ARTHRITIS & RHEUMATISMVol. 44, No. 3, March 2001, pp 508–512© 2001, American College of Rheumatology

EDITORIAL

Treatment of Polyarteritis Nodosa, Microscopic Polyangiitis, andChurg-Strauss Syndrome: Where Do We Stand?

Carol A. Langford

In 1866, Kussmaul and Maier described a uniqueillness they named “periarteritis nodosa” in recognitionof the nodularity and inflammation that involved thesmall muscular arteries (1). Ferrari introduced the term“polyarteritis nodosa (PAN)” in 1903 to illustrate thetransmural arterial inflammation that occurs in thisdisease (2). Despite the subsequent work of many inves-tigators, including an important paper in this issue ofArthritis & Rheumatism (3), many questions regardingthe treatment of PAN remain unanswered.

Developments in nomenclature have complicatedthe conduct and interpretation of therapeutic trials inPAN. Wohlwill in 1923 (4) and Davson et al in 1948 (5)described glomerular and small vessel disease in patientswith PAN that they termed “microscopic polyarteritis.”Although some authors adopted this terminology, mostcontinued to include glomerulonephritis as a manifesta-tion of PAN. In 1993, a committee of clinicians andpathologists convened in Chapel Hill, North Carolina,with the goal of reaching a consensus on the names anddefinitions for the common forms of noninfectious sys-temic vasculitis (6). Under this nomenclature, “poly-arteritis nodosa” is restricted to disease with necrotizinginflammation of the medium-sized and small arteries butwithout involvement of smaller vessels (Table 1). Pa-tients with glomerulonephritis or necrotizing vasculitiswith few or no immune complexes affecting the smallvessels (i.e., arterioles, venules, or capillaries) are con-sidered to have “microscopic polyangiitis” (MPA).

The designation of MPA as a discrete entity hasbeen a subject of controversy, especially concerning theseparation from Wegener’s granulomatosis (WG). Clin-ically, these two diseases have many similarities, includ-

ing small vessel vasculitis of the lung, glomerulonephri-tis, and the presence of antineutrophil cytoplasmicantibodies (ANCA) (Table 2). Furthermore, the glomer-ular lesion of MPA, a focal crescentic glomerulonephri-tis with few or no immune complexes, is histologicallyidentical to WG (7). In the definitions set forth at theChapel Hill Consensus Conference, the diagnosis of WGis restricted to patients with necrotizing granulomatousinflammation (Table 1). Granulomatous inflammationdoes not have to be histologically proven in this nomen-clature system and can be inferred by noninvasive eval-uations. Clinical manifestations, however, do not alwayspredict the presence of granulomatous inflammation. Inone series, only 42% of 126 upper airways biopsy tissuesfrom patients with known WG revealed granulomas (8).Granulomatous inflammation is also often not observedin lung biopsy tissues from patients with WG andpulmonary hemorrhage (9).

The distinction between WG and MPA may beparticularly difficult in certain clinical settings, such aspatients with sinus mucosal thickening, pulmonary hem-orrhage, and glomerulonephritis. In one series, 13% ofpatients with MPA were found to have upper respiratorytract disease (10), while, in another series, such involve-ment was said to exclude this diagnosis (11). In addition,there are reports of patients who meet the definition forMPA but later develop characteristic clinical and histo-logic features of WG (12). These issues highlight thelack of a universally accepted definition for MPA.

In series of patients with PAN described prior tothe separate designation of MPA, those with untreateddisease had a poor prognosis, with a 5-year survival rateof ,15% (13,14). Corticosteroids (CS) were the firstapplied treatment and were found to improve 5-yearsurvival rates to 48–57% (13–16). Beneficial effects werealso observed with the introduction of combined therapywith cyclophosphamide (CYC) and CS (14,17), particu-larly in patients with severe disease (18). However, someinvestigators found that the use of CYC did not improveoutcome beyond that of treatment with CS alone (15).

Carol A. Langford, MD, MHS: National Institute of Allergyand Infectious Diseases, NIH, Bethesda, Maryland.

Address correspondence and reprint requests to Carol A.Langford, MD, MHS, Laboratory of Immunoregulation, NationalInstitute of Allergy and Infectious Diseases, National Institutes ofHealth, Bethesda, MD 20892.

Submitted for publication October 18, 2000; accepted inrevised form October 23, 2000.

508

Such findings raise questions about the optimal thera-peutic strategy for PAN and the necessity for CYC usein all patients.

