WASHINGTON, D.C.—Rheumatology researchers look for next-generation treatments, healthy interventions, and genetic and microbial clues to disease pathogenesis and therapy response, according to new studies presented at a Nov. 15, 2016, press conference at the 2016 ACR/ARHP Annual Meeting.
OA & Physical Function
How do you know when a patient with knee osteoarthritis (OA) has the ability to walk at least 6,000 steps a day, an established benchmark for good physical function? That was the focus of a new study presented by its co-author, Daniel K. White, PT, ScD, MSc, assistant professor of physical therapy at the University of Delaware.1
“Physical activity is incredibly important for health, especially for people with knee osteoarthritis,” said Mr. White. “Currently, we don’t know how much physical capacity you need to have to be physically active or to walk 6,000 steps per day.”
Mr. White and his colleagues used data on 1,790 knee OA patients taken from the Osteoarthritis Initiative (OAI) to measure physical activity and function using three tests: how long it takes a patient to stand up from a chair five times, how long it takes them to walk 400 meters and their speed on a 20-meter walk. From these data, they determined function thresholds for patients to be able to walk 6,000 steps daily: taking 12 seconds or less to get up and down from a chair five times, walking 400 meters in 5.5 minutes or less, or walking slower than 1.2 meters per second, Mr. White said.
The good news: More than two-thirds of the patients met or exceeded these thresholds. Patients who don’t meet these thresholds may have levels of physical function too low to be able to walk 6,000 daily steps and need to be referred to rehabilitation, he said. Tests like timing a patient getting up from a chair five times is something that all physicians can do in their offices. “Some physicians [may] be nervous about getting a patient out in the hallway to time them walking, but getting up from a chair is pretty failsafe,” he said.
Fecal matter of people with antiphospholipid syndrome (APS), an autoimmune disorder associated with higher thrombosis risk, is enriched with particular, phospholipid-producing bacteria, a new study found.2
Emerging literature suggests that microbiota in patients’ guts may interact with the immune system, and the study suggests that these microbes may be involved in APS pathogenesis, said Martin A. Kriegel, MD, PhD, the principal investigator and assistant professor of immunobiology and medicine at Yale School of Medicine in New Haven, Conn.
Sixty stool samples from 22 APS patients were compared at baseline, four and eight weeks with 13 samples from six controls with non-autoimmune thrombophilic conditions, and 49 samples from 19 healthy individuals. Stool DNA and peripheral blood mononuclear cell (PBMC) proliferation to the auto-antigen β2 GPI were measured.
The APS patients’ PBMCs responded preferentially to β2 GPI compared to the controls, said Dr. Kriegel. Their fecal microbiomes showed decreased levels of Bilophila and higher levels of Slackia. In addition, 59% of the APS patients were positive for anti-domain I (anti-DI) antibodies, compared to none of the controls. Anti-DI IgG positivity significantly correlated to increased Slackia and decreased Butyricimonas.
Slackia can secrete cardiolipin, a target lipid in APS that could promote autoreactivity against the major B cell epitope in β2 GPI. Positivity for anti-DI IgG is significantly correlated to increased Slackia. In APS patients, β2 GPI is often bound by phospholipids that make it more immunogenic. Thrombosis risk is much higher in people with these antibodies, so these findings are clinically relevant, he said.
Genetic Signs of Anti-TNF Response
Single-cell gene expression signatures in the pretreatment blood serum of rheumatoid arthritis patients may help rheumatologists predict response to anti-TNF therapy, according to a new study by researchers at the Mayo Clinic.3
“We are beginning to understand what’s happening at the cellular level in patients who do not respond to TNF inhibitors,” said Theresa L. Wampler Muskardin, MD, a rheumatologist and lead author of the study. In their previous research, they found that patients with an interferon (IFN) β/α ratio of greater than 1.3 predicted non-response to anti-TNF therapy. Next, they wanted to identify differences in select gene expression between responders and non-responders.
Using single-cell expression analysis, they isolated single classical and non-classical blood-derived monocytes in the pretreatment blood serum of 15 seropositive RA patients: Six with an IFN-β/α ratio of greater than 1.3 and nine with a ratio of less than 1.3.
[Genetic] research may one day lead to a blood test ‘that could tell us whether a patient would respond to treatment before it is tried, which would expedite achieving control over the disease & allow us to avoid the cost & risk of exposing patients to medicines to which they’re not going to respond.’ —Dr. Muskardin
JAK1 and IL1A expression were retained in models for the prediction of treatment response for all monocytes. TLR9, STAT1 and FCER were retained in the prediction response model in classical monocytes alone. STAT2 and IFI27 were retained in the model in non-classical monocytes alone. Further study of monocyte subsets may reveal molecular differences that determine treatment response to TNFα inhibition in RA, and better understanding of mechanisms of the IFNβ/α ratio may help researchers locate other markers that point to therapy targets, she said. This research may one day lead to a blood test “that could tell us whether a patient would respond to treatment before it is tried, which would expedite achieving control over the disease and allow us to avoid the cost and risk of exposing patients to medicines to which they’re not going to respond,” she said.
