Anyone can develop VEXAS syndrome, but X-linked diseases mean that there are more men affected than women. Most women have two X chromosomes, which gives them 'back-up' genes that most men don't have, with just one X chromosome. Some people have different numbers of X and Y chromosomes, which can change their risk for X-linked conditions like VEXAS. VEXAS is caused by an acquired mutation, a genetic change which happens later in life. This means that all cases found so far have started later in life, upwards of age 40 and more commonly over 50.

Key symptoms include unexplained skin inflammation (skin rash), fever, cartilage inflammation (stiff and sore joints or chest pain if rib cartilage is affected, but most commonly red, swollen ears and nose), periorbital oedema (swelling around eyes), orchitis (swollen testicles), venous thromboembolism (blood clots in veins) and fatigue. Haematological (blood) conditions like cytopenia, macrocytic anaemia, thrombocytopenia, lymphopenia ('penia' means 'lack of', so all these conditions mean low levels of different types of white and red blood cells) are common and indicate bone marrow failure.

In some cases haematological (blood) cancers can develop. Like pretty much all systemic, autoinflammatory diseases, the symptoms can be many and varied and non-specific, so it's easy to get an incorrect diagnosis. VEXAS can look like a lot of other diseases.

Mutations in a gene called UBA1 cause VEXAS. Specifically, 'somatic' mutations. And what that means is that VEXAS is not inherited, but acquired. The problem is that the mutation happens in a type of cell that makes copies of itself (clonal cells) so all of the copies end up with the mutation and none of the copied cells function properly. Mutations like this can happen because the process of copying everything needed for new cells is an error-prone process, it's not because the person did anything wrong.

UBA1 is a gene that provides instructions for cells to make an enzyme called E1. E1 is part of a 'tagging' system of proteins called ubiquitins that flag waste material to be broken down for disposal or re-use inside a cell. (UBA1 = UBiquitin-like modifier-Activating enzyme 1). When E1 doesn't do its job properly, waste material builds up. Vacuoles inside the cell eventually burst from holding too much waste material, and this ultimately causes the cell to self-destruct.

The self-destructing cell is a red flag for the innate immune system to activate inflammatory processes. The problem is that, because of the defective E1 enzyme, this all keeps happening, so the inflammation becomes chronic and that is when the symptoms begin to appear in VEXAS.

VEXAS is a relatively newly identified disease, and many doctors will not yet be familiar with it. Diagnosis will likely be based on a process of eliminating other possibilities (differential diagnosis) which can be frustrating, time consuming, expensive and ultimately harmful as time goes on and the disease is not effectively controlled.

Because the gene has been identified, doctors are able to qualify patients for genetic testing of the UBA1 gene. Patients who have ongoing unexplained skin rash, fever, cartilage inflammation (especially nose and ears), swelling around eyes, blood clots in veins, swollen testicles, low white blood cells and elevated inflammatory markers would be good candidates. The focus is on males aged over 50 but women and younger people should not be excluded if the symptoms are there.

It's important to treat VEXAS because the prognosis without treatment can be grim. New guidelines have just been published on the condition so if you have VEXAS or suspect you have VEXAS, don't be afraid to take a copy to your doctor to bring them up to date in their knowledge.

Glucocorticoids (like prednisolone) are used to treat VEXAS with the goal being to achieve the lowest dose that controls symptoms. Drugs that target inflammatory pathways like tocilizumab (that targets interleukin-6) and ruxolitinib (that targets JAK signalling) have been found to be more effective than disease-modifying antirheumatic drugs (DMARDs) like methotrexate and azathioprine. Another medication, azacitadine, is a chemotherapy drug currently being trialled in Australia.

Reports have been made of successful stem cell transplantation internationally, including two in Australia, but so far there are no reports of any taking place in New Zealand. These cases have been experimental and, due to the high risks involved, this would be a last option treatment. Because VEXAS is so newly discovered, most information so far is based on case studies and larger scale clinical trials are needed.

IMPORTANT NOTE:

Currently, not all medications commonly used to treat SAIDs are available in Australia and New Zealand, and those available may be difficult to access.

ANZFAID is committed to continuing to advocate for improved options, and timely and affordable access to treatment.