|Ahead of print publication
Granulomatosis with polyangiitis: Experience of 42 patients from a single-center, tertiary care hospital in Mumbai
Sunilkumar Rajmani Singh, Jyotsna Oak, Mahin Salim Olickal
Department of Rheumatology, Kokilaben Dhirubhai Ambani Hospital, Mumbai, Maharashtra, India
|Date of Submission||05-Jul-2020|
|Date of Acceptance||02-Oct-2020|
Sunilkumar Rajmani Singh,
Department of Rheumatology, Kokilaben Dhirubhai Ambani Hospital, Four Bungalows, Achutrao Patwardhan Marg, Andheri West, Mumbai - 400 053, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: There is a paucity of data on granulomatosis with polyangiitis (GPA) from western India. The present study describes the clinical manifestations, treatment, and outcome of 42 patients from a single-center, tertiary care hospital in Mumbai.
Methods: This is a retrospective observational study. From our database, patients with a diagnosis of GPA over a 10-year period (January 2010 to December 2019) were included in the study. Clinical manifestations, laboratory features, Birmingham Vasculitis Activity Score (BVAS-v3), treatment, and outcomes were analyzed.
Results: Forty-two patients with GPA were identified. The median age was 48.5 years with an equal number (n = 21) of males and females. Localized, early systemic, generalized, severe, and refractory disease was seen in 4, 11, 15, 8, and 4 patients, respectively. Pulmonary manifestations (n = 27) were most common at presentation followed by renal (n = 21) and ear, nose, and throat (ENT) (n = 20). Ocular and articular disease was seen in 11 patients each. Cutaneous (n = 8) and nervous system (n = 6) involvement was less common. Unusual manifestations included suburethral mass, prostatitis, and pancreatitis. The median BVAS v3 was 14.5. Rituximab was used in 12 patients and achieved remission in 9 patients. The median duration of follow-up was 36 months. Three patients expired. Relapse of disease occurred in 17 patients. Ten patients had episodes of severe infection. No malignancy was observed.
Conclusion: GPA in western India has a similar clinical profile to other parts of the country. Pulmonary, ENT, and renal involvement is common. Relapse rates are high. Rituximab is an effective therapy for severe, relapsing, or refractory disease.
Keywords: Birmingham vasculitis activity score, granulomatosis with polyangiitis, relapse, rituximab, western India
| Introduction|| |
Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody (ANCA) associated small-vessel vasculitis (AAV) that dominantly affects the respiratory tract and the kidneys, although any system can be involved., The disease can manifest with varying degrees of severity from limited organ involvement to life-threatening disease.,
GPA has been reported from India by various centers, but there are limited data available from western India. Literature from different parts of the country suggests that patients present at a younger age with a mean age of 40 years and females are dominantly affected.,,,,,,, Clinical manifestations such as arthritis, renal, and peripheral nerve involvement are less common as compared to the western cohorts. In contrast to certain Asian countries like China and Japan, the majority of Indian patients have proteinase 3 (PR3) antibody positivity.
Treatment of GPA is guided by the severity of clinical presentation. Patients with severe GPA mostly receive steroids and cyclophosphamide, achieving remission rates of 70%–80%. Relapses are common and seen in about 50% of cases. The introduction of rituximab has further improved the outcome, particularly in refractory and relapsing disease.,
Given the geographic variations in manifestations, it is important to study the spectrum of the disease in various parts of India. This may help in making early diagnosis and institute prompt treatment. There is a paucity of data on GPA from the western part of India. We aim to add to the evolving knowledge of GPA in India and share our experience of 42 patients from a single, tertiary care, private health-care center.
| Methods|| |
This was a retrospective observational study. From our database, all adult patients fulfilling at least two of the four modified American College of Rheumatology criteria for the classification of GPA between January 2010 and December 2019 were included in this study. We also included all patients with clinical features of GPA and ANCA positivity or histopathological evidence of vasculitis after carefully excluding other systemic vasculitides.
