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 Table of Contents  
Year : 2018  |  Volume : 13  |  Issue : 2  |  Page : 95-100

Anti-neutrophil cytoplasmic autoantibodies associated vasculitis – Clinical profile and outcomes

Department of Rheumatology, Nizam's Institute of Medical Sciences, Hyderabad, Telangana, India

Date of Web Publication24-May-2018

Correspondence Address:
Dr. Liza Rajasekhar
Deparment of Rheumatology, Millinium Block, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad - 500 082, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_80_17

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Background: Studies on antineutrophil cytoplasmic autoantibodies-associated vasculitis (AAV) from India are scarce. The aim of the present study was to characterize the profile of AAV and experience with rituximab in ocular granulomatous with polyangiitis (GPA) in our cohort.
Methods: Clinical, laboratory, and treatment details of AAV from January 2010 to May 2017 were noted. Continuous variables were reported as mean and standard deviation (SD). In GPA, clinical variables between survivors and nonsurvivors were compared using independent sample t-test and Fisher's exact test. Cox regression analysis was done to estimate the hazard ratios. Our cohort of GPA was compared with other large single-center cohorts from India, USA, Germany, and France.
Results: Thirty-one patients were diagnosed to have AAV. Seventeen were females. GPA was most common phenotype (23/31). Mean (SD) age at onset was 39.8 (15.7) years. Median (IQ) time to diagnosis was 6 (22) months. The most common manifestations in GPA were ocular (n = 20) and lower respiratory tract (n = 13). Mean (SD) Birmingham Vasculitis Activity Score (BVAS) at disease onset was 9.4 (6.9). Pulse methylprednisolone with cyclophosphamide was used as induction regime followed by maintenance with azathioprine. Rituximab was given to four patients with refractory GPA. Six patients succumbed to illness. Remission was achieved in 19/25 survivors. Mean (SD) BVAS at disease onset was significantly higher in nonsurvivors (17.6 ± 10.2) compared to survivors (9.4 ± 4.9) (P = 0.018). Higher proportion of renal involvement was seen in nonsurvivors (P = 0.03). There was three-fold increased mortality with renal and lung involvement. In addition, the risk of death increases by 1.13 fold with each point increase in BVAS score.
Conclusion: Ocular involvement was higher in our GPA cohort. Baseline BVAS, renal, and lung involvement predicts poor prognosis in GPA. Sustained remission with rituximab was seen in all patients with refractory ocular disease.

Keywords: Antineutrophil cytoplasmic autoantibodies, Birmingham Vasculitis Activity Score, granulomatous polyangiitis, rituximab

How to cite this article:
Nunna KD, Devarasetti PK, Prasad Irlapati RV, Rajasekhar L. Anti-neutrophil cytoplasmic autoantibodies associated vasculitis – Clinical profile and outcomes. Indian J Rheumatol 2018;13:95-100

How to cite this URL:
Nunna KD, Devarasetti PK, Prasad Irlapati RV, Rajasekhar L. Anti-neutrophil cytoplasmic autoantibodies associated vasculitis – Clinical profile and outcomes. Indian J Rheumatol [serial online] 2018 [cited 2022 Dec 5];13:95-100. Available from:

  Introduction Top

Antineutrophil cytoplasmic autoantibodies-associated vasculitis (AAV) is a systemic necrotizing granulomatous inflammation predominantly involving small vessels. It includes granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA). They are characterized by their paucimmune nature, presence of necrotizing vasculitis and/or granulomas, and variable presence of circulating antibodies to myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). Ocular involvement in AAV is caused by both granulomatous inflammation (orbital pseudo tumor) and small vessel vasculitis. Ocular manifestations range from conjunctivitis, episcleritis, and nasolacrimal duct obstruction to vision-threatening scleritis, uveitis, retinal vasculitis, and optic neuropathy. Remission induction with high-dose steroids and cyclophosphamide (CYC) has significantly reduced 5 years mortality to 25%.[1] Relapse rates remain significantly high at 30%–50% over 5 years and relapses were more likely in GPA, PR3 ANCA specificity, presence of ear, nose, and throat involvement, and persistent ANCA positivity after induction therapy.[2] Rituximab (RTX) is increasingly being used for induction and maintenance regimes, and it was successful in achieving remission in both ocular granulomatous and vasculitic disease.[3] Studies on AAV from India are limited.[4],[5],[6]

The aim of the present study was to characterize the clinical profile, laboratory parameters, and management and outcome details in AAV. We also analyzed the factors associated with mortality in GPA, the largest group of AAV in our cohort.

