Systemic Lupus Erythematosus (SLE), commonly known as lupus, is a chronic autoimmune condition where the body’s immune system mistakenly attacks its own healthy tissues and organs. This misguided immune response can affect almost any part of the body, including the skin, joints, kidneys, and brain, leading to inflammation and tissue damage. Traditional treatments for lupus have historically relied on broad immunosuppressive medications, which dampen the entire immune system to reduce inflammation.
Immunotherapy represents a more modern approach, seeking to treat the disease by specifically targeting the malfunctioning components of the immune system rather than suppressing the entire defense mechanism. This targeted strategy offers the promise of restoring immune balance while potentially minimizing the side effects associated with widespread immune suppression.
Immunotherapy Targeting B-Cells
B-cells are central players in the pathogenesis of SLE because they are responsible for producing autoantibodies, which are the misdirected proteins that attack the body’s own cells. Targeting these cells is a well-established strategy in lupus immunotherapy, aimed at either eliminating the autoantibody-producing cells or inhibiting their survival and activity. Therapies in this category fall into two main groups: those that deplete B-cells and those that block the signals required for B-cell survival.
One successful approach involves blocking a specific protein known as B-lymphocyte stimulator (BLyS), also called B-cell activating factor (BAFF). BLyS is a naturally occurring survival factor that promotes the maturation and survival of B-cells. The monoclonal antibody belimumab (Benlysta) works by binding to this soluble BLyS protein, which prevents it from interacting with receptors on the B-cell surface. By neutralizing this survival signal, belimumab encourages the death of autoreactive B-cells and reduces the overall level of autoantibodies in the blood. Belimumab holds the distinction of being the first biologic drug specifically approved by the United States Food and Drug Administration (FDA) for the treatment of SLE, including lupus nephritis.
Another method involves directly depleting B-cells from circulation using a different type of monoclonal antibody, such as rituximab. This drug targets the CD20 protein, which is found on the surface of most B-cells, leading to their destruction. Rituximab was originally developed for treating lymphoma and is commonly used off-label for severe lupus flares, particularly when other treatments have failed. While initial clinical trials for its use in SLE did not meet their primary endpoints, the drug’s effectiveness in case series and its profound B-cell depletion capacity have made it a frequently utilized option for severe, active disease.
Immunotherapies Modulating T-Cell Activity
T-cells, another type of white blood cell, function as crucial “helper” cells in the immune system, activating B-cells and coordinating the inflammatory response. For a T-cell to become fully activated and initiate an immune cascade, it requires not only a signal from an antigen-presenting cell but also a secondary co-stimulatory signal. Immunotherapies aimed at T-cells focus on disrupting this required secondary signal to prevent the T-cells from improperly stimulating the autoimmune response.
One therapy that employs this mechanism is the fusion protein abatacept. Abatacept mimics a natural regulatory protein called CTLA-4, which normally acts as a brake on T-cell activation. It works by binding to the co-stimulatory molecules CD80 and CD86 found on the surface of antigen-presenting cells. This binding effectively blocks the interaction between CD80/CD86 and the activating receptor CD28 on the T-cell, thereby preventing the T-cell from receiving the necessary second signal for full activation.
By preventing T-cell activation, abatacept aims to re-establish a state of immune tolerance and reduce the subsequent stimulation of B-cells and cytokine production. Although abatacept is widely used to treat other autoimmune diseases like rheumatoid arthritis, randomized trials in SLE have generally failed to meet their primary outcome goals. Experts suggest that future trials must focus on specific subsets of lupus patients, such as those with active arthritis or kidney involvement, to fully assess the drug’s potential based on its targeted mechanism.
Blocking Inflammatory Signaling Pathways
Beyond targeting specific immune cells, a parallel strategy in lupus immunotherapy involves blocking the molecular messengers that perpetuate the cycle of inflammation. These messengers, known as cytokines, act as communication signals between immune cells, driving the autoimmune response. A significant pathway implicated in lupus involves Type I Interferons (IFN), a group of cytokines whose levels are often elevated in 60% to 80% of adults with SLE. This high level of IFN activity drives the sustained immune activation and gene expression characteristic of the disease.
The drug anifrolumab (Saphnelo) is a monoclonal antibody designed to counteract this overactive signaling pathway. Specifically, anifrolumab binds to and blocks the Type I Interferon receptor subunit 1 (IFNAR1), which is present on the surface of many immune cells. By blocking this receptor, the drug prevents all Type I Interferons—including IFN-alpha, beta, and omega—from initiating their inflammatory signaling cascade. This blockade leads to the internalization of the receptor, effectively shutting down the downstream signaling events, such as the JAK-STAT pathway, which normally drive the expression of inflammatory genes.
Anifrolumab’s action reduces the expression of interferon-stimulated genes, decreases the activation of immune cells, and helps normalize the aberrant immune response seen in lupus. This highly specific mechanism addresses a root cause of the disease in a large subset of patients, leading to its FDA approval for moderate to severe SLE.
The Role of Experimental and Advanced Therapies
The frontier of lupus treatment is moving toward highly specialized, cell-based therapies for patients who do not respond to standard care. Chimeric Antigen Receptor (CAR) T-cell therapy is one such advanced treatment that has generated considerable excitement, adapted from its use in blood cancers. The process involves collecting a patient’s own T-cells and genetically modifying them in a laboratory to express a new receptor, the CAR, which is engineered to specifically recognize B-cells.
These modified CAR T-cells are then infused back into the patient, where they function as targeted assassins, seeking out and destroying B-cells, including the autoreactive ones. Early small-scale studies in patients with severe, refractory lupus have shown promising results, with some individuals achieving deep remission and being able to discontinue other lupus medications. While these initial outcomes are encouraging, the treatment remains highly experimental, and researchers are currently focused on evaluating its long-term safety and effectiveness in larger clinical trials.
Another advanced approach, hematopoietic stem cell transplantation (HSCT), involves a complete reset of the immune system. This procedure uses intense chemotherapy to destroy the existing immune cells before transplanting the patient’s own purified stem cells back into the body. HSCT is generally considered a measure of last resort due to its high risks and complexity, reserved only for those with life-threatening lupus who have failed all other therapeutic options. Both CAR T-cell therapy and HSCT represent the most intensive forms of immunotherapy, offering hope for sustained remission but requiring careful consideration due to their specialized nature and potential side effects.