Proposing a standardized definition of what disease modification looks like in SLE and LN that can drive outcomes measured in clinical trials, is an important step.
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The goal of most treatments for chronic diseases is to provide positive disease modification that offers patients symptom relief by targeting the underlying pathophysiology. Definitions for disease modification are important in clinical research where treatments are evaluated on their ability to produce such a modification.
However, despite definitions for disease modification being established in several other autoimmune diseases, systemic lupus erythematosus (SLE) has flown under the radar for decades without a clear idea of what disease modification means for afflicted patients. A team of researchers, backed by GlaxoSmithKline, is trying to change that.
Systemic lupus erythematosus is an inflammatory autoimmune disease that can impact any system in the body. The disease is hallmarked by a myriad of symptoms caused by inflammation that stems from immune cells mistakenly attacking healthy tissues throughout the body. Symptoms can include extreme fatigue, pain or swelling in the joints, headaches, low-grade fevers, sensitivity to sunlight, loss of hair and rashes.
The disease can be difficult to diagnose as it mimics many others, including other autoimmune diseases such as rheumatoid arthritis, and no one blood test can make an ultimate determination. Not only that, but the disease can look vastly different between two people who are diagnosed. The Lupus Foundation of America estimates that 1.5 million Americans are diagnosed with a form of lupus, a majority of whom are women and racial minorities. SLE is characterized by a series of disease activity flares and remissions, and depending on the severity of symptoms, it can be treated through the use of anti-inflammatories, antimalarials, biologics or immunosuppressive drugs.
But how do patients, clinicians and researchers know that the treatment they’re utilizing to modify SLE is effective or producing a significant result? This is the question the researchers sought to answer in a recent paper published in Lupus Science & Medicine. The group, made up of 12 global lupus experts, came together to conceptualize a framework and criteria for defining disease modification in SLE by utilizing existing disease modification frameworks for other diseases and clinical measurements for SLE already in use.
As a result, the proposed definition is that disease modification in SLE requires minimizing disease activity with the fewest treatment-associated toxicities and slowing or preventing organ damage progression. The definition is specifically for SLE and lupus nephritis (LN), a subset of SLE denoted by inflammation and damage to the kidneys. In LN, it includes that the prevention of organ damage is defined as preventing progression to end-stage kidney disease.
“It’s a really important question to ask why we’ve not previously seen a definition for disease modification for lupus,” said Angela Carroll, U.S. medical affairs scientific director of immuno-inflammation at GSK and the paper’s co-author, in an interview with BioSpace. “I think it has a lot to do with the heterogeneity of the disease. There are so many different outcome measures and instruments that are used and while these instruments are great, they’re imperfect in some instances. No one patient is the same, and I think that has made it really challenging from that perspective.”
In clinical research, scientists may use a variety of instruments to determine disease modification and outcomes in SLE. For example, an assessment called the SLE Disease Activity Index (SLEDAI) consists of 24 different symptoms, conditions and biological markers that may accompany the disease. This provides a quantitative assessment of SLE disease activity in a patient. Although some researchers use the SLEDAI, others may instead refer to the British Isles Lupus Assessment Group (BILAG), which approaches the question of disease activity in SLE by assessing manifestations across eight different bodily symptoms and does not include the use of biological markers. When utilizing these assessments, of which there are many, challenges include deciding which one to employ and whether choosing one assessment over another provides a different outcome in disease modification.
Only adding to the puzzle is the fact that while the use of such instruments is widespread in clinical trials, they are not typically used in clinical practice.
Proposing a standardized definition of what disease modification looks like in SLE and LN that can drive outcomes measured in clinical trials, is an important step. By looking at the same clinical outcomes in trials, researchers can determine which treatments are best-suited to certain patients and truly begin to understand how to impact the cellular origins of the disease.
“I’m really excited about this. I think there is a terrific opportunity to begin harmonizing across clinical trials when we think about the clinical trial objectives. I think in the future, clinical trials are really going to focus on these key areas of that framework of disease modification,” Carroll emphasized. “Ultimately, that’s going to benefit patients. I think it’s going to help health care providers understand that we need to be focused not just on initial signs and symptoms but also on addressing the longer-term implications of a chronic disease like lupus or lupus nephritis.”
Focusing on the underlying disease pathophysiology is extremely important for patients with SLE and LN to avoid future complications. Some treatments, like anti-inflammatories, help to alleviate acute symptoms like pain but often do not target underlying aberrant immune conditions which promote inflammatory environments in the body.
“There’s this systematic approach to assess how patients are doing through different measurements. You ask yourself, ‘Are they on track with disease modification?’ If not, we may need to switch their therapy. I think there’s going to be great value in that instead of relying more heavily on things like steroids which work very acutely but have downstream repercussions as far as long-term irreversible organ damage,” Carroll said.
Moving forward, the team hopes that their proposed definition sparks great discussion and debate amongst the SLE research community so it can continue to be refined and reviewed to make the most influential impact. The team also plans to evaluate whether current treatments for SLE are actually disease-modifying according to their proposed definition, which will ultimately advance the lupus treatment space.
Although not in their confirmed plans for the future, the team is also open to the possibility of evaluating other subsets of lupus in order to propose additional standardized definitions of disease modification. Similar in pathology, subsets such as neuropsychiatric lupus, which is marked by significant brain and nervous system involvement, and cutaneous lupus, which impacts the skin, could also be addressed.
“We are laying the foundation for major positive improvements in lupus and lupus nephritis and I’m delighted to be a part of this,” Carroll said. “We are now looking toward continuing to move the needle and improve the lives of patients living with lupus.”
