CME Author: Zeena Nackerdien
Study Authors: Sarfaraz Hasni, Sarthak Gupta, et al.
Target Audience and Goal Statement: Rheumatologists, primary care physicians, allergy specialists, nurses
The goal was to assess the safety, tolerability, and clinical efficacy of omalizumab in treating mild to moderate systemic lupus erythematosus (SLE).
- What was the safety and tolerability of omalizumab in SLE?
- What were the effects of immunoglobulin E (IgE) blockade on the type I interferon (IFN) gene signature?
Study Synopsis and Perspective:
Omalizumab (Xolair) was well tolerated and associated with improvement in disease activity, according to a study by Sarfaraz Hasni, MD, of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and colleagues.
While rates of all-cause mortality for SLE have declined in recent years due to improved management, there is still room for improvement, the team noted. “Treatment strategies include a variety of immunosuppressive medications used alone or in combination that are limited both in their efficacy and by significant potential toxicities. Clearly there is an unmet need for improved treatment of inflammation in this patient population.”
Molecular mechanisms underlying SLE — a debilitating, multi-organ disease — are known to involve an IgG subclass that contributes to interferon (IFN)-α responses and the eventual proliferation of autoantibodies, the researchers explained. IgE is known for its role in Th2 responses and in the pathogenesis of allergy.
Growing evidence suggests a role for IgE beyond allergy, the investigators noted — for example:
- Autoreactive IgE antibodies were recently implicated in a murine model of lupus
- Autoreactive IgE is believed to increase SLE disease activity through elevated basophil activation
- IFN-α production and DNA-containing immune complexes in phagosomes may be enhanced due to the presence of these autoantibodies in SLE
Overall, IgE might be involved in the maintenance and amplification of autoimmunity in SLE by inducing heightened activation of autoreactive immune responses. Omalizumab, a humanized IgG1 monoclonal antibody against human IgE, is FDA approved for treatment in select patients with moderate to severe persistent asthma and hives (chronic idiopathic urticaria). The drug helps to lower antibodies in the blood that may also be present in some people with SLE.
Hasni and co-authors hypothesized that depleting IgE autoantibodies with omalizumab in SLE patients with elevated autoreactive IgEs might interfere with type 1 IFN production, reduce autoantibodies, and ultimately reduce disease activity. To investigate this, the team randomly assigned 15 SLE patients with elevated levels of autoreactive IgE antibodies (>2 standard deviations above the mean of healthy controls) to receive 16 weeks of treatment with subcutaneous omalizumab at a loading dose of 600 mg followed by 300 mg every 4 weeks or placebo.
A 2:1 ratio was used for randomization. All the patients received open-label omalizumab for 16 weeks and were then observed for 4 weeks following discontinuation of the study medication. Participants were allowed to receive glucocorticoids and immunosuppressive therapy throughout the trial.
Exclusion criteria included the following:
- Having been on biologics prior to study enrollment
- Having a history of asthma, anaphylaxis, or known or suspected helminthic infection/infestation
- Weight >105 kg
- Having a total serum IgE level > 700 IU/mL or serum creatinine > 2.0 mg/dL
Disease activity assessments were made at each visit using the Physician Global Assessment, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K), and the British Isles Lupus Assessment Group index 2004. Type 1 IFN-induced gene signature (IFI27, IFI44, IFI44L, and RSAD2) was determined using quantitative polymerase chain reaction.
Omalizumab-treated patients tended to have a lower type 1 IFN-gene signature, especially if they had a high baseline type 1 IFN gene signature. Compared with the placebo group, these patients also showed a significantly greater improvement in median SLEDAI-2K score from baseline to week 16. But Hasni and colleagues noted that the magnitude of the difference was just two and that no other clinical measures differed between the groups.
Omalizumab was well tolerated, and caused no allergic reactions, the researchers reported. A total of 52 adverse events (AEs) occurred in the 15 patients over the course of 36 weeks. Most of the AEs (94.2%) were mild to moderate in severity. During the first 16 weeks of treatment, omalizumab-treated patients (n=10) had nine AEs, compared with 12 for the five on placebo. Mild to moderate AEs were comparable between the two study arms. Moreover, “no trend of involvement of a particular organ system was identified,” the team said.
Three serious AEs occurred during the study: One was in a patient on placebo who had bronchitis and developed chest pain; the second was a West African patient on omalizumab who had no evidence of immunity to chicken pox and developed varicella infection after exposure to the disease; and the third was in a patient who had a pulmonary embolism shortly after switching from placebo to omalizumab.
The researchers said it is worth noting that this exploratory study was not powered for efficacy and a larger sample size will be needed to ascertain if omalizumab has a potential to treat a selected subset of patients with SLE and high levels of anti-IgE antibodies. Additional mechanistic studies controlling for inter-test variability will also need to be done in the future to fully elucidate the mechanism of action of omalizumab in SLE, the team added.
Source Reference: Arthritis and Rheumatology, online Dec. 29, 2018, DOI: 10.1002/art.40828
Study Highlights: Explanation of Findings
In this proof-of-concept study of omalizumab, an anti-IgE antibody, researchers found its safety profile acceptable as an add-on therapy in SLE and there were no immediate or delayed allergic reactions. Improvements in disease activity, as measured only by a change in the SLEDAI 2 score, were noted, but this change of approximately two points was below the threshold typically considered to be a clinically minimally important change. Outcomes did not worsen while patients were on omalizumab during the study period.
However, the development of a pulmonary embolism in one patient following a switch from placebo to omalizumab is cause for concern, Hasni and co-authors said. Was this event related to the study drug? After all, a 5-year observational study of patients with asthma showed a higher incidence rate of cardiovascular/cerebrovascular events in the omalizumab-treated cohort versus the non-omalizumab group. Those authors attributed this result to differences in asthma severity between the cohorts, but said they could not rule out a possible contribution by the study drug to the AEs.
Hasni and colleagues offered an alternative hypothesis for the pulmonary embolism, that it could have been due to an elevated risk of thromboembolic events in SLE. Taken together, this suggests a need for markers of vascular risk and assessments of vascular dysfunction in future studies of omalizumab in SLE, the researchers advised.
They explained that reduced type 1 IFN gene signatures in omalizumab-treated patients suggest that the mechanism of action of the study drug in SLE may involve abrogation of dysregulated IFN pathways, and suggested expanding the list of potential biomarkers that may be involved in this pathway (e.g., CD62L and Th2 cytokines).
“A potential advantage of omalizumab in SLE is a side effect profile different from immunosuppressive drugs and a convenient once-a-month subcutaneous administration schedule,” Hasni and colleagues wrote. “Overall, this is the first trial to test the safety and potential efficacy of blocking IgE autoantibodies as a novel non-immunosuppressive agent in treatment of SLE. Additional larger studies will be needed to more fully evaluate the efficacy and safety of omalizumab in SLE.”
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco