Lupus is a chronic autoimmune disease that causes the immune system to attack healthy tissues and organs in the body. Systemic lupus erythematosus (SLE), commonly known as lupus, affects various parts of the body including joints, skin, kidneys, blood cells, brain, heart and lungs. According to the Lupus Foundation of America, around 1.5 million Americans and at least 5 million people worldwide have a form of lupus. For years, treatment options for lupus have been limited with corticosteroids and immunosuppressant drugs being the standard therapy. However, recent research and clinical trials have uncovered new therapeutic avenues providing hope to patients living with this debilitating disease.
New Biologic Therapies target specific components of the immune system
Research has shown that abnormal activation of B lymphocytes and increased production of autoantibodies and inflammatory cytokines play a major role in the pathogenesis of lupus. With better understanding of disease mechanisms, biologic therapies targeting specific components of the immune system have emerged. Belimumab (Benlysta), a B-lymphocyte stimulator (BLyS)-specific inhibitor antibody, was the first new drug approved by the FDA in over 50 years for the treatment of lupus in 2011. In clinical trials, Belimumab reduced disease flares and improved symptoms when added to standard therapy. Rituximab, a monoclonal antibody against CD20 antigen present on B cells, has shown efficacy in phase III trials. Other biologics like Atacicept, which targets BLyS and APRIL cytokines, are being investigated in late stage clinical studies. These targeted immunotherapies offer safer options with less severe side effects than conventional drugs.
Complement System inhibitors address specific pathways
Complement system, part of the innate immune response, is hyperactive in lupus and its inhibition could reduce inflammation. Eculizumab, a C5 complement inhibitor, has been effective in small case studies of lupus patients with persistent disease activity despite conventional treatments. Lupus nephritis patients treated with Eculizumab in an open-label trial saw reduced proteinuria levels. Other complement inhibitors in clinical trials include Ravulizumab (targets C5) and Lifitegrast (inhibits C3/C5 activation). Blocking specific complement pathways involved in autoimmunity holds promise for controlling disease while sparing beneficial immune functions. These complement inhibitors represent a novel approach with potential to replace current standard of care therapies.
Therapeutic vaccines aim to restore immune tolerance
Loss of immune tolerance to self-antigens is central to the pathogenesis of lupus. Therapeutic vaccines aim to induce antigen-specific regulatory T cells to re-establish tolerance against autoantigens. One such approach is Lupuzor/LupusVax consisting of autoantigen-presenting dendritic cells. A phase IIb trial showed Lupuzor reducing anti-dsDNA antibodies and improving clinical measures. Iarlo, an oral vaccine containing autoantigens linked to cholera toxin B subunit, completed phase I/II testing showing good tolerability and immune modulation. Other antigen-specific approaches for lupus therapeutics in clinical development include oral and intralymphatic injections of apoptotic cell mimics like Annexin-V. Therapeutic vaccines offer a personalized treatment strategy with durable effects and less side effects than global immunosuppression.
Stem cell transplantation offers hope of remission
High-dose immunosuppression followed by autologous hematopoietic stem cell transplantation (AHSCT) can induce prolonged remissions in severe refractory cases of SLE. In AHSCT, a patient's own stem cells are collected, stored and reinfused after high-dose chemotherapy+/-radiotherapy intended to "reset" the immune system. A recent multicenter trial showed 77% of patients achieving drug-free remission at 2 years after AHSCT. While AHSCT carries risks of treatment-related mortality, it provides prospect of cure for selected patients. Less intense approaches combining immunosuppression with low-dose conditioning and stem cells from family donors (allogeneic HCT) are being assessed aiming for similar benefits with reduced toxicity. As understanding improves, stem cell therapy may become available to appropriate patients failing multiple lines of treatment.
Novel Oral Treatments address unmet medical needs
Despite advances, currently available drugs are inadequate for many patients enduring disease flares, organ damage and debilitating fatigue. New oral treatments are designed to address unmet needs through safer and more convenient administration. Anifrolumab, a type I IFN receptor antagonist, has shown to reduce flares and steroid use in phase III trials. Belamaf, a selective inhibitor of Bruton's tyrosine kinase involved in B cell and myeloid cell signaling, achieved its main efficacy goals versus placebo in phase III trials enrolling over 1000 lupus patients worldwide. Bruton's tyrosine kinase (BTK) represents a promising new target for oral treatment of lupus. Other novel oral candidates undergoing active investigation include inhibitors of IL-6, Protein Kinase C-θ, IRAK1/4 kinases and LFA-1 integrin involved in leukocyte migration. Convenient oral therapies have potential to improve quality of life while easing disease management challenges for lupus patients.
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