimeric anti-CD4 mono-clonal antibody [23,24].

Conclusion

Experience in the treatment of WG has largely comefrom treatment of patients in the generalized phase,which is frequently associated with renal involvement.In an attempt to reduce the toxicity of treatment,several of the less toxic treatment modalities describedabove may be applied not only in the generalizedphase—before renal involvement complicates thecourse of the disease—but also in the initial phase inorder to obtain lasting remissions or at least to post-pone the necessity for standard therapy. Furtherinvestigations are obviously needed, one initiativebeing the formation of the 'European Communityco-ordination of therapeutic trials in systemic vasculitis(ECSYSVASTRIAL)'.

References

1. Walton EW. Giant cell granuloma of the respiratory tract(Wegener's granulomatosis). Br Med J 1958; 265: 973-978.

2. Fauci AS, Barton H, Katz P, Wolff S. Wegener's granulomatosis:prospective clinical and therapeutic experience with 85 patientsfor 21 years. Ann Intern Med 1983; 98: 76

3. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW. Wegener'sgranulomatosis: an analysis of 158 patients. Ann Intern Med1992; 116: 488

4. Anderson G, Coles E, Crabe M et al Wegener's granuloma: aseries of 265 british cases seen between 1975 and 1985. A report

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1222 M. Aurell

by a sub-committee of the british thoracic society researchcommittee. Q J Med 1992; 83: 427

5. Gross WL. Wegener's granulomatosis: new aspects of the diseasecourse, immunodiagnostic procedures, and stage-adapted treat-ment. Sarcoidosis 1989; 6; 15

6. Colby TV, Tazelaar HD, Specks U, Deremee RA. Nasal biopsyin Wegener's granulomatosis. Hum Pathol 1991; 22: 101

7. Reinhold-Keller E, Beigel A, Duncker G, Heller M, Gross WL.Trimethoprim-sulfamethoxazole (T/S) in the long-term treat-ment of Wegener's granulomatosis (WG). Clin Exp Immunol1993; 93 [Suppl. 1]: 38 (Abstract)

8. Reinhold-Keller E, Handrock K, Mertens J, Heller M, GrossWL. Rezidive bei Patienten mit einer ehemals generalisiertenWegener'schen Granulomatose unter Cotrim vs. ohne Therapie.Med Klin 1994; 89 [Suppl. 1]

9. Steppat D, Gross WL. Stage adapted treatment of Wegener'sgranulomatosis. Klin Wochenschr 1989; 67: 666

10. Hoffman GS, Leavitt RY, Fleisher TA, Minor JA, Fauci AS.Treatment of Wegener's granulomatosis with intermittend high-dose cyclophosphamide. Am J Med 1990; 89: 403

11. Haubitz M, Frei U, Rother U, Brunkhorst R, Koch KM.Cyclophosphamide pulse therapy in Wegener's granulomatosis.Nephrol Dial Transplant 1991; 6: 531

12. Falk RJ, Hogan S, Carey TS, Jennette C. Clinical course ofanti-neutrophil cytoplasmic autoantibody-associated glomerulo-nephritis and systemic vasculitis. Ann Intern Med 1990; 113: 656

13. Reinhold-Keller E, Kekow J, Schnabel A et al. Influence ofdisease manifestation and cANCA titer on the response to pulsecyclophosphamide therapy in Wegener's granulomatosis.Arthritis Rheum, in press

14. Hoffman GS, Leavitt RY, Kerr GS, Fauci AS. The treatmentof Wegener's granulomatosis with glucocorticoids and metho-trexate. Arthritis Rheum 1992 35: 1322

15. Schollmeyer P, Grot2 W. Cyclosporin in the treatment ofWegener's granulomatosis (WG) and related diseases. APMIS(Copenhagen) 1990; 19 [suppl]: 54

16. Allen NB, Caldwell DS, Rice JR, McCullum RM. CyclosporinA therapy for Wegener's granulomatosis. In Gross WL, ed.ANCA-Associated Vascuiitides. Plenum Press, London, 1993;473^176

17. Schmitt WH, Haubitz M, Mistry N, Brunkhorst R, Erbsloh-Moller B, Gross WL. Renal transplantation in Wegener's granul-omatosis (Letter). Lancet 1993; 342: 860

18. Jayne DRW, Lockwood CM. Pooled immunoglobulin in themanagement of systemic vasculitis. In Gross WL, ed. ANCA-Associated Vascuiitides. Plenum Press, London, 1993; 469-472

19. Tuso P, Moudgil A, Hay J et al. Treatment of antineutrophilcytoplasmic autoantibody-positive systemic vasculitis and glom-erulonephntis with pooled intravenous gammaglobulin. AmJ Kidney Dis 1992; 20: 504

20. Richter C, Schnabel A, Csernok E, Reinhold-Keller E, GrossWL. Treatment of Wegener's granulomatosis with intravenousimmunoglobulin. In Gross WL, ed. ANCA-AssociatedVascuiitides. Plenum Press, London, 1993; 487-489

21. Mathieson PW, Cobbold SP, Hale G et al. Monoclonal antibodytherapy in systemic vasculitis. N Engl J Med 1990; 323: 250

22. Lockwood CM, Thiru S, Isaacs JD, Hale G, Waldmann H.Long-term remission of intractable systemic vasculitis with mon-oclonal antibody therapy. Lancet 1993; 341: 1620

23. Van Der Lubbe PA, Miltenburg AM, Breedveld FC. Anti-CD4monoclonal antibody for relapsing polychondritis. Lancet 1991;337: 1349

24. Choy EHS, Chikaza IC, Kingsley GH, Panayi GS. Chimaericanti-CD4 monoclonal antibody for relapsing polychondritis.Lancet 1991; 338: 450

Accurate and feasible measurements of GFR—is the iohexol clearancethe answer?

M. Aurell

Department of Nephrology, University of GSteborg, GOteborg, Sweden

Nephrologists continue to argue over the problem ofhow to quantitate renal damage. Despite an adaptiveincrease of the filtration per glomerulus in damagedkidneys, measurement of the total glomerular filtrationrate (GFR) continues to be the single most usefulquantitative index of renal function. Nevertheless,measurement and interpretation of GFR face a numberof theoretical and practical problems. True GFRexhibits considerable biological variation and measure-ment of GFR is confounded by methodological prob-lems, unless the universally accepted GFR markerinulin is used. These difficulties have often been discus-sed [1-3] and most recently illustrated by the observa-tions in the MDRD (modification of diet in renaldisease) study [4].

A brief look into the history of nephrology makes

Correspondence and offprint requests to: Prof. Mattias Aurell,University of Goteborg, Department of Nephrology, Sahlgrenskasjukhuset, &413 45 Goteborg, Sweden.

plain how many of these problems arose. In 1926Rehberg [5] was the first to attempt measurements ofGFR using the renal clearance technique with exogen-ous creatinine as a marker. He applied the classicalformula GFR = UxV/P. In addition to the steady-state technique, single injection techniques werelater introduced. Here, clearance is calculated fromthe exponential fall of the plasma concentration ofan indicator substance. This is based on theStewart-Hamilton indicator dilution principle [6], i.e.flow = dose/area under the curve. Nosslin [7] was ableto demonstrate that this principle can also be used formeasurements of GFR.

Few markers meet the following criteria as usefultest substances to measure GFR: that they (i) arefreely filtered in the glomeruli, (ii) are not secreted,reabsorbed, or metabolized in the tubules and last butnot least (iii) they do not change GFR which they areintended to measure.

Because of the practical difficulties with the use of

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