PLUMM STUDY

Dr. Hermine I. Brunner, MD, MSc, MBA

Pediatric Study Participants Needed

Cincinnati Children’s Hospital is currently recruiting for multiple lupus studies. As an autoimmune disease, lupus can affect many different body systems due to a patient’s immune system having trouble telling the difference between healthy tissue and foreign substances. Two exciting studies focusing on different systems are highlighted below, one for lupus nephritis and another for lupus with brain involvement.

The Pediatric Lupus Nephritis Mycophenolate Mofetil (PLUMM) Study focuses on lupus nephritis, when lupus affects the kidneys. Standard treatment for most persons newly diagnosed with lupus nephritis (LN) includes steroid plus oral mycophenolate mofetil (MMF). The safety and usefulness of MMF for the treatment of LN has been evaluated in adults and some children. When taken orally, MMF is quickly broken down in the body to mycophenolic acid (MPA). MPA helps to calm the immune system and decrease the inflammation of the kidneys. More MPA in a patient’s system is associated with better immune response and less inflammation. However, each patient processes MPA differently in the body, and this is thought to be one of the reasons that MMF does not work as well for LN in some people. Other reasons include differences in the amounts of certain blood proteins, lowered kidney function, and changes in liver function. Studies in adults with LN have shown people with LN have a 36% better response with MMF if the medication is dosed based on the amount of MPA in the blood rather than the standard dosing method based on a patient’s height and weight.1,2

Funded by the National Institutes of Health, Drs. Hermine

Brunner and Prasad Devarajan from Cincinnati Children’s Hospital Medical Center are conducting a clinical trial to look at two different methods for dosing MMF. The study would like to learn if one way is better at reaching the best possible levels of the drug MMF in the body. In this clinical trial, participants will be randomly assigned to one of the two treatment strategies (standard MMF dosed by body-weight or personalized dosing of MMF based on a patient’s MPA levels). The study is blinded so that the doctors and participants will not know which patients are in which groups. The study goal is to determine whether doctors should use personalized-dosing strategies for MMF use in children with LN going forward to achieve better outcomes for children with LN.

The study will be conducted at twenty children’s hospitals across the United States. Newly diagnosed lupus nephritis patients between the ages of 8 and less than 17 years old who are being treated with MMF for their lupus nephritis are eligible. Study participants will be part of the study for 11 visits over the course of one year, during which they will receive MMF free of charge. Participation will include: blood samples collected by fingersticks (to test

MPA levels), collection of medical information, monitoring of patients’ study drug usage and side effects, and completion of questionnaires about patient wellbeing. Participants must have a smart phone to join the study as messages will be sent to remind them to take their MMF daily.

The study is expected to last five years with 105 participants total across twenty sites. The duration of study may be extended, and additional sites may be added depending on the rate of enrollment. If you would like more information, please email plumm@cchmc. org. Patients are reimbursed for their time and effort.

The Vascular Pathophysiology in CNS SLE: The Blood-CSF Barrier study aims to learn more about how lupus affects the brain. Often, organ damage from lupus results from breakdown of blood vessels. And in the brain, blood vessels have special barriers between the blood and brain tissue. The best-known barrier is made up of specialized cells that are tightly connected at the surface of small blood vessels that control how substances can go between the blood and the brain tissue. This is called the blood-brain-barrier (BBB). The BBB is a special tissue layer around the brain protecting it from infections or diseases in other parts of the body. Using brain imaging, researchers have shown that the BBB is leakier in lupus patients compared to healthy persons. Experiments in mice suggest that substances that should stay in the blood can enter the brain, even when the BBB appears to be working properly. These experiments suggest that there might be another way for materials in the blood to leak into the brain. The brain includes fluid, called cerebrospinal fluid, or CSF. CSF surrounds the surface of the brain and fills spaces near the center of the brain called ventricles. It has several functions in the brain, most notably acting as a cushion for brain tissue. Inside the ventricles is a structure floating in the CSF called the choroid plexus that has a large amount of blood vessels. These blood vessels don’t have a BBB and are naturally leaky but they are encased in the choroid plexus by a specialized layer of cells that substances in the blood must pass through to get into the CSF. This is known as the blood-CSF-barrier. Once blood contents enter the CSF in the ventricles through this layer, they can easily enter brain tissue that surrounds the ventricles. So, if there is breakdown of the blood-CSF-barrier, harmful substances from the blood can make their way into the brain tissue surrounding the ventricles.

In multiple sclerosis, which is another disease that affects the brain, some imaging shows that there is damage mainly to the brain tissue that surrounds ventricles, and the damage is worst at the ventricle surface and decreases with distance from the ventricle. This study wants to test the idea that lupus, like multiple sclerosis, can also affect the brain through a leaky blood-CSF-barrier. We will use MRI advanced imaging methods to measure blood flow and leakage into the CSF in the choroid plexus. We will also use imaging methods to measure a variety of tissue and blood vessel properties around ventricles in both patients with lupus and multiple sclerosis to examine the blood-CSF-barrier. If we find blood-CSF-barrier involvement for lupus, it could open new ways to study lupus in the brain and help development of new treatments.

This study is conducted only at Cincinnati Children’s Hospital with target participation of 20 people with active lupus, 20 people with multiple sclerosis, and 40 healthy controls in the age range of 12 to 25 years. There is one visit for this study lasting up to three hours. Each participant will undergo an MRI of their brain as part of the study, lasting about one hour. They will also complete a computer-based battery of cognitive tests, called PedANAM, lasting 30 to 40 minutes. Participants will be compensated $150.00 for their participation. For more information, please contact: Cat Robben (513) 6367299.