SLE, commonly just called lupus, is an autoimmune disease that affects as many as 500,000 people in the United States. In people with the condition, the immune system malfunctions and, instead of attacking infections like it’s supposed to, it attacks healthy tissues. The organs and systems, most commonly affected by lupus include the skin, joints, kidneys and lungs.

“There are not many drugs that are currently effective against lupus, and many of those that are used tend to have a lot of side effects,” says Mary K. “Peggy” Crow, MD, Physician-in-Chief Emerita at HSS, Director of the Autoimmunity and Inflammation Research Program and Co-Director of the Mary Kirkland Center for Lupus Research at the HSS Research Institute. “I think the approval of this drug will be met with a lot of excitement, both by patients and the doctors who treat this disease.”

Anifrolumab is a monoclonal antibody that works by blocking the receptor for a family of molecules called type I interferon. These molecules are essential for the body’s natural defense against viral infections: When they detect an invader, they bind to the interferon receptor, which turns on a number of genes that rally the immune system to fight the infection. In lupus, however, this receptor is activated even when no infection is present, causing the immune system to instead attack its host.

The link between interferon and lupus was made thanks to decades of research. “There were observations going back to the 1970s that interferon was elevated in certain autoimmune diseases, including lupus,” Dr. Crow says. “But it wasn’t until the availability of gene microarrays in about 2000 that my lab was able to begin figuring out exactly what interferon’s role is in the disease.”

In the lab, Dr. Crow and her team began studying the blood of people with lupus and comparing it to the blood of healthy individuals. They looked at which genes were being transcribed in each group, and when they compared the lists they saw that there were substantial differences. “It was like a puzzle, trying to figure out what the data meant,” she remembers. “But as we took a closer look, it became clear that many of the differences between patients and healthy donors were genes that were regulated by type I interferon.”

In 2003, Dr. Crow and her HSS team were one of three groups to publish research confirming interferon’s pivotal role in lupus. Additional important findings came from mouse models of lupus. “The mouse studies helped to make the case that this type I interferon pathway really is contributing to disease pathogenesis,” she says. “They confirmed that this was an appropriate therapeutic target.”

One of the members of Dr. Crow’s lab who worked on this research was physician-scientist Kyriakos A. Kirou, MD, DSc, FACP, an Associate Attending Physician at HSS. Dr. Kirou now leads clinical trials for lupus at HSS and was involved in the anifrolumab trial. “Lupus is a very heterogeneous disease, and it’s difficult to bring it under control,” he says. “One of things that makes anifrolumab so promising is that it appears to work particularly well for patients whose disease is more severe. It was especially effective against the skin rashes that are common in lupus patients.”

He added that because the drug is targeted only at the type I interferon receptor, it appears to have relatively few side effects compared to drugs with more wide-ranging effects like steroids. But because it acts on the immune system, it does appear to increase the risk of upper respiratory infections. People who got the drug were also more likely to develop shingles, so it may be recommended that people get the shingles vaccine before starting the drug.

Dr. Crow says that because interferon is also implicated in other autoimmune diseases, it’s possible that anifrolumab may work in them as well. She adds that there are other promising drugs for lupus currently under investigation. “As an investigator who focuses on translational research, my goal is always to discover something that can benefit patients,” she says. “It’s very gratifying when your research can have a positive impact on people’s lives.”

"Omega-3 fatty acids in krill oil inhibit a number of aspects of inflammation, and krill oil supplementation has been proposed as an over-the-counter supplement for many different indications, including cardiovascular disease. In this trial, we are formally testing its potential to lessen the severity of symptoms associated with lupus," said Jane Salmon, MD, coordinating investigator of the multicenter trial and Director of the Lupus APS Center of Excellence and Co-Director of the Mary Kirkland Center for Lupus Research, both at HSS. "This multicenter clinical trial reflects our responsiveness to the wishes of our patients, a safe option that has the potential to attenuate lupus disease activity and the cardiovascular complications associated with it."

