2021 Arthritis Research Highlights

The 2021 American College of Rheumatology (ACR) Convergence conference was recently held, gathering researchers, clinicians and patients alike for a week of knowledge sharing to advance treatments, understanding and approaches to managing various rheumatic diseases.

Listen now to the Live Yes! With Arthritis Podcast covering some of the 2021 Arthritis Research Highlights as well as a discussion on what the Arthritis Foundation is working on to provide support for these scientific and research initiatives and resources available to help the arthritis community.

Here are some highlights of the latest in science and research presented at this virtual conference.

2021 Rheumatology Year in Review

Karen Costenbader, MD, MPH, director of the lupus program at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, summarized some of the highlights from clinical research for the year, ranging from new treatments to health care disparities to COVID-19 research.

Drug News

Two drugs hold new promise, she says. A phase 3 trial of the oral medication avacopan was tested against prednisone to treat ANCA (antineutrophil cytoplasmic antibody)-associated vasculitis, a group of autoimmune inflammatory diseases that attack small vessels and can affect internal organs as well as skin. Treatments include glucocorticoids (also called corticosteroids, like prednisone) and conventional and biologic disease-modifying drugs, including rituximab (Rituxin). This trial found that avacopan works as well as prednisone, and the U.S. Food and Drug Administration (FDA) has approved its use for ANCA-vasculitis.

An “overwhelmingly positive trial” — a phase 3 trial comparing the oral drug voclosporin to placebo to treat lupus nephritis — found that more patients responded to voclosporin than to placebo. Dr. Costenbader says. The FDA approved its use for lupus nephritis in October 2021.

Janus kinase (JAK) inhibitors were promising new types of drugs when the FDA in 2012 approved tofacitinib (Xeljanz) to treat rheumatoid arthritis (RA). But at the same time, the FDA mandated a post-approval study for safety. Since then, two other JAK inhibitors have been approved — baracitinib (Olumiant) and upadacitinib (Rinvoq). Upadacitinib was approved in recent years to treat ankylosing spondylitis (AS), and this year a trial found that tofacitinib also appears effective for AS.

But in response to the earlier post-approval study, which showed an increased incidence of cardiovascular events and some types of cancer, the FDA now is requiring boxed warnings not only on tofacitinib for RA, but on all three JAK inhibitors for all conditions. Many doctors, however, are not telling patients to stop taking JAK inhibitors unless they already have risk factors for cardiovascular disease or cancer. The full results of the study, which might be more specific about who should or should not take them, have not yet been released.

Clinical Care

Dr. Costenbader also looked at studies that could influence clinical care, including one focusing on whether RA patients in remission should reduce their medication. The answer: “probably not.”

The study looked at RA patients in remission who were taking conventional DMARDs (disease modifying anti-rheumatic drugs). Researchers followed as some continued their full dose while others took half their dose for 12 months. Those on the half dose developed an increased number of flares and disease activity.

The new ACR guideline for treating RA reflects the results, Dr. Costenbader says: “[It] conditionally recommends continuing on the same dose of DMARD vs. reducing it in patients who are stable and in RA remission for at least six months.”

In other studies, a treat-to-target approach to axial spondyloarthritis was found to have some benefits for patients as well as overall cost savings. And patients with knee osteoarthritis (OA) had improved pain when they followed a prescribed exercise program that involved more personal attention according to each patient’s needs.

Health Care Disparities

Health care disparities continue to be a pressing problem. In the past year, studies have highlighted some of the evidence, including a study of RA patients. Researchers determined their neighborhood poverty score by zip code as well as their RA function-status scores. Those in the most impoverished neighborhoods had the worst functional status measures, even after taking into account other confounding factors, including age, sex and race.

A study of OA patients had similar findings. “It’s known that there are disparities in patient self-reported pain and X-ray findings, and even greater disparity in underserved populations,” Dr. Costenbader says. Self-reported pain is typically higher than X-rays indicate. In this trial, researchers used an algorithm measuring pain severity to compare results from a standard X-ray measure. They found that their algorithm more accurately predicted knee OA pain than X-rays. “The author suggested that identifying those with more severe pain than from using X-rays might reduce disparities in treatment access and reduce total knee replacement,” Dr. Costenbader says.

COVID-19 Research

In her final segment, Dr. Costenbader focused on several of the many COVID-19 studies. It included two studies significant for their influence on treatment for children with multi-inflammatory syndrome (MIS-C). While the two studies, one from the U.S. and one international, came to different findings, the takeaway is that the use of intravenous immunoglobulin plus glucocorticoids may have benefit, Dr. Costenbader says, although randomized control trials are needed.