Wnt-Inhibitor Promising for Knee OA
Patients with knee OA who received a single, intra-articular injection of SM04690, a Wnt-inhibitor, showed improved pain and function compared to placebo in a Phase I trial.4 Patients who had the therapy also either maintained their joint space width, a sign of slowed arthritis, or increased width, a potential sign of cartilage growth, said Yusuf Yazici, MD, chief medical officer of Samumed LLC, a biotech company in San Diego where the research was conducted.
Sixty-one patients with moderate to severe knee OA were divided into three cohorts: treatment with one injection of either 0.03, 0.07 or 0.23 mg of the drug in their affected knee, as well as four in each group receiving a placebo. Follow-up examinations were performed at 12 and 24 weeks. The researchers used Outcomes Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) strict responder data to analyze the drug’s effect on pain and function compared to placebo.
More patients in the 0.07 mg group met both pain and function criteria versus placebo at both 12 and 24 weeks, said Dr. Yazici.
The researchers then conducted radiographic analysis on the patients to evaluate changes in joint space width from baseline to 24 weeks.5 Two months after treatment, patients in the 0.07 mg cohort showed statistically significant increases in mean medial joint space width of 0.49 mm from baseline compared to placebo. Phase 2 trials are now underway.
Lowering CVD Risks
People with inflammatory rheumatic diseases are at higher risk for cardiovascular disease (CVD), but too few receive preventive medications or meet target goals to prevent heart attacks and strokes, according to a new study in Norway.6
The researchers studied 2,647 patients with RA, ankylosing spondylitis, psoriatic arthritis or spondyloarthropathies to evaluate the rate of indications for anti-hypertensive or lipid-lowering therapies, the rate of initiation of these therapies for those indicated, and goal attainment for blood pressure and low-density lipoprotein (LDL) cholesterol for those treated, said Anne Grete Semb, MD, a cardiologist at Diakonhjemmet Hospital in Oslo and co-author of the study.
Approximately 25% of patients had an indication for lipid-lowering therapies, and of these, 63% were prescribed treatment. Only one in five of those who received treatment attained recommended LDL goals, said Dr. Semb. Approximately 53% of the patients had an indication for anti-hypertensive treatment, but only about half of those patients were prescribed treatment. Again, only one in five of those treated with anti-hypertensive medications attained blood pressure goals, she said.
The findings suggest “a huge unmet need for improving initiation of CVD risk assessment, and achieving better goal attainment and treatment to prevent cardiovascular disease,” she said.
Susan Bernstein is a freelance medical journalist based in Atlanta.
- Master H, Thoma L, Christiansen M, et al. Minimum physical function needed to walk 6,000 steps/day in people with knee osteoarthritis (abstract). Arthritis Rheumatol. 2016;68 (suppl 10).
- Aguiar CL, Ruff W, Goodman A, et al. Cardiolipin-producing candidate commensals in the gut microbiome of antiphospholipid syndrome patients (abstract). Arthritis Rheumatol. 2016;68 (suppl 10).
- Wampler Muskardin TL, Fan W, Jin Z, et al. Distinct single cell gene expression signatures of monocyte subsets differentiate between tnf-alpha inhibitor treatment response groups in rheumatoid arthritis. Arthritis Rheumatol. 2016;68 (suppl 10).
- Strand V, Swearingen CL, Simsek I, et al. Analysis of pain and function components in OMERACT-OARSI strict responders from a randomized, double-blind, placebo-controlled, phase I study of a novel, intra-articular, injectable Wnt-inhibitor (sm04690) in the treatment of osteoarthritis of the knee (abstract). Arthritis Rheumatol. 2016;68 (suppl 10).
- Strand V, Swearingen CL, Simsek I, et al. Radiographic outcomes from a randomized, double-blind, placebo-controlled, phase I study of a novel, intra-articular, injectable Wnt-inhibitor (SM04690) in the treatment of osteoarthritis of the knee (abstract). Arthritis Rheumatol. 2016;68 (suppl 10).
- Ikdahl E, Rollefstad S, Wibetoe G, et al. Exploring the inadequate cardiovascular disease prevention in inflammatory joint diseases: Results from a nationwide Norwegian project (abstract). Arthritis Rheumatol. 2016;68 (suppl 10).