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Postgrad Med J-2005-Chen-723-7

ORIGINAL ARTICLE

Cinical and pathological characteristics of Chinese patients with antineutrophil cytoplasmic autoantibody associated systemic vasculitides:a study of426patients from a single centre

M Chen,F Yu,Y Zhang,M H Zhao ...............................................................................................................................

See end of article for authors’affiliations ....................... Correspondence to:

Dr M H Zhao,Renal Division and Institute of Nephrology,Peking University First Hospital, Beijing100034,PR China; mhzhao@https://www.wendangku.net/doc/013222416.html,

Submitted

26February2005 Accepted27April2005 .......................

Postgrad Med J2005;81:723–727.doi:10.1136/pgmj.2005.034215 Background:Antineutrophil cytoplasmic autoantibodies(ANCA)are serological markers of ANCA associated systemic vasculitides(AASV),which is one of the most common multisystem autoimmune diseases.Features of Chinese patients with AASV have not been fully investigated.

Objective:To analyse the clinical and pathological characteristics of Chinese patients with AASV. Methods:426Chinese patients with AASV diagnosed in the past eight years were retrospectively studied and their clinical and pathological data were analysed.

Results:Of the426patients,87(20.4%)were Wegener’s granulomatosis,337(79.1%)were microscopic polyangiitis and two(0.5%)were Churg-Strauss syndrome.Only201of426(47.2%)patients were diagnosed within three months.Clinically,the patients had multisystem involvement.Altogether371of 426(87.1%)had kidney involvement and260of426(61.0%)had lung involvement.The prevalences of renal involvement and fatigue were significantly higher in patients with MPO-ANCA than that in patients with PR3-ANCA;the prevalences of ophthalmic,nasal involvement,rash,and arthragia were significantly higher in patients with PR3-ANCA than those in patients with MPO-ANCA.The one and five year death rates were13.1%and22.4%,respectively.The percentage of patients progressing to end stage renal disease at one and five years was15.9%and27.1%,respectively.

Conclusions:AASV is not a rare autoimmune disease in Chinese people.Kidney and lung were the most vulnerable organs.For patients with multiorgan damage,an ANCA test should be performed to make an early diagnosis and to start treatment in time.

V asculitis is an inflammatory process of blood vessels, histopathologically characterised by vessel wall destruc-tion and occlusion of the vascular lumen.An attempt to classify the diverse forms of vasculitis resulted in the Chapel Hill international consensus definition,which used the vessel size as the determinant of classification.1American College of Rheumatology(ACR)has proposed classification criteria for some of the diseases.2Wegener’s granulomatosis(WG), microscopic polyangiitis(MPA),Churg-Strauss syndrome (CSS),and idiopathic rapidly progressive glomerulonephritis (iRPGN)are described as small vessel vasculitides and are acknowledged to be commonly associated with antineutro-phil cytoplasmic autoantibodies(ANCA).They are termed as ANCA associated systemic vasculitides(AASV).Two fluores-cence patterns of ANCAs are distinguished by indirect immunofluorescence(IIF),the cytoplasmic staining pattern (cANCA),and the perinuclear staining pattern(pANCA). Most patients with a cANCA pattern obtained by IIF have ANCAs directed against proteinase-3(PR3),as determined by antigen specific ELISA.Patients with a pANCA mostly have ANCAs directed against one of a variety of antigens,such as myeloperoxidase(MPO).The combination of a cANCA with PR3-ANCA and pANCA with MPO-ANCA are specific for WG, MPA,or iRPGN.3

AASV must be recognised in time if successful treatment is to be implemented.Early diagnosis and appropriate immu-nosuppressive treatment are crucial for reducing the ability of acute vasculitis to cause death from major organ failure,for example,respiratory failure from pulmonary haemorrhage, and to reduce long term morbidity,for example,end stage renal failure.

AASV is one of the most common multisystem auto-immune diseases in the white population.A population based study from Norfolk,England,reported incidences of8.5cases per million for WG,3.6cases per million for MPA,and2.4 cases per million for the CSS.4In two large US cohorts studies of patients with WG,56white people comprised more than 90%of all cases.Regional,geographical,ethnic,and seasonal differences in disease patterns and increasing incidence have been suggested,but lack confirmation.7Studies from Norway suggested a doubling incidence of WG from1992–1994to 1995–1998.These figures probably reflect a real increase in incidence as well as improved awareness and diagnosis. AASV can occur at any age,especially elderly people.

