VEXAS syndrome is a recently discovered inflammatory condition that mainly affects men over age 50, causing widespread inflammation throughout the body and blood-related complications. Managing this challenging syndrome requires a careful combination of medications to control symptoms, reduce inflammation, and address blood cell abnormalities, with ongoing research exploring newer treatment approaches that may offer hope for better outcomes.

Understanding How We Approach VEXAS Syndrome Treatment

When someone receives a diagnosis of VEXAS syndrome, the primary goal of treatment is to control the intense inflammation that affects multiple organs and systems in the body. This inflammation can cause fever, skin rashes, joint pain, lung problems, and blood vessel damage. At the same time, doctors must address the blood-related problems that often accompany this condition, including low red blood cell counts and difficulties with blood clotting. Because VEXAS syndrome is a lifelong condition with no known cure at present, treatment focuses on managing symptoms, slowing disease progression, and improving quality of life for patients.^[1]

The approach to treating VEXAS syndrome varies significantly from person to person. Some patients may respond well to one type of medication, while others may need a combination of treatments. The severity of symptoms, the presence of other blood disorders such as myelodysplastic syndrome (a condition where immature blood cells fail to develop normally), and the patient’s overall health all play important roles in determining the best treatment strategy. Medical professionals typically start with medications that reduce inflammation and calm the overactive immune system, adjusting the treatment plan based on how well the patient responds and what side effects they experience.^[2]

Currently, there are standard treatments that have been used to manage VEXAS syndrome symptoms, but because the condition was only identified in 2020, medical societies are still developing comprehensive treatment guidelines. Doctors rely on their experience treating similar inflammatory conditions, observations from small groups of VEXAS patients, and ongoing clinical trial results to guide their treatment decisions. Additionally, researchers worldwide are actively investigating new therapeutic approaches through clinical trials, testing innovative drugs that may target the underlying mechanisms of the disease more effectively than current treatments.^[3]

Standard Treatment Approaches

Corticosteroids: The First Line of Defense

Corticosteroids, such as prednisone, are typically the first medications doctors prescribe for VEXAS syndrome. These powerful anti-inflammatory drugs work by suppressing the immune system’s overactive response, which reduces the inflammation that causes many of the condition’s symptoms. Corticosteroids can quickly relieve fever, reduce swelling in joints, improve skin rashes, and decrease inflammation in the lungs and other organs. Many patients with VEXAS syndrome initially respond well to corticosteroids, experiencing significant symptom relief within days to weeks of starting treatment.^[8]

However, corticosteroids come with significant limitations. While they may effectively control symptoms in the short term, most patients require high doses to maintain symptom control, and the disease tends to return when doctors try to reduce the dosage. Long-term use of high-dose corticosteroids carries serious risks and side effects. Patients may develop bone thinning (osteoporosis), increased susceptibility to infections, weight gain, elevated blood sugar levels that can lead to diabetes, high blood pressure, cataracts, glaucoma, mood changes, and easy bruising due to thinning skin. Because of these complications, doctors try to reduce corticosteroid doses as much as possible while maintaining disease control, often by adding other medications that can help manage inflammation.^[1]

The duration of corticosteroid treatment varies considerably among patients. Some individuals may need to take these medications for months or years, while others may be able to transition to alternative treatments more quickly. Doctors carefully monitor patients on corticosteroids, checking for side effects through regular blood tests, bone density scans, eye examinations, and blood pressure measurements. The goal is always to find the lowest effective dose that controls symptoms while minimizing harmful effects on the body.^[14]

Immunosuppressive Medications

When corticosteroids alone cannot adequately control VEXAS syndrome or when side effects become problematic, doctors often add immunosuppressive drugs to the treatment regimen. These medications work by dampening the immune system’s activity in different ways than corticosteroids, allowing doctors to reduce corticosteroid doses while maintaining disease control. Various immunosuppressive drugs have been tried in VEXAS patients, though results have been mixed, and many patients do not respond as well to these medications as doctors would hope.^[3]

Traditional immunosuppressive agents that have been used include medications like azathioprine, methotrexate, and cyclosporine. These drugs have been used for decades to treat other autoimmune and inflammatory conditions. However, in VEXAS syndrome, these conventional immunosuppressants often prove disappointing, with many patients showing limited or no response. This treatment resistance is one of the defining characteristics of VEXAS syndrome and one reason why the condition is so challenging to manage effectively.^[9]

Biologic medications represent a newer class of immunosuppressive treatments. These are engineered proteins that target specific parts of the immune system. Several biologics have been tested in VEXAS patients, including medications that block tumor necrosis factor (TNF), a protein involved in inflammation. Anti-TNF drugs like infliximab and adalimumab are commonly used for conditions like rheumatoid arthritis and inflammatory bowel disease. Unfortunately, these medications have generally shown poor effectiveness in VEXAS syndrome, with most patients experiencing little to no benefit.^[11]

Supportive Care and Managing Complications

Beyond anti-inflammatory medications, patients with VEXAS syndrome often require supportive treatments to manage specific complications of their disease. Many patients develop anemia (low red blood cell counts), which causes fatigue and shortness of breath. When anemia becomes severe, blood transfusions may be necessary to restore adequate oxygen-carrying capacity. Some patients need regular transfusions every few weeks to maintain their energy levels and overall function.^[7]

Blood clotting problems also occur in VEXAS syndrome. Some patients develop dangerous blood clots in their legs or lungs, requiring treatment with anticoagulant medications (blood thinners) to prevent further clotting. Conversely, low platelet counts can increase bleeding risk, creating a challenging situation where doctors must carefully balance the risks of clotting versus bleeding when deciding on anticoagulation therapy.^[2]

Because VEXAS syndrome affects multiple organ systems, patients often benefit from coordinated care involving several specialists. Rheumatologists (doctors who specialize in inflammatory conditions), hematologists (blood disorder specialists), pulmonologists (lung specialists), dermatologists (skin specialists), and other experts may all play roles in managing different aspects of the disease. This multidisciplinary approach ensures that all complications receive appropriate attention and treatment.^[5]

Advanced Treatment Options

Bone Marrow Transplantation

For patients with severe VEXAS syndrome who do not respond to medications, bone marrow transplantation, also called stem cell transplantation, may be considered. This procedure involves replacing the patient’s diseased bone marrow with healthy bone marrow from a donor. Because the genetic mutation that causes VEXAS syndrome occurs in bone marrow cells, transplanting healthy bone marrow can potentially cure the disease by replacing the mutated cells with normal ones.^[8]

However, bone marrow transplantation is a major medical procedure with significant risks. The process begins with intensive chemotherapy or radiation to destroy the patient’s existing bone marrow. The patient then receives stem cells from a donor, which travel to the bone marrow and begin producing new blood cells. During the recovery period, which can last several months, patients are extremely vulnerable to infections because their immune system is severely weakened. Other potential complications include graft-versus-host disease (where the donor cells attack the patient’s body), organ damage, and failure of the transplanted cells to grow properly.^[7]

Because of these substantial risks, bone marrow transplantation is typically reserved for younger patients with severe disease who have not responded to other treatments and who have a suitable donor available. The procedure offers the possibility of long-term remission or even cure, but the decision to pursue transplantation requires careful consideration of the potential benefits against the very real risks involved. Age, overall health status, disease severity, and donor availability all factor into whether transplantation is a viable option for a particular patient.^[14]

Chemotherapy Medications

Certain chemotherapy drugs have shown promise in treating VEXAS syndrome, particularly in patients who also have myelodysplastic syndrome or other blood disorders. These medications work by affecting rapidly dividing cells, including the abnormal bone marrow cells that carry the VEXAS mutation. While chemotherapy is typically associated with cancer treatment, lower doses of some chemotherapy agents can help control VEXAS symptoms by reducing the number of mutated cells in the bone marrow.^[8]

The use of chemotherapy in VEXAS syndrome requires careful monitoring because these drugs can further suppress bone marrow function, potentially worsening anemia and increasing infection risk. Patients receiving chemotherapy need frequent blood tests to ensure their blood cell counts remain in safe ranges. Despite the risks, some patients experience significant improvement in both inflammatory symptoms and blood cell counts with chemotherapy treatment, particularly with certain newer agents being tested in clinical trials.^[7]

Treatment in Clinical Trials

DNA Hypomethylating Agents: Azacitidine

One of the most promising treatments being investigated for VEXAS syndrome is azacitidine, a medication classified as a DNA hypomethylating agent. Azacitidine is already approved for treating myelodysplastic syndrome, and because many VEXAS patients also have MDS, researchers began testing whether this drug might help control VEXAS symptoms as well. The medication works by affecting how genes are expressed in cells, potentially reducing the harmful effects of the UBA1 mutation that causes VEXAS syndrome.^[7]

Clinical studies have shown encouraging results with azacitidine. Research indicates that approximately 67% of patients achieve complete symptom control, and about 73% experience at least partial improvement in their condition. These response rates are notably higher than what doctors typically see with conventional immunosuppressive treatments. Azacitidine appears particularly effective in patients who have both VEXAS syndrome and myelodysplastic syndrome, helping to improve both the inflammatory symptoms and the blood cell abnormalities simultaneously.^[12]

