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Drug exposure and subsequent diagnosis with ANCA-associated vasculitis – A population-based case- control study

Inc, Burak ; Rathmann, Jens LU orcid ; Najibi, Seyed Morteza LU orcid ; Gisslander, Karl LU orcid ; Segelmark, Mårten LU ; Jayne, David and Mohammad, Aladdin LU (2024) p.191-191
Abstract
Objective: To determine if prior exposure to certain drugs is associated with increased risk of ANCA associated vasculitis
(AAV).
Patients and Method: We performed a population-based case–control study including patients with AAV diagnosed between
2006 and 2019 from a defined geographic area in southern Sweden. For each case, we identified 10 controls randomly sampled
from the background general population, matched for age, sex and residential area. Using the unique personal identification
numbers, data on drug exposure, for cases and controls, were retrieved from Swedish Prescribed Drug Register (SPDR). The
SPDR includes all pharmaceutical prescription after July 2005 using the Anatomical Therapeutic Chemical... (More)
Objective: To determine if prior exposure to certain drugs is associated with increased risk of ANCA associated vasculitis
(AAV).
Patients and Method: We performed a population-based case–control study including patients with AAV diagnosed between
2006 and 2019 from a defined geographic area in southern Sweden. For each case, we identified 10 controls randomly sampled
from the background general population, matched for age, sex and residential area. Using the unique personal identification
numbers, data on drug exposure, for cases and controls, were retrieved from Swedish Prescribed Drug Register (SPDR). The
SPDR includes all pharmaceutical prescription after July 2005 using the Anatomical Therapeutic Chemical codes. Exposure was
defined as purchase of at least one prescription of corresponding drug during time prior to the date of diagnosis of AAV (and the
index date for controls). A conditional logistic regression model was fitted. To reduce risk of reverse causality, a wash-out time of
6 months was applied (i.e., purchases within 6 months prior to date of diagnosis/index date were excluded).
Results: A total of 168 cases (females 77, 45.8%) and 1763 controls (females 808, 45.8%) were included. PR3 and MPOANCA were positive in 82 (48.8%) and 75 (44.6%) patients. All patients had a clinical diagnosis of small vessel vasculitis which
was supported by histopathology, ANCA analysis and surrogate markers for vasculitis/granuloma. Patients were classified using
the EMA algorithm into: GPA, MPA and EGPA in 86 (51.2%), 68 (40.5%) and 14 (8.3%), respectively.
ATC CODES DRUG GROUPS ALL PATIENTS (n=168) MPO-AAV (n=75) PR3-AAV (n=82)
OR 95% CI OR 95% CI OR 95% CI
A Alimentary drugs and metabolism 1.02 [0.72, 1.45] 1.04 [0.62, 1.77] 0.97 [0.596, 1.578]
C Cardiovascular system 0.68 [0.47, 0.99] 0.88 [0.5, 1.58] 0.48 [0.28, 0.81]
C10AA Statins 0.75 [0.50, 1.12] 1.18 [0.7, 2.01] 0.35 [0.17, 0.72]
C03 Diuretics 0.61 [0.40, 0.92] 0.71 [0.41, 1.24] 0.51 [0.27, 0.97]
C07 Beta-blockers 0.68 [0.46, 1.11] 0.69 [0.41, 1.19] 0.69 [0.38, 1.23]
C08 Calcium antagonists 0.82 [0.53, 1.27] 1.14 [0.64, 2.03] 0.51 [0.24, 1.06]
C09 RAS blockers 0.78 [0.53, 1.16] 1.12 [0.66, 1.93] 0.52 [0.28, 0.95]
C09A ACE inhibitors 0.7 [0.44, 1.1] 1.04 [0.58, 1.87] 0.44 [0.21, 0.93]
C09C ARBs 0.96 [0.58, 1.59] 0.71 [0.33, 1.56] 1.25 [0.62, 2.51]
L Antineoplastic and immunomodulator 1.11 [0.61, 2.02] 1.06 [0.47, 2.4] 1.06 [0.4, 2.76]
H Systemic hormone preparations 1.9 [1.35, 2.69] 2.22 [1.34, 3.68] 1.3 [0.77, 2.2]
H02AB Glucocorticoids 2.02 [1.4, 2.9] 2.35 [1.39, 3.97] 1.25 [0.7, 2.23]
H03A Thyroid hormones 1.96 [1.18, 3.24] 2.6 [1.33, 5.08] 1.68 [0.75, 3.75]
H03B Antithyroids 0.05 [0.001, 2.09] 0.043 N/A 0.04 N/A
J Antiinfectives 0.97 [0.67, 1.4] 1.95 [1, 3.83] 0.58 [0.36, 0.95]
J01 Antibacterials 1.03 [0.72, 1.48] 1.91 [1, 3.65] 0.63 [0.39, 1.01]
J01C Tetracyclins 1.3 [0.9, 1.88] 1.84 [1.10, 3.06] 0.62 [0.33, 1.02]
J01E Penicillins 1.18 [0.84, 1.66] 1.65 [0.96, 2.84] 0.82 [0.51, 1.32]
J01M Quinolones 0.87 [0.54, 1.4] 0.93 [0.48, 1.8] 0.9 [0.45, 1.81]
J05 Antivirals 0.2 [0.05, 0.8] 0.34 [0.08, 1.43] 0.04 N/A
J05AB Nucleosides and nucleotides 0.11 [0.02, 0.77] 0.18 [0.03, 1.32] 0.04 N/A
Table. Odds ratios [95% confidence intervals] for the association between use of drugs and incidence of ANCA associated
vasculitis (AAV). Estimates from conditional logistic regression models excluding any prescriptions within 6 months prior to AAV.
