Introduction:
New treatments called biologic therapies have been developed to treat inflammatory arthritis by targeting specific parts of the immune system. These therapies are also being used to treat primary systemic vasculitis, a type of blood vessel inflammation. They seem to be helpful for patients whose condition does not improve with regular treatments. Using biologics as targeted therapies has also improved an individual's understanding of how vascular inflammation works. However, we still need more research to know exactly when to use drugs like TNF-alpha inhibitors or anti-CD20 monoclonal antibodies. These biologics should be used with extreme caution and only in controlled trials because they can have harmful effects.
What Is ANCA-Associated Vasculitis?
The ANCA (antineutrophil cytoplasmic antibody) -associated vasculitis (AAV) are a group of uncommon autoimmune diseases with an unknown cause. They involve inflammation and damage to blood vessels due to the infiltration of inflammatory cells. The link between ANCA and vasculitis was initially reported in 1982 when the clinical progress of eight patients with a specific type of kidney inflammation called segmental necrotizing glomerulonephritis was described. The ANCA-associated vasculitis (AAV) consist of three distinct conditions, which include:
- Granulomatosis with polyangiitis or GPA (Wegener's granulomatosis).
- Microscopic polyangiitis or MPA.
- Eosinophilic granulomatosis with polyangiitis or EGPA (previously known as Churg-Strauss syndrome).
This rare autoimmune disease can affect multiple systems in the body. They are more frequently seen in older individuals and men. The initial treatment for most AAV patients involves the use of Cyclophosphamide or Rituximab along with glucocorticoids. AAV is considered a chronic condition that requires long-term immunosuppressive therapy. Rituximab can be used as an alternative treatment option for individuals who are at high risk of infertility and infection. Unfortunately, the mortality rate for AAV remains high, with late deaths commonly attributed to cardiovascular disease, infections (as a result of treatment), and malignancies.
What Are the Novel Therapies and Their Mechanisms for the Treatment of Refractory ANCA-Associated Vasculitis?
When conventional therapies are ineffective, novel therapies have come to light as potential treatment options for refractory ANCA-associated vasculitis (AAV). These treatments aim to improve outcomes for refractory AAV patients by focusing on particular immune responses and inflammation-related pathways.
- Anti-CD20 Monoclonal Antibody: The pathogenicity of ANCA in AAV suggests a role for B-cell activation. B cells serve as antigen-presenting cells for T lymphocytes and produce pro-inflammatory cytokines, contributing to neutrophil priming and T-cell hyperactivity. Targeting B-cell depletion could be a promising approach for AAV therapy based on these mechanisms. Rituximab, a monoclonal antibody targeting CD20 on B cells, has demonstrated efficacy in inducing remission. By depleting B cells and disrupting the production of autoantibodies, Rituximab reduces inflammation and immune system dysfunction. It has been successful as both an induction and maintenance therapy in refractory AAV cases. In 2011, the U.S. Food and Drug Administration approved Rituximab, an anti-CD20 IgG1 human monoclonal antibody, for the management of AAV. Patients who are intolerant to Cyclophosphamide, those who are of reproductive age, and those who have had significant prior exposure to Cyclophosphamide may benefit from Rituximab. However, there is no agreement on the ideal dosing schedule, and the efficacy of Rituximab monotherapy in severe AAV has not been established.
- Anti-CD5 Monoclonal Antibody: The presence of eosinophilic inflammation is a characteristic feature of EGPA. IL-5 (a key cytokine responsible for eosinophil activation) is believed to play a role in the development of EGPA. Th2 (Type 2 T-helper) cells produce IL-5, which promotes the differentiation and maturation of eosinophils. Additionally, it also prevents eosinophil apoptosis. Mepolizumab, a humanized anti-IL-5 monoclonal antibody, has demonstrated clinical effectiveness in treating refractory and relapsing EGPA. Patients receiving Mepolizumab experienced a greater duration of remission and a higher remission rate compared to those on a placebo, leading to reduced glucocorticoid usage.
- B-Cell Activating Factor Inhibitor (BAFF): BAFF helps in the growth and survival of B cells in the laboratory. BAFF binds to different TNF receptors, which helps in cell growth and survival. When BAFF attaches to its main receptor, it activates certain pathways in B cells, allowing them to survive and function properly. Belimumab is a type of antibody made by humans that targets a protein called B-lymphocyte-stimulating factor (B-Lys) or BAFF. It is currently being studied as a potential treatment for AAV. B-Lys factor is a substance in the body that helps B cells survive, mature, and function properly. In patients with AAV, especially those with GPA, B-Lys levels in the blood have been found to be higher.
