Clinical advances in systemic lupus erythematosus

The results of two studies presented today at the Annual European Congress of Rheumatology (EULAR 2018) demonstrate exciting advances for individuals suffering from systemic lupus erythematosus (SLE). The first is a phase II clinical study of a promising oral treatment, baricitinib. The second demonstrates the effective use of the shingles vaccine in SLE patients who are particularly prone to this infection.

"Novel therapeutic strategies are needed for SLE, which causes significant morbidity and mortality, and so we are delighted to see the positive results from the phase II trial of baricitinib," said Professor Thomas Dörner, Chairperson of the Abstract Selection Committee, EULAR. "In addition, we welcome data on the vaccination of SLE patients against shingles, as currently there is considerable clinical uncertainty around this issue."

SLE is an autoimmune disease that is also referred to as lupus. It typically affects women between the ages of 15 and 50, and symptoms flare up unpredictably. SLE is caused by complicated interactions between the immune system and environmental factors leading to an imbalance in the way the immune system works. This imbalance causes inflammation which, if untreated, can lead to disability and a shortened lifespan. Different factors may trigger SLE in different people, and symptoms may vary considerably. In some the illness is never life-threatening but can cause chronic skin rashes or arthritis. Others develop potentially life-threatening disease in the kidneys, lungs or heart. Treatment of SLE traditionally involves non-specific anti-inflammatory or immunosuppressive medications. However, this approach is ineffective in many patients, and can be associated with many undesirable side effects.

Baricitinib provides significant clinical improvements with acceptable benefit/risk profile in SLE patients

Baricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 which has been approved for the treatment of rheumatoid arthritis in Europe and Japan. In this phase II study, SLE patients taking baricitinib had a significant improvement in several clinical outcomes compared to placebo.

"Our results demonstrated significant clinical improvements in SLE patients taking baricitinib versus placebo with an acceptable side effect profile," said Daniel Wallace, MD, FACP, MACR, Professor of Medicine, University of California-Los Angeles and Associate Director of the Rheumatology Fellowship Program at Cedars-Sinai Medical Center in Los Angeles, California. "We look forward to progressing baricitinib in further clinical studies as a promising new treatment for people suffering with SLE."

Current biologic agents for SLE target the B-cell due to the importance of autoantibodies in driving the origination and development of the disease. However, the interferon (IFN) pathway and other cytokines (such as IL-23, IL-12 and IL-2) have recently emerged as a promising therapeutic target. By targeting common components of the signalling cascade, such as the JAK-STAT pathway, there may be therapeutic advantages by more complete suppression of IFN and other cytokines in disease-related processes.

This study included 314 patients with SLE receiving stable background therapy who were randomized 1:1:1 to placebo, baricitinib 2- or 4-mg once daily. Patients on baricitinib 4mg achieved significant resolution of arthritis or rash (SLEDAI-2K†) compared with placebo (67% vs 53%, p<0.05) which was the primary endpoint of the study. Patients on baricitinib 4mg also achieved a significantly greater SRI-4‡ response (64% vs 48%, p<0.05), as well as flare reduction (SFI§), improvement in Lupus Low Disease Activity State (LLDAS) and reduced tender joint count. Rates of adverse events leading to treatment discontinuation and serious adverse events (SAE) were higher for both baricitinib doses compared to placebo. There were no deaths, malignancies, major adverse cardiovascular events, tuberculosis, or serious herpes zoster infections; one SAE of deep vein thrombosis was reported in a patient with risk factors.

Shingles vaccine well tolerated in patients with SLE2

Shingles, or herpes zoster (HZ), is a painful reactivation of varicella zoster virus which typically happens decades after an initial infection known as varicella or chickenpox. Patients with SLE are 10 times more likely to contract shingles compared to healthy individuals and it can also affect them at an earlier age.4 Although rarely life-threatening, shingles is associated with significant pain and associated morbidity and may lead to disruption or discontinuation of otherwise necessary immunosuppressant medications.

Specific guidelines about the use of the shingles vaccine in SLE patients have been lacking, largely due to a theoretical concern of vaccine-induced infection as well as the lack of clinical or experimental data upon which to base recommendations.

"Our study showed that the live attenuated shingles vaccine was well tolerated and provoked an expected antibody response in stable SLE patients not receiving intensive immunosuppression," said Dr. C.C. Mok, Department of Medicine, Tuen Mun Hospital, Hong Kong (study author). "This is the first randomised controlled trial to study the shingles vaccine in individuals with SLE. We hope our results will inform guidelines and ultimately lead to the safe administration of the vaccine in appropriate SLE patients to reduce the burden of shingles in these individuals."

The study included 90 patients with stable SLE who were not receiving intensive immunosuppression. All participants had a history of HZ/chickenpox and were randomised to receive shingles vaccine or placebo. After six weeks antibody levels in the vaccine group increased by 59.8% versus a reduction of 2.1% in the control group (p=0.01) demonstrating the effect of the vaccine. Significance was maintained after adjustment for baseline value, lymphocyte count, immunoglobulin levels, SLEDAI, and other clinical variables.

No serious adverse events were reported. In the vaccine group, significantly more patients reported mild pain and redness at the injection site which subsided in a few days. None of the patients had clinical shingles infection post vaccination.