Johns Hopkins University: News Tips from the American College of Rheumatology Annual Meeting, ACR Convergence Virtual Meeting, Nov. 3-9, 2021

Gene Puts Some African Americans with Lupus at Higher Risk of Kidney Failure

Apolipoprotein L1 (APOL1) in African-American SLE: Frequency and Clinical Associations

Poster Session: Saturday, Nov. 6, 8:30–10:30 a.m.

A risk gene carried by approximately half of all African Americans makes some lupus patients especially prone to kidney failure and end-stage kidney disease, according to a new study being presented at ACR by Michelle Petri, M.D., M.P.H., director of the Johns Hopkins Lupus Center.

As many as 1 in 250 African American women will develop lupus in their lifetime. Compared with women of other ethnicities, African American women are diagnosed with lupus at a younger age and develop more severe disease. Understanding the underlying causes of this disparity is key to more effective treatments.

“African American patients have worse outcomes with more end-stage renal disease,” says Petri. “There are complex different reasons, one of which is genetic — the APOL1 gene.”

The APOL1 gene exists in several variants — two of those variants, found only among people with recent African ancestry, are associated with protection against Trypanosoma brucei, a parasite that is endemic in many areas of Africa. However, these variants also confer an increased risk of kidney disease, which can be one complication of systemic lupus erythematosus (SLE).

In what is believed to be the largest ever study of APOL1 in African Americans with lupus, Petri and her colleagues analyzed data on 294 African Americans with SLE. Of the participants, 12% had two copies of an APOL1 variant that conveys kidney disease risk — called a risk allele — and 44% had just one copy of an APOL1 risk allele. People with at least one risk allele were 3.50 times more likely to progress to kidney failure or end-stage kidney disease than people with no risk alleles. The risk alleles had no impact on pulmonary fibrosis, avascular necrosis or atherosclerotic events.

“In the future, we hope there will be treatments for APOL1. It will become essential to identify patients who carry the gene in order to prevent kidney failure,” says Petri.

A New Paradigm for Treating Lupus Nephritis

The Great Debate: Enhancing Lupus Nephritis Therapy. Is Your Next Step Belimumab or Voclosporin?

Saturday, Nov. 6, 9–10 a.m.

Lupus nephritis is one of the most serious complications of the autoimmune disease systemic lupus erythematosus (SLE). Until recently, fewer than half of all patients with lupus nephritis responded to existing treatments at one year after diagnosis, and nearly a quarter of SLE patients developed kidney failure within 20 years.

In the past year, the U.S. Food and Drug Administration approved two new therapies for lupus nephritis: belimumab (Benlysta) and voclosporin (Lupkynis). While encouraging for clinicians and patients, the new approvals also led to many questions among rheumatologists about which drug they should turn to and in what contexts.

In a presentation at ACR Convergence 2021, Michelle Petri, M.D., M.P.H., director of the Johns Hopkins Lupus Center, will review safety and efficacy data on belimumab and voclosporin. The trials to study the drugs were designed differently, she points out, but can still be analyzed side by side. Compared with voclosporin, Petri says after reviewing the studies, belimumab has two-year efficacy data, an excellent safety profile, and may be preferable in nonadherent patients. Moreover, the data on belimumab shows protection of glomerular filtration rate, a measure of kidney function and an important marker of lupus nephritis treatment.

Based on her review of the data, Petri outlines a new suggested paradigm for the use of both belimumab and voclosporin in patients with lupus nephritis. She recommends that clinicians prescribe one of these new treatments to patients at the time of kidney biopsy, or in those not responding to the current standard treatment — mycophenolate — after three months.

A Focus on the Shoulder

Ultrasound of the Shoulder: Clinical Cases and procedural techniques

Saturday, Nov. 6, 9–9:15 a.m.

Most of us take our shoulders for granted — until we hurt one, that is. The shoulders can be affected by diseases ranging from rheumatoid arthritis to lupus, and narrowing down exactly what is giving a patient shoulder pain can be a challenge for rheumatologists. In an ACR Convergence presentation, Jemima Albayda, M.D., director of the Johns Hopkins Medicine Musculoskeletal Ultrasound and Injection Clinic, will review shoulder anatomy and ultrasound imaging.

“The shoulder is one of the most complex joints we deal with as rheumatologists, and also one of the most common joints to be affected in rheumatological diseases,” says Albayda. “So it’s definitely a worthwhile topic for people who want to brush up on their knowledge of the shoulder.”

