Granulomatosis with polyangiitis: a 17 year experience from a tertiary care hospital in Pakistan
Irfan et al. BMC Res Notes
Granulomatosis with polyangiitis: a 17 year experience from a tertiary care hospital in Pakistan
Omar Irfan 0
Haris Khan 0
Zarrar Khan 2
Alina Ashraf 1
Rimsha Ahmed 1
Javaid Ahmad Khan
Ali Bin Sarwar Zubairi
0 Department of Medicine, Aga Khan University , Stadium Road, Karachi 74800 , Pakistan
1 Medical Student, Aga Khan University , Stadium
2 Department of Basic Sciences, Aga Khan University , Stadium Road, Karachi 74800 , Pakistan
Objective: Granulomatosis with Polyangiitis (GPA) is an autoimmune, multi-system, small and medium vessel vasculitis with granulomatous inflammation. Aim of this study was to assess the clinical and radiological presentations of patients with GPA amongst the Pakistani population. It is a single centre retrospective single observation study. Results: Study was conducted at the Aga Khan University Hospital, Karachi with records were reviewed from January 2000 to December 2017. Definitive diagnosis was made using a combination of serological anti-neutrophil cytoplasmic antibody (ANCA) testing along with the clinical and radiological presentation. A total of 51 patients met the diagnostic criteria in the time frame of the study. There were 23 males and 28 females with mean age of 44.0 ± 17.8 years on presentation. Arthritis was the most common symptom present in 41.2% of the cases followed by cough in 32.0%. Sixteen patients showed pulmonary infiltrates on chest X-ray. C-ANCA was positive in all of the patients compared with 21.6% p-ANCA positivity. A total of 13 biopsies were done. The median Birmingham Vasculitis Activity Score was 12. We report a 17.6% mortality rate with 5 deaths occurring due to respiratory failure. GPA is a diagnostic challenge leading to late diagnosis which can contribute to significant morbidity and mortality specially in the Third World.
Granulomatosis with polyangiitis; Vasculitis; c-ANCA; p-ANCA
GPA is an autoimmune small vessel vasculitis associated
with anti-neutrophil cytoplasmic antibodies (ANCA).
The clinical manifestations include systemic
necrotising vasculitis, necrotising glomerulonephritis and
necrotising granulomatous inflammation. GPA was first
described in the literature in a case report in the late
nineteenth century and was previously known as
Wegener’s Granulomatosis [
]. While it is uncommon overall, a
significant geographical variation has been observed in
the prevalence of this disease. A latitudinal gradient has
been identified with increasing trend in prevalence as the
distance from the Equator increases [
In GPA, ANCA is mainly directed against Proteinase
3 (PR3); there is strong evidence from various in vitro
studies that ANCA plays a crucial role in the mediation
of small vessel vasculitis [
]. GPA usually starts as a
localized granulomatous inflammation of the respiratory tract
that later generalizes into small vessel vasculitis [
Older age, pulmonary and kidney involvement are
features associated with poor prognosis and increased
mortality . The first case of GPA was reported by a German
clinician, Heinz Klinger in 1931 who believed it to be
a variant of polyarteritis nodosa, but it was Friedrich
Wegener who proposed this as a separate pathology
based upon the post mortem findings seen in three of his
] Several large case series on GPA have been
published from various countries, with the largest series
reporting 445 patients from Germany . This is the first
large institutional experience on the clinical
manifestations of GPA patients amongst the Pakistani population.
We report a series of 51 cases from our institution. Our
study focuses on the clinical and imaging features of GPA
with the hope that it will assist clinicians in better
identifying and managing this condition. We also summarize
the compare the clinical features of our patients with
those from other ethnic group studies from literature in
a tabulated form.
A retrospective, observational study was conducted at
the Aga Khan University Hospital (AKUH), Karachi.
