Rheumatology

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Rheumatology 2001; 40: 178-184
© 2001 British Society for Rheumatology

Prevalence and spectrum of rheumatic diseases associated with proteinase 3-antineutrophil cytoplasmic antibodies (ANCA) and myeloperoxidase-ANCA

U. Schönermarck, P. Lamprecht, E. Csernok and W. L. Gross

Department of Rheumatology, Medical University of Lübeck and Rheumaklinik Bad Bramstedt, Germany

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Objectives. To evaluate the prevalence and association of antineutrophil cytoplasmic antibodies (ANCA) and their subtypes [proteinase 3 (PR3)-ANCA, myeloperoxidase (MPO)-ANCA] with distinct clinical features in various clinicopathological syndromes.

Methods. All consecutive ANCA-positive patients seen at the combined unit for rheumatology for Bad Bramstedt and the University of Lübeck between 1989 and 1999 were analysed. ANCA were detected by an immunofluorescence technique and ANCA subspecificities were determined by ELISA. Clinical features at presentation and diagnoses were recorded according to standardized procedures.

Results. Among 4620 patients tested, 333 were cytoplasmic ANCA-positive and 291 were perinuclear ANCA-positive. cANCA/PR3-ANCA were strongly associated with Wegener's granulomatosis (WG), whereas pANCA/MPO-ANCA were associated with a diverse disease spectrum. Further investigation of PR3-ANCA-positive (n=80) and MPO-ANCA-positive patients (n=40) revealed a greater extent of disease [disease extent index (DEI); median 8 vs 5, P<0.01] and more frequent involvement of the upper/lower respiratory tract and the eyes in PR3-ANCA-positive than in MPO-ANCA-positive patients. Fewer than 5% of WG patients were MPO-ANCA-positive. Compared with matched PR3-ANCA-positive WG patients, the MPO-ANCA-positive WG patients had a lower DEI (median 5 vs 8) and had a lower frequency of peripheral neuropathy.

Conclusions. ANCA testing is useful due to its high sensitivity and specificity, especially for cANCA/PR3-ANCA in WG. We found a divergence in the disease spectrum between PR3- and MPO-ANCA-positive patients, characterized by higher DEI and extrarenal manifestations in the PR3-ANCA group. MPO-ANCA was rarely found in WG and was associated with less organ involvement.

KEY WORDS: Antineutrophil cytoplasmic antibodies, Proteinase 3, Myeloperoxidase, Vasculitis.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
The discovery that autoantibodies against cytoplasmic antigens of neutrophils (ANCA) are strongly associated with vasculitic disorders has improved the diagnostic approach to patients with clinically suspected vasculitis and/or glomerulonephritis. ANCA testing has been established as a useful diagnostic tool in making a diagnosis of necrotizing vasculitides, especially the ANCA-associated vasculitides (AAV), e.g. Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg–Strauss syndrome (CSS), in which circulating ANCA are commonly found [1, 2]. ANCA have a high positive predictive value for AAV when used in appropriate clinical situations [3]. However, there is no doubt that ANCA testing has also triggered controversies with respect to the clinical relevance of ANCA positivity in situations other than vasculitides, as these autoantibodies have been found in a variety of inflammatory disorders [1, 2].

Several groups have recently attempted to establish precisely the diagnostic value of ANCA positivity, each trying to avoid preselection bias and each with different diagnostic standards [3–8]. However, the results of this work, which has been based mainly on an immunofluorescence technique (IFT), vary considerably. Moreover, studies comparing patients with proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA are scarce [9–12].

It was the aim of this study to summarize the experience of a decade of ANCA testing with both IFT and enzyme-linked immunoassay (ELISA) in a single university-based hospital specializing in rheumatology, and to establish the prevalence and associations of ANCA subtypes with clinical features in various clinicopathological syndromes. Because of their high diagnostic value PR3- and MPO-ANCA-positive, patients were further analysed in detail with respect to clinical features at presentation, histopathological characteristics and diagnoses. Finally, MPO-ANCA-positive WG patients were compared with matched PR3-ANCA-positive WG patients.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Patients
The study population consisted of 4620 patients attending the Departments of Rheumatology in Bad Bramstedt (Rheumaklinik) and Lübeck (Medical School of the University of Lübeck), who had been tested for the presence of ANCA during a 10-yr period between 1989 and 1999. Patients were diagnosed according to international standards leading ultimately to the generally accepted classifications used in routine clinical work by seeking biopsy proof of vasculitis, and applying the 1990 classification criteria of the American College of Rheumatology and the definitions of the 1992 Chapel Hill Consensus Conference [13, 14] in patients with vasculitides. In each patient, the diagnosis of the respective vasculitis was based on a typical history and characteristic clinical findings, and was confirmed by histology where this was available. However, to avoid selection bias, confirmation of diagnosis by histology was not required. WG patients were classified as having localized WG when the symptoms were restricted to the upper and/or lower respiratory tract, without constitutional symptoms. Patients with connective tissue diseases were diagnosed according to internationally accepted classification criteria, e.g. for systemic lupus erythematosus (SLE) [15] and rheumatoid arthritis (RA) [16]. Rheumatoid vasculitis was diagnosed in patients with RA when one of the following symptoms was present: polyneuropathy/mononeuritis multiplex, cutaneous vasculitis, digital gangrene and visceral infarction, not attributable to any other disease.