- Anti-TNF-α Antibody: TNF-α is a cytokine involved in inflammation and the production of other proinflammatory substances in kidney disease. In AAV, TNF-α levels are increased in leukocytes and renal tissue, indicating its role in the disease. Etanercept, Infliximab, and Adalimumab are different biologic agents that have been studied for treating ANCA-associated vasculitis (AAV).
- C5 Receptor Blocking Antibodies: Dysregulated complement activation is a hallmark of AAV pathogenesis. Eculizumab, a monoclonal antibody inhibiting the complement protein C5, has shown potential in treating refractory AAV. By preventing the formation of the membrane attack complex, Eculizumab reduces endothelial damage and inflammatory responses. Initial studies indicate that Eculizumab may be a valuable therapeutic option for patients who do not respond to conventional immunosuppressive therapies.
- Janus Kinase (JAK) Inhibitors: JAK inhibitors are a class of drugs that target signaling pathways involved in inflammation. Tofacitinib and Baricitinib are JAK inhibitors that have shown efficacy in various autoimmune conditions. Early studies investigating their use in AAV have shown promising results. JAK inhibitors modulate immune cell function, reduce cytokine production, and interfere with the inflammatory response. While more research is needed, JAK inhibitors hold potential as alternative therapies for refractory AAV.
- T-cell Modulators: Abatacept, a selective T-cell co-stimulation modulator, is being studied for its potential in refractory AAV. By interfering with the co-stimulatory signals required for T-cell activation, Abatacept can attenuate the immune response. Initial studies have shown promising results in achieving remission in refractory AAV patients. Abatacept has shown good tolerability, and a significant number of patients have achieved disease remission, allowing them to stop taking Prednisone.
- Autologous Hematopoietic Stem Cell Transplantation (HSCT): This is a potential treatment option for refractory AAV. HSCT involves harvesting a patient's own stem cells, ablating their immune system, and then reintroducing the stem cells to rebuild a healthy immune system. This approach has shown promise in achieving sustained remission and reducing the need for immunosuppressive medications. However, HSCT carries significant risks and should only be considered in carefully selected patients in specialized centers.
What Are the Common Immunosuppressive Medications Used for the Treatment of ANCA-Associated Vasculitis?
- Cyclophosphamide: Cyclophosphamide is associated with decreased ovarian reserve, ovarian failure, and male infertility. Prednisolone reduction regimens in clinical trials achieved average doses of 10 mg (after 19 weeks) and 7.5 mg (after 21 weeks) of Cyclophosphamide. Cyclophosphamide is typically administered orally or as pulse therapy for three to six months. After achieving remission, a less toxic agent is used instead of Cyclophosphamide. Intravenous Cyclophosphamide pulse therapy reduces cumulative dose and potential toxicity. One study demonstrated comparable remission rates between daily oral Cyclophosphamide and pulsed Cyclophosphamide in non-immediately life-threatening AAV cases. Pulsed Cyclophosphamide has a lower cumulative dose but a higher risk of recurrence compared to daily oral Cyclophosphamide.
- Methotrexate: Methotrexate can be an alternative to Cyclophosphamide for less severe AAV cases with normal renal function. The recommended dosage is 20 to 25 mg per week, orally or via injection. Methotrexate is generally supported by more substantial evidence in induction trials compared to Mycophenolate Mofetil. Methotrexate is preferred for patients with MPA (microscopic polyangiitis) due to its efficacy and renal function considerations.
- Mycophenolate Mofetil: This drug should not be routinely used in life-threatening situations and has limited research in pulmonary hemorrhage or central nervous system involvement.
Conclusion:
Clinical management of refractory ANCA-associated vasculitis is extremely difficult. Fortunately, improvements in immunomodulatory therapies give patients who do not respond to standard therapies hope. The use of the latest novel strategies holds promise for bringing refractory AAV patients into remission and improving their prognoses. The progress in understanding vasculitis and conducting clinical trials has led to the development of tools that can assess its causes. This knowledge serves as a basis for evaluating new treatments and agents.