The most recent literature on the treatment of

PAN has come from trials performed by the FrenchVasculitis Study Group (FVSG). These studies, whichbegan in 1980, represent the largest experience on thetherapy of PAN and have presented a valuable body ofinformation. In the first trial performed by the FVSG,patients with PAN and Churg-Strauss syndrome (CSS)were randomized to receive prednisone plus plasmaexchanges either alone or in combination with dailyCYC (19). Study recruitment was halted after 71 pa-tients had entered the study because the interim analysisat 3 years demonstrated a greater efficacy of the CYCarm on disease control; fewer relapses also occurred inthe group who had received CYC. No difference, how-ever, was observed in the cumulative 10-year survivalrate regardless of whether the patient had initiallyreceived CYC. Examination of the survival curves fromlater studies similarly failed to demonstrate a differencein survival based on the initial use of CYC therapy (20).While these studies supported the effectiveness of CYCin PAN and CSS, they did not determine whether CYCis necessary in all instances.

To explore whether disease severity could guidetreatment, the FVSG sought to identify the factorsassociated with a poor prognosis in PAN and CSS (20).From a univariate and multivariate analysis, the Five-Factors Score (FFS) was derived. This score integrateditems that had been found to be associated with anincreased mortality and included a serum creatininelevel of .1.58 mg/dl, proteinuria of .1 gm/day, gastro-intestinal (GI) tract involvement (defined as bleeding,

Table 1. Chapel Hill Consensus Conference definitions of polyar-teritis nodosa, microscopic polyangiitis, Wegener’s granulomatosis,and Churg-Strauss syndrome (6)

Polyarteritis nodosa (classicpolyarteritis nodosa)

Necrotizing inflammation ofmedium-sized or small arterieswithout glomerulonephritis orvasculitis in arterioles, capillaries,or venules

Microscopic polyangiitis(microscopic polyarteritis)

Necrotizing vasculitis, with few or noimmune deposits, affecting smallvessels (i.e., capillaries, venules,or arterioles). Necrotizing arteritisinvolving small and medium-sizedarteries may be present. Necrotizingglomerulonephritis is very common.Pulmonary capillaritis often occurs.

Wegener’s granulomatosis Granulomatous inflammationinvolving the respiratory tract,and necrotizing vasculitis affectingsmall to medium-sized vessels(e.g., capillaries, venules,arterioles, and arteries).Necrotizing glomerulonephritis iscommon.

Churg-Strauss syndrome Eosinophil-rich and granulomatousinflammation involving therespiratory tract, and necrotizingvasculitis affecting small tomedium-sized vessels, andassociated with asthma andeosinophilia.

Table 2. Comparison of the clinical and histologic features of 4 different forms of systemic vasculitis*

CharacteristicWegener’s

granulomatosisMicroscopicpolyangiitis

Polyarteritisnodosa

Churg-Strausssyndrome

Size of affected vessels Small vessels; smalland medium-sized arteries

Small vessels; smalland medium-sized arteries

Medium-sized andsmall arteries

Small vessels; smalland medium-sized arteries

Granulomatous inflammation Yes No No YesOrgan system involved, % of patients

Upper airways disease 95 No No 50–60Pulmonary disease 85 50–70 No 40–70Pulmonary hemorrhage 5–15 10–50 No ,3Glomerulonephritis 80 90 No 10–25Gastrointestinal tract ,5 30 25–40 30–50Nervous system 20–50 60–70 50–70 70–80Cardiac 10 10–15 5–30 10–15

Relapsing course, % of patients 50 35 20 30–50Hepatitis associated No No Yes NoEosinophilia Rare Rare Rare YesArteriographic microaneurysms No Uncertain Yes NoANCA, % of patients .85% 50–80 ,20 50–70

* Frequencies reflect data combined from the following sources: for Wegener’s granulomatosis, ref. 39; for microscopic polyangiitis, refs. 10, 11, 33,35, and 42–44; for polyarteritis nodosa, refs. 13–15, 25, and 44; for Churg-Strauss syndrome, refs. 22, 23, 43, and 44. ANCA 5 antineutrophilcytoplasmic antibodies.

EDITORIAL 509

perforation, infarction, or pancreatitis), central nervoussystem (CNS) involvement, and cardiomyopathy. Ascore of 0 was given when none of the 5 factors waspresent, a score of 1 when 1 factor was present, and ascore of 2 when $2 factors were present. Among 336patients enrolled in 5 prospective trials, a 46% 5-yearmortality rate was observed in patients with an FFSscore of .2, compared with a rate of 12% in patientswith a score of 0 (20).