The incidence of AASV in the Chinese population is unknown.In the early1990s,after IIF-ANCA and ELISA using crude neutrophil acid extracts as solid phase ligands were established,a retrospective study of50hospitalised Chinese patients with crescentic glomerulonephritis or end stage renal disease showed that five of the50patients were ANCA positive.8With the commercial IIF-ANCA kits being available and purified MPO and PR3being used in routine ANCA screening assays,the prevalence of AASV increased substantially.In the past eight years,426patients with AASV were diagnosed in Peking University First Hospital.The Abbreviations:ANCA,antinuetrophil cytoplasmic autoantibodies; AASV,ANCA associated systemic vasculitides;WG,Wegener’s

granulomatosis;MPA,microscopic polyangiitis;CSS,Churg-Strauss syndrome;ACR,American College of Rheumatology;ANA,antinuclear antibodies;ESR,erythrocyte sedimentation rate;MMF,mycophenolate mofetil;MPO,myeloperoxidase

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prevalence of ANCA and the antigen specificities,as well as demographic features of some of the Chinese patients with AASV was investigated.9It was suggested that AASV might not be rare in the Chinese population.In this study,the clinical and pathological manifestations of the Chinese patients with AASV were investigated.

METHODS

Patients

A total of 426patients with AASV,diagnosed from 1997to 2004in the Institute of Nephrology,Peking University First Hospital,were enrolled into this retrospective study.All the patients met the criteria of the Chapel Hill consensus conference definition (for WG,MPA,or CSS)and ACR classification criteria (for WG or CSS).Systemic lupus erythematosus,Henoch-Scho ¨lein purpura,rheumatoid arthritis were excluded.Acute renal failure was defined by the presence of progressively raised serum creatinine or 15%declined clearance rate of serum creatinine on the baseline within days or weeks.Clinical data were collected and analysed according to the organ involved.

IIF assay to detect ANCA

Standard IIF assay was performed accoding to the manu-facturer (EUROIMMUN,Lu ¨beck,Germany).Ethanol fixed human polymorphonuclear leucocytes (PMN)were used to detect ANCA and monkey liver sections were used to exclude antinuclear antibodies (ANA).cANCA and pANCA were distinguished according to staining patterns by two experi-enced technicians.

Antigen specific ELISAs

Two highly purified known ANCA antigens,PR3and MPO,were used as solid phase ligands in ELISA,as previously reported.10

Pathological examination

Renal pathological data of 122cases were evaluated using direct immunofluorescence,light and electron microscopy.Specimens of kidney were required to have a minimum of 10glomeruli for classification of glomerulonephritis with light microscopy by the same renal pathologist.

Treatment protocols

Induction treatment included corticosteroids and cyclopho-sphamide (CTX).Oral prednisone was prescribed at an initial dose of 1mg/kg/day for four to six weeks,with reducing doses over time to 12.5to 15mg by three months.CTX started on day 10–14days after corticosteroids,daily oral 2mg/kg/day or intravenous 0.7g/m 2every month.Patients with acute renal failure or pulmonary haemorrhage received three pulses of intravenous methylprednisolone (7–15mg/kg/day)before standard induction treatment.Some patients with severe pulmonary haemorrhage received additionally plasma exchanges.Azathioprine or mycophenolate mofetil (MMF)was given in maintenance treatment.

Remission was defined as the absence of clinical signs or symptoms or laboratory evidence of vasculitis activity.Relapse was defined as the return of clinical signs or symptoms or laboratory evidence of disease activity sufficient to warrant a sustained increase in immunosuppressive treatment.

RESULTS

Prevalence and demographic features

Of the 426patients with AASV diagnosed from 1997to 2004,199(46.7%)were male and 227(53.3%)were female.Most of the patients were from northern China.There was no significant occupation of the patients.The average age was 56.1(range 5–83)years old.Altogether 176(41.3%)cases were older than 65years old and 38(8.92%)cases were younger than 20years old.The number of diagnosed case increased chronologically (fig 1).Eighty seven patients (20.4%)were WG,337(79.1%)were MPA,and two (0.5%)were CSS.Seventy (16.4%)of these patients were positive for cANCA.Sixty nine of them could recognise PR3only and the rest one could recognise both PR3and MPO in antigen specific ELISA.Altogether 354(83.1%)patients were positive for pANCA with antigen specificity for MPO only in 346(346of 354,97.7%)patients,and positive for both MPO and PR3in eight cases (8of 354,2.3%).Two of 426patients were positive for both pANCA and cANCA.One of them could recognise MPO only and the other could recognise both MPO and PR3(table 1).