Another trial looked at COVID-19 fatalities to try to determine risk factors. Among those identified: older age, male sex, hypertension or cardiovascular disease and chronic lung disease. Certain factors specific to rheumatic conditions also were identified as risks, including the use of 10 mg or more per day of glucocorticoids, moderate to high disease activity, and immunosuppressant medications including sulfasalazine, rituximab and glucocorticoids.

Certain medications also reduce the efficacy of COVID-19 vaccines, according to another study. It found that prednisone, drugs that deplete B cells (such as rituximab and belimumab) and JAK inhibitors reduce anti-spike antibodies as well as neutralizing antibodies. As a result, a third vaccine dose is recommended for people who are immunosuppressed as well as elderly people and others who are at higher risk, such as health care workers, Dr. Costenbader says. —BY JILL TYRER

Watch now as Karen Costenbader, MD, tackles questions from our arthritis community about recent FDA warnings about JAK inhibitors, the effectiveness of treat-to-target strategies, tapering of DMARDs, new medications for lupus and vasculitis and addressing disparities in osteoarthritis care for under-served and minority patients.

FDA Updates Safety Issues in Rheumatic Disease Treatments

U.S. Food and Drug Administration (FDA) medical officers Amit Golding, MD, Nadia Habal, MD, and Anil Rajpal, MD, discussed emergency use authorizations (EUAs) and drug safety at the 2021 American College of Rheumatology Convergence conference.

If there’s one term that epitomizes the coronavirus pandemic, it’s probably emergency use authorization or EUA. It’s a temporary measure in a public health emergency that allows the FDA to authorize the use of unapproved products or approved products for other uses. Though EUAs sometimes seem controversial and arbitrary, they must meet four conditions.

The targeted disease must be life-threatening.
Benefits of the drug must outweigh the risks.
The drug “might” be capable of diagnosing, preventing, or treating a particular condition (such as COVID-19), but its actual effectiveness may not be known.
There’s no approved alternative.

COVID-19 meets these conditions. As a result, the FDA — among other things — repurposed two arthritis drugs, tocilizumab (Actemra) and the Janus kinase (JAK) inhibitor baricitinib (Olumiant). They’re approved to treat certain adults and kids 2 years of age and older hospitalized with severe COVID symptoms. The trials used to gain the EUAs were generally small, and some didn’t meet their endpoints. But taken together, the FDA felt there was enough evidence that the drugs could help prevent death or the need for ventilators in some patients.

Recently Approved Arthritis Drugs

In 2021, the FDA approved three new drugs for rheumatic diseases and expanded the uses for several others. New drugs include:

Vaclosporin (Lupkynis), the first oral drug specifically approved for active lupus nephritis — a serious kidney disease that’s a complication of lupus. It’s used along with standard lupus medications and has a black box warning for serious infections and cancer.
Anifrolumab (Saphnelo) for the treatment of active lupus along with standard lupus medications. It carries a risk of serious, possibly deadly infections and cancer and should not be used for lupus nephritis.
Avacopan (Tavenos) for antibody-associated vasculitis, a relatively rare autoimmune disease that affects blood vessels.

New Uses for Older Drugs

Belimumab (Benlysta) for lupus nephritis
Anakinra (Kineret) and rilonacept (Arcalyst) for DIRA, a rare genetic disease
Tocilizumab (Actemra) for interstitial lung disease, a serious complication of systemic sclerosis
The FDA also approved a rituximab biosimilar called rituximab-arrx (Riabni). Biosimilars are nearly identical to the original drug but may cost less. Rituximab-aarx carries a boxed warning for potentially fatal infusion reactions.

Safety Warnings

The FDA issued or revised safety warnings for several commonly used drugs, including:

The Janus kinase (JAK) inhibitors, tofacitinib (Xeljanz), baricitinib (Olumiant) and upadacitinib (Rinvoq) because new data shows a significantly increased risk of heart attack, stroke, blood clots, cancer and death compared to tumor necrosis factor (TNF) blockers, even at lower doses. The boxed warnings were updated to indicate the drug may have life-threatening side effects. The FDA has limited use of JAK inhibitors to people who have failed one or more TNF blockers and is re-evaluating their overall safety and effectiveness.
Nonsteroidal anti-inflammatory drugs (NSAIDs) in light of new data showing they can cause kidney damage in unborn children after 20 weeks of pregnancy. After 30 weeks, NSAIDs can cause the artery connecting the heart and lungs to close too soon, potentially leading to high blood pressure in the lungs and even death. —BY LINDA RATH

FDA Updates in Pediatric Rheumatology

U.S. Food and Drug Administration (FDA) officials Jouhayna Saliba, PharmD, Juwaria Waheed, MD, and John Alexander, MD, weighed in on drug shortages, new drug approvals and biosimilars for pediatric use at the 2021 American College of Rheumatology (ACR) Convergence conference.