Azacitidine is typically given as an injection under the skin or into a vein. Patients usually receive the medication in cycles, with treatment days followed by rest periods to allow the body to recover. The most common side effects include low blood cell counts (which can increase infection risk and cause fatigue), nausea, injection site reactions, and fatigue. Some patients develop fever or infections while on treatment, requiring temporary interruption of therapy. Despite these side effects, many patients tolerate azacitidine reasonably well, and the benefits in symptom control often outweigh the risks for those with severe disease.^[7]

Clinical trials of azacitidine for VEXAS syndrome are ongoing in various locations, including the United States and Europe. These studies are examining optimal dosing schedules, identifying which patients are most likely to respond, and monitoring long-term safety and effectiveness. Early results from Phase II trials (which test whether a treatment works effectively) have been promising enough that many doctors now consider azacitidine as one of the preferred treatment options for patients with VEXAS syndrome, especially those who also have myelodysplastic syndrome.^[12]

JAK Inhibitors: Targeting Inflammatory Pathways

JAK inhibitors, or Janus kinase inhibitors, represent another class of medications showing promise in clinical trials for VEXAS syndrome. These drugs work by blocking specific enzymes called Janus kinases, which play crucial roles in transmitting inflammatory signals inside cells. When JAK enzymes are blocked, the inflammatory cascade is interrupted, potentially reducing the widespread inflammation that characterizes VEXAS syndrome. Several JAK inhibitors are already approved for treating other inflammatory conditions like rheumatoid arthritis and inflammatory bowel disease.^[14]

The JAK inhibitors that have been tested in VEXAS patients include ruxolitinib (brand name Jakafi), tofacitinib (brand name Xeljanz), and baricitinib (brand name Olumiant). These medications are taken as pills, making them more convenient than injected treatments. Clinical studies have found that JAK inhibitors produce complete symptom control in about 42% of patients and partial improvement in approximately 79% of cases. While these complete response rates are somewhat lower than those seen with azacitidine, the high partial response rate suggests that many patients experience meaningful benefit from JAK inhibitor therapy.^[12]

One significant advantage of JAK inhibitors is their mechanism of action, which differs from corticosteroids and other immunosuppressants. By specifically targeting JAK enzymes, these drugs can reduce inflammation while potentially allowing doctors to lower corticosteroid doses, thereby reducing steroid-related side effects. Some patients who have not responded well to other treatments find that JAK inhibitors provide the symptom relief they need to maintain a reasonable quality of life.^[10]

However, JAK inhibitors also have potential side effects that require monitoring. These medications can increase the risk of serious infections because they suppress immune function. Patients may also experience elevations in cholesterol levels, liver enzyme abnormalities, low blood cell counts, and blood clots. There have also been concerns about increased risks of certain cancers and heart problems with prolonged use of JAK inhibitors, though these risks appear relatively low. Doctors carefully monitor patients on these medications with regular blood tests and clinical evaluations.^[8]

Clinical trials of JAK inhibitors for VEXAS syndrome are ongoing in multiple countries, including the United States, Europe, and other regions. These Phase II and Phase III trials (Phase III compares new treatments with standard treatments) are working to determine which JAK inhibitor works best for VEXAS syndrome, what doses are most effective, and which patients are most likely to benefit. Preliminary results have been encouraging enough that many specialists now include JAK inhibitors in their treatment algorithms for VEXAS patients who do not respond adequately to corticosteroids alone.^[12]

IL-6 Inhibitors: Blocking a Key Inflammatory Protein

Interleukin-6, or IL-6, is a protein that plays a central role in driving inflammation in many autoimmune and inflammatory conditions. Medications that block IL-6, called IL-6 inhibitors, have been tested in VEXAS syndrome based on the theory that blocking this inflammatory protein might reduce the widespread inflammation patients experience. The most commonly used IL-6 inhibitor is tocilizumab (brand names Actemra and Tyenne), which is given as an injection or intravenous infusion.^[8]

Clinical studies of IL-6 inhibitors in VEXAS syndrome have shown that about 24% of patients achieve complete symptom control, while approximately 72% experience at least partial improvement. These results suggest that while IL-6 inhibitors may not work as dramatically as azacitidine or even JAK inhibitors for many patients, they can still provide meaningful benefit for some individuals. The high partial response rate indicates that many patients see some improvement in their symptoms, even if they don’t achieve complete disease control.^[12]

Tocilizumab works by binding to IL-6 receptors on cell surfaces, preventing IL-6 from attaching and triggering inflammatory responses. This targeted approach can reduce inflammation throughout the body, potentially improving fever, joint pain, skin problems, and other inflammatory symptoms. Some patients who have not responded to other treatments find that adding tocilizumab to their regimen helps better control their symptoms, particularly when combined with other medications.^[10]