ANCA detection
Detection of ANCA by IFT [17] and testing of ANCA target antigens by ELISA [18] were performed according to standardized European guidelines. In this study, only cytoplasmic (cANCA)-positive and perinuclear (pANCA)-positive sera (not atypical ‘aANCA’ or ‘xANCA’ sera) were recorded as a positive ANCA result (Table 1). Sera were screened on ethanol-fixed neutrophils. For the differentiation of pANCA and antinuclear antibodies (ANA), sera that give perinuclear staining were further tested on formalin-fixed neutrophils and on HEp-2 cells. ANCA titres >1:8 were regarded as positive. The presence of antibodies against PR3 and MPO was detected by ELISA and recorded as positive when the concentration was >20 U/ml.

View this table: [in this window] [in a new window]   TABLE 1. Numbers of positive ANCA results by IFT or ELISA in patients with inflammatory rheumatic disorders seen over a 10-yr period at the combined unit of rheumatology of Bad Bramstedt and the University of Lübeck

 

Assessment of disease extent and activity
At each visit patients were examined by a team of specialized clinicians in a standardized manner. The extent of disease was determined as the disease extent index (DEI), as reported previously [19, 20]. Briefly, organ involvement was recorded as follows: upper respiratory tract (E); lung (L); kidney (K); rheumatological symptoms (A); inflammatory eye involvement (Ey); peripheral nervous system (P); central nervous system (C); heart (H); gastrointestinal tract (Gi); skin (S); and constitutional symptoms (B). Each organ involved counted for 2 points and constitutional symptoms for 1 point; the maximum possible score was 21. All organ manifestations that occurred during a period of 6 months before the diagnosis was established were scored cumulatively.

Statistical analysis
Sensitivity, specificity and positive and negative predictive values (PPV and NPV respectively) were calculated for all patients tested. For comparison of frequency distributions in different groups, the ² test or, where appropriate, Fisher's exact test, was used. The Bonferroni correction for multiple tests was used for the comparison of all PR3- and MPO-ANCA-positive patients (P_corr; number of organ systems=11). Differences in DEI were assessed using the Wilcoxon rank sum test. P-values <0.05 were considered to be significant.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Prevalence of ANCA in rheumatic diseases
Between 1989 and 1999, sera from 4620 patients were screened for the presence of ANCA by IFT and further investigated with antigen-specific ELISA. During this time, 624 ANCA-positive patients were observed (cANCA, n=333; pANCA, n=291). However, the ANCA subspecificity for PR3 or MPO could be detected in only half of these patients (312/624) (Fig. 1).

View larger version (22K): [in this window] [in a new window]   FIG. 1. Summary of ANCA-positive patients seen at the combined unit of rheumatology of Bad Bramstedt and the University of Lübeck over a 10-yr period. ANCA were detected by IFT and ELISA. All MPO-ANCA-positive patients and a group of 80 consecutive PR3-ANCA-positive patients were analysed in detail for disease extent and organ involvement at time of diagnosis.

 
The majority of cANCA-positive patients were found to have a diagnosis of WG. However, cANCA were also seen in a few other primary vasculitides, such as MPA (n=1), CSS (n=3), cryoglobulinaemic vasculitis (n=3), giant cell arteritis (n=1) and unclassified vasculitides (n=7), but rarely in other chronic inflammatory disorders without vasculitic symptoms (polymyalgia rheumatica, hypereosinophilic syndrome, ulcerative colitis, juvenile chronic arthritis, spondylarthropathy, neoplasia) (Table 1). More precisely, cANCA were found in 81% of WG patients, with a lower frequency in localized WG (39%) than in generalized WG (86%). However, cANCA were found in up to 15% of patients with other small-vessel vasculitides. In contrast, only 23% of pANCA-positive patients (67/291) had a diagnosis of a primary vasculitis. pANCA were seen most frequently in MPA (65%), but only occasionally in WG (3.6%) or CSS (6.5%). In addition, pANCA were detected in SLE (11%), Sjögren's syndrome (6%), RA (9%), chronic inflammatory bowel diseases (17%) and sarcoidosis (6%), but rarely in other inflammatory rheumatic diseases (<5%).