When hydroxychloroquine was touted as a potential therapy for COVID-19 early in the pandemic, supplies of the drug shrank for arthritis patients who relied on it. Sixty percent of Canadian rheumatologists reported shortages of hydroxychloroquine in a 2020 survey. Today, the FDA says about 100 drugs are in short supply, along with vials for storing vaccines and the plastic pipettes used in newborn screening tests and basic science. Many shortages are related to an increased demand for critical drugs, emergency use authorizations (EUAs) that repurpose approved drugs for other uses and supply chain backups. Though the FDA tries to ensure an ongoing supply of medical products and drugs, it can’t make manufacturers increase drug production and has no control over allocation. It does require that manufacturers notify the agency about expected shortages and discontinuations six months in advance.

New Drug Approvals

The FDA recently approved several drugs for childhood arthritis:

The tumor necrosis factor (TNF) blocker Golimumab IV (Simponi IV) for polyarticular juvenile idiopathic arthritis (JIA) and psoriatic arthritis (PsA) in children 2 years of age and older
Oral tofacitinib (Xeljanz) for polyarticular JIA. Since its approval, the FDA has increased safety warnings for this drug based on new data about a significantly increased risk of heart attack, stroke, blood clots and cancer. The risk to children isn’t known.
Anakinra (Kineret) and rilonacept (Arcalyst) for DIRA, a rare inherited autoimmune disease
The biosimilar rituximab-arrx (Riabni) for microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), both inflammatory blood vessel disorders
Tocilizumab (Actemra) and baricitinib (Olumiant) for adults and children 2 years of age and older hospitalized with severe COVID-19.

Biosimilars

These drugs are nearly identical to a medication manufactured by a different company — often called the reference product. They are marketed after the original drug goes off patent, increasing the number of available medications at potentially lower costs. Biosimilars can be approved for pediatric use without additional clinical trials in children.

Warnings

In September 2021, the FDA issued new warnings about the safety of the Janus kinase (JAK) inhibitors tofacitinib (Xeljanz), baricitinib (Olumiant) and upadacitinib (Rinvoq) based on new data showing a significantly increased risk of heart attack, stroke, blood clots, cancer and death. The FDA is limiting their use to patients who haven’t done well on one or more TNF blockers and is continuing to weigh the risks and benefits. The post-marketing study that revealed the new data was conducted on adults 50 and older, not children. —BY LINDA RATH

COVID-19: Impact and Outcomes in Rheumatology Patients

When COVID-19 became a threat in the U.S. and across the world, people with autoimmune conditions had extra cause to worry: Did having a dysfunctional immune system and taking medications that suppress the immune system make them especially vulnerable to this potentially deadly disease? What factors might raise their risks of contracting the new coronavirus or becoming seriously ill from it?

Physicians caring for these people urgently wanted to know, too, and a Twitter chat among professionals quickly led to the establishment of a global registry. Rheumatologists throughout the world recorded information in this database about their patients to help inform research and let others know about potential risk factors and treatments.

In a year and a half, this registry has grown to include more than 20,000 patients, which has made possible several studies unveiling valuable information about the impact of COVID-19 on people with rheumatic conditions, says presenter Jinoos Yazdany, MD, MPH, professor of medicine at the University of California, San Francisco, and chief of the Division of Rheumatology at San Francisco General Hospital.

Some of these studies have influenced not only the care of patients with arthritis and related conditions (including guidelines issued by the American College of Rheumatology) but have shed light on which patients are more vulnerable and why, she explains.

Comorbidity Risks

Using the global registry as well as registries in other countries, investigators found that people with autoimmune, inflammatory conditions seemed to be only slightly more likely to contract COVID-19 than the general population. However, certain comorbidities common with arthritis and related conditions, including diabetes, cardiovascular or lung disease and obesity, increased those chances — significantly in some cases.

“We’ve learned the risk of severe disease outcomes in patients with rheumatic diseases is closely tied to age and comorbidities, like the general population,” Dr. Yazdany says. However, “our patients have a lot of comorbidities and comorbidities do play [a role] in higher risk.”

Drug Risks

Research also has found that certain drugs, especially corticosteroids and some disease-modifying antirheumatic drugs (DMARDs), might put people with autoimmune diseases at greater risk from COVID-19. “Those older or with comorbidities had higher risk of hospitalization, especially with use of [corticosteroids],” Dr. Yazdany adds.

Other drugs associated with higher risks: conventional DMARDs, including cyclophosphamide, mycophenolate, azathioprine, tacrolimus and sulfasalazine. Janus kinase (JAK) inhibitors and the biologic rituximab (Rituxan) also raise risks of contacting and developing severe COVID-19.

