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The progression toward more targeted, disease-modifying options for the historically difficult rheumatic disease made more headway in 2023.
Lupus therapy has been undergoing a transformation in recent years. Traditionally, drugs like hydroxychloroquine have been a mainstay in treatment, but recent clinical trials involving targeted pathways have shown success, signaling a shift towards improved outcomes in systemic lupus erythematosus (SLE). The BLISS study on belimumab over a decade ago and recent TULIP trials on anifrolumab revealed promising benefits in lupus care.1,2
These results create an opportunity for more treatment options, targeted therapies, and potential upcoming drugs in the next decade.
“Lupus is the most common rare disease, affecting approximately one in 1,000 patients,” Chris Wincup, MBBS, MRCP, consultant rheumatologist at King’s College Hospital Lupus Unit, explained to HCPLive. “Many of the symptoms of lupus cannot be seen physically, which means that the delay in getting diagnosed. This is why lupus is often termed ‘an invisible illness.’”
Although lupus is often misrepresented as a mild illness with symptoms like fatigue, mouth ulcers, joint pain, and rashes, the reality is these symptoms can be devastating for a patient. For instance, approximately 50% of people with lupus will develop kidney disease which could lead to severe, life-threatening damage.3
The unmet needs of this patient population include insufficient efficacy of current medications and the side effects and toxicities of medications, which can limit use and contribute to intolerability, further underscoring the demand for better treatment options.
“Morbidity and mortality are still at unacceptable levels and increased compared to the general population, particularly noted in women of color,” Rosalind Ramsey-Goldman, MD, DrPH, John P. Gallagher Research Professor of Rheumatology at Northwestern University Feinberg School of Medicine, told HCPLive. “For example, the response rate for treatment of lupus nephritis trials is less than 50% and this segues into a significant number of patients going on to end-stage renal disease (ESRD) needing renal replacement (dialysis or transplant). These outcomes are especially notable outcome disparities in lupus.”
Lupus is generally treated with US Food and Drug Administration (FDA)-approved medications including anti-malarials (hydroxychloroquine), glucocorticoids (corticosteroids, prednisone, and methylprednisolone), immunosuppressants (voclosporin), and biologics (belimumab and anifrolumab).
The recent approvals of voclosporin, belimumab, and several other biologic disease-modifying antirheumatic drugs (DMARDs) offer a chance to not only improve long-term renal outcomes but also address the challenges associated with conventional immunosuppressants, including poor tolerance, low drug adherence, high disease flare rates, and cumulative steroid toxicity.
“The role of conventional immunosuppressants in SLE, such as mycophenolate, azathioprine and methotrexate, alongside antimalarial therapy is well established,” said Jack Arnold, MBBS, MRCP, clinical research fellow at Leeds Centre of Rheumatic and Musculoskeletal Medicine. “Targeted therapies are more selective in the way they target the pathology of SLE. In the case of belimumab and anifrolumab, their longer-term outcome data allows us to start to think of these medications as longer-term disease modifying agents in SLE.”
Ultimately, the short-term goals of treatment are to control the disease quickly to prevent disease flares and organ damage, minimize the use of glucocorticoids, recognize and support symptoms most bothersome to patients, such as pain and fatigue, and aim for low disease activity.
DMARDs are agents designed to target the underlying autoimmunity responsible for lupus and lupus nephritis to prevent the disease from activating or reactivating. Brad Rovin, MD, a nephrologist specializing in autoimmune kidney disease and professor of internal medicine at Ohio State University Wexner Medical Center, thinks of DMARDs as a “reset” to the immune system.
These drugs would likely be used in combination with other treatments, especially when significant efforts are required to control organ inflammation. The strategy would involve initiating therapy to swiftly control inflammation while concurrently introducing drugs to inhibit autoimmunity. This dual approach aims to minimize the risk of recurrent disease as inflammation comes under control.
“This does not necessarily translate to cure,” he explained to HCPLive. “I suspect that for some or all of such treatments, the treatment will need maintained for a long time, and/or applied intermittently. But the hope would be prolonged intervals between disease activity, or no disease activity with maintenance of the therapy at a low and tolerable level indefinitely.”
In addressing active lupus nephritis, for example, where swift reduction of kidney inflammation is crucial to prevent chronic injury, the current primary approach involves glucocorticoids. These are complemented by other immunosuppressive agents that globally suppress the immune system to control autoimmunity. While this approach can manage the disease for some patients, it often falls short in modifying the disease itself, leading to ongoing sub-clinical activity or periodic relapses.
“In current DMARDS, we are looking for an approach that targets a specific aspect of the immune system and leaves the rest of the immune system intact to prevent infection, cancer, etc,” Rovin said. “I am not entirely sure we are there yet.”
There's also considerable excitement surrounding a new approach: CAR-T therapy, which utilizes genetically engineered cells for immunotherapy in autoimmune diseases, including refractory lupus.4 Although the research involved a small number of patients, the outcomes have been impressive.
“CAR-T is currently used in treating cancer by altering the immune response, thus it was logical to consider it in lupus and other autoimmune disorders too,” added Ramsey-Goldman.
Despite promising results, numerous unanswered questions persist, such as patient selection, the longevity of the response, pre-treatment side effects, potential complications post-cell infusion, and the substantial considerations of cost and resources required for administering this treatment. Multiple studies are underway to delve deeper into this strategy.
The management of SLE is a holistic approach and the focus on long-term outcomes should encompass more than just disease activity. Considerations must extend to factors like glucocorticoid toxicity, cardiovascular outcomes, and malignancy outcomes. Therefore, when evaluating patients, a comprehensive approach is imperative.