Important information has been gained from thePAN studies performed by the FVSG; several issues,however, have complicated their interpretation. Whilethese trials have been prospective, randomized, andstandardized, they have generally been of insufficientsize to draw definitive conclusions with regard to differ-ences between treatment arms. For some series, cohortsfrom different treatment trials have been combined toexamine outcome. Although this increases the samplesize, the use of diverse therapeutic regimens from pa-tient to patient may confound the analysis.

The lack of a homogenous disease population hasbeen another area of potential concern. From workpioneered by the FVSG, it has been recognized thatantiviral agents together with minimization of immuno-suppression are important in the treatment of hepatitisB virus (HBV)–associated PAN (21). Despite this verydifferent therapeutic approach, patients with HBV-associated PAN have continued to be combined withthose who have noninfectious PAN in longitudinal ana-lyses. In studies by the FVSG, patients with CSS havealso been included. While the investigators have dis-cussed the clinical and histopathologic differences be-tween PAN and CSS (22,23), they have suggested thatthe similarity in prognosis supports this trial design (20).The separation of PAN and MPA may further affect thehomogeneity of the study population because a substan-tial number of enrolled patients have glomerulonephri-tis. These methodologic issues highlight the challengesthat are faced in conducting clinical trials in rare dis-eases. PAN and CSS are among the least common formsof systemic vasculitis. With the Chapel Hill ConsensusConference reclassification, PAN in particular appearsto be exceedingly rare (24). Even with such formidableobstacles, the work of these investigators has continued,and their efforts to better understand these rare diseasesare to be commended.

In the current issue of Arthritis & Rheumatism,Gayraud and colleagues from the FVSG present data onthe long-term followup of 278 patients with PAN andCSS enrolled in 4 prospective trials between 1980 and1993. With a mean patient followup time of 7.3 years

(range 3 months to 16 years), this paper contains themost comprehensive longitudinal data for patients withPAN and provides an extension of their previous analy-ses in 1992 and 1996 (20,25). Outcome was examined asit relates to the type of vasculitis, the treatments admin-istered, and the presence of prognostic factors as as-sessed by the FFS and the Birmingham Vasculitis Activ-ity Score (BVAS) at the time of diagnosis. In addition,the investigators went back to their cohort and reclassi-fied them as having PAN, HBV-related PAN, MPA, orCSS according to the criteria of the American College ofRheumatology, the Chapel Hill Consensus Conference,and their own recommendations for the diagnosis ofMPA.

The findings from this study indicate that theinitial treatment for patients with severe vasculitisshould consist of CS together with CYC. In combineddata from 215 patients treated across 4 different proto-cols, survival was found to be comparable for those whoreceived CS or CS plus CYC. However, when these samepatients were stratified according to FFS, those with ascore of $2 had prolonged survival when treated withCYC. A tendency toward prolonged survival with CYCtreatment was also observed for patients with a BVASscore of .30. Overall, the death rate reflected diseaseseverity as assessed by both the FFS and the BVAS. Norelationship was observed between disease severity andrelapse. Treatment with CYC also did not appear toprevent relapses.

The use of daily versus intermittent CYC therapyin systemic vasculitis continues to be a topic of somecontroversy. For WG, findings of 3 prospective trialssuggest an increased rate of disease relapse with inter-mittent administration of CYC (26–28). However, PANmay be pathophysiologically distinct from WG and thuscould respond differently to intermittent CYC. In arandomized trial by the FVSG comparing intermittentwith daily CYC in 25 patients with good-prognosis PANor CSS (FFS 5 0), no superiority of efficacy could beestablished between the 2 regimens (29). Haubitz et alalso conducted a prospective trial in which 47 patientswith either WG or MPA and renal involvement wererandomized to receive either intermittent or daily CYC(30). No difference in patient survival, remission rate,time of remission, relapse rate, or outcome of renalfunction was observed between the 2 groups. Whilethese results appear encouraging, both studies are ofinsufficient size to demonstrate equivalence.

Reduction of bladder cancer risk has been fre-quently cited as a rationale for favoring intermittentCYC, but to date there remains limited long-term

510 LANGFORD

experience with this administration schedule. Talar-Williams et al found that the mean time from the firstdaily CYC dose to the development of transitional cellcarcinoma of the bladder was 9 years (31); the studypopulation described by Gayraud and colleagues has notyet reached this point. While intermittent administrationmay lower the cumulative CYC dose, the benefit of alowered cumulative dose is not clear. In the only trial inwhich a risk analysis has been performed, the total doseof CYC was not found to be an independent risk factorfor the development of bladder cancer (31).