“One of the signals that emerged early on was that rituximab [Rituxan] was associated with a very significant elevated odds of mortality — almost a four-fold increase here,” Dr. Yazdany says.

Other biologics, however, including tumor necrosis factor (TNF) inhibitors and interleukin-6 (IL-6) inhibitors seem to be associated with lower risks in comparison.

One clear message has come through, adds Dr. Yazdany: Make sure your arthritis or related condition is under control.

“One of the unique things the registry has highlighted is the impact of having uncontrolled rheumatic disease on [COVID-19] outcomes,” she says. “Those with moderate or high disease activity — regardless of whether they’re inflammatory arthritis patients or people with connective tissue disease — have higher mortality. The really important message for patients is to make sure they come in and get care.” —BY JILL TYRER

Watch now as Jinoos Yazdany, MD, tackles questions from our arthritis community about COVID-19 infection risk, including breakthrough infections after vaccination, severe illness and hospitalizations after COVID-19 infection by disease type (rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, gout and lupus) and medications (biologics and DMARDs).

JA Parenting and COVID

Liz Morasso, MSW, LCSW, OSW-C, a clinical social worker with UCLA Health who specializes in working with kids and teens tackles questions from our JA parent community about the mental health impact of COVID on kids and teens, navigating challenges of returning to school vs virtual learning, dealing with family dynamics and communication challenges about re-engaging with friends and activities and tips for productive conversations and caregiver self-care.

Watch now

Heart Problems in Rheumatic Disease

Jorge Plutzky, MD, and Christina Charles-Schoeman discussed cardiovascular disease in patients with rheumatoid arthritis (RA) at the 2021 American College of Rheumatology (ACR) Convergence conference.

People with RA have a two-fold increased risk of heart disease. Though they may have one or more traditional risk factors such as older age, high blood pressure, diabetes and smoking, their greatest risk factor may be inflammation, which is particularly associated with heart disease and a greater chance of potentially fatal heart attack and stroke.

In an interesting twist — often called the lipid paradox — systemic inflammation in RA is also associated with low levels of LDL or “bad” cholesterol — the cholesterol that clogs arteries. In studies, the lower the LDL cholesterol in people with RA (less than 70mg dL), the higher the risk of serious heart problems — the opposite of what happens in the general population.

Another paradox: When people with RA take drugs that lower inflammation, their LDL cholesterol goes up. The greater the decreases in inflammation and disease activity, the higher the LDL and HDL (“good” cholesterol).

HDL cholesterol, normally an anti-inflammatory particle that helps protect against the buildup of plaque in artery walls, becomes dysregulated and pro-inflammatory in active RA. As with LDL cholesterol, effective RA treatment can reverse these changes, though in both cases, improvement varies, depending on the type of medication, the patient and the length of therapy.

Whether to start RA patients on cholesterol-lowering drugs, even when LDL is low, depends on their other risk factors, such as smoking and high blood pressure, and possibly the results of carotid ultrasound, which examines blood flow through the main blood vessels to the brain.

One other important point: Patients aren’t told enough about diet, exercise and other lifestyle factors that can go a long way toward lowering heart disease risk. “We don’t do a good enough job of that,” the experts say. —BY LINDA RATH

Is It AxSpA or AxPsA?

Rheumatologists Nigil Haroon, MD, Anna Molto, MD, and Atul Deodar addressed this thorny question at the virtual 2021 American College of Rheumatology (ACR) Convergence conference.

Some rheumatological diseases — osteoarthritis (OA) for example — cause distinct symptoms that are hard to miss. Others are so similar they’re hard to tell apart. That’s the case with two types of inflammatory arthritis: axial spondyloarthritis (axSpA), which mainly affects the low back and spine, and axial psoriatic arthritis (axPsA), a type of psoriatic arthritis (PsA) that also involves the spine. Adding to the confusion is that some people with axSpA have psoriasis, a distinguishing feature of PsA. And though there are classifications for axSpA, definitions for axPsA vary considerably, leading one expert panelist to conclude, “We don’t really know what this disease is.”

That hasn’t stopped researchers from trying to distinguish between the two. This is important because despite their shared features, some treatments that work for axPsA are surprisingly ineffective for axSpA, especially ankylosing spondylitis (AS), the more advanced form.

Here's how they stack up:

Axial Spondyloarthritis (AxSpA)

Affects more men than women; starts at a young age
Patients much more likely to report back pain as their chief complain; about 15% to 30% have inflammation in other joints
Inflammation in both sacroiliac joints (sacroiliitis) — the two joints where the spine attaches to the pelvis
Symmetrical syndesmophytes — bony growths in spinal ligaments that can cause the bones to fuse
About 90% of patients have the HLA-B27 gene.
Effective treatments include non-steroidal inflammatories (NSAIDs), tumor necrosis factor (TNF) blockers like etanercept (Enbrel) and adalimumab (Humira), and interleukin (IL)-17 blockers like secukinumab (Cosentyx).
Interleukin (IL)-23 blockers such as guselkumab (Tremfya), which work well for psoriasis, are NOT effective for AxSpA.

