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Rheumatology Network's Top 5: July 30, 2021

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Take 5 minutes to catch up on Rheumatology Network's highlights from the week ending July 30, 2021.


The Clinical Disease Activity Index (CDAI) responses to biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) and the proportion of adverse events were comparable between patients with elderly-onset rheumatoid arthritis (EORA) and non-EORA, according to a study published in 

Patients with EORA, defined as developing RA after 60, have different, and often more severe, disease characteristics when compared with younger-onset RA (YORA). However, the comparison between EORA and non-EORA patient groups is underexplored.

“Biological factors such as serological findings, organ function, and fragility differ between elderly vs younger patients,” explained investigators. “Therefore, comparing EORA patients with the same age group of patients with RA who have had a longer disease duration is as important as comparing patients with EORA and YORA.”

Investigators utilized data the FIRST registry to study a cohort of patients aged ≥ 60 years with RA who were receiving b/tsDMARDs. Those who had developed RA over the age of 60 were included in the EORA group, and patients under the age of 60 were categorized as non-EORA. Data were collected, such as demographics, disease characteristics, disease activity, functional status, and treatment. Initial follow-ups were conducted at 2, 22, and 54 weeks, and then yearly until discontinuation of therapy.

Data from a total of 1040 patients in the EORA cohort and 710 in the non-EORA group were analyzed. At baseline, age and high disease activity (HDA; CDAI > 22.0) were higher in the EORA group. However, during follow-up visits, low disease activity (LDA; CDAI ≤ 10.0) was similar between the 2 cohorts. By week 54, 41.9% (n = 436) patients in the EORA group and 38.9% (n = 276) patients in the non-EORA group chose to discontinue the trial. Reasons included less efficacy, infection, and adverse events.

After controlling for variables, which included sex, glucocorticoid (GC) usage, methotrexate (MTX) dose, and previous use of b/tsDMARDs, investigators determined EORA was not indicative of changes in CDAI scores over time. However, there was a definite correlation between GCs and higher CDAI scores. Patients who received MTX (1-10 mg/week) had lower scores when compared with nonusers. Health Assessment Questionnaire-Disability Index (HAQ-DI) analysis showed male sex, MTX, and EORA were associated with lower scores, while patients over the age of 70 receiving GC had higher scores.

There were no significant differences in the lack of efficacy in b/tsDMARDs as a reason for discontinuation in either group.

The ratios of infection and serious adverse events were calculated to determine the drug safety. In total, 16 patients dropped out due to infection, and 88 discontinued treatment due to serious adverse events. After controlling for variables, there were no differences between the 2 groups.

Three response patterns were identified using trajectory analysis of fluctuations in CDAI responses to b/tsDMARDs through 54 weeks. Group 1 was comprised of rapid responders with lower baseline CDAI scores and LDA weeks (EORA: n = 859, 83.0%; non-EORA: n = 572, 81.6%). Group 2 included the slower responders with higher baseline CDAI scores that continued to improve over the 54-week period (EORA: n = 75, 7.2%; non-EORA: n = 62, 8.8%). Group 3 was comprised of non-responders (EORA: n = 101, 9.8%; non-EORA: n = 67, 9.6%). Investigators determined percentages of patients in each group were similar between both patients with EORA and non-EORA.

The retrospective nature of the study is intrinsically limiting, as investigators had a finite amount of access to detailed patient data. Further, a few patients were treated with several different agents and comorbidities were not included. Lastly, the number of dropouts was small, which impacted the Cox regression analysis and created uncertainty as to whether this indicated an actual lack of difference or if the sample size was too small.

“The importance of early intervention for elderly patients with RA is underscored by the observation that multiple or widespread chronic pain may lead to declined activity and onset of disability among elderly people. Thus far, low doses of GC appear to be preferred in such situations,” concluded investigators. “However, GCs increase the risk of osteoporosis and pathological fracture, so they may also contribute to comorbidities among the elderly. In addition, GC use could increase the risk of poor treatment outcomes and serious infectious diseases. Therefore, when elderly patients are refractory to conventional therapy, introduction of a b/tsDMARD would be a treatment option that can be used to minimize GC doses.”

Ochi S, Mizoguchi F, Nakano K, Tanaka Y. Similarity of Response to Biologics Between Elderly-onset Rheumatoid Arthritis (EORA) and Non-EORA Elderly Patients: From the FIRST Registry [published online ahead of print, 2021 Feb 15]. 

. 2021;jrheum.201135. doi:10.3899/jrheum.201135

After controlling for variables, eldery-onset rheumatoid arthritis (EORA) was not indicative of changes in Clinical Disease Activity Index (CDAI) scores over time when compared with a non-EORA cohort. Further, there were no significant differences in the efficacy and safety of receiving biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs).

Elderly-Onset Rheumatoid Arthritis DMARD Response Similar to Non-EORA Counterparts

Investigators identified 3 overarching themes that will allow for improved medication adherence research and created a comprehensive list of recommendations, according to a study published in BMC Rheumatology.

 Investigator-informed recommendations included specifying the targeted adherence phase when designing future studies, developing a core domain set for international studies, and utilizing a glossary of terms to ensure consistency.

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Medication non-adherence in rheumatic diseases can be as high as 90% in patients with gout, 70% in patients with rheumatoid arthritis (RA), and 43% in patients with systemic lupus erythematosus (SLE).

“Our study confirms challenges in selecting an appropriate outcome in interventional studies targeting medication adherence and the ways in which the lack of guidance in this area hinders research and limits our ability to compare interventions and draw conclusions about their effectiveness,” stated investigators.

Investigators at the Outcome Measures in Rheumatology (OMERACT) Adherence Working Group conducted audio conference interviews with a small sample of professionals who had experience in medication adherence research (clinical trials, observational studies, etc). Participants were recruited from collegial and professional networks internationally. Purposive sampling was used to collect an array of perspectives and ensure variation regarding demographic characteristics, expertise, and research discipline.

Using interview transcripts, categories and themes were analyzed until investigators reached saturation, which was defined as the point when no new insights emerged. Afterwards, results were shown to participants to ensure the accuracy of their perspectives. Quotes were also provided.

A total of 13 (8 males, 5 females) researchers from 7 countries (Australia, Belgium, Canada, Netherland, Thailand, United Kingdom, and United States of America) participated in the study. All held a doctoral level degree and led between 2 and 5 adherence research studies in recent years. Most (75%) worked in academia.

Three themes emerged: improving measurement of adherence, challenges faced when designing and appraising adherence intervention studies, and advancing the outcome assessment within these studies.

Strengths included the collaborative effort of the interview guide with Working Group members, purposive sampling for diversity of perspectives, investigator triangulation, and member checking. Limitations of the study were only interviewing English-speaking researchers and soley focusing on adherence of patients with rheumatic diseases. However, as these issues are not exclusive to rheumatology, investigators believe the findings may be applied to all adherence intervention research.

“Overall, adherence intervention research in rheumatology has been hindered by lack of standardization and guidance on terminology, measurement and outcome selection,” concluded investigators. “Our study forms the basis for recommendations for improving the design, conduct and evaluation of adherence intervention studies in rheumatology, particularly for developing a core domain set of outcomes to improve consistency and facilitate comparisons.”

Salmasi S, Kelly A, Bartlett SJ, et al. Researchers' perspectives on methodological challenges and outcomes selection in interventional studies targeting medication adherence in rheumatic diseases: an OMERACT-adherence study. 

. 2021;5(1):26. Published 2021 Jul 8. doi:10.1186/s41927-021-00193-4

Expert Perspectives: Improved Medication Adherence in Rheumatic Diseases

While functional humoral immunity to the first dose of the COVID-19 vaccine BNT162b2 (Pfizer-BioNTech) is hindered by methotrexate (MTX), it is unaffected by targeted biologics, according to a study published in 

 Further, the cellular responses were preserved.

MTX and biologics designed to target tumor necrosis factor (TNF), such as interleukin (IL)-17 and IL-23, are common immunosuppressant therapies for patients with rheumatic disease. However, they also increase risk of serious infection, especially with respiratory pathogens.

“Individuals with immune-mediated inflammatory diseases receiving therapeutic immunosuppression were excluded from COVID-19 vaccine trials; therefore, characterization of vaccine efficacy in this vulnerable population is important,” explained investigators. “Given the roll-out of extended interval vaccination programs, the effect of immunosuppression on the immunogenicity of a single dose of vaccine is of major public, and personal, health importance.”

A total of 84 patients with a confirmed diagnosis of psoriasis who were being treated with either MTX or biologic monotherapy were entered in the cohort study between January 14 and April 4, 2021. Volunteers without psoriasis (n = 17) were included as the control cohort. To be eligible for inclusion, participants needed to be able to receive the BNT162b2 vaccine. Investigators collected blood samples, as well as clinical and safety data, at 3 visits: baseline, 28 days later, and 14 days after the second dose. Data included demographics, comorbidities, psoriasis details, and any adverse events that occurred after vaccination.

The primary endpoints were focused on humoral immunity to the SARS-CoV-2 spike glycoprotein and spike-specific T-cell responses 28 days after the first dose. Secondary endpoints included antibody seroconversion rates, the presence of T cells secreting IL-17A and IL-22, adverse events, and worsening psoriasis symptoms. Adverse events were categorized as local or systemic, and subcategorized as mild, moderate, or severe.

Humoral immunogenicity was calculated by seroconversion and the plasma’s ability to neutralize the prototypic strain of SARS-CoV-2 and the B.1.1.7 variant.

The 2 pre-determined hypotheses were that patients receiving MTX would have lower humoral or cellular immunogenicity to the first dose of the vaccine compared with healthy controls; and that patients receiving MTX would have lower humoral or cellular immunogenicity to the first dose compared with patients receiving targeted biologics.

Of the 84 patients in the psoriasis cohort, 17 were on MTX, 27 on TNF inhibitors, 15 were receiving IL-17 inhibitors, and 25 were taking IL-23 inhibitors. The average dose of MTX was 15 mg per week. The median age was 43 years, 56% were males, and 84% were White.

During the first 28 days, 75% (n = 63) patients in the psoriasis cohort reported mild adverse events, compared with 94% (n = 16) of controls. The most common effects were pain at injection site, fatigue, and headache.

Seroconversion rates were lower in the group receiving immunosuppressants (60 [78%; 95% CI 67–87] of 77) than in the healthy control group (17 [100%; 80–100] of 17), with the lowest rate in patients currently receiving MTX (7 [47%; 21–73] of 15).

Immune response was reported in all groups, regardless of immunosuppressant status. Positive T-cell responses were confirmed across the cohorts, and rates were similar.

Patients receiving MTX had lower median neutralization titers (129) against the wild-type SARS-CoV-2 when compared with both the healthy control cohort (317) and those receiving targeted biological therapy (269). Patients on IL-17 or IL-23 inhibitors had neutralization titers against wild-type SARS-CoV-2 that were comparable to the control group. However, neutralization activity against B.1.1.7 were low across all groups.

The study was limited by the number of participants and absence of immunogenicity data after the second dose. However, baseline demographics were well matched and immune responses were profiled, thus helping further research on this topic. Additionally, longer-term data is not available as the investigators focused on the immune efficacy of the first dose.

“While global mass COVID-19 vaccination programs are underway, there remains concern over vaccine efficacy in immunosuppressed patients,” concluded investigators. “Although our data indicating preserved cellular immunogenicity across biological classes and methotrexate, independent of neutralizing activity, are reassuring, ongoing pharmacovigilance studies will determine whether this finding translates into clinical effectiveness of vaccines.”

Mahil SK, Bechman K, Raharja A, et al. The effect of methotrexate and targeted immunosuppression on humoral and cellular immune responses to the COVID-19 vaccine BNT162b2: a cohort study [published online ahead of print, 2021 Jul 8]. 

. 2021;10.1016/S2665-9913(21)00212-5. doi:10.1016/S2665-9913(21)00212-5

Common immunosuppressant therapies for patients with rheumatic disease, such as methotrexate and targeted biologics, increase risk of serious infection, especially with respiratory pathogens. A recent study investigates the connection between these drugs and functional humoral immunity to the first dose of the COVID-19 vaccine BNT162b2 (Pfizer-BioNTech).

Targeted Biologics Did Not Affect Humoral Immunity to First Dose of COVID-19 Vaccine

Patients with juvenile idiopathic arthritis (JIA) were more likely to have lower anti-vaccine antibody levels against vaccines due in part to incomplete vaccination, arthritis, and immunosuppressive drugs like biologics and methotrexate (MTX), according to a study published in 

Investigators urge continued vaccination in this patient population, especially for those with incomplete vaccination and low anti-vaccine antibody levels, as they are deemed safe and effective.

“Patients with JIA are at greater risk of infections than healthy children due to their aberrant immunity and the use of immunosuppressive drugs,” explained investigators. “Vaccinations can decrease the number of infection episodes, maintain treatment of the disease, and restrain remission. However, many children with pediatric rheumatic disease (PRD) stop vaccinating when a diagnosis of rheumatic disease is established… As a result, we have a rather large cohort of immune-compromised children with incomplete vaccination.”

The cross-sectional Russian study analyzed 170 children, aged 2 to 17 years, with JIA who had received routine vaccinations, including measles, rubella, mumps (MMR), diphtheria, and hepatitis B. Patients were divided into 2 categories: complete and incomplete vaccination. Incomplete vaccination was defined as having fewer vaccines or doses to age according to the Russian national vaccine schedule.

Post-vaccination antibodies (IgG) were measured using ELISA. Survival data as well as the continuous, quantitative, and categorial variables were analyzed. The log-rank test compared survival curves in this patient population.

The study found that protective levels of antibodies in this cohort ranged from 50% (against hepatitis B), 52% (diphtheria), 58% (measles), 80% (mumps), and 98% (rubella).

A total of 50 (42%) of patients did not achieve a complete vaccine dosing schedule against MMR. Among patients deemed to have an incomplete MMR vaccination, 39% of patients were being treated with biologics, 22% were treated with MTX, and 14% were using non-steroidal anti-inflammatory drugs (NSAIDs). All patients, however, received all doses against hepatitis B.

When comparing patients with complete and incomplete vaccinations, those with incomplete status had a lower level of antibodies against mumps and diphtheria (p = 0.024). Investigators hypothesized that MTX ([odds ratio] OR = 9.5 [95%CI: 1.004; 90.3]) and biologics (OR = 4.4 [95%CI: 1.6; 12.1]) were strong indicators of diphtheria revaccination omission. Incomplete vaccination was also a risk factor of non-protective levels of antibodies against measles ([hazard ratio] HR = 2.03 [95%CI: 1.02; 4.0], p = 0.042).

Approximately 1 out of 3 patients with JIA continued vaccination, during periods of remission, without incidence of flare or serious adverse events.

Most patients with JIA were without non-protective levels of antibodies, most likely due to the limited number of vaccines they had received. In this study, 100% of young patients received 1 MMR vaccine, and 55.9% (n = 95) received 2 doses. A total of 82 patients (48.3%) received 1-4 doses of the diphtheria vaccine and 88 (51.7%) had received 5-6 vaccines.

Cox proportional regression models confirmed that incomplete vaccination is a risk factor for a non-protective level of antibodies against measles, mumps, and diphtheria. It was also a factor in the severity of arthritis symptoms and immunosuppression. Investigators noted a positive correlation between biologic therapies and incomplete vaccination against MMR and diphtheria. Non-protective levels against measles occurred more in JIA patients with extended MTX treatment (2.8 vs. 2.2 years). Biologic-treated patients were in the lowest probability group of having protective antibodies against diseases such as hepatitis B, mumps, measles, and diphtheria when compared with MTX and NSAIDs.

Investigators theorized that JIA diagnosis, treatment modalities, vaccination coverage, and time since last vaccine injection influenced the level of antibodies against the vaccine.

The study was limited due to the differences in age, onset ages, JIA categories, treatment approaches, disease duration, and an inconsistent time gap between vaccinations. Additionally, the small sample size hinders generalizability.

“Children with JIA have lower antibody levels, and many JIA patients have non-protective levels of antibodies and require a routine check. Individual vaccination schedules are required for JIA patients without protective antibody levels and should be tailored individually with antibody level sampling,” concluded investigators. “It is necessary to decrease the level of apprehension among Russian parents and healthcare providers regarding vaccinations. Further studies on the safety and efficacy of vaccinations in JIA patients are required.”

Kostik MM, Lubimova NA, Fridman IV, Goleva OV, Kharit SM. The vaccine coverage and vaccine immunity status and risk factors of non-protective levels of antibodies against vaccines in children with juvenile idiopathic arthritis: cross-sectional Russian tertiary Centre study. 

. 2021;19(1):108. Published 2021 Jul 5. doi:10.1186/s12969-021-00594-2

Many children with juvenile idiopathic arthritis stop vaccinating when diagnosis is established, despite them being at a greater risk of infections than healthy children due to their aberrant immunity and the use of immunosuppressive drugs. 

Lower Anti-Vaccine Antibody Levels Observed in Patients With Juvenile Idiopathic Arthritis 

In patients with rheumatoid arthritis with diabetes mellitus (RA-DM), the use of cardiovascular disease (CVD) medication and prevalence of atherosclerotic cardiovascular disease (ASCVD) were higher than patients with rheumatoid arthritis without diabetes mellitus (RAwoDM), according to a study published in 

However, CVD prevention programs are lacking in this patient population.

“Prevention of ASCVD in patients with RA is advocated both by the European League Against Rheumatism (EULAR) and other recent recommendations,” stated investigators. “Despite these efforts, ASCVD prevention in patients with RA was noted to be incomplete across the world in our international audit, Survey of Cardiovascular Disease Risk Factors in Patients with Rheumatoid Arthritis (SURF-RA).”

Both RA and DM are historically associated with increased risk of ASCVD. Surveys like SURF-RA can be used to improve quality of care and treatment strategies.

Investigators analyzed the prevalence of CVD among RA-DM and RAwoDM groups utilizing data from already established clinical cohorts in the SURF-RA survey, which included patient records from 53 centers in 19 countries on 3 continents. Centers were divided into Western Europe, Eastern Europe, North America, and Asia. Patients were separated into 2 groups: those with ASCVD and those without ASCVD. They then compared both risk factors and preventative treatment between the RA-DM cohort and the RAwoDM cohort.

