Title: An Opportunistic Infection in a Patient with Psoriatic Arthritis treated with Apremilast
Authors: Stephanie Kydd Dondero, DO; Barry Waters, MD
Program: Rheumatology Fellowship, Larkin Community Hospital, South Miami, FL
Introduction: Apremilast (Otezla) was first marketed in March of 2014 for the treatment of adults with active psoriatic arthritis. To date, there is no inclusion statement in the package insert stating the possibility of increased opportunistic infection while on the drug based on the Psoriatic Arthritis Long Term Assessment of the Clinical Efficacy (PALACE) study. The PALACE study demonstrates a non-significant, 0.6 and 0.0 exposure-adjusted incidence rate/100 patient years of opportunistic infection in placebo vs Otezla, respectively.1 The ACTIVE trial produced consistent safety profile results. 2 Apremilast is an immunomudulating drug, which is a small molecule inhibitor of phosphodiesterase 4(PDE4) specific for cyclic adenosine monophosphate (cAMP), administered orally. By inhibiting PDE4, intracellular cAMP levels are increased. Though the exact mechanism of action is not known, the PALACE study evaluation of biomarkers revealed an increase in anti-inflammatory mediator (IL-10) and a decrease in pro-inflammatory mediators TNF-alpha, IL-17A and IL-23. Although no increased risk of opportunistic infections was identified, alterations in inflammatory cytokine levels were observed. There is a potential this alteration of the inflammatory milieu has immunosuppressive effects.
Case Presentation: A.P. is a 71 year old male with PMHX of psoriatic arthritis, psoriasis, a history of aortic valve replacement (2015), maxillary osteotomy (1983), and tonsillectomy (1952), who presented with opportunistic Streptococcus salivarius bacteremia while on Otezla. Pt was initially diagnosed with psoriatic arthritis in 1981 and previously had been on multiple NSAIDS, Methotrexate (2-3 years), and Humira (starting in 1995). Humira was stopped for patient preference as he was concerned for potential cardiovascular side effects. He was switched to Otezla on 6/10/2015. Five months later he had an aortic valve replacement for symptoms that predated Otezla initiation. The procedure was performed without incident. Pt remained on Otezla with no noted toxicities or side effects until three years later. With no provoking factors, he developed low grade fever and chills in July of 2018. Blood cultures were performed and he was found to have Streptococcus salivarius bacteremia, a known opportunistic pathogen.3 He was placed on IV Rocephin from 7/25/18 thru 9/7/18. TEE and TTE were both negative. Otezla was withheld 8/29/18 while on treatment for bacteremia. This potential side effect was reported to the FDA by MedWatch.
Discussion: This case identifies an opportunistic infection in a patient on Otezla. Contrary to previous thought, the decrease in pro-inflammatory mediators TNF alpha, IL-17 and IL-23 in Apremilast may create immunosuppressant effects. Caution should be used and further studies should be performed in this area.
Authors: Stephanie Kydd Dondero, DO; Barry Waters, MD
Program: Rheumatology Fellowship, Larkin Community Hospital, South Miami, FL
Introduction: Apremilast (Otezla) was first marketed in March of 2014 for the treatment of adults with active psoriatic arthritis. To date, there is no inclusion statement in the package insert stating the possibility of increased opportunistic infection while on the drug based on the Psoriatic Arthritis Long Term Assessment of the Clinical Efficacy (PALACE) study. The PALACE study demonstrates a non-significant, 0.6 and 0.0 exposure-adjusted incidence rate/100 patient years of opportunistic infection in placebo vs Otezla, respectively.1 The ACTIVE trial produced consistent safety profile results. 2 Apremilast is an immunomudulating drug, which is a small molecule inhibitor of phosphodiesterase 4(PDE4) specific for cyclic adenosine monophosphate (cAMP), administered orally. By inhibiting PDE4, intracellular cAMP levels are increased. Though the exact mechanism of action is not known, the PALACE study evaluation of biomarkers revealed an increase in anti-inflammatory mediator (IL-10) and a decrease in pro-inflammatory mediators TNF-alpha, IL-17A and IL-23. Although no increased risk of opportunistic infections was identified, alterations in inflammatory cytokine levels were observed. There is a potential this alteration of the inflammatory milieu has immunosuppressive effects.
Case Presentation: A.P. is a 71 year old male with PMHX of psoriatic arthritis, psoriasis, a history of aortic valve replacement (2015), maxillary osteotomy (1983), and tonsillectomy (1952), who presented with opportunistic Streptococcus salivarius bacteremia while on Otezla. Pt was initially diagnosed with psoriatic arthritis in 1981 and previously had been on multiple NSAIDS, Methotrexate (2-3 years), and Humira (starting in 1995). Humira was stopped for patient preference as he was concerned for potential cardiovascular side effects. He was switched to Otezla on 6/10/2015. Five months later he had an aortic valve replacement for symptoms that predated Otezla initiation. The procedure was performed without incident. Pt remained on Otezla with no noted toxicities or side effects until three years later. With no provoking factors, he developed low grade fever and chills in July of 2018. Blood cultures were performed and he was found to have Streptococcus salivarius bacteremia, a known opportunistic pathogen.3 He was placed on IV Rocephin from 7/25/18 thru 9/7/18. TEE and TTE were both negative. Otezla was withheld 8/29/18 while on treatment for bacteremia. This potential side effect was reported to the FDA by MedWatch.
Discussion: This case identifies an opportunistic infection in a patient on Otezla. Contrary to previous thought, the decrease in pro-inflammatory mediators TNF alpha, IL-17 and IL-23 in Apremilast may create immunosuppressant effects. Caution should be used and further studies should be performed in this area.