Studies Highlight Risk of Damage from Lupus Treatments

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WASHINGTON, D.C.—Conference goers who braved the final day of the 2016 ACR/ARHP Annual Meeting were awarded for their stamina by learning about issues relating to the damage caused by systemic lupus erythematosus (SLE) during the session Systemic Lupus Erythematosus—Clinical Aspects and Treatment V: Damage and Morbidity.

Minimizing Damage: Early Use of GC-Sparing Strategies

Jayne Little, MSc, National Institute for Health Research, Manchester Musculoskeletal Biomedical Research Unit, Central Manchester University Hospital NHS Foundation Trust, Manchester, U.K., presented the results of a study that showed the importance of using glucocorticoid (GC)-sparing strategies early to minimize the risk of damage in patients with SLE.¹

Using data from 1,700 SLE patients in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort, Ms. Little reported on the cumulative incidence of total and GC-related damage.

The SLICC cohort recruited 1,848 patients between 2000 and 2011, all of whom had developed four or more 1997 ACR criteria for SLE within 15 months prior to recruitment. This current study included 1,700 patients from the cohort who had a minimum of one follow-up visit (in addition to their enrollment visit) and a SLICC Damage Index (SDI) score recorded at least once. Most patients were female (88.6%), white (50%) and had an average age of 33 years at baseline. Most patients (70%) were on an oral GC at enrollment, but oral GC use declined with increasing disease duration. However, 90.5% of patients received oral GCs at some time during the study. Parenteral GC use was uncommon prior to enrollment (13.8%), as well as during the study period (approximately 4.3%).

To assess the accumulation of damage, the investigators explored the trend in total SDI scores and cumulative incidence of SDI damage items over time. The individual damage items had previously been grouped (through a consensus exercise performed among SLICC) into those items “definitely,” “probably” or “not” associated with the use of GCs.

The study found that the total SDI score increased over time in a linear fashion. At enrollment, 23% of patients had some damage (SDI >0). At 10 years, this percentage increased to 54% (with a mean SDI of 2).

When looking at individual items, the study found that the most common damage in early disease (within two years of diagnosis) was alopecia, proteinuria and cognitive impairment, occurring in about 3% of patients, followed by diabetes and cataracts, occurring in about 2% of patients. Of these, diabetes and cataracts, and probably cognitive impairment, were linked to the usage of GCs. At 10 years, the cumulative incidence of alopecia and cataracts was 10% of the population.

‘These data on secular trends & disparities call to action the need to develop targeted research & public health programs to identify the modifiable risk factors in order to promote health equity among patients of all backgrounds with SLE.’ —Dr. Ram R. Singh

When looking at musculoskeletal items, the study found that although the cumulative incidence of avascular necrosis was relatively low at two years, by 10 years it was within the top five items, with a cumulative incidence of 6.8%. Other musculoskeletal items that were relatively common included deforming erosive arthritis and GC-related damage, including osteoporotic fracture and muscle atrophy/weakness, with cumulative incidences of 2.6% and 3.6%, respectively, at 10 years.

When these items were grouped together, 15.9% of all damage that occurred during the first two years was found to be associated with GCs, a figure that rose to 36.8% in Year 10. The annual incidence rate of items definitely related to GCs was 3.1% in the first two years and 3.7% in Year 10.

Ms. Little emphasized the importance of recognizing that the annual incidence rate of damage related to steroids is almost the same in the first two years as it is in Year 10. This shows “that steroid-related damage can occur early,” she said.

Because of this, Ms. Little concluded that “early introduction of GC-sparing strategies is essential to minimize the risk of short- and long-term damage in SLE.”

Mortality Trends

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Several presentations reported on mortality trends in SLE patients. April Jorge, MD, Department of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, presented the results of a large population-based matched cohort study that looked at the changes in mortality trends over recent years among SLE patients.²

Using data from the medical record database of the Health Improvement Network in the U.K, Dr. Jorge and colleagues identified cases of SLE and up to 10 controls matched on age, sex and entry time and compared mortality rates between an early cohort (1999–2006) of SLE patients (n=1,470) and controls (n=7,348) and a late cohort (2007–2014) of SLE patients (n=1,666) and controls (n=8,318).