Axial Psoriatic Arthritis (AxPsA)

Affects men and women equally; starts at an older age
Fewer patients have inflammatory back pain; most have inflammation and more damage in other joints.
More back pain equates with more severe disease and worse disease activity overall.
Frequently affects the neck (cervical spine), and the neck joints are more likely to fuse than other parts of the spine
Less severe, more asymmetrical sacroiliitis
Less symmetrical syndesmophytes
Fewer than half of patients are HLA-B27 positive; they’re more likely to have HLA-B08 or HLA-B38 genes.
Effective treatments may include the interleukin (IL)-23 blockers guselkumab (Tremfya) and ustekinumab (Stelara), NSAIDs and TNF blockers. A randomized controlled trial of the IL-17 blocker secukinumab — already used to treat PsA and axSpA — showed positive results.

It’s not clear what causes these differences. It may be a combination of factors, including different genes, mechanical stress or changes in the gut microbiome — the trillions of bacteria that live in the gut and interact with the immune system.

The panel stressed that patients with back pain should be checked for inflammation in other joints, and patients with joint pain should be checked for spine inflammation. —BY LINDA RATH

The Latest Research in Juvenile Arthritis

Mara Becker, MD, professor of pediatrics at Duke Medical Center, and Tiphanie Vogel, MD, an assistant professor at Baylor College of Medicine, discussed the most significant research in juvenile rheumatology from the past year at the 2021American College of Rheumatology (ACR) Convergence conference.

As might be expected, a lot of current research has focused on COVID-19, including its effect on kids with rheumatic diseases. The American College of Rheumatology published guidelines on how to manage these kids during the pandemic as well as recommendations for treating multisystem inflammatory syndrome in children (MIS-C), a severe, potentially deadly body-wide inflammation.

Other studies found that saliva tests for the coronavirus may be almost as accurate as nasal swabs — a real boon for younger kids. And still other research found that children have more immune cells in their nose than adults, a possible explanation for why they tend to get less sick.

Effects of Childhood Stress

A critical and burgeoning field of study is how chronic childhood stress may contribute to serious, long-term health problems, including juvenile idiopathic arthritis (JIA). Using data from the 2016 Survey of Children’s Health, researchers found that children who reported four or more adverse childhood events such as violence, neglect and household dysfunction were 9.4 times more likely to have arthritis than healthy kids and nearly four times more likely to have arthritis than children with other chronic physical diseases.

Researchers have also examined whether Black children with JIA have worse outcomes than their white peers. They found that disease activity scores for Black children were 5.5 times higher than for white kids at their first visit and 2.4 times higher than for all other races combined. When Black children were treated with a treat-to-target (TTT) approach, their disease improved, but not as much as for other kids.

There is no doubt that racial disparities exist in the care and outcomes of children with rheumatic disease, and, Dr. Becker stresses, it is imperative that providers find ways to overcome barriers to equitable care and improve outcomes.

STOP JIA (Juvenile Idiopathic Arthritis)

This first-of-its-kind, multi-center prospective study using data from the CARRA Registry, which collects information about people with childhood rheumatic diseases, compared three treatment approaches:

A step-up, or pyramid plan, where patients were started on a nonbiologic disease modifying anti-rheumatic drug (DMARD) like methotrexate, with a biologic added if needed.
An early combination plan, where kids were started on both a nonbiologic DMARD and a biologic.
A treatment plan that started kids on a biologic only.

There were no significant differences in disease activity at 12 months, but the combination group achieved low disease activity and ACR70 or better more often than the other groups.

One important point: Some kids did very well on methotrexate alone and never needed a biologic. The trick, researchers say, is finding out which kids those are so they’re not given drugs they don’t need.

Other Studies

In the past year, researchers also showed that:

Canakinumab can be safely tapered in kids with systemic JIA.
Rituximab (Rituxan) is safe for worsening systemic sclerosis, an autoimmune connective tissue disease.
Baricitinib (Olumiant), a Janus kinase (JAK) inhibitor approved for adult RA, may treat juvenile dermamyositis. That’s an inflammatory condition marked by rash and muscle weakness.
Abatacept (Orencia) is safe and effective for both juvenile and adult localized scleroderma.

The FDA also issued an emergency use authorization (EUA) for combined abatacept and remdesivir (Veklury) for adults and kids 2 years and older hospitalized with severe COVID-19. —BY LINDA RATH

Watch now as Mara Becker, MD, share more details on the latest in JA research.