The duration of illness based on the first symptom related to GPA, demographic data, clinical manifestations, organ involvement, and disease activity at baseline were recorded. Laboratory data included complete blood count, erythrocyte sedimentation rate, C-reactive protein, serum creatinine, routine urinalysis and microscopy, and 24-h urine protein. ANCA testing was done by indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) to anti PR3 and myeloperoxidase (MPO). Histopathological details of the relevant tissue were recorded. GPA was classified into localized, early systemic, generalized, severe, and refractory categories as per the European Vasculitis Study Group (EUVAS) definitions. Disease activity was scored according to the Birmingham Vasculitis Activity Score (BVAS v. 3). Permanent organ damage was scored by the Vasculitis Damage Index (VDI). Remission was defined according to the British Society for Rheumatology guidelines. Relapse was defined as a disease that has been previously well controlled with or without drugs and has become active.
The different therapeutic options used for induction and maintenance of disease were recorded. The choice of therapy was based on the extent and severity of the manifestations. Methotrexate (15–25 mg/week) was used in most patients with nonorgan threatening disease, while cyclophosphamide was used for induction in organ or life-threatening disease. Cyclophosphamide was used either intravenously at 15 mg/kg, 3–4 weekly or per oral (2 mg/kg/d) for 3–6 months. Rituximab 500 mg weekly (2–4 doses) was used in severe, refractory, or relapsing disease. Azathioprine (2 mg/kg/day) and mycophenolate mofetil (MMF) at 1–2 g/day were used for maintenance of remission. All patients received steroids (intravenous pulse methylprednisolone or prednisolone [0.5–1 mg/kg/day]) at the onset of treatment with gradual tapering. Treatment outcomes and follow-up data were analyzed.
Continuous variables were summarized as medians with interquartile range (IQR) and categorical variables were summarized as proportions or percentages. Data were analyzed using SPSS software for Windows (version 25, 2007, IBM Corporation, Armonk, New York, United States). Cross tabulations were computed for categorical data and compared using Chi-square test. Normality of continuous data was assessed using Shapiro–Wilk test. As the data were not normally distributed, the difference in data of remission and relapse group was analyzed using Mann–Whitney U-test. P < 0.05 was considered to be statistically significant.
| Results|| |
Demographics and clinical manifestations
Forty-two patients with GPA were identified. The median (IQR) age was 48.5 (16.5) years with an equal number (n = 21) of males and females. The median time to diagnosis from onset of symptoms was 3.5 (IQR 4) months. The different subtypes of GPA as per the EUVAS included localized (4), early systemic (11), generalized (15), severe (8), and refractory (4).
Various organs' involvement at presentation is shown in [Figure 1]. Pulmonary involvement was most common at presentation, followed by renal, ear, nose, and throat (ENT), eye, joints, skin, and nervous system in that order. Abdominal and cardiac involvement was uncommon. [Table 1] shows the spectrum of manifestations at presentation and during the course of the disease. Computerized tomography (CT) of the chest showed cavitary lesions (n = 9) and nodules (n = 8) in most patients with lung involvement. Pleural effusions were seen in only two patients along with other manifestations, while alveolar hemorrhage was found in four patients. Simultaneous upper and lower respiratory tract involvement was seen in 12 (29%) patients. Coexistent pulmonary and renal involvement was seen in 17 (40.5%) patients, while coexistent ENT and renal manifestations were seen in 6 (14%) patients. Among the ENT manifestations, sinusitis (n = 13) was most common, followed by subglottic stenosis.
|Figure 1: Organ involvement at presentation among 42 patients of granulomatosis with polyangiitis (in terms of percentage). ENT: Ear, nose, and throat|
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|Table 1: Manifestations of various systems' involvement in our patients with granulomatosis with polyangiitis (n=42)|
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There were five patients with subglottic stenosis (four females and one male), of which four manifested with stridor. Four patients needed tracheostomy with microlaryngoscopic dilatation over and above aggressive immunosuppressive therapy with cyclophosphamide in three patients and rituximab in one patient.
