Malignancy is increased in ANCA-associated vasculitis

T. Pankhurst, C. O. S. Savage, C. Gordon1 and L. Harper

Division of Medical Sciences and 1 Division of Immunology and Infection, The Medical School, University of Birmingham, Birmingham, UK.

Correspondence to: L. Harper. E-mail: l.harper{at}bham.ac.uk


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objective. In the light of previous reports of an association between malignancy and renal vasculitis, we aimed to investigate the association of malignancy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, either Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA), and compare it with the general population and disease control groups comprising patients with systemic lupus erythematosus (SLE) or Henoch–Schönlein purpura (HSP).

Methods. A retrospective review of 200 consecutive patients with WG or MPA was performed. Malignancies preceding or concurrent with vasculitis were recorded and the incidence of malignancy was compared with those in a population of 129 patients with HSP, 333 patients with SLE and a normal population in the West Midlands of the UK.

Results. Twenty patients had a diagnosis of malignancy, 14 had MPA and six had WG. Patients with ANCA-associated vasculitis had an increased risk of malignancy compared with HSP patients, of whom six patients had malignancy (relative risk 0.85, confidence interval 0.69–1.05; P = 0.034), or SLE patients, of whom five patients had malignancy (relative risk 0.31, 95% confidence interval 0.14–0.7; P<0.0001). The rate of malignancy compared with an age-matched control group was increased in patients with ANCA-associated vasculitis and HSP (ANCA-associated vasculitis, relative risk 6.02, 95% confidence interval 3.72–9.74; HSP, relative risk 5.25, 95% confidence interval 2.4–11.5). The presence of ANCA was not predictive of malignancy.

Conclusion. In conclusion, patients with ANCA-associated vasculitis have an increased risk of preceding or concurrent malignancy.

KEY WORDS: Vasculitis, Renal, Malignancy, Cancer, Wegener's granulomatosis, Henoch–Schönlein purpura


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Malignancy may present initially with an acute vasculitis. Five per cent of patients with vasculitis have a related malignancy, which may not be clinically obvious at presentation [1]. The most common form of vasculitis is a cutaneous leucocytoclastic vasculitis associated with haematological malignancy [2–6]. However, reports suggest that vasculitis involving the kidney may be linked to malignancy [4, 7–11]. Renal carcinoma has been associated with Wegener's granulomatosis (WG) and may precipitate the onset of WG [10]. There are further case reports and a small series suggesting a link between malignancy and Henoch–Schönlein purpura (HSP) [6, 12–17]. Most of these reports link HSP with solid organ tumours, but haematological malignancy has also been reported. Interestingly, other rheumatological conditions associated with vasculitis have also been linked with malignancy, including rheumatoid arthritis with an increased risk of lymphoma [18].

The pathogenic link between malignancy and vasculitis is unclear; suggestions include a common genetic susceptibility, chronic stimulation of the immune system and the generation of autoantibodies against various autoantigens [19]. We wished to confirm the increased rate of malignancy in WG and assess whether this increased rate was also present in patients with microscopic polyangiitis (MPA), another autoimmune vasculitis characterized by antineutrophil cytoplasmic antibodies (ANCA). We aimed to compare these diseases with HSP, an immune complex vasculitis, and postulated that the malignant associations would differ as these vasculitides differ in their pathogenesis. We also compared the rates of malignancy with the rates for a cohort of patients with systemic lupus erythematosus (SLE), an autoimmune condition, and a normal control population.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The records of 200 consecutive patients with ANCA-associated vasculitis (78 patients with WG and 122 patients with MPA) and 129 consecutive patients with HSP diagnosed between 1982 and 2002 were reviewed retrospectively. All patients had focal necrotizing glomerulonephritis comprising either pauci-immune ANCA-associated vasculitis or Henoch–Schönlein vasculitis associated with immunoglobulin A. Frequencies and types of malignancies occurring before or concurrent with the diagnosis of small vessel vasculitis were recorded as retrieved from the medical notes. All patients fulfilled the Chapel Hill Consensus Conference definitions of each type of vasculitis [20]. Vasculitis diagnosed within 6 months of malignancy was recorded as concurrent disease. Malignancy diagnosed more than 6 months after the diagnosis of vasculitis was excluded because of the possibility of immunosuppression-induced malignancy.

Comparison of the incidence of neoplastic disease in patients was compared with a control group of 333 consecutive patients with systemic lupus erythematosus (SLE) collected prospectively over a 10-yr period between 1991 and 2000. All patients diagnosed with SLE fulfilled 4 of 11 ARA criteria [21]. In addition, the patients were also compared with an age- and gender-matched population from the West Midlands UK Cancer Registry (excluding non-melanoma cutaneous neoplasms).

Demographic details were collected for all patients (Table 1). Type of malignancy, time of diagnosis, and treatment of both malignancy and vasculitis or SLE was recorded (Table 2). ANCA serology was recorded where available. Patients with ANCA-associated vasculitis and HSP were compared. Both groups of patients were compared with the SLE cohort and with the general population of the West Midlands. Data were analysed using Fisher's exact test.


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TABLE 1. Demographics of study groups

 

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TABLE 2. Types of vasculitis in patients with malignancy, treatment, ANCA serology, and months between malignancy and diagnosis of vasculitis

 

    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
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Twenty patients with ANCA-associated vasculitis were found to have histologically confirmed malignant disease; six patients with WG and 14 patients with MPA. Six patients with HSP had malignancy. There was an increase in the relative risk (RR) of malignancy with ANCA-associated vasculitis compared with HSP [RR 0.85, confidence interval (CI) 0.69–1.05; P = 0.034]. There was no difference in age between those presenting with or without malignancy with ANCA-associated vasculitis. Five patients with SLE had a diagnosis of malignancy. Patients with ANCA-associated vasculitis had a slightly increased risk of malignancy compared with SLE patients (RR 0.31, CI 0.14–0.7; P<0.0001).