European Alliance of Associations for Rheumatology (EULAR) guidelines recommend combining antimalarial therapy with conventional DMARDs and, if that is not effective, biologic medications like belimumab and rituximab are added.5 In addition to pharmacologic treatments, a variety of supportive treatments to minimize side effects and manage potential or existing co-morbidities, such as smoking cessation, exercise, and eating a healthy diet are also often added to the treatment strategy.
Biologics like rituximab or belimumab are often used in combination with standard disease-modifying drugs. Trials, like BEAT-LUPUS combining rituximab and belimumab, indicate increased efficacy and good safety.6 As more biologics emerge, questions arise about combining them and defining who receives what. Moving forward, CAR-T cell therapy may also be considered in combination with other treatments as well.
“SLE and lupus nephritis can be difficult to manage, but several new treatment options have the potential to improve outcomes,” April M. Jorge, MD, rheumatologist at Massachusetts General Hospital, told HCPLive. “[Now,] the challenge is how to best incorporate these medications into clinical care.”
Currently, lupus trials commonly enroll patients with more severe disease. While they excel in treating active kidney or non-kidney lupus, their broader use could extend to moderate cases. With these new treatment options, the landscape could shift towards using biologics earlier in the disease and may change the conventional treatment approach.
“I think that if we truly get drugs that can very finely focus on the aberrant pathways that predispose to autoimmunity, we could change our approach to control and relieve the active inflammation damaging organs right at the beginning, and then, remove these broadly acting agents which put patients at risk for complications of global immunosuppression,” Rovin said. “If such agents in fact did more than simply suppress these aberrant pathways, but actually corrected the pathways, one could maybe start to talk about a real cure.”
The 3 FDA approved therapies for SLE in the past few years, 1 for systemic lupus (anifrolumab) and 2 for lupus renal disease (voclosporin and belimumab), provide hope for patients living with lupus and their clinicians.
“After many disappointing clinical trials and a decade without new lupus treatments, the past few years brought about several much-needed breakthroughs in lupus treatment,” said Jorge.
In a phase 3 trial, treatment with anifrolumab, a biologic immunosuppressant that targets interferon signaling, demonstrated a statistically significant difference in response compared with placebo (47.8% vs 31.5%, respectively). Additionally, among patients with a high interferon gene signature, response was shown in 48.0% of those receiving the study drug and 30.7% in the placebo group. Other endpoint studies also favored anifrolumab versus standard of care alone.7
Results of the phase 3 trial of voclosporin, a novel therapeutic developed for the treatment of adults with lupus nephritis, showed the primary complete renal response at week 52 was achieved in significantly more patients in the voclosporin group compared with the the placebo group (41% vs 23%, respectively).8
A phase 3 trial of belimumab, a B-cell targeted strategy, revealed a statistically significant difference in response to the drug after 2 years, with a greater percentage of subjects in the belimumab group achieving primary efficacy renal response compared with placebo (43% vs 32%, respectively). Thirty percent of patients in the belimumab cohort were able to achieve complete renal response compared with 20% of those in the placebo group. Further, the risk of a renal-related event or death was lower among patients who received belimumab compared with placebo.9
Ramsey-Goldman emphasized the importance of these findings lies in the way these drugs specifically target a pathway involved in the pathogenesis of lupus and lupus renal disease. However, as the response rate did not reach 50% in any of these trials, there is still an urgent need to develop new treatments or to use current treatments more effectively while minimizing potential side effects.
Other exciting developments include phase 2 trial results of litifilimab targeting interferon in lupus, results of which were recently published in the New England Journal of Medicine, exploring patients with active skin and joint disease in lupus.10 This agent is particularly of interest as it targets plasmacytoid dendritic cells producing interferon in lupus.
Two additional promising targeted therapies are deucravacitinib for systemic lupus and obinutuzumab for lupus renal disease, both of which are in phase 3 status.11,12
Deucravicitinib, an oral Tyrosine Kinase 2 (TYK2) inhibitor, showed favorable results in a phase 2 trial, successfully meeting as primary and all secondary endpoints. TYK2, which is closely related to the Janus kinase (JAK) inhibitor family, a mainstay in the treatment of rheumatoid arthritis. Response rate for this drug was 54% compared with 34% in standard of care alone. The benefit of this particular drug is its oral administration, which may be better tolerated and preferred by patients.11
“We know in lupus, adherence is a major barrier to many treatments,” Wincup explained. “And so, the use of an oral agent will be interesting, in particular for the small targeted molecules, as it is something new and relatively novel.”
According to a randomized, double-blind, placebo-controlled trial, patients with lupus nephritis treated with obinutuzumab plus standard therapies were more likely to achieve complete renal response at week 52 compared with those receiving placebo (35% vs 23%, respectively). Long-term response was maintained and slightly improved through week 104 in this patient population (41% vs 23%, respectively).12
Along with the treatments being currently explored, the focus of rheumatologists specializing in lupus is heavily centered on cell therapies, exploring their potential to reset the immune system and eliminate autoimmunity. While promising, these procedures need streamlining for broader accessibility.
Moving into 2024 and beyond, Jorge and Wincup believe the most exciting facet of current lupus research is the prospect of cellular therapy to transform lupus treatment. If results are supported by larger studies, CAR-T therapy has the potential to change the way autoimmune conditions are treated and the way clinicians think about the disease and deliver treatment.
“It is really exciting to suddenly see an entirely new area develop, and we hope that the results will continue showing that it is effective and safe in the longer term,” Wincup said.
Additionally, novel trial designs, including those looking at time in Lupus Low Disease Activity State (LLDAS), might provide a better representation of how effective these newer therapies are. As the field continues to move towards this strategy, it may enable better access to targeted therapies in the future.
“We are making significant progress discovering more about how the immune system works and leading to new ways to think about treating lupus, we are building on lessons learned from early trials and now are finally seeing the results of this work,” Ramsey-Goldman said.