Hematuria (n = 14) was the most common renal manifestation. Rapidly progressive glomerulonephritis was seen in five patients. Three patients developed end-stage renal disease (ESRD). Unusual manifestations included vaginal vault suburethral mass, prostatitis, and pancreatitis. One of our patients had prostatitis as the presenting manifestation with prostate biopsy revealing nonnecrotizing granulomas. Vaginal vault suburethral mass as the initial presentation was a diagnostic and therapeutic challenge for one of our patients. Both these patients responded well to steroids and cyclophosphamide. We had two patients with pancreatitis. Both these patients had pancreatitis along with other manifestations at the onset of the disease itself and responded to steroids and cyclophosphamide.
All patients were tested for ANCA by either IIF or ELISA or both. Testing for ANCA by IIF and ELISA was performed in 35 and 34 patients, respectively. All 42 patients were ANCA positive by either IIF or ELISA or both. Thirty-four patients (97%) were positive for cytoplasmic ANCA (c-ANCA) and only one patient had perinuclear ANCA positivity. Anti-PR3 antibodies on ELISA were present in 30 patients (88%), anti-MPO antibodies were present in two patients, and two patients were ANCA negative by ELISA. Twenty-three patients had both c-ANCA and anti-PR3 antibodies positive. Two patients with c-ANCA positive were negative for anti-PR3 antibodies. One patient was c-ANCA positive but had anti-MPO antibodies on ELISA. Seven patients were tested for ANCA by ELISA alone and all were anti-PR3 antibody positive.
Histopathology diagnosis was established in 18 patients. Paranasal sinus tissue biopsy was obtained in seven patients. Five patients had granulomatous inflammation, while necrotizing inflammation was seen in two patients. Three patients had a CT-guided biopsy of pulmonary mass, while two had bronchoscopy biopsy of lesions in the airway. Necrotizing inflammation was seen in all these patients. Renal biopsy was done in four patients. Crescentic glomerulonephritis was seen in all these patients. Skin biopsy was performed in two patients. Both had evidence of leukocytoclastic vasculitis. One patient each had biopsy samples from prostate, cervical lymph node, and suburethral mass with evidence of granulomatous inflammation on prostate and lymph node tissue and necrotizing inflammation with vasculitis in the suburethral tissue.
Treatment and outcome
All patients received steroids and immunosuppressants. Methotrexate was used in 11 patients for primary induction with localized or early systemic GPA. Of these patients, sustained remission was achieved in four patients, progression to generalized disease was seen in three patients requiring a change of immunosuppressive drug, and four patients had minor relapses. Intravenous (n = 20) or oral cyclophosphamide (n = 3) was used for induction in 23 patients with systemic forms of GPA. MMF and azathioprine were used for induction in three patients and two patients, respectively. Rituximab was used in 12 patients. It was used for primary induction in three patients with severe disease and after cyclophosphamide in nine patients for relapsing disease (n = 4) or refractory disease (n = 5). Five patients received all four doses of 500 mg, while seven patients received only two doses of 500 mg. Of these seven patients, five were given low-dose rituximab for induction as they had dominantly refractory or relapsing lung manifestations, one patient expired before the third dose, and one patient developed a severe infection requiring discontinuation of rituximab therapy. Rituximab was successful in inducing remission in 9 of 12 patients [Figure 2]. Plasmapheresis was done in only one patient with severe pulmonary–renal syndrome. Azathioprine (n = 15) and MMF (n = 13) were almost equally used for maintenance therapy. Cotrimoxazole prophylaxis was used in 14 patients.
|Figure 2: Cyclophosphamide refractory pulmonary cavitary lesion (a) in a case of granulomatosis with polyangiitis showing complete resolution (b) after two doses of 500 mg rituximab|
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The median duration of follow-up was 36 months (IQR 40.5). Thirty-four patients are on follow-up, five patients were lost to follow–up, and three patients expired. Sustained remission of disease was achieved in 23 patients (55%) and two (4.5%) patients had refractory disease. Relapse of disease occurred in 17 (40.5%) patients. Nine patients had a major relapse and eight patients had a minor relapse. The organ system involved in relapses included pulmonary, renal, articular, ENT, ocular, and cutaneous in six, four, three, two, and one each, respectively. Time to relapse was at 2 years or beyond in 12 patients, while five patients relapsed between 1 and 2 years. Two patients had the second relapse at 3 years and 4 years, respectively, after achieving remission. One patient had third relapse 3 years after achieving the last remission. Of these relapsed cases, 4 patients developed refractory disease, while 13 patients responded to treatment and remission was achieved. Refractory disease on relapse resulted in ESRD in three patients and one patient expired.