Many shoulder problems, Albayda says, can present with similar symptoms and, in some cases, more than one pathology can be affecting the shoulders at the same time. This means that a precise physical exam coupled with soft-tissue imaging are critical for diagnosis and guiding treatment.

Albayda will review clinical cases in which patients presented with shoulder pain and show how ultrasound imaging was able to clarify the diagnosis or point to a diagnosis that would not have been initially considered.

The Two-Way Street Between COVID-19 and Lupus

Poster Presentation

Effect of COVID Infection and COVID Vaccination on SLE Activity, Including Antiphospholipid Antibodies

Poster Session: Sunday, Nov. 7, 8:30–10:30 a.m.

Among the chronic diseases suspected to make people more susceptible to the COVID-19 virus is systemic lupus erythematous (SLE), not only because of the underlying autoimmune defects that cause lupus, but also because patients are often treated with drugs that suppress their immune systems. Clinicians have wondered whether, in turn, infection with SARS-CoV-2 — or vaccination against the virus — has any effect on the symptoms and severity of lupus.

Michelle Petri, M.D., M.P.H., director of the Hopkins Lupus Center, obtained data on COVID-19 infection and vaccination in 860 patients previously enrolled in a lupus cohort. Sixty-five patients in the cohort had a positive RNA test for COVID-19 during the study period. Data from those patients revealed that not only was there no increase in lupus activity after COVID-19 infection, but cutaneous (skin) symptoms actually decreased — likely due to the lack of sun associated with quarantine. However, some laboratory values associated with SLE, such as anti-phospholipid antibodies, did increase a small degree after infection with the virus. And unfortunately, death from COVID has occurred in lupus patients, including a 16-year-old.

In the same cohort, 228 patients with SLE were vaccinated against COVID-19 during the study period. Thirteen of those patients had been infected with the virus prior to vaccination. Vaccination, Petri showed, affected neither lupus activity nor laboratory values.

“COVID vaccination was thought to be a risk because mRNA vaccines act through interferon, which might have triggered SLE flares. Luckily, this has not proven true,” says Petri.

Learning How to Diagnose and Treat Lyme Arthritis

Treatment of Lyme Arthritis, Post-Infectious Lyme Arthritis and Complications

Sunday, Nov. 7, 4–4:25 p.m.

Lyme disease is the most common tickborne infection in the United States, affecting more than 400,000 people each year. Despite a growing awareness of Lyme disease and its early symptoms, the disease is often diagnosed months later when it causes Lyme arthritis — a swelling of the joints.

John Aucott, M.D., director of the Johns Hopkins Lyme Disease Clinical Research Center, has spent two decades studying Lyme disease, including Lyme arthritis. At ACR Convergence 2021, he’ll present his latest recommendations on how to diagnose and treat Lyme arthritis based on national guidelines as well as his own clinical experience and research.

The diagnosis of Lyme arthritis, Aucott says, is best made by testing blood to determine the presence of Lyme antibodies, as well as testing fluid from affected joints for certain inflammatory cells and molecules.

Clinicians generally treat Lyme arthritis with oral antibiotics, but approximately 10% of people have continued symptoms even after multiple courses of antibiotics — dubbed postinfectious Lyme arthritis. Aucott’s research suggests these cases may be related to persistent dysfunction of the immune system. His lab continues to study the molecular changes to the immune system that occur with Lyme disease and Lyme arthritis, as well as risk factors that make patients more prone to postinfectious Lyme arthritis.

Drug Prevents Lupus Flares Across Many Patient Groups

Belimumab Reduces Severe Flares in Systemic Lupus Erythematosus Across Multiple Patient Subgroups: Results of a Large Integrated Analysis

Poster Session: Monday, Nov. 8, 8:30–10:30 a.m.

Michelle Petri, M.D., M.P.H., director of the Johns Hopkins Lupus Center, will present the results of a study that shows the effectiveness of the lupus drug belimumab across a diverse group of patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects hundreds of thousands of people in the United States; women of childbearing age have the highest incidence. There is no cure for lupus, but treatments aim to prevent flares and reduce long-term complications such as organ damage.

Belimumab (trade name Belysta), was the first FDA-approved biologic to treat lupus, approved for use in adult SLE in 2011. It has since been given the greenlight for pediatric SLE as well as lupus nephritis, an inflammation of the kidney caused by SLE. However, few studies have evaluated the effectiveness of belimumab in specific patient subgroups.