Interval between onset of the disease and diagnosis The mean and median time between onset of the disease and testing for ANCA were 237.6(ranging from 3to 1460)and 60days,respectively.Only 99cases (23.2%)were diagnosed within 30days,47.2%(201)cases within 90days,252cases (59.2%)within 180days,47(11.0%)cases more than one year,and one case was even diagnosed four years after the onset of the disease.There was no significant difference of the interval between onset of the disease and diagnosis between patients with PR3-ANCA and MPO-ANCA.Non-specific symptoms

Of the 426cases,260(61.0%)had fatigue,242(56.8%)had fever,171cases (40.1%)had significant weight loss,84cases (30.8%)had arthralgia,110(25.8%)cases had muscle pain,and 78(18.3%)cases had a rash.

Renal manifestations

A total of 371cases (371of 426,87.1%)had renal involvement,of which 334(90.0%)had haematuria,314(84.6%)had proteinuria,307(82.7%)had raised serum creatinine with 229(61.7%)diagnosed to have acute renal failure,and only 31cases (8.36%)had nephrotic syndrome.Altogether 122cases (32.9%)had a renal biopsy,of which 38(31.1%)had focal segmental fibrinoid necrosis in glomeruli,12(9.84%)had fibrinoid necrosis in arterioles,83(68.0%)reached the criteria of crescentic glomerulonephritis (over

80

60

40

20

Year

N u m b e r

Figure 1

Patients with AASV diagnosed chronologically.

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50%glomeruli had large crescents formation),and 11(9.02%)had granulomatous lesion in renal interstitium.Pulmonary manifestations

Two hundred and sixty cases (260of 426,61.0%)had lung symptoms such as cough,often with sputum production,of which 104(40.0%)had haemoptysis.One hundred and fifty cases had alveolar infiltrates or interstitial changes on chest films or computed tomography,of which 130cases (86.7%)had shadows in one or both lungs and 79(52.7%)had pulmonary interstitial fibrosis,multiple nodules,or cavita-tions.

Manifestations of other organs

Of the 426patients,83cases (19.5%)had ophthalmic disease manifested as conjunctivitis,keratohelcosis,episcleritis and uveiitis,optical nerve vasculitis,and declining vision.Ninety nine cases (23.2%)had ear involvements,manifested as tinnitus,perforation of the tympanic membrane,and declin-ing or loss of hearing.Thirty five cases (8.22%)had nasal involvement,manifested as sinusitis,stuffiness,epistaxis,and brown or bloody crusts,rhinitis,septal erosions,or even septal perforation.One hundred and eighty three cases (43.0%)had gastrointestinal involvement manifested as nausea,vomiting,anorexia,abdominal pain,loose bowels,or bloody faeces.Five patients had a gastrointestinal ulcer.Sixty seven cases (15.7%)had neurological disorders such as peripheral mononeritis multiplex,dizziness,headache,and coma.Three patients has cerebral haemorrhage.One patient had Guillain-Barre syndrome (fig 2).

Further analysis showed that the prevalences of renal involvement and fatigue were significantly higher in patients with MPO-ANCA than that in patients with PR3-ANCA (90.2%v 79.7%,x 2=6.21,p ,0.05;63.7%v 46.4%,x 2=7.24,p ,0.01,respectively);the prevalences of ophthalmic,nasal involvement,rash,and arthragia were significantly higher in patients with PR3-ANCA than those in patients with MPO-ANCA (31.9%v 16.7%,x 2=8.53,p ,0.01;21.7%v 5.76%,x 2=19.1,p ,0.01;27.5%v 16.4%,x 2=4.76%,p ,0.05;43.5%v 28.0%,x 2=6.54,p ,0.05,respectively)(table 2).