Distribution of ANCA with subspecificity for PR3 or MPO
Eighty-one per cent of all cANCA-positive sera were directed against PR3. In contrast, only 14% of pANCA-positive patients had MPO as the target antigen. PR3-ANCA were predominantly found in WG; they were seen only in a few other patients with vasculitides, i.e. CSS (3/46) and cryoglobulinaemic vasculitis (2/26), and only occasionally in those with SLE or spondylarthropathy. MPO-ANCA were detected mainly in patients with MPA (19/40), and rarely in other primary vasculitides (Table 1). MPO-ANCA were also found in a minority of patients with SLE (3/167) and RA (1/1412); however, even in RA with secondary vasculitis only 2/44 patients were positive for MPO-ANCA. Whereas all MPO-ANCA-positive patients revealed a pANCA pattern by IFT, in the PR3-ANCA group, five patients were pANCA-positive by IFT (WG, two patients; CSS, SLE and spondylarthropathy, one patient each). Furthermore, sera from patients with AAV which were negative for cANCA and pANCA in IFT were also negative for PR3- and MPO-ANCA.

Diagnostic value of ANCA testing for AAV
Specificity, sensitivity and predictive values were calculated for patients with AAV, i.e. WG, MPA and CSS (Table 2). cANCA were highly sensitive (81%) and specific (99.5%) for WG, resulting in a high positive predictive value (PPV) (94%). Combining the IFT and ELISA results (cANCA/PR3-ANCA) increased specificity and the PPV close to 100%, but reduced sensitivity to 69%. In contrast, pANCA were detected in only 3.6% of WG patients. Sensitivity and specificity of combined testing for cANCA and pANCA were 85 and 93% respectively for WG, with a PPV of 52%. In MPA, pANCA were more prevalent than cANCA, with a sensitivity of 65% and specificity of 94%. However, determination of pANCA by IFT alone yielded a PPV of only 9% for MPA. Although combination of IFT and ELISA results increased specificity (99.5%) and PPV (47.5%), only half of the MPA patients were positive for both pANCA and MPO-ANCA. The low prevalence (13%) of ANCA positivity in CSS resulted in a low PPV (<5%). Considering patients with all types of AAV together, the detection of cANCA or pANCA indicated a sensitivity of 76%, a specificity of 94%, a PPV of 58% and an negative predictive value (NPV) of 97%. Combination with ELISA results improved specificity (99.6%) and PPV (95%), with loss of sensitivity (63%).

View this table: [in this window] [in a new window]   TABLE 2. Patients with AAV: sensitivity, specificity and PPV (all as percentages) for ANCA positivity by IFT alone or in combination with ELISA results for PR3 and MPO specificity

 

Comparison between patients with ANCA specific for PR3 and MPO
To define the clinical features of ANCA-positive patients with specificity for PR3 or MPO, irrespective of the diagnoses given and without selection for any particular organ manifestations, all patients with MPO-ANCA (n=40) were compared with a group of consecutive PR3-ANCA-positive patients (n=80). The PR3-ANCA group consisted of 77 WG patients, two patients with cryoglobulinaemic vasculitis and one patient with spondylarthropathy. The MPO-ANCA group summarized patients with primary vasculitides (80%) as well as other rheumatic diseases (Table 1).

Whereas the male and female genders were equally distributed in the PR3-ANCA group (38:42), the ratio was skewed towards the female gender in the MPO-ANCA group (13:27). Patients with MPO-ANCA had a lower disease extent (median DEI 5 vs 8; P<0.01), the upper (40 vs 78%; P<0.001, P_corr<0.01) and lower (18 vs 43%, P<0.01, P_corr=0.07) respiratory tract being less often involved than in PR3-ANCA-positive patients at the time of diagnosis (Fig. 2). Moreover, in the MPO-ANCA group, eye involvement (8 vs 36%; P<0.001, P_corr=0.01) and peripheral neuropathy (20 vs 38%, P=0.052) were seen less frequently. The combination of respiratory tract and renal involvement occurred less frequently in the MPO-ANCA group (25 vs 50%; P<0.01). Histopathological confirmation of vasculitis or necrotizing crescentic glomerulonephritis did not differ significantly overall between the MPO-ANCA and PR3-ANCA groups. True granulomas were seen in 8 and 9% of these patients respectively.