Kyriakos Kirou, MD, rheumatologist at HSS and site coordinator for the trial, said that if the trial is positive, he foresees using krill oil in people with active and inactive lupus. "This supplement is predicted to help the lipids in the bodies of patients with lupus," said Dr. Kirou. "People with lupus may develop premature cardiovascular disease because of dyslipidemia, problems with levels of lipids. When people affected by lupus are in their 40s, they are more at risk for developing heart attacks or strokes than others without the disease. Even people whose lupus has become quiet may develop atherosclerosis and heart disease."

Lupus, most often diagnosed between the ages of 15 and 45, is an acute and a chronic autoimmune, multisystem illness in which the body attacks its healthy tissues, resulting in redness or swelling, pain, and organ damage. It affects each person differently and can be very mild or severe. A panoply of symptoms, such as facial rash, painful or swollen joints, and inflammation of organs may come and go without warning. 

Researchers are launching the new trial, in part, because there is evidence that polyunsaturated fatty acids (PUFA) such as omega-3s inhibit inflammation, that people diagnosed with lupus are deficient in omega-3 PUFA, and that krill oil decreases disease activity in patients with rheumatoid arthritis. "Polyunsaturated fatty acids in animal models of lupus and lupus nephritis have shown improvement in survival, kidney disease, and levels of autoantibodies," said Dr. Kirou. "Omega-3s are the backbone for the synthesis of Specialized Pro-Resolving Molecules (SPM), anti-inflammatory mediators." In particular, krill oil contains omega-3 fatty acids that are bound to phospholipids, which significantly helps your body’s cells absorb the omega-3s better.

Patients in the double-blind trial will be randomized to receive either a soft gel formulation of krill oil (Aker BioMarine [AKBM]-3031, Omega-3 Phospholipids from krill) or placebo for 6 months and then all patients will receive the active supplement for another six months. "It is a safe supplement. There is strong rationale that it will effectively decrease inflammation in lupus," said Dr. Kirou.

Matts Johansen, CEO at Aker BioMarine said, "Lupus is a frustrating, chronic disease with no known cure which affects millions of people all over the world. We are so excited that molecules from krill can potentially reduce the symptoms associated with lupus."

The trial’s primary objective is to assess the ability of the supplements to replenish the omega-3 dietary deficiency in people with lupus, by measuring the omega-3 index and red blood cells in patients. Secondary objectives include assessing safety and quality of life, whether the correction of the omega-3 deficiency may reduce disease activity in patients with lupus, and whether it has a steroid-sparing effect.

HSS began enrolling patients on January 11. While in the clinical trial, patients will be maintained on stable doses of other medications, except for glucocorticoids; decreases in doses of glucocorticoids will be encouraged during the first 20-weeks of both the randomized and open-label extension portions of the trial. The trial will exclude patients on anticoagulants and those with shellfish allergies.

FDA-approved treatments for lupus are very limited, with only one new drug approved in that last 60 years. Researchers don’t expect krill oil to reverse very serious, life-threatening organ damage, but think it could be used an adjuvant and that it could attenuate disease by increasing the production of specializing pro-resolving molecules, thus decreasing the symptoms of lupus. 

"Krill oil may help the natural mechanisms of healing," said Dr. Salmon. "Steroids and immunosuppressive drugs have a range of side effects that people with lupus find hard to tolerate. If we can give them alternative therapies that allow them to take lower doses of their traditional drugs, it would make a very big difference to their quality of life. I don’t expect krill oil to be as potent as the immunosuppressive therapies we administer, but if it is even modestly effective, we may be able to maintain low disease activity with less medication."

HSS rheumatologist Kyriakos A. Kirou, MD, DSc, FACP, who was not involved with the study, commented on the results.

"This finding, if confirmed, may allow for a more patient-targeted approach when treating lupus, a notoriously heterogeneous disease," Dr. Kirou said.

"More epratuzumab studies are needed in patients with SLE and associated Sjogren's syndrome before we can conclude that this treatment is effective in this subgroup of patients," he added.