In the new study, Petri and colleagues used data from five separate double-blind, placebo-controlled studies of patients with SLE. In total, the analysis included data on 1,869 patients receiving the drug and 1,217 patients receiving a placebo. Over 52 weeks, 13.8% of patients receiving belimumab had a severe SLE flare, while 22.2% of patients on placebo had a flare — a reduction of 39% in the risk of severe flare. Moreover, the drug reduced the risk of flares across many patient subgroups, including those who had been diagnosed with SLE for different amounts of time, those with different levels of inflammatory biomarkers, those taking different concomitant medications (medications taken in addition to the study drug), and those with different levels of progressive damage related to SLE.

“This large combined dataset allowed us to show the reduction in severe lupus flares in multiple subsets of SLE patients, including those early in disease with no organ damage,” says Petri.

Can Urine Replace Kidney Biopsies in Lupus Nephritis?

Urinary CD163 Predicts Proliferative Lupus Nephritis in SLE Patients with Proteinuria: A Practical Liquid Biopsy Approach

Monday, Nov. 8, 9:30–9:45 a.m.

A urine test for the protein CD163 may be useful for guiding the treatment of lupus nephritis, according to this new study by Andrea Fava, M.D., a rheumatologist and instructor of medicine at the Johns Hopkins Lupus Center, and Michelle Petri, M.D., director of the center.

Lupus nephritis, a type of inflammatory kidney disease caused by systemic lupus, can be subdivided into two subtypes: proliferative, which generally causes more severe disease, and non-proliferative. Patients require an invasive kidney biopsy to determine which kind they have; the results are key for clinicians to determine their treatment.

“Proliferative lupus nephritis is associated with a higher risk of permanent kidney damage,” says Fava. “Once we know they have proliferative disease, we treat them much more aggressively.”

Fava, Petri and their colleagues analyzed urine samples of 237 patients with lupus nephritis who were also undergoing kidney biopsies. They measured levels of 1,200 proteins in each urine sample and compared the proteins with the results of the biopsy. While a number of proteins showed an association, CD163 levels were most strongly correlated with whether a patient had proliferative or non-proliferative disease. Moreover, levels of CD163 changed as patients were treated for lupus nephritis, suggesting that a urine test could be used to quickly gauge whether a treatment is effective or not.

“Patients typically get just one kidney biopsy, and we base all our decisions on that one point in time, even though we know things in the kidneys can change quickly,” says Fava. “Having a urine test to monitor lupus nephritis would be a revolution in the way we diagnose, monitor and treat the disease.”

Early Recognition Key for Treating Lupus-Related Blood Disorders

Hematological Manifestations in SLE

Monday, Nov. 8, 2–3 p.m.

Patients with lupus deal with a host of symptoms, from muscle and joint pain to rashes and extreme fatigue. Many patients also develop blood problems. As many as a quarter of patients with lupus, for instance, have thrombocytopenia, a low number of blood platelets — cells that help blood clot. Another 20% have antiphospholipid syndrome (APS), a coagulation disorder that instead causes an increased risk of blood clots.

At a presentation at ACR Convergence 2021, Michael Streiff, M.D., medical director of the Johns Hopkins Hospital Anticoagulation Management Service, will review the current approach to the diagnosis and management of platelet and coagulation disorders in patients with lupus. His presentation will be based on his extensive experience managing these disorders and well-accepted diagnostic criteria and treatment guidelines.

Thrombocytopenia, he says, most often occurs due to antibodies that are directed against the patient’s platelets, leading to increased destruction. Once the disorder is diagnosed, there are a number of effective therapies that can treat this condition.

APS is a more complex diagnosis that requires the presence of characteristic clinical conditions such as blood clots or recurrent miscarriages and positive laboratory testing on at least two occasions at least 12 weeks apart. Once confirmed, long-term anticoagulation with warfarin is the standard treatment for patients with blood clots. Newer oral anticoagulants such as rivaroxbana and apixaban have been shown to be less effective and should not be used. For both lupus-related blood disorders, raising awareness about proper detection and management is critical to ensuring that patients are recognized early and treated appropriately.

Connecting Cancer and Scleroderma

The Link Between Scleroderma & Cancer

Tuesday, Nov. 9, 11–11:20 a.m.