Laboratory findings

A total of 300of 337cases (89.0%)had anaemia,of which only 83cases (27.7%)had mild anaemia with haemoglobin (Hb)over 90g/l,172cases (57.3%)had moderate anaemia with Hb between 60and 90g/l,and 45(15.0%)had severe anaemia with Hb less than 60g/l.Altogether 125of 287(43.6%)cases had leucocytosis and 56of 195(28.7%)had thrombocytosis.A total of 265of 285cases (93.0%)had raised erythrocyte sedimentation rate (ESR),of which 92(34.7%)were over 100mm 1st h and 178(67.2%)were over 60mm 1st h.Altogether 132of 185cases (71.4%)had raised C reactive protein.No significant difference was found in these laboratory findings between PR3-ANCA and MPO-ANCA positive patients.

Outcomes

A total of 44of 130(33.8%)and 86of 130(66.2%)cases received prednisone together with daily oral or monthly intravenous CTX,respectively.After the induction phase treatment,105of 130(88.5%)cases had complete or partial remission.One hundred and seven cases were followed up.The average duration of follow up was 29.7(1–108)months.A total of 24of 107(22.4%)patients died and 29of 107(27.1%)patients progressed to end stage renal disease and received renal replacement treatment.The one and five year death rates were 13.1%and 22.4%,respectively.The percentage of patients progressing to end stage renal disease at one and five years was 15.9%and 27.1%respectively.

DISCUSSION

AASV is one of the most common multisystem autoimmune diseases in the white population.It is an important cause of mortality (if untreated)and morbidity (despite current aggressive treatment).The annual incidence and point prevalence of renal vasculitis in Europe is 10–20/million/year and 150–200/million,respectively.711In China,after improved awareness and diagnostic techniques,more patients with AASV were diagnosed in recent years,but there is lack of systemic investigation on incidence.Over 400patients with AASV were diagnosed in our centre in the past eight years and the number of patients increased chronolo-gically.It was suggested that AASV was not rare in China.In this study,it was found that the average age of Chinese patients with AASV was 56.1(ranging from 5to 83)years old.Over 40%of the cases were more than 65years old,and nearly 1of 10of the cases were younger than 20years old,showing that AASV could affect people of all age—elderly people were more susceptible,but children and teenagers were not rare.This is consistent with our previous studies and similar to the white population.11–14

MPO and PR3are the two important target antigens of ANCA for Chinese patients with AASV,which is consistent with the epidemiology reports in white populations.715However,in our study,patients with MPA were about four times as many as patients with WG.Substantial evidences suggested that throughout Europe,there is a different proportion of WG and MPA.In northern Europe and Germany there are many more patients with WG than MPA,whereas in southern Europe,a study from Spain

Table 1ANCA results of serum samples in IIF and ELISA

anti-PR3

anti-MPO anti-PR3and MPO Total cANCA 690170pANCA

03468354cANCA and pANCA 0112Total 69

347

10

426

100

80

6040200

P r e v a l e n c e (%)

Figure 2Prevalences of organ involvement.

Characteristics of Chinese patients with AASV

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suggested that patients with MPA were about two to three times as many patients with WG.1116–18This may be attributed to the geographical,environmental,or genetic differences as there had been evidence that geographical and genetic factors both played a part in the pathogenesis of AASV.The preponderance of MPA might be one of the epidemiological characteristics of Chinese patients with AASV.

Kidney and lung are the two most vulnerable organs to be involved in patients with AASV.In this study,nearly90%of cases had renal involvement and more than60%of them had acute renal failure,which might be the major cause for long term end stage organ damage.However,the high prevalence of renal involvement might be to some extend a result of selective bias,because most patients with renal diseases were referred to us.Another possible reason might be the unawareness of the systemic disease by physicians and thus resulted in late diagnosis and increased prevalence of renal involvement.The prevalence of renal involvement and acute renal failure reported by the respiratory department in our hospital was76.9%(10of13)and38.5%(5of13), respectively.19More than60%had pulmonary involvement with40%having pulmonary haemorrhage,which was the major cause of acute respiratory failure or death.Although 43%and15.7%of the cases had gastrointestinal and nervous involvement respectively,they were often neglected by clinicians and these might be under-evaluated in this retrospective study.Besides visceral vasculitis,about8%to 23%also suffered from auditory,ophthalmic,and nasal involvements.All the above mentioned findings showed that AASV is characterised by multisystem injury.

