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Hydroxychloroquine Protective Against Premature Mortality in SLE

Prior cardiovascular disease and prior cancer were the strongest predictors of premature mortality in patients with systemic lupus erythematosus (SLE), while the use of hydroxychloroquine was protective, according to an analysis of a large UK biologics register.

"Even in the biologics era with the expansion of new therapies, there remains significant excess death [rate] in young patients with SLE," said Dr Sarah Dyball from the University of Manchester, who led the study and presented the results at this year's British Society of Rheumatology (BSR) conference on Monday. 

"The median age of death in our analysis was harrowing, at 55.6 years, and this really brings it home as to why we need to take action to change this," stressed Dr Dyball. "The life expectancy in these patients seems to have stagnated since the early 2000s, so if we can find factors that are protective, or harmful, then this can help us as we strive for better care and reduce mortality in our patients." 

Dr Dyball highlighted the cardiovascular implications as well as the protective effect of hydroxychloroquine. "The study findings speak to the cardiovascular burden in patients with lupus making them more likely to die, but also, we found a that a key predictor of - and protector against - all-cause mortality was the use of hydroxychloroquine in these patients," she said, speaking to Medscape News UK

Hydrochloroquine Protective Against All-Cause Mortality

Hydroxychloroquine, which was part of treatment in all study patients, was found to be protective against all-cause mortality, raising questions about expanding its use in patients with SLE.

"This analysis shows us that hydroxychloroquine is protective against all-cause mortality. However, the literature suggests [only] 40-70% of lupus patients take this drug, so moving forward we need to consider why more patients aren't taking hydroxychloroquine and what we, as clinicians, can do to help them start it," asserted Dr Dyball.

The study aimed to assess the cause of death and characteristics of patients with SLE using data sourced from the British Isles Lupus Assessment Group Biologics Registry (the BILAG-Biologics Register) between 2010 and 2021, and from patients who had received biological or standard of care therapy (including mycophenolate or azathioprine).  

Demographic data, clinical, and laboratory data were gathered and recorded at recruitment, as well as information relating to date and cause of death. "Most patients in this register have moderate to severe disease activity, so these results won't necessarily apply to all patients with lupus," noted Dr Dyball. 

The researchers then determined the relationship between mortality and different patient variables to see if any clear associations were found over the 11-year study period. Of the nearly 1500 patients recruited to the BILAG-BR by February 2021, 69.3% of those still alive had taken rituximab, 10.4% belimumab, and 1.5% an investigational drug, while 18. 4% had received standard of care therapy. 

A total of 54 deaths were recorded, resulting in a standardised mortality rate of 5.97 (6.92 to 11.80) per 1000 person years, while the cause of death was documented in 96.2% of patients and included infection (38.9%), active SLE (18.5%), malignancy (11.1%), cardiovascular disease (11%), thrombosis (5.6%), opiate toxicity (1.9%), and cerebral haemorrhage (1.9%).  

Of patients who died, 88.9% were on rituximab (compared with 69.3% of those who lived), 1.9% on belimumab (10.9% of those who lived) and 1.9% on another biologic (1.5% of those who lived), and 7.4% on standard of care (18.4% of those who lived). Other characteristics at registration comprised greater White ethnicity in those who died (73.4% versus 57.4%); and longer disease duration (8.2 years versus 6.6 years). 

The average age at registration was higher in the group of patients who died (51.8 years versus 39.4 years). "This might be related to a more multi-morbid population, however age was independently associated with mortality too. Disease duration was higher in those that died, however, this did not come out as significant in the analysis," said Dr Dyball.

There were also some marked differences in co-morbidities at registration in patients who died versus those that lived, with myocardial infarction having been experienced by 12.5% versus 2.5%; hypertension recorded in 38.3% versus 24.2%; and diabetes mellitus in 17.0% versus 5.4%, respectively. Previous cancer was recorded in 27.8% versus 9%.

The analysis of factors associated with mortality showed that use of hydroxychloroquine, which was protective, generated an adjusted hazard ratio (HR) of 0.32 (0.12 to 0.65). Previous myocardial infarction was associated with an adjusted HR of 2.82 (1.16 to 6.86), diabetes mellitus HR 1.75 (0.65 to 4.71), previous cancer HR 2.23 (1.05 to 5.13), and hypertension HR 0.92 (0.43 to 1.99).

Implications for Cardiovascular Care

Session chair, Dr Sarah Tansley, consultant rheumatologist at the Royal United Hospitals Bath NHS Foundation Trust, commented on the implications for cardiovascular care. "How should we address the increased cardiovascular mortality– should we do it as part of our holistic care, or should we ask our primary care colleagues to take this on?"

Dr Dyball agreed on the importance of this. "We do need to actively monitor these patients. I see how busy my primary care colleagues are and I think I probably have more time to address these issues. We have a long-term relationship and good continuity of care so secondary care is a good place for this. However, we need to research exactly what and how screening should take place."

Dr Luay Zebouni, consultant rheumatologist at Epsom and St. Helier University Hospitals NHS Trust, also remarked on the need to screen for cardiovascular risk. "We should be more vigilant of the cardiovascular health in these patients. We need to bear this in mind with all inflammatory conditions. It [cardiovascular screening] was delegated to all primary care physicians but this is not the case everywhere, and perhaps it might be better to add it into the screening process in secondary care, where we can look at cholesterol, blood pressure and so on. Someone needs to take charge of this and do it properly and regularly. Unsure if leaving it to primary care is optimal at the moment."

Dr Dyball discloses grants/research support; MRC, GSK, and UCB. Dr Zebouni declares Dr Zebouni has declared no relevant conflicts of interest. Dr Tansley has declared no conflicts.