Healthy lifestyle associated with lower risk of systemic lupus erythematosus

14th August 2021

The adherence by women to four or more healthy lifestyle factors appears to halve of the risk of developing systemic lupus erythematosus.

Lupus is a condition which causes skin rashes, joint pains and fatigue and systemic lupus erythematosus (SLE) is the most common form of lupus, accounting for around 70% of cases. SLE is a chronic, autoimmune disease with a significant disease burden and has been ranked as among the top 20 causes of death in women aged between 5 and 64 years of age. The cause of SLE remains unclear although external factors such as exposure to UV radiation, obesity and cigarette smoking, have all been implicated in worsening of the disease, potentially due to increased oxidative stress and systemic inflammation.

The adoption of a healthy lifestyle, e.g., increased exercise, maintaining a healthy weight, stopping smoking etc, reduces the risk of many chronic conditions such as cardiovascular disease, risk of stroke etc and a recent study has shown that nearly a third of cases of the autoimmune disease, rheumatoid arthritis could be attributed to unhealthy lifestyle factors, e.g., obesity and smoking. With the possibility that lifestyle measures could impact on autoimmune diseases, a team from the Division of Rheumatology, University of Calgary, Canada, decided to prospectively evaluate the effect of healthy lifestyle measures on the development of SLE. The researchers turned to the two Nurses’ Health Studies which were in 1976 and 1989 respectively and are long-term prospective studies, following the health of women. Participants in these two studies, are required to self-complete lifestyle questionnaires every four years. The team identified participants who did not have SLE or any other connective tissue disorder at the start of the study but subsequently identified incident cases from their follow-up questionnaires and cross-referenced with medical records. The team used the healthy living index score (HLIS) which assesses physical activity, cigarette smoking, body mass index and dietary habits and ranges from 0 (least healthy) to 5 (most healthy). The score was calculated at baseline and every 2 years and the researchers used multivariate analysis to determine the relationship between HLIS scores and the risk of systemic lupus erythematosus.

Findings
A total of 185,962 women with mean age of 52.1 years included in the analysis. There were 203 incident cases of systemic lupus erythematosus were diagnosed a median of 10.8 years after enrolment in the study. Overall, the researchers calculated that adoption of each additional healthy lifestyle behaviour was associated with a 19% lower risk of developing SLE (hazard ratio, HR = 0.81, 95% CI 0.71 – 0.94). Among women within the highest HLIS category who had at least four healthy lifestyle behaviours, the risk of developing SLE was more than halved (HR = 0.42, 95% CI 0.25–0.70) compared with women who had less than or equal to one healthy behaviour.

Commenting on their findings, the authors suggested that it was likely that the combination of healthy lifestyle behaviours acted synergistically to mitigate the biological processes involved in the development of systemic lupus erythematosus. They concluded that healthy lifestyle measures should be adopted to help reduce the risk of developing SLE.

Citation
Choi MY et al. A combination of Healthy Lifestyle Behaviours Reduces Risk of Incident Systemic Lupus Erythematosus. Arthritis Rheumatol 2021

Anifrolumab approved by FDA for systemic lupus erythematosus

6th August 2021

The interferon antagonist anifrolumab has been cleared for the treatment of adults with moderate-to-severe systemic lupus erythematosus by the FDA.

Systemic lupus erythematosus (SLE) is a rare, chronic autoimmune disease which affects approximately six-times more women than men. It is the most common form of lupus, accounting for approximately 70% of all cases. There is a wide geographical variation in the incidence of SLE and has been found to vary between 23.2 cases per 100,000 in North America to 0.3 cases per 100,000 in Africa and the Ukraine. Other estimates suggest a general prevalence of approximately 1 to 10 per 100,000 person-years.

SLE is a systemic illness affecting many different organ systems including the skin, with a typical butterfly rash across the cheeks, the musculoskeletal system, producing arthritis and myositis, and constitutional symptoms such as fatigue, fever and weight loss. The cause of SLE remains unclear but the condition is characterised by the presence of autoantibodies and guidance from EULAR in 2019 has suggested treatment with hydroxychloroquine, glucocorticoids, immunosuppressants and biologics, in particular, belimumab. However, it has been shown that in patients with SLE, there is excessive production of type 1 interferon (IFN) and in particular, INF-alpha. Blockage of type 1 IFN could therefore represent a potential therapeutic modality for SLE.

Anifrolumab
Cell signalling in SLE occurs via activation of the IFN pathway mediated via the type 1 IFN receptor. Moreover, blockage of this IFN pathway may reverse immune dysregulation and the tissue damage seen in SLE. Anifrolumab binds to the IFN receptor and therefore potentially reduces some of the immune dysregulation seen in SLE.