  Methods Top

This was an observational, retrospective cohort study conducted from the Department of Rheumatology, Nizam's Institute of Medical Sciences. We searched the electronic medical record database of our department between January 2010 and May 2017 for search terms such as AAV, GPA, Wegener's granulomatosis, EGPA, Churg-Strauss syndrome, MPA, and small vessel vasculitis. Records were classified according to European Medicines Agency algorithm,[7] Chapel Hill Consensus Conference 2012[8] and modified ACR [9] into GPA, EGPA, and MPA.

Complete demographic data, clinical features, and imaging details of these patients were noted. ANCAs testing done by indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) to anti Proteinase 3 (PR3) and myeloperoxidase (MPO) were noted. European Vasculitis Society (EUVAS) disease staging [10] was done for GPA records. Birmingham Vasculitis Activity Score version-3 (BVAS-v3)[11] was used as disease activity measure at onset of disease, before initiating induction regime and after completion of induction. Response criteria as per EULAR recommendations [10] were used to define the outcome. Remission was defined as BVAS of zero. Sustained remission was defined as remission for more than 6 months with or without maintenance immunosuppression.

Baseline characteristics were presented as mean and standard deviation (SD). GPA patients were divided into two groups: survivors and nonsurvivors. The demographic data, clinical, laboratory variables, and disease activity (BVAS-v3) at baseline were compared between the two groups.

Statistical analysis

Continuous variables were compared using independent sample t-test and categorical variables using Fisher's exact test. Cox regression analysis was done to estimate the hazard ratios of clinical variables on survival in GPA. P < 0.05 was considered statistically significant. Statistical analysis was done using SPSS software (version 21.0, IBM).

Ethical approval

The study was approved by the ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.

  Results Top

Thirty-one patients with AAV were included in the study. Demographic and clinical parameters are summarized in [Table 1]. Median time (IQR) to diagnose disease was 6 (22) months. Most common AAV subset in our cohort was generalized GPA. Ocular involvement was the most common clinical manifestation observed in GPA (20/23) followed by lung (13/23). None of our patients had granulomatous orbital disease. Diffuse alveolar hemorrhage (DAH) occurred in 8 GPA and 1 EGPA patient. In EGPA patients, lung involvement was most common feature (5/6). Two patients in EGPA had rare renal manifestations, one had interstitial nephritis and the other membranous nephropathy with nephrotic syndrome.
Table 1: Demographic and clinical features of autoantibodies associated vasculitis patients

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Details of ANCA testing, imaging, and histopathology were shown in [Table 2]. On computed tomography chest, pulmonary nodules were the most common finding. Pauci-immune glomerulonephritis was present in six out of eight biopsies done with four having associated crescentic glomerulonephritis. Granulomas were seen in nasal, conjunctival, and lung biopsies. Three out of six EGPA had tissue eosinophilia demonstrated in skin, nerve, muscle and bone marrow biopsies.
Table 2: Laboratory, histopathology, and imaging details of autoantibodies associated vasculitis patients