Records of all patients diagnosed with GPA from
January 2000 to December 2017 were reviewed. Age, gender,
clinical features at the time of diagnosis, laboratory and
histo-pathological findings, imaging, type of treatment,
response to treatment and complications were collected
in a predesigned questionnaire. The files were retrieved
using international classification of diseases-9 (ICD-9)
coding. No experimentation on Human and animals was
done. This study was approved by the local ethical
committee of the institution. SPSS IBM version 20 was
utilized to analyze the data. Each categorical item from the
questionnaire was summarized by frequency count and
We used non-standardized criteria to diagnose the
disease. The 1990 American College of Rheumatology
and 2012 Chapel Hill Consensus Conference criteria for
the classification of the vasculitis have been accepted
], however they are not intended to be used as
diagnostic criteria. The ACR criteriawas devised before the
widespread recognition of microscopic polyangiitis as a
separate disease as well as prior to recognition of
antineutrophil cytoplasmic autoantibody (ANCA) testing
as a significant diagnostic tool. Therefore being a non
invasive test, we used serological evaluation as the initial
step for diagnosis of GPA at our institution. C-ANCA is
known to have sensitivity of 91% and specificity of 99%
for GPA [
]. Birmingham Vasculitis Activity Score
version 3 (BVAS-v3) was used to determine the disease
activity. Outcomes recorded were death, cause of death
and number of relapses.
During the study period, 51 patients diagnosed with
GPA were identified. The mean age of presentation was
44.0 ± 17.8 years with 23 males and 28 females. The
respiratory system was most commonly affected in 41
(80.4%) patients, followed by renal in 28 (54.9%), Ear
Nose and Throat (ENT) in 25 (49.0%),
musculoskeletal system in 22 (43.1%), nervous system in 9 (17.6%),
integumentary system in 8 (15.7%) and ocular system
in 6 (11.8%) patients. Arthralgia was the most common
presenting symptom seen in 21 patients followed by
cough in 16 patients. The clinical symptoms on
presentation are as shown in Table 1.
All of the selected patients underwent both p-ANCA
and c-ANCA on initial work up. The c-ANCA was
positive in all patients whilst only 11 patients were positive
with p-ANCA. Thirty three patients had a raised ESR
(> 20 mm/h). The radiological findings are outlined in
The most common finding on chest X-ray was
pulmonary infiltrates seen in 16 patients (31.4%), followed by
pulmonary nodules, alveolar hemorrhages and
cavitations in 9 patients each. A total of 13 biopsies were done
which included 7 renal, 3 nasal, 2 lung and 1 skin
specimen. Four renal biopsies showed crescenteric
glomerulonephritis, while focal necrotizing glomerulonephritis was
noted in 3 specimens. Chronic granulomatous
remodeling along with necrotic change was well appreciated
in all the nasal biopsies. A mixed picture of acute and
chronic inflammation with scattered multinucleated
giant cells and vasculitis could be identified in the lung
and skin biopsy results.
Forty five patients received a pulse dose (1 g/day) of
intravenous methyl prednisone. Remission was achieved
in 32 patients while 9 patients relapsed. Prednisolone
was the most common agent used for induction therapy
in 32 (62.6%) patients followed by cyclophosphamide
in 11 (21.6%) patients. Other therapies include
Methotrexate, Rituximab, Plasma exchange and Azathioprine.
Prednisolone was the most common agent used for
maintenance therapy in 41 (80.3%) patients followed by
azathioprine in 8 patients (15.7%). The complications that
developed after the initiation of treatment were divided
into 3 categories: opportunistic infections, malignancy
and cytopenia. Sixteen patients developed
opportunistic infections. Malignancies and cytopenia were noted
in four each. Nine patients passed away during the study
period; of these 5 deaths occurred due to respiratory
failure, 3 deaths happened due to sepsis and 1 patient
succumbed to heart failure. The median BVAS-v3 score at
presentation among all patients was 12.0 with range from
4.0 to 24.0. BVAS-v3 score was higher among patients
who expired compared to those who survived (14.1 vs.
11.1, P > 0.05). However the difference was insignificant
therefore we cannot conclude if the BVAS-v3 score at
presentation is useful in determining severity of disease
and in determining prognosis.
This study, documenting 17 years of experience, is the
most comprehensive, single-institution study describing
the clinical and radiological characteristics, management,
and outcome of patients with GPA from the Pakistani
population. Respiratory manifestations were recorded
in 80% of our patients as compared to 50% involvement
observed in the literature whilst alveolar hemorrhage,
lung nodules, and respiratory failure were the key
presenting features of this condition [
]. The second organ
system most commonly involved includes the kidneys
with focal segmental necrotizing
glomerulonephritis being the most consistently presenting feature [
More than half of the patients (55%) in our study had
renal manifestations and one-third of them developed
renal failure. Our study reports 49% of the cases
presenting with ENT manifestations. Hearing loss and epistaxis
were the most frequent symptoms. Previously, more than
70% of cases have been reported to have presented with
signs related to ENT ranging from crusting rhinorrhea
to damage of the facial cartilage causing deformities [
Other rare symptoms involved the mucocutaneous,
nervous and ocular systems.