Success Strategies for Arthritis Pain Management

Christine Stamatos, DNP, ANP-C, tackles questions from our arthritis community about managing inflammation, sleep, mood and fibromyalgia symptoms, the role of medications and how to develop a comprehensive pain management plan.

Watch now

Foot Symptoms Associated With Mortality

Yvonne Golightly, PhD, MS, PT, form the University of North Carolina at Chapel Hill, presented an abstract on the association between severe foot symptoms and mortality as part of The Johnson County Osteoarthritis Project at the 2021American College of Rheumatology (ACR) Convergence conference.

Problems of the foot are linked to restricted physical activity, impaired physical function, poor balance, disability and falls, however, their contribution to mortality was previously not known. The purpose of Golightly’s study was to examine whether presence and severity of foot symptoms, defined as pain, aching and stiffness, were associated with mortality in a prospective community-based cohort.

Based on patient-reported foot symptoms, their presence, severity and foot symptom severity count (a sum of the severity across both feet), key findings (accounting for many covarities including basic demographics as well as comorbidities, medication and other lifestyle and health measures) show any foot symptoms were related to a 16% greater hazard of all-cause mortality, with no statistically significant differences by sex, race, obesity or diabetes. Compared to no foot symptoms, severe foot symptoms were associated with a 59% greater hazard of excess mortality, with no statistically significant differences by subgroup. For foot symptom severity count, every one-unit increase was associated with a 7% greater hazard of all-cause mortality, with no differences by subgroup.

“Although mechanisms for this relationship are not yet understood, foot symptoms may contribute to less physical activity and loss of physical function, which over time leads to factors that impact mortality such as comorbid conditions from increased BMI or falls from muscle weakness and impaired balance,” says Golightly. “Strategies aimed at preventing and treating more severe foot pain may be needed to reduce mortality.” —BY BRYAN D. VARGO

Changes in Gait & Knee Pain

Kathryn Bacon, PhD, MPH, from Boston University, presented an abstract on gait alterations associated with worsening knee pain over a two-year period at the 2021American College of Rheumatology (ACR) Convergence conference.

While it’s known that altered gait is related to structural worsening of knee osteoarthritis (OA), including specific types of altered gait over two years, such as those with varus thrust (lateral bowing of the knee) during walking, what was previously unknown is what features of gait alterations are associated with worsening knee pain over time. Bacon’s new study has also set a standard for wearable gait sensors to assess gait or adjust for confounders.

The purpose of Bacon’s study was to identify markers of gait alterations in people with worsening knee pain by applying machine learning approaches to identify important variables from gait data collected in a large epidemiological cohort and to evaluate associations of important variables with worsening knee pain over two years.

Using the National Institutes of Health-funded MultiCenter Osteoarthritis (MOST) study, participants were aged 45 to 90 with or at risk for knee OA. Gait characteristics were captured via sensors worn on the participants’ trunk and ankles during a 20-meter walk test at the 144-month visit and an initial pain assessment was taken. The outcome, or pain change per knee, was assessed two years later, other data was compiled including baseline pain during walking, demographic and health date, and predictors for modeling were selected using machine-learning to assess important variables. Then a generalized estimating equation (GEE) model was established to account for correlated outcomes, i.e. two knees per person and other potential confounders such as age, sex, BMI, baseline walking pain, etc.

Results revealed baseline variables that contribute to predicting worsening knee pain over two years include (from most to least important) depressive symptoms, walking gait speed, BMI and a series of gait variables such as bilateral coordination of gait, stride time variation, gait asymmetry, phase difference, walking pain at baseline, stride time and step length. However, when GEE was applied, longer step length was associated with increased likelihood of worsening pain over two years. Gait asymmetry was somewhat associated.

“The clinical relevance here,” says Bacon, “is that walking with longer step length is associated with greater knee joint loading. So shortening step length has been recommended as a gait intervention to reduce knee joint loading in people with knee OA.” —BY BRYAN D. VARGO

Does Limited Stair Use Lead to Poor Health?

To determine if avoiding stairs can lead to poor health, Jason Jakiela, MS, from the University of Delaware, studied the relationship between short-term trajectories of stair climbing frequency and incident slow gait speed over one and two years in adults with knee osteoarthritis (OA).

It’s well-known that knee OA causes pain and functional limitations like climbing stairs. In fact, difficulty climbing stairs is one of the first reported limitations to function in older adults with knee OA. But is reduced frequency of stair climbing an early warning sign of poor health outcomes? Little is known about stair use patterns over time, and in particular, slow gait speed.