Side effects of IL-6 inhibitors include increased infection risk (particularly upper respiratory infections), elevated cholesterol and liver enzymes, low blood cell counts, injection site reactions, and gastrointestinal symptoms. There is also a potential risk of gastrointestinal perforations (holes in the intestine), though this complication is rare. Patients taking IL-6 inhibitors need regular monitoring with blood tests to check for liver problems, cholesterol elevations, and blood cell abnormalities.^[14]

Research into IL-6 inhibitors for VEXAS syndrome continues in clinical trials across multiple locations. Scientists are investigating whether combining IL-6 inhibitors with other treatments might produce better results than using them alone. They are also working to identify which patients are most likely to respond to IL-6 blockade, as individual responses to this treatment vary considerably.^[10]

Other Experimental Approaches

Beyond the main treatments being investigated, researchers are exploring several other potential therapies for VEXAS syndrome. Some scientists are looking at whether blocking other inflammatory proteins, such as interleukin-1 (IL-1), might help control symptoms. Anti-IL-1 medications have shown some benefit in other autoinflammatory conditions, leading researchers to test whether they might work in VEXAS syndrome as well. However, early results with IL-1 inhibitors have been disappointing, with most patients showing little response.^[11]

Other potential treatments being considered include newer immunosuppressive medications, combinations of existing drugs that might work better together, and approaches that target the specific genetic defect causing VEXAS syndrome more directly. Scientists are also investigating whether certain medications might work better in patients with specific types of UBA1 mutations, as there are several different mutations that can cause VEXAS syndrome, and they may respond differently to various treatments.^[3]

Clinical trials are essential for advancing our understanding of VEXAS syndrome treatment. Patients interested in participating in clinical trials can ask their doctors about available studies or search clinical trial databases for VEXAS studies accepting participants. Eligibility for trials typically depends on factors such as disease severity, previous treatments, presence of other medical conditions, and geographic location. Participating in a clinical trial gives patients access to potentially promising new treatments while contributing to scientific knowledge that may help future VEXAS patients.^[7]

Most common treatment methods

• Corticosteroids
  • Prednisone and other corticosteroid medications to reduce inflammation and control symptoms
  • Often the first treatment prescribed, with high initial effectiveness but significant long-term side effects
  • Used to manage fever, joint pain, skin rashes, and inflammation in various organs
  • Doctors attempt to reduce doses over time to minimize bone loss, weight gain, diabetes risk, and other complications
• JAK Inhibitors
  • Ruxolitinib (Jakafi), tofacitinib (Xeljanz), and baricitinib (Olumiant) block Janus kinase enzymes
  • Taken as oral pills, providing convenient administration
  • About 42% of patients achieve complete response and 79% experience partial improvement
  • Help reduce corticosteroid doses while controlling inflammation through a different mechanism
  • Require monitoring for increased infection risk, elevated cholesterol, and other side effects
• IL-6 Inhibitors
  • Tocilizumab (Actemra, Tyenne) blocks the inflammatory protein interleukin-6
  • Given as injections under the skin or intravenous infusions
  • Complete response achieved in about 24% of patients, with 72% experiencing partial improvement
  • Targets a specific inflammatory pathway to reduce systemic inflammation
  • Side effects include increased infection risk and elevated cholesterol levels
• DNA Hypomethylating Agents
  • Azacitidine affects gene expression in cells, reducing harmful effects of the UBA1 mutation
  • Particularly effective in patients with both VEXAS syndrome and myelodysplastic syndrome
  • About 67% of patients achieve complete response and 73% experience partial improvement
  • Given as injections in treatment cycles with rest periods
  • Can cause low blood cell counts, nausea, and increased infection risk
• Conventional Immunosuppressants
  • Azathioprine, methotrexate, and cyclosporine have been tried in VEXAS patients
  • Generally show limited effectiveness compared to newer targeted therapies
  • May be used in combination with other treatments to help reduce corticosteroid doses
  • Treatment resistance to these medications is common in VEXAS syndrome
• Bone Marrow Transplantation
  • Replaces diseased bone marrow with healthy donor stem cells
  • Offers potential cure by replacing mutated cells with normal cells
  • Reserved for younger patients with severe disease who have not responded to other treatments
  • Involves significant risks including infections, graft-versus-host disease, and organ damage
  • Requires intensive chemotherapy or radiation before transplantation
• Supportive Care
  • Blood transfusions for severe anemia to improve energy levels and oxygen delivery
  • Anticoagulant medications (blood thinners) to prevent or treat blood clots
  • Management of specific organ complications by appropriate specialists
  • Regular monitoring with blood tests, imaging studies, and clinical evaluations
  • Multidisciplinary care coordinating rheumatologists, hematologists, and other specialists