In the abstract of their paper, Gayraud et alconclude that the initial treatment intensity shouldreflect disease severity. While mortality was associatedwith disease severity, 15 patients taking CS alone died ofuncontrolled disease, and only patients treated with CShad uncontrolled disease. These data suggest that cau-tion should be used when deciding to treat a patient withCS alone and that this should be considered only in theabsence of manifestations that could result in mortalityor severe morbidity.

As discussed by the investigators in this andprevious publications, clinical judgment is needed whenassessing the presence of severe disease (11,32). Fewpeople would dispute that the renal, GI, cardiac, andneurologic parameters contained within the FFS reflectsevere disease in major organ sites. However, the FFS isnot all-inclusive, and the presence of severe disease mustbe assessed in the context of the individual patient,particularly with regard to MPA. In the study on whichthe FFS was based, no patients had pulmonary hemor-rhage; thus, the impact of this manifestation could notbe tested (20). Pulmonary hemorrhage is potentiallylife-threatening, and current clinical experience supportsthe use of CS plus CYC in patients with this manifesta-tion of small vessel vasculitis.

The FFS also does not address the possibility thatcertain manifestations, in particular glomerulonephritis,may require a cytotoxic agent to control disease. In 3British studies of microscopic polyarteritis performedprior to the Chapel Hill Consensus Conference, com-bined therapy with CS and a cytotoxic agent appeared toimprove outcome (33–35). Hogan et al found that therisk of death in patients with ANCA-associated MPAand necrotizing crescentic glomerulonephritis was 5.56times lower in the CYC-treated patients than in thosetreated with CS alone (10). In WG, there is strongevidence that CS alone is insufficient to treat patientswith glomerulonephritis (36,37). The only 2 regimensused to date that have effectively induced remission ofactive WG-related glomerulonephritis are prednisone in

combination with either CYC or methotrexate (38–40).These data would suggest that a patient with an ANCA-associated necrotizing glomerulonephritis and few or noimmune complexes should initially be treated with CSand a cytotoxic agent, even if the creatinine level is,1.58 mg/dl and proteinuria is ,1 gm/day.

CSS presents unique problems in management,ones that are often related to the severity of reactiveairways disease (23). In examining long-term outcome,Gayraud et al found that the survival curve for patientswith CSS paralleled that of PAN and MPA. While thereappear to be many instances in which the use of CSalone may effectively treat CSS, life-threatening mani-festations can occur. The data reported by these inves-tigators suggest that patients with manifestations ofsevere disease, particularly involving the heart, GI tract,CNS, or kidneys, should initially be treated with CYCcombined with CS.

An important contribution of the article by Gay-raud and colleagues lies in its outlook toward futurestudies. Despite advances in therapy, the overall mortal-ity of people with certain vasculitic diseases is signifi-cantly higher than that of the general population, asdemonstrated in this study. A plan to explore treatmentstrategies adapted to the type of vasculitis, its severity,and predicted outcome has much merit. In WG, therehave been successful therapeutic approaches based onminimizing exposure to CYC through staged regimens(41) or, alternatively, the use of methotrexate and CS toinduce remission in patients with less severe disease(40). To date, CYC remains the only cytotoxic agent forwhich there has been a published prospective experiencein the treatment of PAN, MPA, or CSS. This collabora-tive group’s planned investigation of other immunosup-pressive agents as well as the specific indications forCYC remains of great importance. In the years to come,we will continue to follow their progress and await theirfindings with interest.

REFERENCES

1. Kussmaul A, Maier K. Ueber eine bisher nicht beschriebeneeigenthumliche Arterienerkrankung (Periarteritis nodosa), die mitMorbus Brightii und rapid fortschreitender allgemeiner Muskel-lahmung einhergeht. Dtsch Arch Klin 1866;1:484–518.

2. Ferrari E. Ueber Polyarteritis acuta nodosa (sogenannte Periar-teritis nodosa), und ihre Beziehungen zur Polymyositis und Poly-neuritis acuta. Beitr Pathol Anat 1903;34:350–86.

3. Gayraud M, Guillevin L, Toumelin PL, Cohen P, Lhote F,Casassus P, et al. Long-term followup of polyarteritis nodosa,microscopic polyangiitis, and Churg-Strauss syndrome: analysis offour prospective trials including 278 patients. Arthritis Rheum2001;44:668–77.