RA variables, such as rheumatoid factor and anti-citrullinated protein antibody positivity, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), antirheumatic medication, and Disease Activity Score were recorded. CVDs, such as coronary heart disease and stroke, as well as self-reported CVD risk factors, such as smoking, hypertension, waist circumference, and physical activity, were also entered into the database. Finally, lipids, glucose, glycosylated haemoglobin A1c (HbA1c), and lipid-lowering agents were analyzed.

The goal of antihypertensive treatment was <140/90mm Hg for RAwoDM and <140/80mm Hg for RA-DM. The low-density lipoprotein cholesterol (LDL-c) goal was set to ≤2.5 mmol/L for those in the high-risk group and ≤1.8 mmol/L for patients with ASCVD.

CVD risk factors and management between patients with and without DM were analyzed separately from those with and without ASCVD.

A total of 10543 patients with RA, 1381 (13%) in the RA-DM cohort, were reviewed. Of the study population, 1434 had an established ASCVD diagnosis and 9109 patients did not. In the RA-DM group, 26.7% had an ASCVD diagnosis, compared with only 11.6% in the RAwoDM group. Coronary heart disease (CHD), stroke, heart failure, and peripheral artery disease were more prevalent in patients with RA and DM. Hypertension, hyperlipidaemia, and the use of antihypertensive agents were more common in that cohort as well.

Among patients with ASCVD, the majority were not able to achieve the lipid goal (<1.8mmol/L), however attainment was significantly higher in those with RA and DM when compared with the RAwoDM group, regardless of ASCVD diagnosis.

Interestingly, LDL-c, high-density lipoprotein cholesterol (HDL-c) and cholesterol levels were generally lower in the DM group. The RA-DM cohort without ASCVD and receiving preventative lipid-lowering treatment had significantly lower LDL-c when compared with RAwoDM.

ASCVD prevention was notably better in patients with RA and DM group when compared with the RAwoDM group, exemplified by the higher number of patients in this group achieving their lipid goals, regardless of ASCVD status.

The SURF-RA survey was limited by the variations in the recorded prevalence of ASCVD risk factors among 3 continents, including primary care records, rheumatology outpatient clinics, and cardiology outpatient clinics. Data extracted from pre-existing registries added to the differences across regions. The importance of increasing awareness of this field was highlighted by the rates of missing data on CVD risk factors, thus indicating that the screening and recording of these variables are lacking. Additionally, medication adherence was not evaluated. Lastly, investigators utilized European recommendations in achieving treatment targets throughout all countries and continents surveyed, and there were a disproportionate amount of patients recruited from North America and Western Europe. However, these audits are important tools for improving clinical outcomes in this patient population.

“Despite the knowledge of the increased risk of ASCVD in patients with RA, their CVD risk factors often remain underdiagnosed, and they receive poorer CVD prevention than general population,” concluded investigators. “We found that patients with RA with DM more often used lipid-lowering and antihypertensive medications compared with their counterparts without DM, regardless of if they had ASCVD or not. This may reflect the well-developed CVD preventive programs in patients with DM.”

Semb AG, Rollefstad S, Ikdahl E, et al. Diabetes mellitus and cardiovascular risk management in patients with rheumatoid arthritis: an international audit. 

. 2021;7(2):e001724. doi:10.1136/rmdopen-2021-001724

While prevention of atherosclerotic cardiovascular disease (ASCVD) in patients with rheumatoid arthritis (RA) is advocated by recent recommendations, ASCVD prevention in patients with RA was underwhelming, according to an international audit. 

Cardiovascular Disease Prevention Remains Lackluster in Patients With Rheumatoid Arthritis and Diabetes Mellitus

Rheumatology Network sat down with Roy Fleischmann, MD, to discuss the recent Pfizer press release touching upon the safety of JAK inhibitors. Fleischmann is Clinical Professor of Medicine at the University of Texas Southwestern Medical Center at Dallas and co-Medical Director of the Metroplex Clinical Research Center in Dallas. He explains the recent scrutiny of JAKs, the concerns some rheumatologists have in regard to JAK inhibitors, and his personal opinions on prescribing JAK inhibiting drugs to his patients.

What do rheumatologists need to know about the recent press release from Pfizer regarding the safety of JAK inhibitors?

 Well, we have a press release from Pfizer talking about ORAL surveillance and that the primary endpoints were not met. The FDA had an advisory in February, which said that they were going to look into the information that was provided to them by Pfizer, and they would come out with their recommendations. But as of today, July 20th, I haven't seen it yet. What we do know is that the European Medicines Agency (EMA) has come out with recommendations, or proposed recommendations, to change the label as of last week. And they were interesting, actually, because what the EMA recommendation stated was that it was patients over the age of 65, not over the age of 50, who had other risk factors for cardiovascular disease, and particularly, patients who had ever smoked or they were current smokers, were at increased risk for cardiovascular events and for malignancy. And obviously, patients over the age of 65 who have smoked are more likely than someone who's much younger, who's never smoked or have malignancy, or heart disease. So, they recommend that tofacitinib should not be given to a patient over the age of 65, who has any of those risk factors. But they didn't say anything about patients under the age of 65, which was interesting. And we'll see what the FDA concludes from their data review.

According to analysts, the response to the safety of JAK inhibitors is not surprising. Did you expect this scrutiny in JAK inhibitors?