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Treatment details and outcomes of GPA were shown in [Table 3]. Methotrexate was started at a dosage of 15 mg/week and increased to 25 mg/week as per requirement. One patient of early systemic GPA diagnosed before 2000 received oral cyclophosphamide (CYC) 50mg/day for induction for 5 years. Intravenous (IV) CYC was used at a dose of 0.75–1 g/m 2. After 2010, patients received CYC according to the EUVAS protocol ( first three doses of CYC two weeks apart and then next four doses 3 weeks apart). Seven GPA patients had disease refractory to 12 weeks of IV CYC use. Of these, three received rituximab (RTX); two patients died (one due to DAH with vasculitic ulcers and other to meningitis with ear discharge). RTX (for refractory scleritis and nephritis each) was planned in two others. Totally, five patients received RTX as induction agent (1 g 2 doses fortnightly) in our cohort. Patients received RTX for refractory scleritis (three patients), one for relapsing scleritis and lung cavities and one for active generalized disease in pregnancy as a first-line induction agent. Mean (SD) time to start RTX after onset of ocular disease was 5.1 (3.1) months. Mean (SD) time spent in remission in RTX group was 13.8 (11.3) months. Repeat dosing of RTX to maintain remission was used in two patients at 11 months (B cell reconstituted, and ANCA was negative) and 10 months (C-ANCA was positive, B cells could not be done) after initial dose. Remission was maintained in two other GPA patients for 23 months and 39 months after first RTX infusion. Most common maintenance regime in GPA was azathioprine-2 mg/kg/day (n = 9) followed by mycophenolate-2 gm/day (n = 3). All patients who received IV CYC and RTX were given three doses of pulse methylprednisolone. Data on cumulative steroid dose was unavailable. In seven patients, we were able to stop steroids and maintain steroid free state for 30.4 (11.2) months. All these seven patients had generalized GPA.
Table 3: Treatment details and outcome of granulomatous with polyangiitis patients

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Drug-related adverse events included recurrent MTX transaminitis in one patient with limited GPA, azathioprine-related pancytopenia in one EGPA patient with intermediate activity of thiopurine methyltransferase enzyme. No infusion reactions to CYC or RTX were noted. Glioblastoma multiforme occurred after 8.3 years of disease onset in one GPA patient who received 7g of CYC.

Remission was achieved in 19 of 31 patients. All EGPA patients achieved disease remission. One was lost to follow-up. Death occurred in six patients (five GPA and one MPA). Three deaths were attributed to disease activity, one to sepsis, and one to a combination of sepsis and disease activity and one to coronary artery disease. Relapses were seen in 19 (19/31) patients (16 GPA and 3 EGPA). Twenty-one major and 22 minor relapses were noted over mean (SD) follow-up of 42.2 (44.6) months. Thirteen GPA patients had major relapses, eight of which were nonocular.

In GPA, clinical variables such as age at onset, time to diagnosis of AAV, clinical manifestations, BVAS at disease onset and before induction were compared between survivors and nonsurvivors. Mean BVAS before induction was significantly higher in nonsurvivors compared to survivors (P = 0.018) whereas no significant difference was found for age at onset and time to diagnosis. Higher proportion of renal involvement was seen in nonsurvivors (P = 0.03).

Cox regression analysis showed higher three-fold increased mortality with renal and lung involvement in GPA. In addition, with each point increase in BVAS score, there was 1.13 fold increase in mortality and these estimates were statistically significant.

  Discussion Top

The present study was a large retrospective case series from South India describing the demographics, clinical details, and outcomes of patients with AAV. To the best of our knowledge, only three clinical studies exist on AAV from India.[4],[5],[6]

Details of comparison with other GPA cohorts are detailed in [Table 4]. Consistent with other Indian studies,[4],[5],[6] age of onset of GPA in our cohort is a decade earlier compared to Europe and German cohorts.[9],[12] There was equal representation of both genders unlike male predominance seen in European and USA cohorts.[9],[12] Has it been defined earlier, the frequency of URT involvement was consistent with other Indian cohorts [4],[5],[6] and less than Western GPA cohorts.[9],[13] Western cohorts have more frequent renal involvement. This could be due to a referral bias of patients with nephritis to the nephrology unit at our institution. Lower frequency of renal involvement has also been reported in other Indian cohorts.[4],[5],[6] Ocular involvement was more frequent in our cohort compared to other Indian [3],[4],[5],[6] and Western cohorts.[9],[13] This again reflects a referral bias since our institution receives a lot of referrals for autoimmune ocular disease.
Table 4: Comparison of present with other granulomatous with polyangiitis cohorts

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In a study comparing ANCA testing by ELISA and IIF, diagnostic performance of PR3-ANCA and MPO-ANCA by immunoassays was better than IIF in discriminating AAV from disease controls.[14] In our cohort, there was 100% concordance for C-ANCA and P-ANCA patterns by IIF with its antigens PR3 and MPO respectively on ELISA.