EDITORIAL 511

4. Wohlwill F. Uber die nur mikroskopisch erkennbare Form derPeriarteritis nodosa. Virchows Arch 1923;246:377–411.

5. Davson J, Ball J, Platt R. The kidney in periarteritis nodosa. QJM1948;17:175–202.

6. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL,et al. Nomenclature of systemic vasculitides: proposal of an inter-national consensus conference. Arthritis Rheum 1994;37:187–92.

7. Jennette JC, Falk RJ. The pathology of vasculitis involving thekidney. Am J Kidney Dis 1994;24:130–41.

8. Devaney KO, Travis WD, Hoffman GS, Leavitt RY, Lebovics R,Fauci AS. Interpretation of head and neck biopsies in Wegener’sgranulomatosis: a pathologic study of 126 biopsies in 70 patients.Am J Surg Pathol 1990;14:555–64.

9. Travis WD, Colby TV, Lombard C, Carpenter HA. A clinicopath-ologic study of 34 cases of diffuse pulmonary hemorrhage withlung biopsy confirmation. Am J Surg Pathol 1990;15:315–33.

10. Hogan SL, Nachman PH, Wilkman AS, Jennette JC, Falk RJ.Prognostic markers in patients with antineutrophil cytoplasmicautoantibody-associated microscopic polyangiitis and glomerulo-nephritis. J Am Soc Nephrol 1996;7:23–32.

11. Guillevin L, Durand-Gasselin B, Cevallos R, Gayraud M, Lhote F,Callard P, et al. Microscopic polyangiitis: clinical and laboratoryfindings in eighty-five patients. Arthritis Rheum 1999;42:421–30.

12. Bosch X. Microscopic polyangiitis (microscopic polyarteritis) withlate emergence of generalised Wegener’s granulomatosis. AnnRheum Dis 1999;58:644–7.

13. Frohnert PP, Sheps SG. Long-term follow-up study of periarteritisnodosa. Am J Med 1967;43:8–14.

14. Leib ES, Restino C, Paulus HE. Immunosuppressive and cortico-steroid therapy of polyarteritis nodosa. Am J Med 1979;67:941–7.

15. Cohen RD, Conn DL, Illstrup DM. Clinical features, prognosisand response to treatment in polyarteritis. Mayo Clin Proc 1980;55:146–55.

16. Sack M, Cassidy JT, Bole GG. Prognostic factors in polyarteritis.J Rheumatol 1975;2:411–20.

17. Fauci AS, Katz P, Haynes BF, Wolff SM. Cyclophosphamidetherapy of severe systemic necrotizing vasculitis. N Engl J Med1979;301:235–8.

18. Fauci AS, Doppman JL, Wolff SM. Cyclophosphamide-inducedremissions in advanced polyarteritis nodosa. Am J Med 1978;64:890–4.

19. Guillevin L, Jarrousse B, Lok C, Lhote F, Jais JP, Le Thi HuongDu D, et al, and the Cooperative Study Group for PolyarteritisNodosa. Longterm followup after treatment of polyarteritis no-dosa and Churg-Strauss angiitis with comparison of steroids,plasma exchange and cyclophosphamide to steroids and plasmaexchange: a prospective randomized trial of 71 patients. J Rheu-matol 1991;18:567–74.

20. Guillevin L, Lhote F, Gayraud M, Cohen P, Jarrousse B, Lortho-lary O, et al. Prognostic factors in polyarteritis nodosa andChurg-Strauss syndrome: a prospective study in 342 patients.Medicine (Baltimore) 1996;75:17–28.

21. Guillevin L, Lhote F, Cohen P, Sauvaget F, Jarrousse B, Lortho-lary O, et al. Polyarteritis nodosa related to hepatitis B virus: aprospective study with long-term observation of 41 patients.Medicine (Baltimore) 1995;74:238–53.

22. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitiswith asthma and eosinophilia: a clinical approach to Churg-Strausssyndrome. Medicine (Baltimore) 1984;63:65–81.

23. Guillevin L, Cohen P, Gayraud M, Lhote F, Jarrousse B, CasassusP. Churg-Strauss syndrome: clinical study and long-term follow-upof 96 patients. Medicine (Baltimore) 1999;78:26–37.

24. Watts RA, Jolliffe VA, Carruthers DM, Lockwood M, Scott DGI.Effect of classification on the incidence of polyarteritis nodosa andmicroscopic polyangiitis. Arthritis Rheum 1996;39:1208–12.