They may be thinking that the FDA response will be that there will be an additional black box warning on tofacitinib. And they may be thinking that it's going to be severe; that any patient treated with tofacitinib is at increased risk for malignancy and for cardiovascular disease. But if you take a look at the data, and that data was in the Pfizer press release in February, the endpoints were not met. But the incident rates of malignancies and cardiovascular events are only slightly higher in the tofacitinib group than it was the tumor necrosis factor (TNF) group. Because the rate was that low, and you calculate the hazard ratio by dividing 1 incident rate by the other, it turns out that the hazard ratio was a little bit higher, but these are very rare events. They occur in patients who have rheumatoid arthritis, probably much more frequently if they're not treated. Active rheumatoid arthritis leads to malignancy and leads to cardiovascular events. I was taught that, when I trained in the last century, that that's the reason why rheumatoids died earlier. And we know that all the drugs that we use, whether it be biologics, or even conventional synthetics, reduce the risk of cardiovascular events. So, the conundrum is that tofacitinib was not quite as good as TNF as shown by this 1 study, the ORAL surveillance study. But it doesn't show what tofacitinib does to the population. Does it actually reduce the risks, but not quite as well as a TNF? And that's why I am waiting for the FDA review of this data, I'm sure they will do very thoroughly, and we'll see what else. I would not be surprised if it's not different from what the FDA said: that there is a particular subgroup, and it's the patients who are over 65, who have a history of smoking, with significant cardiovascular risks. And in those patients, you should use tofacitinib with caution. So, I'm assuming that that's what it's going to be. And then if the analysts feel that this would be really adverse to tofacitinib, I'd be surprised, because the benefit of tofacitinib is actually quite good. The numbers needed to harm, which you can calculate from the Pfizer press release, is really in the hundreds for additional case of malignancy versus a TNF. I've been involved in the studies comparing the JAKs to the TNFs, and the JAKs are just as good if not better. So, we take a look at the relative risk-to-benefit ratio in a patient who's under 65, hasn't smoked, and doesn't have significant cardiovascular risk factors, it’s probably beneficial to use tofacitinib. The other question, which you haven’t asked, but which is actually suggested, is this a class of factors of tofacitinib. And we'll see what the FDA does with this. The FDA may turn around and say this is just specifically for tofacitinib, because no similar trial has been done with upadacitinib, where they may say it's a class effect. From your statement about what the analysts have concluded, my guess is the analysts are overreacting to some extent. So, in summary, I think there will be some change in label, I think it will be to the patients who are greatest risk, which are where the patients are over 65, history of smoking, and additional cardiovascular risk factors.

What are some of the concerns rheumatologist have in regards to the safety of JAK inhibitors?

I think that these are the most prevalent. We know that JAK inhibitors can increase liver function tests. But we know that they do that in combination with methotrexate. We know that they can increase cholesterol, but we've actually published that the increase in cholesterol is actually safer than not increasing it because it changes the molecule changes what the lipids will look like. We know that there is a risk of herpes zoster. Therefore, we do recommend that all patients be vaccinated with it. Now that we have a dead vaccine, that's really much easier to do. We know that there is a risk of serious infections. But these are not different from what you see with biologics. Actually, with conventional synthetics, their rates may be a little bit different but you see the same side effects. So, the concern now is what I've heard in a community, which is really what you're asking, is that there are rheumatologists who say that looking at this data before it's even been published or presented anywhere or the FDA said anything about it. They just look at the press release, saying well, tofacitinib raises the risk. I don't know that that's true. I actually don't think it's true. So there are rheumatologists who are reading this press release literally, “I think it may raise the risk,” and they’ll be concerned. And there are others who feel that “the risk is just slightly worse.” Right? And if the benefit of the tofacitinib outweighs the risk, then they would use it. And I'm hearing 50/50 from rheumatologists, but we'll wait and see what the FDA says. We'll then see what the reaction of rheumatologists really are.

What are your thoughts on prescribing JAK inhibiting drugs to your patients?

So, I think JAK inhibitors are very effective. And given my druthers, if I developed rheumatoid arthritis, probably even psoriatic arthritis although not all the JAKs are approved, and maybe even ankylosing spondylitis. I would think about using a JAK before I would use anything else if I could afford it. They are oral, they're easy to take, and they are effective. What I tell patients though, is we always start with methotrexate for rheumatoid arthritis and if they don't have a response to that, and an adequate response to that, then I would add it. And then it's a discussion with the patient. If the patient's 75 years old, with a history of smoking, I'm not going to suggest to JAK number 1, I would suggest to TNF, number 1. But if the patient's you know, your age, right, way under the age of 65, and is employed in a professional way that traveling or coming into the doctor's office to get an infusion, or to have to refrigerate medication and be home all the time is inconvenient, I would certainly think about offering a JAK as I would a biologic at the same time. Tell the patient what the data does show, particularly from what the FDA concludes, and then let the patient make the decision as to what they will do. But I'm not against JAKs. I mean, I'm very pro-JAK if a patient is someone who's not in the high risk group.

What does this mean for the future of JAK inhibitors?

So depends upon what the FDA actually does. And they may do it. I mean, they've been working on this since February. You know, we may see it very quickly, depending upon what they do. I mean, I think rheumatologists will take that into consideration. Again, the manuscript has not been published yet. It hasn't been presented yet. So, all rheumatologists can go by is 1 press release.

Is there anything else you'd like our audience to know before you wrap up?

Well, no, I would just summarize by saying I think that we need to see the data. We need to see all the data. I think that the data that I've seen from Pfizer and from the EMA actually makes me feel relatively comfortable with the JAKs. The incident rate of the events is low, just a little bit higher than with the TNF. But if the patient is not in that high risk group, then I feel very comfortable offering the JAK to the patient. But again, the patient has to make the decision and the patient should be given all the information.

Dr. Fleischmann, thank you so much for joining me today. I really appreciate it.

Videos

Roy Fleischmann, MD, discusses the recent Pfizer press release touching upon the safety of JAK inhibitors. He explains the recent scrutiny of JAKs, the concerns some rheumatologists have in regard to JAK inhibitors, and his personal opinions on prescribing JAK inhibiting drugs to his patients.

Roy Fleischmann, MD: Safety of JAK Inhibitors

Guselkumab led to significant and sustained improvements in fatigue through 1 year in patients with active psoriatic arthritis (PsA), according to a study published in 

Additionally, superior Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores were independent of effects on other outcomes.

Fatigue is associated closely with chronic inflammatory diseases, and can impact disease activity, pain, sleep, depression, physical and mental work, and health-related quality of life (HRQoL). Guselkumab, an interleukin-23p19-subunit inhibitor, has been clinically proven to treat psoriatic arthritis, but was not previously focused on this symptom.