On radiological evaluation, 16 of 51 patients
demonstrated pulmonary infiltrates in the form of
consolidations making it the most common presentation in our
setting. Cordier et al reported pulmonary infiltrates to be
the second most common presentation making up 53%
of the patient population in their study [
]. In 1990 the
American College of Rheumatology endorsed a criterion
for the diagnosis of GPA. One of the clauses of the
criteria was the presence of abnormal radiological findings
on chest X ray [
]. Chest CT is considered superior to
chest X-ray in the diagnosis of small vessel vasculitis [
Out of the 51 patients, 18 had an HRCT done. Six out of
18 patients showed airspace consolidation, making it the
most common finding. Multiple studies have shown that
abnormal radiological findings are found in 50–75% of
the population with GPA [
] with nodules and masses
being the two most common radiographic
manifestations. Studies have also labeled the presence of
bronchiectasis as a rare presentation [
] as supported by the
presence of bronchiectasis in only 4 patients in our study.
Moving on to serological investigations, ANCA
testing has been employed as diagnostic criteria for GPA
at our institution. Anti-neutrophilic cytoplasmic
antibody (ANCA) sensitivity can be as low as 60% in
localized disease [
] whereas ANCA is both sensitive and
specific for GPA being present in 80–90% of patients
with systemic disease. Still, there are some reported
cases where the ANCA was negative [
]. A previous
study by Chloe et al showed an 80% c-ANCA
]. Prednisolone and Cyclophosphamide were the
most commonly used drugs for induction in 32 and
11 patients respectively. For severe disease, plasma
exchange in addition to oral corticosteroids and
cyclophosphamide administration has been recommended
to halt the progression to end stage renal failure [
Oral corticosteroid therapy in conjunction with daily
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oral cyclophosphamide or intravenous pulsatile
cyclophosphamide is recommended for systemic disease
with organ dysfunction [
]. We had 33 cases
maintained with prednisolone.
A literature review revealed a relative paucity of
studies available on ANCA associated vasculitis from the
developing world. Our institution reported a 13 patient
registry in 2004 [
]. A 20 case series of Rhinological
manifestations of GPA was also reported from
Rawalpindi in 2011 [
]. To our knowledge, this is the biggest
experience from Pakistan. Our neighboring Country,
India has reported three institutional experiences of
60, 45 and 105 patients. They also assessed the disease
activity and damage through the Birmingham Vasculitis
Activity Score v.3 (BVAS v. 3) [
]. The Indian series
have been presented in Table 3 along with other ethnic
groups Table 3. Compares the summaries of GPA series
from literature. A comparable prevalence of organ
system involvements are seen. In our opinion, tertiary care
centers need to maintain a registry of all the ANCA
associated vasculitis cases so that their clinical
presentation and response to treatment can be well
documented for our population.
The results from our study indicate that GPA is not
uncommon in Pakistan. We believe that larger studies on
GPA will assist physicians in timely diagnosis and
management of the disease.
A few notable shortcoming of our study include the small
sample size making it difficult to develop significant
associations between variables. Likewise, we report data from
only one tertiary care hospital of the country and so the
results we present cannot be generalized due to the
possibility of referral bias.
ANCA: antinuclear cytoplasmic antibody; GPA: granulomatosis with
polyangiitis; MPA: microscopic polyangiitis; cANCA: cytoplasmic ANCA; pANCA:
perinuclear ANCA; PR3: proteinase 3; MPO: myeloperoxidase; ENT: ear nose
AZ and JK proposed the idea of conducting the study. Proforma was made
by AZ and ZK. Protocol was written by OI and JK. ZK, OI and HK did literature
search and contributed to manuscript writing. OI did critical review and
editing of the manuscript. RA and AA contributed to data collection. OI and HK
have performed the data analysis. RA and AA contributed to table formations.
All authors have also attended to the GPA patients during their clinical
rotations. All authors read and approved the final manuscript.
Road, Karachi 74800, Pakistan. 4 Department of Medicine, Aga Khan University
Hospital, Stadium Road, Karachi 74800, Pakistan.
The authors declare they have no competing interests.
Availability of data and materials
The datasets generated and/or analysed during the current study are not
publicly available because the data is patient medical records but are available
from the corresponding author on reasonable request.
Consent for publication
Ethics approval and consent to participate
Aga Khan University Institutional Approval was obtained. Aga Khan Ethics
Review Committee is a licensed review board registered with the Office of
Human Subjects Protection.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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