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Using Systems Biology-based Analysis Approaches to Identify Mechanistically Significant Adverse Drug Reactions: Pulmonary Complications from Combined Use of Anti-TNFα Agents and Corticosteroids.

Sarangdhar M, Kushwaha A, Dahlquist J, Jegga A, Aronow B - AMIA Jt Summits Transl Sci Proc (2013)

Bottom Line: Anti-TNF drugs are frequently associated with serious Adverse Events (AEs), which necessitates an improved understanding of individual factors that determine efficacy and safety of anti-TNF agents.We demonstrate the existence of patient subgroup and anti-TNF agent-specific associations for relative risks of developing known and novel AEs including infections, edema, and organ damage associated processes.Concomitant use of anti-TNFs with corticosteroids significantly increased risk of AEs (p < 0.001) including pulmonary fibrosis and pulmonary edema.

View Article: PubMed Central - PubMed

Affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

ABSTRACT
Anti-TNF drugs are frequently associated with serious Adverse Events (AEs), which necessitates an improved understanding of individual factors that determine efficacy and safety of anti-TNF agents. We mined the US FDA's Adverse Event Reporting System (AERS) for anti-TNF-associated AEs to identify and stratify patient subgroups and drug combinations that exhibit specifically correlated complications. We demonstrate the existence of patient subgroup and anti-TNF agent-specific associations for relative risks of developing known and novel AEs including infections, edema, and organ damage associated processes. Concomitant use of anti-TNFs with corticosteroids significantly increased risk of AEs (p < 0.001) including pulmonary fibrosis and pulmonary edema. Using these tightly correlated phenotypes, we mined mouse phenotype data to identify the molecular basis of these AEs. Multiple pathways and networks that regulate injury response, fluid regulation, and wound healing were implicated suggesting modification of anti-TNF-based therapeutic strategies to minimize corticosteroid-based combinatorial risk of severe AEs.

No MeSH data available.


Related in: MedlinePlus

(a) The comparative rates of AE occurrences in T+C and T+M appeared to indicate risk increase with C intake, which was not observed with concomitant methotrexate, Rx = non-TRIADs (b) By means of the occurrences in non-TRAIDs demographics as the control event rate (CER) and occurrences in the T+M and T+C groups as exposed event rate (EER), we calculated the RRI (>0) or RRR (<0) for each AE using (EER-CER)/CER. Pneumonia, interstitial lung disease, pulmonary edema, pulmonary fibrosis exhibited RRI in the T+C demographics compared to T+M.
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f1-amia_tbi_2013_151: (a) The comparative rates of AE occurrences in T+C and T+M appeared to indicate risk increase with C intake, which was not observed with concomitant methotrexate, Rx = non-TRIADs (b) By means of the occurrences in non-TRAIDs demographics as the control event rate (CER) and occurrences in the T+M and T+C groups as exposed event rate (EER), we calculated the RRI (>0) or RRR (<0) for each AE using (EER-CER)/CER. Pneumonia, interstitial lung disease, pulmonary edema, pulmonary fibrosis exhibited RRI in the T+C demographics compared to T+M.

Mentions: The AERS received 1,927,191 patient-reports with non-cancer indications, which included 134,384 (6.97%) patients with TRIADs and 1,792,807 (93.3%) patients with non-TRIADs indications. A 1-way ANOVA with a p-value cutoff of 0.05 identified 301 statistically significant AEs across adults and elderly subgroups when grouped by drug therapy. These AEs were selected from a list of 495 significant AEs with reporting rates of at least one report per thousand and included pulmonary edema, fibrosis, interstitial lung disease, pleural effusions and infections among various other complications that were significantly higher (p < 0.001) in patients on corticosteroids. The occurrence of AEs in T cohorts were relatively lower than C and T+C therapy groups suggesting an increased risk of serious complications with concomitant corticosteroids (p < 0.0001) compared to methotrexate. This is particularly important in view of the treatment regimen, which advocates the concomitant use of corticosteroid therapy until the effect of the TNF-antagonists is clinically observed8. This prescribed intake of anti-TNFs with corticosteroids for TRIADs symptoms necessitates the need to investigate the risks of concomitant medications that may result in severe and life-threatening complications. The adverse effect of the pharmacological interactions of T+C translated to significant risk increase (at least 1.5-fold) of pulmonary fibrosis (2.5), interstitial lung disease (1.9), sepsis (2.3), septic shock (1.8), pulmonary edema (2.5) and pneumonia (1.6) within the T+C cohorts in comparison with T+M therapy group. The risks of interstitial lung diseases, sepsis, pneumonia, pulmonary edema and other serious AEs were also elevated in the elderly T+C subgroups that were at most risk of life threatening adverse effects (table 1). The relative risks increase (RRI) or reduction (RRR) for AEs varied in the adult and elderly sub-groups on T+M and T+C (fig. 1b, only elderly males shown). The TRIADs indications are characterized by elevated levels of pro-inflammatory cytokines, especially TNFα, known for its role in the pathogenesis of autoimmune and inflammatory disorders, host defense mechanisms and initiating response to local injury. However, in excess, TNFα leads to inappropriate inflammation and consequent tissue damage16, which may explain the increased probability of tissue injury in patients with autoimmune and immunoinflammatory disorders.