“The mechanism underlying fatigue is complex and undefined, and it can involve physiological, psychological, and social aspects,” stated investigators. “Signs and symptoms of PsA are effectively treated with biologics that block specific cytokines and reduce inflammation. Improvement of fatigue has also been evaluated in biologic clinical trials, with variable measurement tools and results.”

In the phase 3 DISCOVER-1 and DISCOVER-2 trials, patients with PsA were given either subcutaneous injections of guselkumab 100 mb ever 4 weeks (Q4W, N = 373), guselkumab 100 mg at week 0, 4 and then every 8 weeks (Q8W, N = 375), or placebo (N = 372) through week 24 before switching to Q4W. The DISCOVER-1 trail continued through week 48 and DISCOVER-2 through week 100. All patients enrolled did not respond to or were intolerant of non-biologic disease-modifying antirheumatic drugs (DMARDs), non-steroidal anti-inflammatory drugs, and/or apremilast. Patients in DISCOVER-2 were biologic-naïve. Baseline characteristics and FACIT-Fatigue scores were consistent across the treatment groups and patients exhibited substantial disease burden.

Fatigue was measured using the FACIT-Fatigue instrument, a 13-item patient-reported outcome (PRO) tool that determined the association of fatigue with impact on daily activities and physical function. Scores ranged from 0-52, with higher scores signifying less fatigue.

Mediation analysis aimed to adjust for for improvements that may be indirect of fatigue and instead indicating positive progression in other outcomes, such as the American College of Rheumatology criteria (ACR20), minimal disease activity (MDA), or C-reactive protein (CRP). This was determined post hoc.

According to FACIT-Fatigue scores, patients with PsA had higher levels of baseline fatigue when compared with the general population (29.1-31.4, 43.6, respectively). Patients in the Q4W and Q8W demonstrated significant improvements at week 24 in both DISCOVER-1 and DISCOVER-2 trials (ranging from 5.6 [54%] and 7.6 [63%]) when compared with the placebo group (2.2-3.6 [35-46%]). Additionally, these results were sustained through week 52, with mean changes reported as 6.7-6.9 in DISCOVER-1 and 7.2-8.4 in DISCOVER-2. More patients in both Q4W and Q8W achieved ≥2 to ≥12-point increases when compared with the placebo group by week 24. By week 52, patients in the placebo group who switched to Q4W at week 24 had comparable improvements with those who had originally received guselkumab.

After adjusting for ACR20, MDA, and CRP, analyses indicated much of the improvements on fatigue were a direct effect of receiving guselkumab. In the Q4W cohort, 69% and 70% (DISCOVER-1 and DISCOVER-2, respectively) of the drug’s impact on the FACIT-Fatigue scores was independent of ACR20 and 12% and 36% of the effect was independent of other factors in the Q8W group.

The results of this analysis cannot be compared to other biologic therapies, in which FACIT-Fatigue scores have also been observed, because of differences in assessment tools, study populations, and study designs. Additional research may help differentiate guselkumab from other biologics. Investigators caution interpreting the mediation analyses indicating the drug’s effect on fatigue independent of ACR achievement, MDA response, or CRP due to the complex nature of the symptom. It should be noted that FACIT-Fatigue scores also improved in the placebo group, especially in the DISCOVER-2 trial. Cumulative distribution curves, however, demonstrated that patients receiving guselkumab fared far better.

“Taken together, results of these analyses indicate a strong impact of guselkumab on the fatigue of PsA when assessed via the FACIT-Fatigue instrument,” concluded investigators. “Although further research is needed to more fully characterize the mechanism by which guselkumab improves patient fatigue, our findings may further inform treatment decisions, additional research on this topic, and future consensus deliberations surrounding PsA core set assessments.”

Rahman P, Mease PJ, Helliwell PS, et al. Guselkumab demonstrated an independent treatment effect in reducing fatigue after adjustment for clinical response-results from two phase 3 clinical trials of 1120 patients with active psoriatic arthritis. 

. 2021;23(1):190. Published 2021 Jul 14. doi:10.1186/s13075-021-02554-3

Guselkumab, an interleukin-23p19-subunit inhibitor, led to clinically significant and sustained improvements in fatigue through 1 year in patients with active psoriatic arthritis. 

Guselkumab Significantly Improves Fatigue in Patients With Psoriatic Arthritis 

Cardiovascular autonomic neuropathy (CAN) was frequently self-reported in patients with systemic lupus erythematosus (SLE) and associated with impaired health-related quality of life (HRQoL), according to a study published in 

Further, this patient population showed impaired parasympathetic function, even without CAN, when compared with a control cohort.

“Dysfunction of the autonomic nervous system (ANS) is increasingly studied in rheumatic diseases, including SLE,” stated investigators. “Dysfunction of the ANS may present as impaired cardiovascular regulation, denoted as CAN.”

In this cross-sectional, controlled study, CAN, which is assessed by heart rate variability (HRV) measures and cardiovascular autonomic reflex tests (CARTs), was measured in a group of patients with SLE and a group of healthy controls (HCs). Investigators used 5-minute HRV and 3 CARTs to understand parasympathetic and mixed sympathetic-parasympathetic function in these cohorts. HRQoL was determined by the self-reported Short Form 12 (SF-12) and split into a mental health component score with weighted scorings of 12 individual items. CAN was split up into 3 categories: no, early, or definitive.

A total of 111 patients were recruited from the Prospective Lupus Study on Cardiovascular Risk Factors (PLUSheart) between October 2018 and March 2019. Data from 100 control subjects were used for matching the SLE cohort. After exclusion criteria was applied, including cardiac arrythmias, and considering sex and age, 55 patients were matched in each cohort. These patients tended to be older, with a higher BMI, and a lower hip/waist ratio.

During the passive HRV test, patients relaxed for 5 minutes while the pattern of changes in R-peaks (RR intervals) and normal heart beats (NN intervals) were analyzed. Afterwards, 3 CARTs were performed, determining the response to standing (RS) ration, expiration inspiration (EI) ration, and Valsalva maneuver (VM) ration. CAN scoring was utilized in patients who completed >2 CARTs, with 2 or more abnormal CARTs being classified as definitive CAN and 1 abnormal CART signifying early CAN.