The median BVAS v3 score at presentation was 14.5 (IQR 11.75). BVAS score between those who achieved sustained remission (median 11) or relapse (median 16) was not statistically significant. Higher percentage of participants with relapse had skin involvement as compared to patients with remission (P < 0.05). There was no other statistically significant difference in involvement of other organs or use of cotrimoxazole between relapse and remission group (P > 0.05).
The median VDI was 2 (IQR 2). Subglottic stenosis requiring surgery, ESRD, hypertension, cataract, chronic breathlessness, and hearing loss were the most common damage components. Mortality in our study was due to concurrent active disease and sepsis in one patient, disease activity during relapse in another, while in one patient, death was unrelated to the disease after 5 years of remission. Ten patients had episodes of severe infection requiring hospitalization and three patients developed herpes zoster. The severe infections included pulmonary involvement in seven patients, complicated urinary tract infection in two patients, and pancreatic cyst infection in one patient. All these were bacterial infections except one patient with pulmonary aspergillosis. There was no statistically significant difference in patients who got an infection when classified based on whether or not they received cotrimoxazole. Azathioprine-related pancytopenia was seen in one patient and hemorrhagic cystitis developed in one patient. None of the patients developed any malignancy.
| Discussion|| |
GPA typically affects the upper and lower respiratory tract as well as the kidneys, though any other organ can be affected with a wide spectrum of manifestations. GPA has been previously reported from various centres in India, mainly from northern India with the largest series of 105 patients by Sharma et al.,,,,,, However, there is a paucity of data from western India. It also appears that the frequency of manifestations differs in various parts of the country. Our study is a large retrospective case series from western India describing the spectrum of manifestations, treatment, and outcome of GPA at a single-center, tertiary care hospital in Mumbai.
We had 42 patients of GPA over 10 years with an equal number of male and female patients. This is similar to other Indian studies, unlike the male predominance seen in the western GPA cohorts., However, the median age at presentation in our study was 48.5 years. This is in contrast to earlier studies from India which had patients at a younger age of onset., Details of the comparison with other GPA cohorts are shown in [Table 2].
|Table 2: Comparison of clinical features of granulomatosis with polyangiitis with Western and Indian series|
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ENT manifestations were seen in only 50% of our patients. This is significantly lower than the reported 90%–95% involvement among European and American patients. However, this is consistent with the lower frequency (21%–80%) of upper airway involvement reported in previous studies from India.,, Pulmonary manifestations were the most common system involvement seen in 27 (64%) patients in our cohort. Pradhan et al. from western India reported pulmonary involvement in 91.3% of their patients with GPA; however, other series from India have reported similar (49%–68%) pulmonary involvement to that seen in our study. Simultaneous upper and lower respiratory tract involvement was seen in 12 (29%) patients. Coexistent pulmonary and renal involvement was seen in 17 (40.5%) of our patients, while coexistent ENT and renal manifestations were seen in only 6 (14%) patients. Three patients presented with pulmonary–renal syndrome. Similar findings were reported in a recent study by Sharma et al. with pulmonary–renal syndrome in 5 (7%) patients and coexistent ENT and renal manifestations in 18 (26.1%) patients with GPA. Gokhale et al. from Mumbai reported seven patients with GPA as an important differential in patients with pulmonary–renal syndrome. Subglottic stenosis is a challenging and life-threatening manifestation of GPA and was seen in about 12% of patients in our study. In a series of 26 patients with GPA and tracheobronchial stenosis, 16 patients had subglottic stenosis. Females were dominantly affected and the median age was 32 years. Swain et al. reported six patients with GPA with subglottic stenosis from eastern India with four females and two males. Five patients required a tracheostomy and microlaryngeal surgery.