ACE: Angiotensin converting enzyme, ARB: Angiotensin receptor blocker, RAS: Renin-angiotensin system.
192
Poster
Tours
With the 6-months wash-out period, the prior use of thyroid hormones was associated with increased risk of AAV (ORs 1.96
(95% CI 1.18-3.24) (Table). However, ORs of <1 were obtained for the exposure to cardiovascular (CV) drugs and antivirals (ORs
0.68 (95% CI 0.47-0.99) and 0.2 (95% CI 0.05-0.8), respectively. Exposure to certain drugs had different impact on subsequent
development of MPO- vs. PR3-AAV. Glucocorticoid (GC) use prior to AAV had resulted in OR >1 but only in patients who later
diagnosed with MPO-AAV. The exposure to anti-bacterial drugs and thyroid hormones was associated with increased risk of MPOAAV only. On the contrary, exposure to CV drugs (statins, ACE inhibitors, diuretics) were only reducing risk of PR3-AAV. The prior
use of antivirals was associated with reduced risk of AAV in the main analysis but not in antibody-specific analysis.
Discussion: This is the first pharmacoepidemiologic study investigating the association between development of AAV and
prior drug exposure. The association of anti-bacterial agents with diagnosis of MPO-AAV is in line with our previous study on
impact of infections on subsequent AAV diagnosis. The possible protective effect of CV drugs and antivirals is a novel finding for
AAV. Patients with MPO-AAV may suffer a longer prodromal phase of disease or being treated for symptoms suggestive of a nonspecific inflammatory disease and ORs in GC analysis are probably due to pre-diagnosis AAV manifestations rather than have a
causative impact. Our study has a limitation of small sample size and limited power, further larger studies are needed to explore
these associations. (Less)
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pages
191 - 191
DOI
10.5281/zenodo.11068008
language
English
LU publication?
yes
id
86fcc584-4a30-49b8-ba32-01eba34e5bba
date added to LUP
2024-09-13 17:12:05
date last changed
2024-09-16 08:50:33
@misc{86fcc584-4a30-49b8-ba32-01eba34e5bba,
  abstract     = {{Objective: To determine if prior exposure to certain drugs is associated with increased risk of ANCA associated vasculitis<br/>(AAV).<br/>Patients and Method: We performed a population-based case–control study including patients with AAV diagnosed between<br/>2006 and 2019 from a defined geographic area in southern Sweden. For each case, we identified 10 controls randomly sampled<br/>from the background general population, matched for age, sex and residential area. Using the unique personal identification<br/>numbers, data on drug exposure, for cases and controls, were retrieved from Swedish Prescribed Drug Register (SPDR). The<br/>SPDR includes all pharmaceutical prescription after July 2005 using the Anatomical Therapeutic Chemical codes. Exposure was<br/>defined as purchase of at least one prescription of corresponding drug during time prior to the date of diagnosis of AAV (and the<br/>index date for controls). A conditional logistic regression model was fitted. To reduce risk of reverse causality, a wash-out time of<br/>6 months was applied (i.e., purchases within 6 months prior to date of diagnosis/index date were excluded).<br/>Results: A total of 168 cases (females 77, 45.8%) and 1763 controls (females 808, 45.8%) were included. PR3 and MPOANCA were positive in 82 (48.8%) and 75 (44.6%) patients. All patients had a clinical diagnosis of small vessel vasculitis which<br/>was supported by histopathology, ANCA analysis and surrogate markers for vasculitis/granuloma. Patients were classified using<br/>the EMA algorithm into: GPA, MPA and EGPA in 86 (51.2%), 68 (40.5%) and 14 (8.3%), respectively.