Using data from the Osteoarthritis Initiative (OAI), which includes cohort of adults with or at high risk for knee OA aged 45 to 79, 58% female and from four clinical sites, Jakiela looked at stair climbing frequency assessed at baseline visit as well as one-year and two-year follow-up visits using the question: “How often do you climb up a total of 10 or more flights of stairs during a typical week, in the past 30 days?” Answer choices: none, 1-2 days per week, 2-3 days per week, 4-5 days per week, nearly every day, every day. Incident slow gait speed was also examined at two-, three- and four-year follow-ups and defined as walking less than 1.22 meters per second over 20 meters, about the time needed to safely cross an intersection at a time crosswalk signal and an established indicator of walking about 6,000 steps per day. Participants were restricted to those with a gait speed equal to or greater than the 1.22 m/s over 20 meters.

Just over 45% of participants reported frequent stair use, 18% reported rebounding stair use, 15.5% were in the decreasing stair use group and 20.8% fell in the minimal stair use group.

“We found that relative to those who engaged in frequent stair climbing, the adults in the three other trajectory groups (rebounding, decreasing and minimal) were at greater risk of developing a slow gait speed and this relationship was observed at both follow-up timepoints — one and two years later,” says Jakiela. Results revealed that high frequency of climbing stairs appears to be positively associated with lowered risk for developing slow gait speed.

“Stair use is an easy-to-capture metric for clinicians and patients are usually able to report on difficulty using the stairs much easier than if they feel like they are walking slower,” adds Jakiela. “It’s possible that stair use may be a more sensitive litmus test. Given the significance of each trajectory group, it may be useful to ask about both current and past stair use to paint a full picture of this high-demand functional test. As of such, adults with knee OA who report decreased stair use may be prime targets for early intervention to prevent future loss of function and a potential cascade of other future poor health outcomes.” —BY BRYAN D. VARGO

Knee Pain After Knee Replacement Surgery

To answer the question, “Why does my knee hurt after I got my knee replaced?” Devin Driscoll, MD, from Boston University and Boston Medical Center, examined the neuropathic-like symptoms and objective signs of neuropathy post-knee replacement in patients with knee osteoarthritis (OA) at the 2021American College of Rheumatology (ACR) Convergence conference.

While knee replacement surgery is often marketed as the definitive or curative therapy for knee OA and the pain associated with it, “we found in studies that there’s about 20% to 30% of patients who report persistent knee pain after knee replacement,” says Dr. Driscoll. And the cause is not well-known. “If you think about the fact that we are removing the pathologic tissue contributing to the pain with the knee replacement, it has been proposed in the literature that post-surgical neuropathy is playing a role in this persistent knee pain. And that’s what we wanted to look at.”

In a post-knee replacement sample, Dr. Driscoll evaluated several scenarios: 1) the relation of neuropathic-like pain using the PainDETECT questionnaire (PDQ) and its relation to persistent pain post knee replacement; 2) objective assessments of neuropathy and its relation to persistent pain post knee replacement; and 3) the PDQ and its relation to objective assessments of neuropathy on exam.

Participants included those from the National Institutes of Health-funded MultiCenter Osteoarthritis (MOST) study, which include adults with or at risk for knee OA. Dr. Driscoll specifically looked at those who had knee replacements and had been seen in clinic about 12 months post knee replacement. Data gathered included objective assessment neuropathy on exam, a PainDETECT questionnaire (PDQ) and pain severity using the WOMAC pain scale.

For the objective assessment of neuropathy, the Standard Evaluation of Pain Protocol (StEP) for the knee was used to evaluate pain measures using normally non-painful and painful stimuli via monofilaments and pinprick during different scenarios.

OA patients with a PDQ score equal to or greater than 12 (out of total of 38) are in neuropathic-like pain. Persistent pain was defined by participants who had a WOMAC score greater than 5 out of a total of 20.

Results showed, “as the pain score increased per standard deviation unit, there was about a two-fold increased likelihood of having persistent pain post knee replacement,” says Dr. Driscoll. “Also, for participants who were scoring in the neuropathic-like pain range, there was almost a four-fold increased likelihood of having persistent pain post knee replacement. However, for patients who had any abnormality on objective assessments of neuropathy, did not have any statistically significant association with having persistent pain.

In relation to PDQ and its objective assessment of neuropathy, despite whether it was per standard deviation unit or participants who scored in the neuropathic-like pain range, there was no statistically significant association.

“We found that neuropathic-like pain on PDQ was associated with persistent pain post knee replacement,” says Dr. Driscoll. “However, objective assessments of neuropathy were not associated with persistent pain post knee replacement, and furthermore, PDQ was not associated with objective assessments of neuropathy. This data shows us that post-knee replacement persistent pain is likely not due to neuropathy based on our findings of the objective assessments. And that the PainDETECT or PDQ may be reflective of pain severity in general, and possibly nociplastic pain, rather than neuropathic-like pain.” —BY BRYAN D. VARGO

New Osteoarthritis Therapies

Tonia Vincent MD, PhD, FRCP, Director, Center for Osteoarthritis Pathogenesis, Professor of Musculoskeletal Biology, Consultant Rheumatologist, Oxford University, tackles questions from our Arthritis Community about the inflammatory process in osteoarthritis, physical activity do’s and don’ts and new therapies for OA management.