View larger version (31K): [in this window] [in a new window]   FIG. 2. Organ involvement in MPO-ANCA-positive (n=40) and PR3-ANCA-positive patients (n=80) at time of diagnosis. E, upper respiratory tract; L, lung; K, kidney; Ey, inflammatory eye involvement; A, rheumatological symptoms; S, skin; H, heart; P, peripheral nervous system; C, central nervous system; Gi, gastrointestinal tract; B, constitutional symptoms.

 
Considering MPO-/PR3-ANCA-positive patients with different forms of AAV, these differences remained similar. When comparing PR3-ANCA-positive WG (n=77) with MPO-ANCA-positive MPA (n=19) patients, the former exhibited a higher DEI (median 8 vs 5, P<0.02) and more frequent involvement of the upper respiratory tract (81 vs 32%, P<0.001, P_corr<0.01), lower respiratory tract (43 vs 11%, P<0.01) and the eyes (36 vs 11%, P<0.05), whereas the kidneys were more often affected in the latter group (58 vs 89%, P<0.05). In contrast, when comparing MPO-ANCA-positive WG (n=7) and MPA (n=19) patients, there was no difference in DEI. However, upper respiratory tract involvement was a hallmark of MPO-ANCA-positive WG (86 vs 32%, P<0.05), whereas the kidneys were more often affected in MPA (29 vs 89%, P<0.01).

Clinical aspects of WG patients with PR3- and MPO-ANCA specificity
Only seven pANCA/MPO-ANCA-positive WG patients were observed among the total of 384 WG patients. In contrast to the equal gender distribution in the whole WG group (195 males:191 females), female patients seemed to predominate in the MPO-ANCA group (2:5). To minimize bias due to different age and gender distributions, these seven patients were compared with sex- and age-matched PR3-ANCA-positive WG patients (n=21). At the time of diagnosis, MPO-ANCA-positive WG patients showed less organ involvement than PR3-ANCA-positive WG patients (median DEI 5 vs 8, P=0.07). There was no difference regarding the involvement of the upper respiratory tract (86 vs 95%) and lower respiratory tract (43 vs 33%). However, the kidneys (29 vs 52%), eyes (14 vs 38%) and peripheral nervous system (0 vs 48%, P<0.05) tended to be less often involved in MPO-ANCA-positive WG patients.

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

 
ANCA testing has been introduced world-wide over the last decade as a useful tool in the clinical work-up of patients with suspected systemic vasculitides. Previous studies have attempted to establish predictive values for ANCA testing; however, the wide ranges of specificity and sensitivity of both pANCA and cANCA reflect the highly selected patient populations studied. It was the aim of this study to summarize the experience of a decade of ANCA testing with standardized forms of both IFT and ELISA in a combined effort within the European Union [18] in a single university-based unit specializing in rheumatology and clinical immunology. However, the results reflect the particular patients who were referred to, evaluated and treated by university-based rheumatologists and clinical immunologists, and these patients may differ from those seen by other specialists.

During a 10-yr period, the detection of cANCA or pANCA by IFT resulted in an overall sensitivity of 76% and specificity of 94% for AAV; higher values were obtained for cANCA with PR3 as the main target antigen in WG, and to a lesser extent for pANCA with MPO as the main target antigen in MPA. These data confirm those described over the last decade [4, 8, 21–23]; however, the proportions of individuals with cANCA and pANCA among WG and MPA patients can vary depending on the clinical setting, the method of ANCA detection and the classification criteria used. In their meta-analysis of cANCA in WG, Rao et al. [6] reported a sensitivity of 66% and a specificity of 98%. In a recent study, pANCA and cANCA were observed in 65 and 10% of MPA patients respectively [22]. ANCA have been reported to occur in variable percentages of patients with CSS, and recently a proportion of up to 50% has been reported [24]. In our study, the lower number of ANCA-positive CSS patients may reflect either referral bias or other factors that have not yet been characterized, e.g. regional differences. Furthermore, pANCA can also be found in various other rheumatic disorders: they have been reported in up to 30% of patients with SLE or RA, and rarely in other connective tissue diseases (<5%), though usually without specificity for PR3 or MPO [25–27].