Over recent years, scientists and clinicians have discovered a heightened risk of cancer in patients with scleroderma, an autoimmune disease that can cause thickening of the skin and affect internal organs. Recent data discovered through precision medicine techniques suggest that unique subgroups of patients with scleroderma may be at high risk of cancer around the time of scleroderma onset, often with a cancer diagnosis shortly preceding the first signs of scleroderma. These data have raised a question of whether cancer could be a trigger of the disease in some patients.

Ami Shah, M.D., co-director of the Johns Hopkins Scleroderma Center, and colleagues have studied scleroderma patients with cancer to better understand the molecular links between the two diseases. At ACR Convergence 2021, she will present an overview of research findings on the association.

Recent data demonstrate that the presence of certain autoantibodies — antibodies that react to a person’s own tissues, such as in autoimmune disease — could be useful tools to determine which patients with scleroderma are at highest risk of cancer. Patients with anti-RNA polymerase III (POLR3) antibodies, which are associated with more severe scleroderma and skin thickening, have an approximately threefold increased risk of cancer within three years of scleroderma onset compared with that expected in the general population. Biologic data suggests that cancer may trigger scleroderma in patients with anti-POLR3. Aside from antibodies, the subtype of scleroderma that a patient is diagnosed with — diffuse or limited — may also inform cancer risk and type.

Taken together, the evidence on scleroderma and cancer suggests that distinct subgroups of scleroderma patients may benefit from targeted cancer screening strategies, Shah says. An important question is whether early cancer detection and treatment can improve scleroderma outcomes in these patients.

The Role of Neutrophil Immune Cells in Lupus Nephritis

A neutrophil degranulation signature identifies proliferative lupus nephritis

Tuesday, Nov. 9, 4:15–4:30 p.m.

By analyzing the urine of 195 patients, Andrea Fava, M.D., a rheumatologist and instructor of medicine at the Johns Hopkins Lupus Center, and Michelle Petri, M.D., director of the center, discovered that properties of immune cells called neutrophils are associated with more severe lupus nephritis. Lupus nephritis, which affects the kidneys, is one of the more serious complications of systemic lupus erythematosus.

Researchers had previously suspected that neutrophils played a role in lupus nephritis, but studying them was difficult since they rarely turned up in kidney biopsies.

“These cells tend to be elusive, so many in the field have just ignored them,” says Fava.

But Fava, Petri and their colleagues analyzed urine samples from patients with lupus nephritis who were undergoing kidney biopsies and found that the cells could be noninvasively monitored through the urine. In particular, they determined that whether neutrophils were granulated — a change to their proteins seen in some inflammation — was associated with the severity of lupus nephritis. The observation not only suggests a way to track the severity of lupus nephritis through neutrophils, but also points toward neutrophils as playing a role in disease.

“The more we understand the mechanisms of lupus nephritis, the more we can develop new treatments,” says Fava. “I think in the future we might see treatments that actually target neutrophils to treat lupus, and perhaps studies like this will provide the impetus for that.”

Sweet 16: Interleuken-16 ID’d As Possible Therapeutic Target for Lupus Nephritis

IL-16 Is Linked to Lupus Nephritis Activity

Tuesday, Nov. 9, 4:30–4:45 p.m.

The immune molecule interleukin-16 (IL-16) has been implicated as a player in autoimmune and infectious diseases ranging from irritable bowel syndrome to asthma. Now, Andrea Fava, M.D., and Michelle Petri, M.D., of the Johns Hopkins Lupus Center, add to the growing body of evidence that the molecule plays a role in lupus nephritis, the severe kidney disease caused by systemic lupus.

In their study, Fava, Petri and colleagues analyzed the levels of more than a thousand proteins in urine samples from 174 patients with lupus nephritis. Urinary IL-16 levels were correlated with lupus activity in two separate cohorts of patients, with higher levels measured in patients with more active disease and more inflammation of the kidneys.

Clinicians most often use total levels of protein in the urine as a marker for kidney inflammation in lupus nephritis, but the test is not always accurate — levels of protein can remain high from kidney scarring even as disease becomes less active. The new results, Fava says, suggest that urinary IL-16 may be more useful than total protein as a marker of active lupus nephritis. Moreover, since IL-16 has been implicated as not only a biomarker but a trigger of many inflammatory diseases, the new research also points toward IL-16 as a possible therapeutic target for lupus nephritis.

“We’re now working to better understand the role of IL-16 in lupus nephritis, and developing preclinical models to test the effect of drugs that target IL-16,” says Fava.

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