Read the full article at medpagetoday.com

HSS rheumatologist Michael D. Lockshin, MD, and director of the Center, shared his conversations with patient Barbara Volcker, wife of former U.S. Federal Reserve Chairman Paul Volcker. According to the article, Mrs. Volcker met Dr. Lockshin in the 1970s to treat her rheumatoid arthritis.

"She was the type of patient that I really enjoyed taking care of because she challenged me on everything. She would say, 'But that answer doesn't make sense. Give me the information behind it. Convince me.' She drove me to question my own assumptions to respond to her," said Dr. Lockshin.

In the late 1990s, Mrs. Volcker's health worsened, and the Volckers offered to establish a center at HSS to honor her. Dr. Steven Paget, who was physician in chief at HSS, and Dr. Charles Christian, who was the emeritus physician in chief, invited Dr. Lockshin, then acting director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), to discuss the center's mission, and he was ultimately offered the job as director, a position he still holds.

The Center was established in 1997. Mrs. Volcker passed away the following year at the age of 68.

"Her questions are the core of the Center that bears her name," noted Dr. Lockshin.

The Center convened a conference on the biology of sex differences in autoimmune illness—the first of its kind—within a year of opening its doors, notes Dr. Lockshin. The topic later gained national attention for all human health when the Institute of Medicine (later renamed the National Academy of Medicine) convened a committee to address the same question and published a report in 2001, according to Dr. Lockshin, who served on the committee. Doruk Erkan, MD, MPH, a rheumatologist at HSS whose early research focused on antiphospholipid syndrome, joined the Center in 2005 as physician-scientist.

Today, the Center is marking 20 years of research and clinical work devoted to women with various rheumatic conditions. According to Dr. Lockshin, physicians at the Center see more than 3,000 individual patients for issues of pregnancy and contraception, antiphospholipid syndrome, and other rheumatic illnesses.

As part of the Center's research, HSS rheumatologists Jane E. Salmon, MD and Lisa R. Sammaritano, MD are co-investigators of a study on hormone treatment in lupus as well as pregnancy in lupus patients.

Additionally, HSS research associate Mikhail Olferiev, MD received a grant from the center to study the expression of genes across health donors and patients with lupus. "I hope that my study will contribute to a better understanding of an autoimmune disease and possibly identify new therapeutic targets," Dr. Olferiev said.

HSS scientist Theresa T. Lu, MD, PhD also received a grant to study whether fat tissue might influence stromal cells in lymph nodes to contribute to sex differences in rheumatic diseases.

Dr. Lockshin explained that concepts and ideas about pregnancy and issues related to women with rheumatic diseases have changed over time in part because of research discoveries coming out of HSS.

Additionally, the Center recently welcomed a new member, HSS rheumatologist Medha Barbhaiya, MD, MPH. Dr. Barbhaiya explained that she joined HSS because of the Center's strong emphasis on clinical care and clinical research related to lupus, antiphospholipid syndrome, and pregnancy in rheumatic diseases.

Several of its members hold leadership positions associated with the Center's mission, according to Dr. Lockshin. For example, Dr. Erkan chairs both the Antiphospholipid Syndrome Alliance for Clinical Trials and International Networking, headquartered at the Center, and the 15th International Congress on Antiphospholipid Antibodies. Kyriakos Kirou, MD, conducts lupus nephritis clinical trials, and Dr. Sammaritano chairs the ACR Reproductive Health Guideline Project. With a background in environmental causes of autoimmune illnesses, Dr. Barbhaiya is involved with the ACR. In addition, Dr. Lockshin served on committees with a focus on pregnancy, sex differences, and other aspects of autoimmune illness and he is past editor in chief of Arthritis & Rheumatism (now Arthritis & Rheumatology).

In a phone interview, Mr. Volcker said that he is delighted with the Center's accomplishments over the years. Furthermore, he said he is sure if Mrs. Volcker were alive she would be "very pleased and happy that her name was attached to it, no doubt in my mind".

Read the full article at the-rheumatologist.org. This also appeared in the January 2018 print issue.