Relapse rates were higher in our cohort (70%) compared to other Indian (26%,[6] 53%,[2] 31%[5]) and Western cohorts (47%,[12] 35%[13]). But when nonocular flares were considered, relapse rate falls to 35% which was comparable to other cohorts. The reason for higher relapses in our cohort could be more number of refractory GPA with ocular flares.

In our cohort, RTX was used in five ocular scleritis patients, and all achieved remission. This was consistent with other studies reported in literature on the efficacy of RTX in vasculitic manifestations.[3],[15] Joshi et al. reported equal efficacy of RTX in both granulomatous and vasculitic manifestations involving eye in 31 GPA patients followed for 2 years.[3] This was supported by another study done by Lindsay Lally et al. in 99 patients of otolaryngologic GPA where patients being treated with RTX were 11 times less likely to have active ENT disease than patients being treated with other therapies.[16] Holle et al. reported the excellent response of RTX in refractory vasculitic manifestations compared to granulomatous disease.[15] However, their outcomes were measured at 4 months only and longer periods of follow-up in former mentioned cohorts allow to observe for the maximal benefit of RTX. The use of RTX as induction agent in one of our generalized GPA patient (since CYC was contraindicated due to pregnancy) has also resulted in long-lasting remission (10 months).

In the study by Sharma et al.,[5] renal and gastrointestinal tract involvement was associated with poor outcome whereas Reinhold-Keller et al. study showed more than threefold mortality with age >50 years age at onset, renal, and lung involvement in GPA. In the present study, renal involvement and baseline BVAS were associated with poor outcome. In addition, renal and lung involvement were associated with three-fold mortality.

Increased risk of malignancy in AAV compared to generalized population has been reported with increased incidence of nonmelanoma skin cancers, bladder cancer, and myeloid leukemia observed with exposure to cumulative CYC dose of more than 36 g [17] whereas the use of RTX has been reported to decrease the malignancy risk.[18] The risk of malignancy continues to increase even after ≥20 years of disease onset.[17] Five brain malignancies among 1065 GPA patients followed for 25 years have been reported.[19] In Indian cohorts [4],[5] including ours which have a follow-up duration of <5 years we are reporting the only malignancy (glioblastoma) at a cumulative CYC dose of seven grams.

The limitations of this study are its retrospective design leading to missing data on renal limited GPA, cumulative steroid dose, minor infections during the course of disease, minor adverse reactions related to drugs used. In addition, damage assessment could not be captured adequately.

In this cohort of Indian patients with AAV, GPA occurred earlier with less frequent upper respiratory and renal but high frequency of ocular involvement. Baseline BVAS, renal and lung involvement were associated with poor prognosis. Sustained remission was achieved in all who received rituximab.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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Joshi L, Tanna A, McAdoo SP, Medjeral-Thomas N, Taylor SR, Sandhu G, et al. Long-term outcomes of rituximab therapy in ocular granulomatosis with polyangiitis: Impact on localized and nonlocalized disease. Ophthalmology 2015;122:1262-8.  Back to cited text no. 3
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Holle JU, Gross WL, Latza U, Nölle B, Ambrosch P, Heller M, et al. Improved outcome in 445 patients with wegener's granulomatosis in a German vasculitis center over four decades. Arthritis Rheum 2011;63:257-66.  Back to cited text no. 13
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  [Table 1], [Table 2], [Table 3], [Table 4]

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1 Azathioprine/cyclophosphamide/methotrexate
Reactions Weekly. 2018; 1708(1): 68
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