25. Guillevin L, Lhote F, Jarrousse B, Fain O. Treatment of poly-arteritis nodosa and Churg-Strauss syndrome: a meta-analysis of 3

prospective controlled trials including 182 patients over 12 years.Ann Med Interne (Paris) 1992;143:405–16.

26. Hoffman GS, Leavitt RY, Fleisher TA, Minor JR, Fauci AS.Treatment of Wegener’s granulomatosis with intermittent high-doseintravenous cyclophosphamide. Am J Med 1990;89:403–10.

27. Reinhold-Keller E, Kekow J, Schnabel A, Schmitt WH, Heller M,Beigel A, et al. Influence of disease manifestation and antineutro-phil cytoplasmic antibody titer on the response to pulse cyclo-phosphamide therapy in patients with Wegener’s granulomatosis.Arthritis Rheum 1994;37:919–24.

28. Guillevin L, Cordier J-F, Lhote F, Cohen P, Jarrousse B, Royer I,et al. A prospective, multicenter, randomized trial comparingsteroids and pulse cyclophosphamide versus steroids and oralcyclophosphamide in the treatment of generalized Wegener’sgranulomatosis. Arthritis Rheum 1997;40:2187–98.

29. Gayraud M, Guillevin L, Cohen P, Lhote F, Cacoub P, Deblois P,et al. Treatment of good-prognosis polyarteritis nodosa andChurg-Strauss syndrome: comparison of steroids and oral or pulsecyclophosphamide in 25 patients. Br J Rheumatol 1997;36:1290–7.

30. Haubitz M, Schellong S, Gobel U, Schurek HJ, Schaumann D,Koch KM, et al. Intravenous pulse administration of cyclo-phosphamide versus daily oral treatment in patients with antineu-trophil cytoplasmic antibody–associated vasculitis and renal in-volvement: a prospective, randomized study. Arthritis Rheum1998;41:1835–44.

31. Talar-Williams C, Hijazi YM, Walther MM, Linehan WM, Halla-han CW, Lubensky I, et al. Cyclophosphamide-induced cystitis andbladder cancer in patients with Wegener granulomatosis. AnnIntern Med 1996;124:477–84.

32. Guillevin L, Lhote F. Treatment of polyarteritis nodosa andmicroscopic polyangiitis. Arthritis Rheum 1998;41:2100–5.

33. Adu D, Howie AJ, Scott DG, Bacon PA, McGonigle RJ, MichaelJ. Polyarteritis and the kidney. QJM 1987;62:221–37.

34. Rodgers H, Guthrie JA, Brownjohn AM, Turney JH. Microscopicpolyarteritis: clinical features and treatment. Postgrad Med J1989;65:515–8.

35. Savage CO, Winearls CG, Evans DJ, Rees AJ, Lockwood CM.Microscopic polyarteritis: presentation, pathology and prognosis.QJM 1985;56:467–83.

36. Hollander D, Manning RT. The use of alkylating agents in thetreatment of Wegener’s granulomatosis. Ann Intern Med 1967;67:393–8.

37. Hoffman GS. Wegener’s granulomatosis. Curr Opin Rheumatol1993;5:11–7.

38. Fauci A, Haynes B, Katz P, Wolff S. Wegener’s granulomatosis:prospective clinical and therapeutic experience with 85 patients for21 years. Ann Intern Med 1983;98:76–85.

39. Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS,Travis WD, et al. Wegener granulomatosis: an analysis of 158patients. Ann Intern Med 1992;116:488–94.

40. Sneller MC, Hoffman GS, Talar-Williams C, Kerr GS, HallahanCW, Fauci AS. An analysis of forty-two Wegener’s granulomatosispatients treated with methotrexate and prednisone. ArthritisRheum 1995;38:608–13.

41. Langford CA, Talar-Williams C, Barron KS, Sneller MC. A stagedapproach to the treatment of Wegener’s granulomatosis: inductionof remission with glucocorticoids and daily cyclophosphamideswitching to methotrexate for remission maintenance. ArthritisRheum 1999;42:2666–73.

42. Specks U. Pulmonary vasculitis. In: Schwarz MI, King TE, editors.Interstitial lung disease. 3rd ed. Hamilton (Ontario): BC Decker;1998. p. 507–34.

43. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med1997;337:1512–23.

44. Lhote F, Guillevin L. Polyarteritis nodosa, microscopic polyangi-itis, and Churg-Strauss syndrome: clinical aspects and treatment.Rheum Dis Clin North Am 1995;21:911–47.

512 LANGFORD