With a mean follow-up time of 3.3 years, the study found that SLE patients had a higher risk of mortality compared with controls in both the early cohort (15.9 deaths vs. 7.9 deaths/1,000 person-years) and late cohort (31.8 vs. 7.0 deaths/1,000 person-years), with a hazard ratio of 2.15 (95% CI, 3.5–10.0) and 2.12 (95% CI, 1.61–2.80), respectively. The corresponding absolute mortality rate differences were 8.1 (95% CI, 1.3–11.8) deaths/1,000 person-years in the early cohort, and 6.9 (95% CI, 3.5–10.0) deaths/1,000 person-years in the late cohort.

The similar hazard ratios and absolute mortality rate differences found, after adjusting for age, sex and entry time, suggest similar levels of excess mortality in SLE patients in the two cohorts, said Dr. Jorge.

The study shows that “excess mortality for lupus patients has not improved relative to matched controls over the recent 16-year period,” Dr. Jorge said. This finding is in contrast to the substantial improvement in survival seen for other autoimmune diseases during the same time period.

In proposing possible explanations for this, Dr. Jorge said it could be because of suboptimal care of comorbidities, such as cardiovascular disease, medication side effects or lack of adequate treatment options for disease control.

Population Trends in Mortality

Ram R. Singh, MD, professor of medicine, Division of Rheumatology, University of California, Los Angeles (UCLA), on behalf of lead author Eric Y. Yen, MD, followed up with another study that looked at the trends in SLE mortality by assessing the temporal trends in and population characteristics associated with mortality for SLE vs. non-SLE causes over 46 years in the U.S.

Data on SLE deaths from death certificates from the Centers for Disease Control and Prevention (CDC) national mortality database was used to calculate the annual percentage change in mortality in the U.S. between 1968 and 2013. To examine the population characteristics associated with SLE mortality, investigators used grouped-data logistic regression to model SLE mortality as a function of these characteristics (i.e., gender, race and geographic region).

The study found that SLE mortality, relative to non-SLE mortality, has not decreased over the 46 years of the study. Compared with a 44% reduction in non-SLE mortality from 1968 to 2013, SLE mortality dropped by 24%.

Using a joinpoint analysis to examine the ratio of SLE and non-SLE mortality rates based on age-standardized mortality rates (ASMRs), the study found that an annual percent reduction of -1.2 in SLE mortality from 1968–1974 was followed by an increase of 6.5% annually from 1975–1980, an increase of 1.4% annually from 1980–1989 and a drop of 1.2% annually from 1999–2013.

When looking at the SLE and non-SLE mortality rates by gender, race and geographic region, the study found that non-SLE mortality continued to decline over the 46-year period regardless of gender, race or geographic region.

The study found, however, that being female, being black and living in the West or South resulted in higher levels of SLE mortality. Highlighted in the study were significant inequities associated with SLE mortality when considering sex, race and geography.

Using national estimates for SLE prevalence per 100,000 to calculate SLE case-fatality based on these variables, the study found men had a higher mortality than women (OR 1.94, P<0.001), the mortality rate of blacks was higher than of other racial groups (OR 5.24, P<0.001), and the mortality rate of people living in the South and West was higher than those living in the Northeast (OR 1.55, P<0.001; and 1.44, P<0.001, respectively).

Compared with whites, blacks died from SLE at a younger age, with 50% of total deaths in blacks occurring by age 45 compared with age 59 in whites. Hispanics also died younger, with 50% of deaths occurring by age 44 compared with age 54 for non-Hispanics.

“These data on secular trends and disparities call to action the need to develop targeted research and public health programs to identify the modifiable risk factors in order to promote health equity among patients of all backgrounds with SLE,” said Dr. Singh.

Mary Beth Nierengarten is a freelance medical journalist based in Minneapolis.

References

1. Little J, Lunt M, Parker B, Bruce IN. Total and glucocorticoid-related damage accrual in the systemic lupus international collaborating clinics inception cohort [abstract 3167]. Arthritis Rheumatol. 2016;68(suppl 10).
2. Jorge A, Lu N, Rai SK, Choi H. Mortality trends in systemic lupus erythematosus: A general population-based cohort study [abstract 3169]. Arthritis Rheumatol. 2016;68(suppl 10).
3. Yen E, Shaheen M, Woo JM, et al. Temporal trends in SLE mortality according to sex, race, ethnicity, and geographic region in the United States over the past five decades [abstract 3172]. Arthritis Rheumatol. 2016;68(suppl 10).