Although cANCA/PR3-ANCA was mainly found in patients with WG and pANCA/MPO-ANCA was mainly found in patients with MPA and iRPGN,it was not exclusive.Our study also found that there were some difference in the clinical manifestations between patients with PR3-ANCA and MPO-ANCA.The prevalences of fatigue and renal involve-ment were significantly higher in patients with MPO-ANCA than those in patients with PR3-ANCA.The prevalences of ophthalmic,nasal invlovement,rash,and arthragia were significantly higher in patients with PR3-ANCA than those in patients with MPO-ANCA.Some authors argued that one of the possible reasons for higher proportion of renal disease in patients with MPO-ANCA positive might be attributable to the delay of diagnosis.More patients with PR3-ANCA positive had upper respiratory and ophthalmic involvements, which probably reduce the patients’and doctors’delay. Earlier diagnosis and start of treatment might reduce the frequecy of renal involvements.20–23In this study,however, there is no significant difference of the intervals between onset of disease and diagnosis between PR3-ANCA and MPO-ANCA groups.Whether there are different mechanisms in the pathogenesis of renal disease in these ANCA subsets remains unclear.

Aberrant laboratory findings suggestive of active vasculitis included severe anaemia unparalleled with the degree of renal failure or pulmonary haemorrhage,or both,leucocy-tosis,thrombocytosis,increased non-specific inflammatory markers such as ESR and C reactive protein.24The laboratory findings of our patients showed that most of them were in active phase at the time of diagnosis.

This study also preliminarily analysed the outcome of the patients.However,there were many patients lost during follow up,so the actual mortality and rate of end stage renal disease might be much higher.

The prognosis of untreated AASV is poor,with up to90%of patients dying within two years.5Early diagnosis is crucial, otherwise life threatening disease such as acute renal failure or respiratory failure may develop quickly.In this study, unfortunately,more than40%of the patients were diagnosed six months after onset of the disease,and more than10%of the cases were more than one year,which would undoubt-edly worsen the prognosis.This showed that the awareness of this disease still needs to be improved in clinicians. Vassilopoulos25reported that in patients with severe multi-organ dysfunction or pulmonary disorders,there was a high prevalence of ANCA.Therefore,for the suspected patients, prompt ANCA detection is crucial for the early diagnosis of AASV.

CONCLUSION

AASV is not rare in the Chinese population.Renal and pulmonary involvement was common and life threatening. For patients with multisystem involvement,ANCA testing using both IIF and antigen specific ELISA is recommended and it provides a helpful tool facilitating earlier diagnosis. ACKNOWLEDGEMENTS

We are grateful to Dr Yanping Peng for assistance in collecting the data of the patients.

Authors’affiliations .....................

M Chen,F Yu,Y Zhang,M H Zhao,Renal Division and Institute of Nephrology,Peking University First Hospital,Beijing,PR China Funding:none.

Conflicts of interest:none.

Ethics approval and patient consent:this research was approved by the ethnics committee of Peking University First Hospital(Peking University First Hospital,Beijing100034,PR China)and with informed consent of patients.

Table2Clinical manifestations of426patients with AASV

Number(%)PR3-ANCA(n=69)MPO-ANCA(n=347)

Fever242(56.8)44(63.8)190(54.8)

Fatigue**260(61.0)32(46.4)221(63.7)

Weight loss171(40.1)23(33.3)144(41.5)

Muscle pain110(25.8)18(26.1)92(26.5)

Arthragia*131(30.8)30(43.5)97(28.0)

Rash*78(18.3)19(27.5)57(16.4)

Renal*371(87.1)55(79.7)313(90.2)

Pulmonary260(61.0)38(55.1)217(62.5)

Ophthalmic**83(19.5)22(31.9)58(16.7)

Ear99(23.2)21(30.4)74(21.3)

Nasal**35(8.22)15(21.7)20(5.76)

Gastrointestinal183(43.0)24(34.8)157(45.2)

Nerve system67(15.7)11(15.9)55(15.9)

*p,0.05;**p,0.01.

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2005 81: 723-727

Postgrad Med J

M Chen, F Yu, Y Zhang, et al.

single centre

vasculitides: a study of 426 patients from a cytoplasmic autoantibody associated systemic Chinese patients with antineutrophil

Cinical and pathological characteristics of

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