The mean age at diagnosis of all ANCA-associated vasculitis was 66.5 ± 19.5 yr, but all patients with HSP were significantly younger (mean age 48 ± 20 yr, P<0.001). Patients with HSP with malignancy were older (mean age 63.3 ± 11 yr) than those without (48 ± 20 yr), although this was not statistically significant (P = 0.065). The patients with SLE were significantly younger (31.3 ± 8 yr) than both patients with HSP (P<0.001) and ANCA-associated vasculitis (P<0.001). There was no increased risk of malignancy in HSP patients compared with SLE patients (RR 0.63, CI 0.32–1.1; P = 0.08).

When compared with an age-matched control group from the West Midlands, the rate of malignancy in those patients with any small vessel vasculitis was significantly increased (RR 7.55, 95% CI 5.01–11.36). The increased rate of malignancy was present in both groups (HSP, RR 5.25, 95% CI 2.40–11.50; ANCA-associated vasculitis, RR 6.02, 95% CI 3.72–9.74) when compared with the normal control population.

Six patients had a diagnosis of ANCA-associated vasculitis and malignancy made concurrently. Fourteen patients presented with malignancy predating vasculitis (median duration 96 months, range 12–516 months). There was no difference in those patients developing malignancy and ANCA-associated vasculitis concurrently compared with concurrent diagnoses in those with HSP or SLE (in ANCA-associated vasculitis 6 of 20, in HSP 2 of 6, and in SLE 2 of 5 were concurrent). In patients in whom malignancy predated vasculitis, there was no evidence of subsequent relapse of the malignancy following development of ANCA-associated vasculitis. Three patients with MPA had relapse of their vasculitis 1, 10 and 43 yr after the first diagnosis of malignancy.

The most common malignancy was colon cancer, presenting in two patients with HSP and three patients with MPA. No patients with WG had colon cancer. In our series, there was only one patient with renal cell carcinoma, which was associated with MPA. Three patients with HSP, all smokers, had lung cancer. Two patients with SLE had breast cancer.

ANCA serology was available in 17 of the 20 patients diagnosed as having WG or MPA associated with malignancy and in 169 patients with WG or MPA without malignancy. Four patients with malignancy and 17 without malignancy were ANCA-negative. ANCA serology was not predictive of malignancy in patients with WG or MPA (P = 0.15).

The mean follow-up of all vasculitis patients was 59.4 months (2–185 months). Two of the six patients with HSP were dead at the time of review, aged 60 and 70 yr, respectively; one died of malignancy and the other of sepsis. Ten of the 20 patients with ANCA-associated vasculitis were known to be dead at the time of review; the mean age of death in this group was 71.5 yr (range 57–86 yr). In the ANCA-associated vasculitis group, of those who died, three had concurrent disease and four had malignancy that preceded vasculitis. In the HSP group, malignancy had preceded the vasculitis in both patients.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this analysis, we have confirmed the increased association of malignancy with renal vasculitis. This study presents new information that malignancy is increased in MPA as well as WG compared with the normal population, and that the RR is greater than in other diseases associated with vasculitis, including HSP and SLE. Patients with HSP have an increased risk of malignancy compared with the normal population but not compared with SLE. Due to the small numbers of patients with malignancy, we could determine no differences in the type of malignancy associated with vasculitis. We also confirm previous reports of an association of solid organ malignancy with ANCA-associated vasculitis but have not reproduced the previously reported association with renal cancer [10]; however, our numbers are small.

This study fails to confirm an increased risk of malignancy in HSP patients, as previously suggested [16] when using a disease control group. A larger study is required to confirm these results. However, it confirms previous smaller reports, when malignancy in association with HSP does occur solid organ tumours are more common than haematological malignancy [16]. Patients with HSP and malignancy in this study had a tendency to be older than HSP patients without malignancy, although this did not reach statistical significance, reflecting the published literature [16]. It is unclear from this study, due to the small numbers, if elderly patients presenting with HSP have an exaggerated risk of malignancy; larger epidemiological studies are required. However, HSP is commonly a disease of the young and it would be wise to consider malignancy in those presenting in later life.

The use of patients with SLE as a control group may be criticized, as these patients were significantly younger than patients with HSP and those with ANCA-associated vasculitis. However, the increased risk of malignancy in patients with ANCA-associated vasculitis was confirmed using an age- and gender-matched control population from the West Midlands.

Malignancy may trigger vasculitis [10]. However, in patients with ANCA-associated vasculitis, there were no differences in presentation between patients with and without malignancy; specifically, the absence of ANCA was not predictive of malignancy. This report provides additional support for the association of ANCA-associated vasculitis with malignancy, but does not provide information as to the pathogenesis.

In conclusion, this study supports previous evidence that malignancy is associated with ANCA-associated vasculitis and suggests that malignancy should be considered as part of the differential diagnosis in patients presenting with ANCA-associated vasculitis.


    Acknowledgments
 
We would like to acknowledge the support of Lupus UK for the lupus cohort, and Stephanie Heaton, Veronica Toescu and Dr M. H. Leung for collecting and analysing data on SLE patients. We thank Dr Ball for helpful review of the manuscript.

The authors have declared no conflicts of interest.


    References
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Submitted 18 February 2004; revised version accepted 13 July 2004.