For the interpretation of test results, the expected disease prevalence in the population tested is a key variable in determining the usefulness of the test. As has been proposed by Rao et al. [6], cANCA testing for WG is most valuable where the prevalence of WG is 5–10%. In our study, in which the prevalence was 8%, the detection of cANCA resulted in a high PPV for WG (94%). However, the detection of cANCA and/or pANCA by IFT revealed a lower PPV for WG (52%) as well as for all forms of AAV together (58%). These values were considerably improved if IFT was combined with ELISA results. Therefore, as has been suggested in international consensus studies [8, 28], a combination of IFT and ELISA should be used to detect ANCA specific for PR3 and MPO.

Studies comparing patients with PR3- and MPO-ANCA are rare [9–12]. Furthermore, the specificity and sensitivity of ANCA detection may differ from centre to centre due to variation in the methods used [29]. In the present study, PR3- and MPO-ANCA-positive patients had different disease spectra. Whereas PR3-ANCA was highly specific for WG, the diagnoses of MPO-ANCA-positive patients were more diverse, including primary vasculitides and non-vasculitic disorders, e.g. RA and SLE.

MPO-ANCA-positive patients had fewer organs involved than those with PR3-ANCA; in particular, the upper and lower respiratory tract and the eyes were less often affected. The combination of respiratory tract and renal involvement occurred less frequently in the MPO-ANCA group. In this regard, the data we present confirm the findings of Franssen et al. [11, 12], who reported that PR3-ANCA-positive patients with various vasculitides had a higher vasculitis activity index, a higher number of affected organs (especially the upper respiratory tract, the nervous system and the eyes) than patients with MPO-ANCA. We extended these studies by analysing subgroups of patients with WG or MPA according to ANCA specificity.

WG and MPA are closely related in many respects, including clinical features, association with ANCA, and small-vessel involvement [1]. However, when analysing PR3- or MPO-ANCA-positive patients with these subtypes of AAV, there were substantial differences that allowed the subtypes to be distinguished: upper respiratory tract involvement was the hallmark for WG and kidney involvement that for MPA.

MPO-ANCA are found in fewer than 5% of WG patients [30]. In the present study, special attention was directed to this subgroup as it has not been analysed previously with regard to the clinical spectrum of vasculitis manifestations. We compared MPO-ANCA-positive WG patients with matched PR3-ANCA-positive WG patients. Although statistical analysis was difficult because of the small numbers of patients, MPO-ANCA-positive WG patients had a lower disease extent than the matched PR3-ANCA-positive patients. There was no difference regarding respiratory tract involvement, but the kidneys, eyes and the peripheral nervous system tended to be less often affected in MPO-ANCA-positive WG. Therefore, MPO-ANCA-positive WG patients seemed to resemble the MPO-ANCA group in terms of disease extent and their lower frequency of peripheral neuropathy and eye involvement, but were comparable to the PR3-ANCA group concerning respiratory tract involvement. Thus, apart from their diagnostic value, PR3- and MPO-ANCA seem to have a role in the pathophysiology of WG and MPA. Recently, PR3-ANCA have been found to be more potent in inducing the respiratory burst and degranulation of polymorphonuclear neutrophils than MPO-ANCA [31]. Nonetheless, certain clinical features (e.g. respiratory tract involvement) clearly differ between WG and MPA, even when the ANCA specificity is found to be the same in patient subgroups in both vasculitides, i.e. MPO-ANCA-positive WG and MPA.

In conclusion, we confirm the high sensitivity and specificity of ANCA for AAV, especially of cANCA/PR3-ANCA for WG, and to a lesser extent of pANCA/MPO-ANCA for MPA. However, diagnoses in pANCA/MPO-ANCA-positive patients are more diverse, and thus the immunodiagnostic value of these autoantibodies depends on the pretest situation much more than with cANCA/PR3-ANCA.

The PR3- and MPO-ANCA-positive patients diverged in their disease spectrum and the extent of organ involvement, with a higher DEI and extrarenal manifestations in the PR3-ANCA group. Furthermore, the detection of MPO-ANCA was a rare finding in WG and was associated with less organ involvement. Subanalysis indicated that MPO-ANCA-positive WG patients shared some features with both PR3-ANCA-positive WG and MPO-ANCA-positive patients. This supports the idea of a close relationship between disease entities characterized by the presence of ANCA. However, the differences observed make it possible to distinguish among subgroups, even between PR3-ANCA-positive WG and MPO-ANCA-positive WG, and might therefore reflect the involvement of different pathogenic mechanisms in different subtypes of ANCA. This appears to us to be of great importance, as in many controlled trials patients with different forms of AAV will be compared regardless of ANCA subspecificity.

	Notes

 
Correspondence to: E. Csernok, Rheumaklinik Bad Bramstedt, D-4572 Bad Bramstedt, Germany

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Submitted 15 December 1999; Accepted 2 September 2000

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