The FDA based its approval of anifrolumab on the results of three separate trials. The first in 2016, undertaken in 305 patients, showed that treatment with intravenous anifrolumab (300mg or 1000mg) every 4 weeks for 48 weeks led to a substantial reduction in disease activity in patients with moderate-to-severe SLE. Further studies included TULIP-1 and TULIP-2, both of which were Phase III trials. The primary endpoint was the rate of British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA), which is a validated global measure of treatment response among those with SLE. Interestingly, anifrolumab failed to reach the BICLA endpoint in TULIP-1 (37% vs 27%, anifrolumab vs placebo) when added to standard therapy. In contrast, significantly more patients assigned to anifrolumab than placebo, achieved the primary endpoint in TULIP-2, (47.8% vs 31.5%, anifrolumab vs placebo, p = 0.001).

An ongoing clinical trial in approximately 360 participants with moderate-to-severe SLE, is currently assessing the efficacy and safety of a subcutaneous form of anifrolumab in adults receiving standard therapy, over a 52-week period.

Anifrolumab is under regulatory review in both the EU and Japan.

Source. AstraZeneca August 2021

Gradual withdrawal of steroids safe in systemic lupus erythematosus

21st July 2021

Gradual reduction of glucocorticoids in patients with quiescent systemic lupus erythematosus does not increase flares or damage accrual.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects the joints, skin, brain, lungs and kidney, leading to widespread inflammation and tissue damage. Treatment involves the use of hydroxychloroquine and according to guidance issued by the European Alliance of Associations for Rheumatology (EULAR), chronic maintenance therapy with glucocorticoids. The long-term use of glucocorticoids in SLE however, is associated with organ damage and in one study of over 2,000 patients, it was found that a 1mg/day increase in use of the glucocorticoids, in particular prednisolone, was associated with 2.8% increase in the risk of developing new organ damage. Furthermore, even above a relatively low dose of 4.42mg daily, glucocorticoids can still exert damage in SLE. Not surprisingly, clinicians wish to withdraw glucocorticoids, with one survey finding that 96% of clinicians would withdraw an oral steroid after 5 years in serologically quiescent disease, while the patient continued with hydroxychloroquine.

Nevertheless, an important barrier to glucocorticoid withdrawal in systemic lupus erythematous is that the rate of withdrawal is yet to be determined. In a 2020 study abrupt withdrawal of low-dose prednisolone (5mg) in patients with clinically inactive disease was found to increase the incidence of disease flares compared to those who were maintained on the drug over the following 12 months. But what if gradually tapering the dose of glucocorticoid was used instead and this was a question posed by a team from the University of Toronto Lupus Clinic, Ontario, Canada. They decided to explore the impact of slowly reducing the dose of glucocorticoid in systemic lupus erythematous patients who had been in clinical remission for at least 2 years. Patients taking 5mg of prednisolone were instructed to reduce their dose by 1mg/day as follows: in the first week, maintain 5mg daily for six days and reduce to 4mg on day 7; for the second week, maintain at 5mg for 5 days and reduce to 4mg for 2 days; for the third week, maintain 5mg for 4 days and 4mg for three days and so on. At week 7, the patients remained on the reduced dose until their next clinic appointment with an overall aim of stopping the glucocorticoid after 9 to 18 months. The main outcome of interest was the proportion of patients who experienced a disease flare within the 2 years, assessed in terms of the SELDAI-2K score, which is a global index of ongoing disease activity.

Findings
In total, 204 patients with SLE were included and were equally assigned to a withdrawal or maintenance group. In the withdrawal group, the mean age of participants was 44.1 years (90.2% female). The disease flare rate (i.e., an increase in SELDAI-2k) scores occurred in 17.6% of the withdrawal group compared to 29.4% in the maintenance group (p = 0.023) after 12 months. After 24 months, the corresponding flare rates were 33.0% vs 50% (withdrawal vs maintenance, p = 0.01). At 24 months, the proportion of flares requiring an escalation in systemic therapy, was 14.7% vs 27.5% (withdrawal vs maintenance, p = 0.024). Additionally, after 24 months, a higher proportion of patients in the maintenance group accrued new damage (6.9% vs 17.6%, withdrawal vs maintenance, p = 0.022).
The authors discussed how their results indicated that gradual withdrawal of prednisolone in patients with SLE, did not lead to an increased incidence of flares or organ damage over 24 months. They concluded that the gradual withdrawal of glucocorticoids was a much better strategy that abrupt discontinuation and called for this approach to be examined in a randomised trial.

Citation
Tselios K et al. Gradual glucocorticosteroid Withdrawal Is Safe in Clinically Quiescent Systemic Lupus Erythematosus. ARC Open Rheum 2021