Using Systems Biology-based Analysis Approaches to Identify Mechanistically Significant Adverse Drug Reactions: Pulmonary Complications from Combined Use of Anti-TNFα Agents and Corticosteroids.

Sarangdhar M, Kushwaha A, Dahlquist J, Jegga A, Aronow B - AMIA Jt Summits Transl Sci Proc (2013)

(a) The comparative rates of AE occurrences in T+C and T+M appeared to indicate risk increase with C intake, which was not observed with concomitant methotrexate, Rx = non-TRIADs (b) By means of the occurrences in non-TRAIDs demographics as the control event rate (CER) and occurrences in the T+M and T+C groups as exposed event rate (EER), we calculated the RRI (>0) or RRR (<0) for each AE using (EER-CER)/CER. Pneumonia, interstitial lung disease, pulmonary edema, pulmonary fibrosis exhibited RRI in the T+C demographics compared to T+M.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3814486&req=5

f1-amia_tbi_2013_151: (a) The comparative rates of AE occurrences in T+C and T+M appeared to indicate risk increase with C intake, which was not observed with concomitant methotrexate, Rx = non-TRIADs (b) By means of the occurrences in non-TRAIDs demographics as the control event rate (CER) and occurrences in the T+M and T+C groups as exposed event rate (EER), we calculated the RRI (>0) or RRR (<0) for each AE using (EER-CER)/CER. Pneumonia, interstitial lung disease, pulmonary edema, pulmonary fibrosis exhibited RRI in the T+C demographics compared to T+M.
Mentions: The AERS received 1,927,191 patient-reports with non-cancer indications, which included 134,384 (6.97%) patients with TRIADs and 1,792,807 (93.3%) patients with non-TRIADs indications. A 1-way ANOVA with a p-value cutoff of 0.05 identified 301 statistically significant AEs across adults and elderly subgroups when grouped by drug therapy. These AEs were selected from a list of 495 significant AEs with reporting rates of at least one report per thousand and included pulmonary edema, fibrosis, interstitial lung disease, pleural effusions and infections among various other complications that were significantly higher (p < 0.001) in patients on corticosteroids. The occurrence of AEs in T cohorts were relatively lower than C and T+C therapy groups suggesting an increased risk of serious complications with concomitant corticosteroids (p < 0.0001) compared to methotrexate. This is particularly important in view of the treatment regimen, which advocates the concomitant use of corticosteroid therapy until the effect of the TNF-antagonists is clinically observed8. This prescribed intake of anti-TNFs with corticosteroids for TRIADs symptoms necessitates the need to investigate the risks of concomitant medications that may result in severe and life-threatening complications. The adverse effect of the pharmacological interactions of T+C translated to significant risk increase (at least 1.5-fold) of pulmonary fibrosis (2.5), interstitial lung disease (1.9), sepsis (2.3), septic shock (1.8), pulmonary edema (2.5) and pneumonia (1.6) within the T+C cohorts in comparison with T+M therapy group. The risks of interstitial lung diseases, sepsis, pneumonia, pulmonary edema and other serious AEs were also elevated in the elderly T+C subgroups that were at most risk of life threatening adverse effects (table 1). The relative risks increase (RRI) or reduction (RRR) for AEs varied in the adult and elderly sub-groups on T+M and T+C (fig. 1b, only elderly males shown). The TRIADs indications are characterized by elevated levels of pro-inflammatory cytokines, especially TNFα, known for its role in the pathogenesis of autoimmune and inflammatory disorders, host defense mechanisms and initiating response to local injury. However, in excess, TNFα leads to inappropriate inflammation and consequent tissue damage16, which may explain the increased probability of tissue injury in patients with autoimmune and immunoinflammatory disorders.

Bottom Line: Anti-TNF drugs are frequently associated with serious Adverse Events (AEs), which necessitates an improved understanding of individual factors that determine efficacy and safety of anti-TNF agents.We demonstrate the existence of patient subgroup and anti-TNF agent-specific associations for relative risks of developing known and novel AEs including infections, edema, and organ damage associated processes.Concomitant use of anti-TNFs with corticosteroids significantly increased risk of AEs (p < 0.001) including pulmonary fibrosis and pulmonary edema.

View Article: PubMed Central - PubMed

Affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

ABSTRACT
Anti-TNF drugs are frequently associated with serious Adverse Events (AEs), which necessitates an improved understanding of individual factors that determine efficacy and safety of anti-TNF agents. We mined the US FDA's Adverse Event Reporting System (AERS) for anti-TNF-associated AEs to identify and stratify patient subgroups and drug combinations that exhibit specifically correlated complications. We demonstrate the existence of patient subgroup and anti-TNF agent-specific associations for relative risks of developing known and novel AEs including infections, edema, and organ damage associated processes. Concomitant use of anti-TNFs with corticosteroids significantly increased risk of AEs (p < 0.001) including pulmonary fibrosis and pulmonary edema. Using these tightly correlated phenotypes, we mined mouse phenotype data to identify the molecular basis of these AEs. Multiple pathways and networks that regulate injury response, fluid regulation, and wound healing were implicated suggesting modification of anti-TNF-based therapeutic strategies to minimize corticosteroid-based combinatorial risk of severe AEs.

No MeSH data available.


Related in: MedlinePlus