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Non-Drug Strategies for Arthritis Pain

Daniel Clauw, MD, tackles questions from our arthritis community about sources of pain (nociceptive, nociplastic and neuropathic) and non-drug approaches for pain, sleep and mood.

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New Guidelines Focus on Reproductive Health

Mehret Birru Talabi, MD, and Lisa Sammaritano, MD, discussed the latest American College of Rheumatology (ACR) reproductive health guidelines at the organization’s 2021 Convergence conference.

ACR’s reproductive health guidelines (RHG) published in 2020, cover contraception, pregnancy, medication management in pregnancy and lactation, fertility and assisted reproductive technologies, and menopause. Key takeaways include:

Contraception

Women who don’t have antiphospholipid antibodies or lupus can safely use most forms of contraception, but should aim for the ones that are most effective and don’t interact with their medications.
Women with high levels of antiphospholipid antibodies have an increased risk of blood clots and should avoid combination estrogen-progestin birth control. Good alternatives include the copper intrauterine device (IUD), which contains no hormones, the progestin IUD or progestin-only pill.
Some estrogen-containing contraceptives are safe for women with well-controlled lupus and no antiphospholipid antibodies, but all women with lupus should avoid the estrogen patch.
Emergency contraception is safe and effective for all women with rheumatic disease.

Pre-Pregnancy

Women with rheumatic disease can have healthy children as long as their symptoms are well-control several months before becoming pregnant.
Patients taking meds that can be harmful during pregnancy should switch to safe drugs before attempting to get pregnant. Doctors should talk to all women of reproductive age about contraception and pregnancy-safe medications.
Women with lupus, SS-A/B antibodies or antiphospholipid antibodies are at higher risk for complicated pregnancies. Ideally, all women with lupus should be tested for these antibodies before or early in pregnancy.

Medications

Some arthritis medications are safe during pregnancy and breastfeeding, including:
- Hydroxychloroquine (Plaquenil)
- Sulfasalazine (Azulfidine)
- Colchicine (Colcrys, others)
- Azathioprine (Imuran)
- Steroids at less than 20mg; delay breastfeeding for four hours
Nonsteroidal anti-inflammatories (NSAIDs) are only safe until week 20 of pregnancy; ibuprofen recommended during breastfeeding.
Most tumor necrosis factor (TNF) blockers are safe in the first two trimesters, but ideally should be stopped at 30 weeks, when they’re more likely to be transferred to the baby.
Non-TNF biologics, such as anakinra (Kineret), belimumab (Benlysta) abatacept (Orencia) and tocilizumab (Actemra) should be discontinued during pregnancy but are safe for breastfeeding.
Methotrexate, leflunomide, mycophenolate and thalidomide should be stopped three months before a woman tries to get pregnant.
Small-molecule drugs like baricitinib (Olumiant) and tofacitinib (Xeljanz) aren’t safe during pregnancy. The FDA has also issued new warnings about the drugs’ safety for the general population.
Many arthritis drugs are safe for men who are trying to conceive with their partner, but thalidomide and cyclophosphamide (Cytoxin) should be discontinued before trying.

Assisted Reproductive Therapy (ART)

ART is safest for people with stable rheumatic disease.
Other than cyclophosphamide, most arthritis drugs can be used when a woman’s eggs are retrieved for freezing or surrogacy.

—BY LINDA RATH

Watch now as Lisa Sammaritano, MD tackles questions from our arthritis community about contraception use, planning for pregnancy, what to expect during and after pregnancy including disease activity, medication use, impact on the fetus, breastfeeding and more.

Microbiome & Gut Health

Renuka Nayak, MD, PhD, and Julia Manasson, MD, tackles questions from our arthritis community about the terms “microbiome,” “microbes,” and microbial balance, the effect of the microbiome on rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, how it affects the clinical response of DMARDs and biologics, as well as the role of prebiotics and probiotics.

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Medical Cannabis and Arthritis

Mary Ann Fitzcharles, MD, Associate Professor of Medicine, Division of Rheumatology at McGill University and Consultant Rheumatologist, Montreal General Hospital, tackles questions from our Arthritis Community about medical cannabis including an overview of the effects of CBD and THC, the available evidence for pain, sleep and anxiety, different modes of administration, safety considerations and how to talk to your doctor about medical cannabis.

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