Calcineurin Inhibitors and Lupus

Calcineurin inhibitors are important medications for lupus that are particularly important for people with lupus nephritis.

Calcineurin is a hardworking molecule found in everything from plants to insects to humans. Calcineurin gets its name from the metal calcium (Ca on the periodic table) which is one of the materials that is used to build this molecule. Calcineurin inhibitors prevent calcineurin from doing its job and are used as immunosuppressant medications to treat lupus. Calcineurin inhibitors are under investigation for people with kidney focused lupus (lupus nephritis) that does not respond to other treatments. 

Is this a good idea? The answer is complicated.

What is Calcineurin?

Calcineurin is a phosphatase, a molecule that breaks apart and deactivates certain molecules that contain phosphate. In this case, it affects serine and threonine, which are involved in many different functions throughout the body. The nervous system is one area where calcineurin is involved, the kidneys are another. However, one of calcineurin’s other functions is activating T-cells, the immune system cells in the body produced in the thymus. 

T-cells are one of the immune system cells involved in autoimmune diseases such as lupus, which makes controlling calcineurin an important avenue for treating lupus. In many autoimmune diseases, some research indicates that calcineurin might not be doing its job properly. People with lupus might benefit from calcineurin being less active.

What is a Calcineurin Inhibitor?

Calcineurin inhibitors are used to treat autoimmune disorders such as lupus. Calcineurin inhibitors, also known as CNIs, include cyclosporine, tacrolimus, pimecrolimus, and voclosporin. 

Calcineurin inhibitors are highly fat soluble, which makes them able to easily reach organs that have a high fat content or insulation, such as the lymph nodes and kidneys. In general, calcineurin inhibitors work by taking up space on receptors on cells that would usually accept calcineurin, blocking the molecule from the receptor. Fewer calcineurin molecules are able to signal to the cells that they need to produce cytokines and activate t-cells. Tacrolimus and pimecrolimus work this way. Voclosprin, also known as “Lupkynis” does the same thing, but is actually more like Cyclosporin:  

Cyclosporin actually does the opposite – it attaches itself to cyclosporin, holding it back from attaching to receptors.

Most CNIs are taken orally (by mouth,) but some can be given topically (on the skin.) Either way, this reduces inflammation and the symptoms of autoimmune diseases such as lupus. 

Generally, tacrolimus and cyclosporine are used for lupus, and CNIs are taken alongside other treatments. Tacrolimus is a calcineurin inhibitor that doesn’t constrict the blood vessels as much as the others and doesn’t encourage scarring in injured organs which makes Tacrolimus a potential alternative for people who already have kidney damage. Other CNIs can also be used for lupus: Voclosporin seems to be especially beneficial for patients who are already on immunosuppressants. 

CNIs are not excreted in breast milk, so they are sometimes used to manage LN during that time. However, overall, CNIs are not usually recommended for use in pregnancy. A modified version of cyclosporin is approved for use in children. Lower doses might be needed for older kidney transplant patients because of the possibility that it can exacerbate kidney damage. 

Calcineurin and the Kidneys

Calcineurin is also involved in proper function of the membranes in the kidneys that filter the bloodstream. These membranes are on special cells called podocytes which act as the barrier between the bloodstream and the kidneys. When there is too much calcineurin, or when it isn’t functioning correctly in the body, then the podocytes can start to weaken and collapse. This may potentially be one of the main ways that the kidneys are damaged in lupus, both SLE and LN.

Calcineurin Inhibitor Side Effects

Patients on CNIs generally start with a higher dose (0.1mg/kg per day) and are gradually reduced to a lower chronic dose (dependent on patient.) This lower dose is generally tolerated well, but CNIs are stored in fat and will stay in the system for a significant amount of time.

On higher doses, CNIs can exacerbate kidney damage – this is the main reason why doctors are cautious before prescribing CNIs for lupus. However, there is some evidence that implies that the reduced kidney functionality might be from lupus damage instead. Doctors are still cautious, however, but do use CNIs when there is both a lower risk of kidney damage in the patient and a need for less immunosuppression for some reason.

Neurological and sensory symptoms can be exacerbated, and hypertension can be a potential side effect. Diabetes is also a side effect, mainly of tacrolimus. Gastrointestinal symptoms have also been reported. Tacrolimus doesn’t appear to have effects on fertility or pregnancy, though, fortunately.

Additionally, a 2024 study using the Lupus Registry of Nationwide Institutions (LUNA)  found that calcineurin inhibitors did not increase the risk of cancer in people with lupus.