Renal disease was established in 21 patients in our study. Most of these patients had hematoproteinuria and only five patients presented with rapidly progressive glomerulonephritis. ESRD was also uncommon. Renal disease of variable severity has been reported in previous studies from India. While patients from North India had less severe renal involvement in series by Sharma et al., patients from South India had severe renal disease as reported by Shobha et al., This may be due to different referral patterns or time to diagnosis from onset of disease or true geographic variation. Ocular, articular, and cutaneous manifestations were less common in our study compared to the western cohorts., Nunna et al. reported higher ocular involvement in their series, but other studies from India have reported similar ocular involvement to that seen in our study., We had three patients presenting as palindromic rheumatism with scleritis and anti-PR3 antibody positivity. None of the patients had any ENT, lung, or kidney involvement. All these patients were negative for rheumatoid factor or anti-CCP antibody. Although palindromic rheumatism and scleritis are both well described in GPA, we did not find any report of the combination being the only manifestation of the disease. Cutaneous and neurological manifestations were less common in our cohort. Abdominal and cardiac manifestations were rare, similar to that described in the literature.,
Some of the uncommon manifestations seen in our patients included prostatitis, vaginal vault suburethral mass, and pancreatitis. Urogenital tract involvement is rare in GPA, and in a large series of 174 patients of GPA, the incidence was about 2.3%. The prostate is most commonly affected, followed by the seminal vesicles and epididymis. Pancreatitis is an unusual manifestation of GPA and can be the presenting feature. Patients can rapidly progress to multisystem organ involvement. Pancreatitis in GPA has been reported mostly in the form of case reports.,
The role of rituximab as a potent agent for the remission of induction has been established in the RAVE and RITUXVAS study., It has particularly been useful in relapsing disease and also shown promising results for refractory disease., We used rituximab in 12 patients in severe, relapsing, or refractory disease and was successful in achieving remission in 75% of these patients. This is consistent with the results of other studies from India., Low-dose rituximab has been shown to have similar results to conventional doses in other autoimmune diseases. Takakuwa et al. reported similar cumulative complete remission in patients with a low-dose and high-dose rituximab. Low-dose rituximab achieved remission in five patients in our study.
Relapse of GPA was seen in 40% of our patients. This is similar to the relapse rates described in the literature and previous studies from India.,, The majority of relapse occurred after 2 years of treatment and may be due to the tapering of steroids and immunosuppressants. We did not perform repeat ANCA values to study its role in predicting relapses. The BVAS scores between those who relapsed and those who achieved remission were not statistically different. The mortality rate of 7% in our study is significantly lower than other studies from India. This may be due to early presentation and diagnosis, increased awareness among other specialties leading to early referral and aggressive therapy. We also had dominantly pulmonary manifestations and fewer patients with severe renal involvement, the latter being a significant risk factor for mortality. The median BVAS at a presentation in our study was 14.5, reflecting less severe disease compared to other studies from India., Due to low mortality of only three patients in our group, survival analysis or association of mortality with initial severity, BVAS, organ involvement, or relapse could not be statistically analyzed.
Retrospective nature of the study and the relatively small number of patients are limitations of our study. Our center is a tertiary level, corporate hospital in Mumbai and may not represent the disease manifestations seen in the community or public hospitals of western India. We suggest nationwide, multicentric, prospective study involving the public and private hospitals to have comprehensive data and understand the implications of treatment choices.
| Conclusion|| |
GPA in western India has a similar clinical profile to other parts of the country. Pulmonary and renal manifestations are common, while neurological and cutaneous involvement is infrequent. Pancreatitis, prostatitis, and suburethral mass are unusual manifestations of GPA and must be suspected in appropriate clinical scenarios. Most patients respond to steroids and immunosuppressants. Relapses are frequent and rituximab is an effective therapy for severe, refractory, and relapsing disease.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]