Within the 2 cohorts, CAN was present in 24.1% of patients with SLE and 1.9% of HCs. HRV and CART scores were lower in patients with SLE controls (RS ratio: 14.3%, EI ratio: 5.7% and VM ratio: 11.1%.

Autonomic modulation was more prevalent in patients with SLE and no CAN when compared with the control group. Definitive CAN was reported in 24.8% of patients with SLE, and 57.8% had either definitive or early CAN.

When comparing patients with SLE and definitive CAN with patients without CAN, ANS was similarly associated with impaired modulation of parasympathetic nervous system (PNS) activity as well as mixed sympathetic nervous system (SNS)-PNS activity. The PNS and SNS-PNS were significantly lower in the group of patients with SLE and no CAN. Patients in the SLE cohort with definitive CAN presented signs of mixed sympathetic-parasympathetic dysfunction, while those without CAN and impaired parasympathetic activity. These dysfunctions were also linked to low physical SF-12 component scores.

The cross-sectional design limits the study by being unable to determine the natural of the course of autonomic dysfunction of SLE as well as the relationship of dysfunction and HRQoL. Additionally, sympathetic function measures, such as blood pressure CARTs, were not included in the study. However, this was the first study to show how ANS dysfunction can influence the physical symptoms of SLE, which may be a clinically useful way to show poor HRQoL that is not easily explained by traditional disease characteristics of this condition.

“We found that compared with controls, patients with SLE presented more frequently with CAN characterized by mixed parasympathetic/sympathetic impairment,” concluded investigators. “Furthermore, even in patients without clinical signs of CAN, we demonstrated impaired parasympathetic function. These impairments were in patients with SLE associated with self-report of poor physical quality of life.”

Zinglersen AH, Iversen KK, Leffers HCB, Laugesen E, Fleischer J, Jacobsen S. Characteristics of cardiovascular autonomic dysfunction and association with quality of life in patients with systemic lupus erythematosus. 

. 2021;8(1):e000507. doi:10.1136/lupus-2021-000507

Patients with systemic lupus erythematosus presented more cardiovascular autonomic neuropathy, along with impaired health-related quality of life and parasympathetic function, when compared with a control cohort. 











Cardiovascular Autonomic Neuropathy Associated with Impaired Quality of Life in Patients with Lupus 

Rheumatology Network's Top 5: July 23, 2021

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Rheumatology Network's Spotlight: Clinical Updates in PsA

Catch up on Rheumatology Network's most recent highlights in psoriatic arthritis news. 


Rheumatology Network's Spotlight: Clinical Updates in Psoriatic Arthritis July 2021

The painTRAINER program reported improvements for patients with systemic lupus erythematosus (SLE) in physical and psychological outcomes, according to 

 While pain coping skills training (PCST) have shown potential benefit in this patient population, investigators believe strategies need to be put in place to improve engagement rates and aid in customization for specific symptoms and challenges.

“Patients with SLE often experience pain and other symptoms that negatively impact quality of life. Interventions that enhance the use of behavioral and cognitive coping strategies may lead to improved outcomes among patients with SLE,” stated investigators. “PCST programs have been shown to improve outcomes among patients with other rheumatic conditions, but there have been no trials of PCST among patients with SLE. This study was a preliminary assessment of the feasibility and efficacy of painTRAINER, an automated, internet-based PCST program, among patients with SLE.”

A total of 60 patients with SLE were assigned to either the painTRAINER program or a control group. The internet-based program included 8 weekly modules in addition to coping skill activities, which took approximately 30-45 minutes to complete. Investigators measured outcomes at baseline and after the 8-week program, including the Pain Catastrophizing Scale (focusing on and exaggerating pain and one’s ability to deal with pain), pain interference, physical function, anxiety and depression, fatigue, sleep disturbances, and a LupusPRO questionnaire.

Data was collected via telephone and follow-ups were conducted by blinded study team members. Eligible patients were found within the University of North Carolina at Chapel Hill (UNC) Health Care System.

Patients rated their current pain on a 0-10 scale (with a minimum score of 4 for inclusion) and completed baseline assignments before being randomized into the 2 cohorts. A patient’s pain was analyzed by how it impacted social, cognitive, emotional, physical aspects of life, as well as recreational activities.

The secondary outcomes were determined using the coping strategies questionnaire and the LupusPRO questionnaire, which focused on self-reported coping strategies, such as coping self-statements, and lupus-related symptoms and medication usage.

In the painTRAINER cohort, approximately 50% accessed the program. Participants reported issues with not receiving instructions via email. Positive feedback included the flexibility of the program, however, many noted that the descriptions of pain were not always accurate for patients with SLE. Despite some critical feedback, those in the painTRAINER group had better improvements in PROMIS Pain Interference, Depression scores, PROMIS sleep disturbance, anxiety, fatigue, and Quality of Life Scores when compared with the control group. Both groups had decreased PROMIS Physical Function scores.

Limitations included generalizability, as the pilot was quite small and participants were selected from a singular medical center. Additionally, as painTRAINER was a free program, there is a small chance that the control cohort were also utilizing the program during the study period.

“Our next step to address this is to work with patient stakeholders to develop strategies for incorporating SLE-related content into painTRAINER,” concluded investigators. “Although the convenience of the online painTRAINER format was very appealing to participants in this study, adding the support and accountability of participating in the program alongside others may boost engagement and efficacy. Therefore, our study team and patient stakeholders will consider potential real-time delivery strategies within the study design.”

Allen KD, Beauchamp T, Rini C, et al. Pilot study of an internet-based pain coping skills training program for patients with systemic Lupus Erythematosus. 

. 2021;5(1):20. Published 2021 Jun 17. doi:10.1186/s41927-021-00191-6

The painTRAINER program included 8 weekly modules, in addition to coping skill activities, in which investigators measured outcomes including the Pain Catastrophizing Scale, pain interference, physical function, anxiety and depression, fatigue, and sleep disturbances.

PainTRAINER Program Improves Outcomes for Patients With Systemic Lupus Erythematosus

Ingrid Torjesen is a UK-based freelance health journalist with more than 30 years of experience in health and medical communications. She works for numerous publications including Rheumatology Network, the BMJ and the Economist’s Intelligence Unit. Before her freelance career, her staff jobs included news editor of both Pulse and GP (the two leading UK weekly titles for primary care doctors), and opinion and features editor of the Health Service Journal (the UK’s leading health policy title). She also spent a few years working in Australia, including on Australian Doctor.

