A detailed report from GlobalData Expert Insights examines the pressing need for improved Lupus treatments
The signs and symptoms of systemic lupus erythematosus (SLE) and lupus nephritis (LN) are almost always associated with an overactive immune system, so the majority of current treatment options aims to suppress the host immune response, which has the unfortunate consequence of increasing the risk of acquiring secondary infections or viral reactivation. Indeed, GlobalData’s primary and secondary research has revealed that infections in lupus patients are more likely to result in sepsis and pneumonia, thereby further accelerating morbidity and mortality in these patient populations compared with the general population, and underscoring the need to develop new therapeutic options for those living with SLE and LN.
GlobalData identified three studies and one expert review about SLE and lymphopenia that support key opinion leaders’ (KOLs’) concerns about the mortality risk due to infections and their causes in SLE patients. The studies were aimed at identifying the risk of infections in SLE patients using data derived from the US Healthcare Cost and Utilization Project National Inpatient Sample (NIS) from 1996–2011, as well as Taiwan’s National Health Insurance (NHI) program from 1995–2007. Two of the three studies identified bacteria as major cause of infection, which resulted in pneumonia, sepsis, and acute respiratory syndrome in many cases. The third study identified an increased risk for herpes zoster reactivation and indifference in the occurrence of bacterial infections among SLE and non-SLE patients. The results of the third study are particularly interesting, as viral reactivation has been identified as a major adverse event of current immunosuppressive agents prescribed for lupus, such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, whereas bacterial infections have been cited as resulting from prolonged use of steroids and/or as a result of the natural course of lymphopenia (Martin et al., 2017). While the causes of infections can be multifactorial, GlobalData notes that all studies clearly show that lupus patients are exposed to an increased risk of serious infections with a potentially deadly outcome.
The first study examined the NHI database from 1996–2011 and found that 4,382 SLE patients were hospitalized with pneumonia, 2,305 were hospitalized with sepsis, and 370 were hospitalized with opportunistic infections. When compared to the general population in the US, this reflects an adjusted odds ratio of 1.52 (95 percent confidence interval [CI], 1.12–2.07) for acquiring opportunistic infections in SLE patients. Other infections such as sepsis and pneumonia were associated with an increased mortality risk (Tektonidou et al., 2015).
The second study looked at hospitalization rates in the NHI database from 2000–2011 and identified a total of 361,337 SLE hospitalizations. In contrast to the first study, the control group was comprised of other non-SLE hospitalizations. GlobalData notes that this adjustment resulted in no statistical difference in the incidences of bacterial infections,but showed a disproportionate decrease in pneumocystic pneumonia among SLE patients (from 5.1 to 2.5 per 10,000) compared to non-SLE patients (from 0.9 to 1.3 per 10,000).However, the study did show that compared to non-SLE hospitalizations, SLE patients had an increased rate of herpes zoster infections, with 54–79 per 10,000 SLE hospitalizations reporting symptoms of the viral infection compared to only 24–29 per 10,000 in the non-SLE hospitalization control group (Murray et al., 2016).
Finally, a third studyutilizing the NHI database identified an increased risk of respiratory failure among SLE patients of Asian ethnicitycompared to a non-SLE cohort. The study reported an adjusted hazard ratio of incident respiratory failure of 5.80 (95 percent CI, 5.15–6.52, p< 0.0001) for the SLE cohort compared with the non-SLE cohort (Yeh et al., 2016).
Experts interviewed by GlobalData largely blame broad-acting immunosuppressive agents, such as cyclophosphamide, for the increased risk of opportunistic infections because they non-selectively suppress the immune system. With the exception of antimalarial therapy, all other medications currently used in the management of disease flares in SLE and LN are associated with the occurrence of infections, further contributing to lupus disease morbidity and mortality. Based on the current clinical trial design for lupus drugs, where newly developed drugs are evaluated as add-on therapies to the standard of care, GlobalData does not expect the current pipeline drugs to replace broad-acting steroids and cyclophosphamide, but instead to help reduce the long-term exposure to these medications.
GlobalData anticipates that, once approved for SLE and/or LN, targeted B-cell therapies such as GlaxoSmithKline’s Benlysta (belimumab), Anthera’sblisibimod, Merck KGaA’s atacicept, and Bristol-Myers Squibb’s Orencia (abatacept), as well as other specific immuno-pathway targeted drugs such as AstraZeneca’s anifrolumab, Aurinia’s voclosporin, and ImmuPharma’s Lupuzor, will reduce the infectious burden in lupus patients. As for patients suffering from lymphophenia not related to drug therapy, vaccination remains the only available option for infection control. GlobalData sees a major opportunity for the pharmaceutical industry to develop novel immune-stimulatory agents for this SLE sub-patient population.
Tektonidou MG, et al. (2015). Burden of Serious Infections in Adults with Systemic Lupus
Erythematosus.Arthritis Care Res (Hoboken); 67(8): 1078-1085.
Martin M, et al. (2017). Systemic lupus erythematosus and lymphopenia: Clinical and pathophysiological features. La Revue de Médecine Interne; available from: http://www.sciencedirect.com/science/article/pii/S024886631730027. Accessed on [February 21, 2017].
Murray SG, et al. (2016).National Lupus Hospitalization Trends Reveal Rising Rates of Herpes Zoster and Declines in Pneumocystis Pneumonia.PLoS ONE; 11(1): e0144918..
Yeh JJ, et al. (2016). Effect of Systemic Lupus Erythematosus on the Risk of Incident Respiratory Failure: A National Cohort Study. PLoS ONE; 11(9): e0163382
GlobalData (2017).Low Drug Compliance in Lupus: Are Patients Really to Blame?,February 2017, GDHC1208EI
GlobalData (2016). PharmaPoint: Systemic Lupus Erythematosus and Lupus Nephritis – Global Drug Forecast and Market Analysis to 2025, December 2016, GDHC136PIDR
GlobalData (2016). Expert Insight: Encouraging Phase II Data Boost the Prospects of Voclosporin for Lupus Nephritis, December 2016, GDHC1163EIGlobalData (2016). Expert Insight: Lupus Low Disease Activity State (LLDAS): A Complementary Secondary Endpoint in Clinical Trials, January 2017, GDHC1164EI