<br/>ATC CODES DRUG GROUPS ALL PATIENTS (n=168) MPO-AAV (n=75) PR3-AAV (n=82)<br/>OR 95% CI OR 95% CI OR 95% CI<br/>A Alimentary drugs and metabolism 1.02 [0.72, 1.45] 1.04 [0.62, 1.77] 0.97 [0.596, 1.578]<br/>C Cardiovascular system 0.68 [0.47, 0.99] 0.88 [0.5, 1.58] 0.48 [0.28, 0.81]<br/>C10AA Statins 0.75 [0.50, 1.12] 1.18 [0.7, 2.01] 0.35 [0.17, 0.72]<br/>C03 Diuretics 0.61 [0.40, 0.92] 0.71 [0.41, 1.24] 0.51 [0.27, 0.97]<br/>C07 Beta-blockers 0.68 [0.46, 1.11] 0.69 [0.41, 1.19] 0.69 [0.38, 1.23]<br/>C08 Calcium antagonists 0.82 [0.53, 1.27] 1.14 [0.64, 2.03] 0.51 [0.24, 1.06]<br/>C09 RAS blockers 0.78 [0.53, 1.16] 1.12 [0.66, 1.93] 0.52 [0.28, 0.95]<br/>C09A ACE inhibitors 0.7 [0.44, 1.1] 1.04 [0.58, 1.87] 0.44 [0.21, 0.93]<br/>C09C ARBs 0.96 [0.58, 1.59] 0.71 [0.33, 1.56] 1.25 [0.62, 2.51]<br/>L Antineoplastic and immunomodulator 1.11 [0.61, 2.02] 1.06 [0.47, 2.4] 1.06 [0.4, 2.76]<br/>H Systemic hormone preparations 1.9 [1.35, 2.69] 2.22 [1.34, 3.68] 1.3 [0.77, 2.2]<br/>H02AB Glucocorticoids 2.02 [1.4, 2.9] 2.35 [1.39, 3.97] 1.25 [0.7, 2.23]<br/>H03A Thyroid hormones 1.96 [1.18, 3.24] 2.6 [1.33, 5.08] 1.68 [0.75, 3.75]<br/>H03B Antithyroids 0.05 [0.001, 2.09] 0.043 N/A 0.04 N/A<br/>J Antiinfectives 0.97 [0.67, 1.4] 1.95 [1, 3.83] 0.58 [0.36, 0.95]<br/>J01 Antibacterials 1.03 [0.72, 1.48] 1.91 [1, 3.65] 0.63 [0.39, 1.01]<br/>J01C Tetracyclins 1.3 [0.9, 1.88] 1.84 [1.10, 3.06] 0.62 [0.33, 1.02]<br/>J01E Penicillins 1.18 [0.84, 1.66] 1.65 [0.96, 2.84] 0.82 [0.51, 1.32]<br/>J01M Quinolones 0.87 [0.54, 1.4] 0.93 [0.48, 1.8] 0.9 [0.45, 1.81]<br/>J05 Antivirals 0.2 [0.05, 0.8] 0.34 [0.08, 1.43] 0.04 N/A<br/>J05AB Nucleosides and nucleotides 0.11 [0.02, 0.77] 0.18 [0.03, 1.32] 0.04 N/A<br/>Table. Odds ratios [95% confidence intervals] for the association between use of drugs and incidence of ANCA associated<br/>vasculitis (AAV). Estimates from conditional logistic regression models excluding any prescriptions within 6 months prior to AAV.<br/>ACE: Angiotensin converting enzyme, ARB: Angiotensin receptor blocker, RAS: Renin-angiotensin system.<br/>192<br/>Poster<br/>Tours<br/>With the 6-months wash-out period, the prior use of thyroid hormones was associated with increased risk of AAV (ORs 1.96<br/>(95% CI 1.18-3.24) (Table). However, ORs of &lt;1 were obtained for the exposure to cardiovascular (CV) drugs and antivirals (ORs<br/>0.68 (95% CI 0.47-0.99) and 0.2 (95% CI 0.05-0.8), respectively. Exposure to certain drugs had different impact on subsequent<br/>development of MPO- vs. PR3-AAV. Glucocorticoid (GC) use prior to AAV had resulted in OR &gt;1 but only in patients who later<br/>diagnosed with MPO-AAV. The exposure to anti-bacterial drugs and thyroid hormones was associated with increased risk of MPOAAV only. On the contrary, exposure to CV drugs (statins, ACE inhibitors, diuretics) were only reducing risk of PR3-AAV. The prior<br/>use of antivirals was associated with reduced risk of AAV in the main analysis but not in antibody-specific analysis.<br/>Discussion: This is the first pharmacoepidemiologic study investigating the association between development of AAV and<br/>prior drug exposure. The association of anti-bacterial agents with diagnosis of MPO-AAV is in line with our previous study on<br/>impact of infections on subsequent AAV diagnosis. The possible protective effect of CV drugs and antivirals is a novel finding for<br/>AAV. Patients with MPO-AAV may suffer a longer prodromal phase of disease or being treated for symptoms suggestive of a nonspecific inflammatory disease and ORs in GC analysis are probably due to pre-diagnosis AAV manifestations rather than have a<br/>causative impact. Our study has a limitation of small sample size and limited power, further larger studies are needed to explore<br/>these associations.}},
  author       = {{Inc, Burak and Rathmann, Jens and Najibi, Seyed Morteza and Gisslander, Karl and Segelmark, Mårten and Jayne, David and Mohammad, Aladdin}},
  language     = {{eng}},
  month        = {{04}},
  pages        = {{191--191}},
  title        = {{Drug  exposure  and  subsequent  diagnosis  with ANCA-associated  vasculitis  – A  population-based  case- control study}},
  url          = {{http://dx.doi.org/10.5281/zenodo.11068008}},
  doi          = {{10.5281/zenodo.11068008}},
  year         = {{2024}},
}