Patients who have not been previously treated with either biologic disease-modifying antirheumatic drugs (DMARDs) or targeted synthetic DMARDs

Patients who have had an inadequate response to biologic DMARDs or targeted synthetic DMARDs

All patients with early or established rheumatoid arthritis

Targets may be more difficult to achieve in this group than in treatment-naïve patients

Failure to achieve targets may be disheartening for patients

The incremental benefits of treat-to-target over usual care in this patient population are uncertain

Number of remaining available treatment options

Impact of non-inflammatory causes of pain

Patient’s threshold for changing medications

Remission is not a reasonable initial goal for patients with early disease and no prior exposure to DMARDs

Remission may not be achievable for many patients

Failure to achieve remission may be disheartening for some patients

Treat-to-target remains a key strategy for the treatment of rheumatoid arthritis. However, some changes to the recommendations were made in the 2021 American College of Rheumatology Guidelines on the Management of Rheumatoid Arthritis.
Check your knowledge on how to approach a treat-to-target strategy with this quiz.


Rheumatoid Arthritis Quiz: Treat-to-Target

Initiation of biologics in children hospitalized with systemic juvenile idiopathic arthritis (sJIA) has both increased over time and may be associated with reduced glucocorticoid exposure, thus reducing treatment-related side effects, according to a study published in 

Glucocorticoids are historically a driver of morbidity in this patient population, including adverse effects such as growth inhibition, osteoporosis, avascular necrosis, obesity, cataracts, hypertension, and psychologic issues. Investigators analyzed the effect of biologic therapies, such as interleukin-1 (IL-1) or interleukin-6 (IL-6), in order to determine the effectiveness of this first-line biologic approach in treating sJIA and reducing the exposure of glucocorticoids.

“The current draft of the American College of Rheumatology (ACR) 2020 JIA guidelines explicitly recommend biologic DMARDs (IL-1 and IL-6 inhibitors) as first-line monotherapy and avoidance of oral glucocorticoid monotherapy (grade C recommendations),” explained investigators. “Paralleling this recent recommendation, we have shown an increasing trend toward biologic monotherapy, which is encouraging as it should reduce the negative consequences of glucocorticoid-reliant therapeutic approaches.”

Pseudo-trials were conducted analyzing biologic initiation in children with sJIA using observational data from 52 hospitals in the Pediatric Health Information System (PHIS) between January 2008 and March 2019. Investigators collected information such as demographics, discharge disposition, dates of service, and billing data for medications. Both biologic and non-biologic cohorts were aligned for eligibility window, treatment, and start of follow-up. Covariates included demographics, hospital characteristics, year of discharge, and disease severity.

Eligible patients were required to have had no previous glucocorticoid exposure. Glucocorticoids included oral or intravenous dexamethasone, hydrocortisone, methylprednisolone, prednisolone, or prednisone.

The source population was 468 patients with sJIA who were discharged from 1 of the PHIS institutions. Within this group, 19% of patients had initial biologic therapy without initiation of immunomodulatory medications, such as methotrexate or glucocorticoids. Throughout the 12-year period, the proportion of patients initially receiving biologics increased significantly over time, culminating in approximately 40% of patients between 2017 and 2019.

The time from admission to receiving biologic medication was 4 days. A total of 51.3% of patients received glucocorticoids, with the time from admission to initiation of medication being 5 days.

A total of 1451 patients were included in 4 pseudo trails, of which 1380 were in the non-biologic cohort and 71 subjects were in the biologic cohort. There was a trend towards reducing glucocorticoid initiation in the biologic group when compared with the non-biologic group (0.13, 1.15, respectively). Exposure to methotrexate was more common in the biologic non-initiators group (8.6% vs. 2.8%, respectively). After the 4th trial, 19 patients receiving biologic therapy were added to the biologic non-initiator group. Analysis showed that these patients were less likely to receive glucocorticoids than other patients in the same cohort (36.8% vs. 56.9%, respectively).

The study was limited by its inability to evaluate treatment after patients were discharged from the hospital, however, it was designed to analyze the association of biologics on glucocorticoid exposure. The inclusion of 19 patients who started biologics after the eligibility window may have reduced investigators’ ability to detect this effect of biologics and glucocorticoid initiation. Additionally, the treatment groups were not randomized, and outcomes were limited to information provided in the administrative claims database. Macrophage activation syndrome (MAS) was not included to balance out the 2 groups as data was not clear if MAS was present before initiating biologics, however, MAS was similar in both study arms. Lastly, as only 1 patient was treated using an IL-6 inhibitor, the results may not be able to be generalized to this treatment approach.

“Our results coupled with other observational studies suggest that initial therapy with a biologic may reduce the use of glucocorticoids in hospitalized children with new onset sJIA but is only utilized in a minority of patients,” concluded investigators. “Further studies are needed to assess other important clinically relevant long-term outcomes that may be related to glucocorticoid use or avoidance in sJIA, including hospital readmissions for disease flares or infection, MAS, sJIA-related pulmonary disease, and long-term glucocorticoid toxicity. These studies will help to develop a more evidence-based approach to glucocorticoid usage in sJIA.”

Peterson RG, Xiao R, Katcoff H, Fisher BT, Weiss PF. Effect of first-line biologic initiation on glucocorticoid exposure in children hospitalized with new-onset systemic juvenile idiopathic arthritis: emulation of a pragmatic trial using observational data. 

. 2021;19(1):109. Published 2021 Jul 5. doi:10.1186/s12969-021-00597-z

Investigators analyzed the effect of biologic therapies in order to determine the effectiveness of this first-line biologic approach in treating systemic juvenile idiopathic arthritis (sJIA) and reducing the exposure of glucocorticoids, a driver of morbidity in this patient population. 

First-Line Biologics Reduce Glucocorticoid Exposure in Patients With Systemic Juvenile Idiopathic Arthritis 

Rheumatology Network's Top 5: July 16, 2021

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