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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

Articles

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 

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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 

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Steadily lowering glucocorticoid doses over a prolonged period of time did not increase clinical flares or damage at the end of 2 years in patients with inactive systemic lupus erythematosus (SLE), according to a study published in 

Approximately 50% to 80% of patients with SLE are prescribed glucocorticoids indefinitely, even though their long-term side effects are well known.

“The vast majority of physicians (>90%) were willing to reduce or withdraw prednisone before immunosuppressives and antimalarials in cases of prolonged clinical inactivity,” stated investigators at the University of Toronto Lupus Clinic (UTLC).

Patients from UTLC who achieved 2 years of remission were included in this study. Participants were split into either the maintenance group, in which they maintained a low dose (5 mg/day) of prednisone, or the withdrawal group, who followed a tapering schedule over the course of 2 years. Of the 270 eligible patients, with 156 participants placed in the maintenance group and 114 placed in the tapering cohort. Remission was based on the SLE Disease Activity Index 2000 (SLEDAI-2K) of 0. After the initial 2 years, patients had follow-up visits for the following 2 years. Investigators analyzed clinical flares as well as any damage that occurred.

In the withdrawal cohort, their medication was reduced according to this method:

With this approach, participants were able to reach the first reduced dose by Week 7. They then remained on that dose until their next clinic visit, where they were instructed to continue tapering their glucocorticoids. This method ensured patients would ultimately be able to discontinue medication by 9 to 18 months, depending on withdrawal symptoms, personal preferences, and frequency of appointments.

Flares were defined as any increase in SLEDAI-2K (excluding serology), an increase in SLEDAI-2K accompanied by an increase in glucocorticosteroids, antimalarials, or immunosuppressives, or an increase in 4 or more in SLEDAI-2K. Outcomes were analyzed at 12 and 24 months. Damage was assessed at 24 months, based on the Systemic Lupus International Collaborating Clinics Damage Index (SDI).

Patients with flares or increased dosages during the 2-year period were excluded, however, they were studied separately and compared to the maintenance group in order to assess the “success rate” of the tapering approach.

A propensity score-matching (PSM) analysis was performed to account for independent variables such as sex, age, Black race, disease duration, SLEDAI-2K, SDI at index date, and duration of clinical remission prior to the index date. Using this method, 204 patients (102 in each group) were matched.

When compared with the maintenance group, the withdrawal group had lower flare rate at both 12 (17.6%, 29.4%; P = 0.023) and 24 (33.3%, 50%; P = 0.01) months. Increases in SLEDAI-2K or an increase of 4 or more was seen more often in the maintenance group when compared with the tapering cohort at 24 months (51 versus 34, respectively), although half of these flares were considered mild. Symptoms of flare included skin involvement, hematologic involvement, mild arthritis, and mild vasculitic lesions.

Moderate to severe flares were not statistically different between both groups at 12 months, but at 24 months the withdrawal group had far fewer flares (14.7% versus 27.5%, respectively). Additionally, damage was less frequent in the withdrawal cohort when compared with the maintenance group (6.9% versus 17.6%, respectively).

Observational studies are inherently limited and the choice to maintain or taper prednisone was up to the patient’s physician. As the withdrawal rate was based on multiple variables, it was not standardized for all patients. The PSM attempted to mitigate these factors to account for covariates and potentially impacted outcomes, which reduced baseline bias.

“Gradual withdrawal of prednisone seems safer than abrupt discontinuation in patients with clinically quiescent SLE and could be attempted because the vast majority of these patients will not develop a moderate to severe flare within 24 months,” concluded investigators. “A randomized controlled trial could confirm whether gradual glucocorticoid tapering is preferable to abrupt withdrawal in such patients.”

Tselios K, Gladman DD, Su J, Urowitz MB. Gradual Glucocorticosteroid Withdrawal Is Safe in Clinically Quiescent Systemic Lupus Erythematosus [published online ahead of print, 2021 Jul 10]. 

. 2021;10.1002/acr2.11267. doi:10.1002/acr2.11267

Glucocorticoid withdrawal over a prolonged period of time did not increase clinical flares or damage for patients with inactive systemic lupus erythematosus. 

Gradual Glucocorticoid Withdrawal Does Not Increase Flares in Systemic Lupus Erythematosus 

While current advice recommends testing for anti-Sjögren's-syndrome-related antigen A (anti-SSA) and anti–Sjögren's-syndrome-related antigen B (anti-SSB) in patients with rheumatoid arthritis (RA) who would like to conceive, this practice should be reconsidered given the low prevalence of these antibodies, according to a study published in 

Higher levels of anti-SSA have been linked to a higher risk of CHB and other cardiac complications. Additionally, higher titers of anti-SBB is linked to the non-cardiac elements of NLS. Due to this, preventive screenings have been utilized in high-risk populations to detect CHB as early as possible.

However, the association between anti-SSA antibodies and congenital heart block (CHB) or neonatal lupus syndrome (NLS) only occurs in 1%-2% of exposed fetuses.

“Only 1.5% of all [CHB] cases were observed in women diagnosed with RA. This observation was in line with previous literature, in which no maternal diagnosis of RA in children born with congenital cardiac manifestations related to anti-SSA were observed,” stated investigators.

The study was conducted using 2 cohorts, PARA cohort and PreCARA cohort, which analyzed RA and pregnancy. Further, investigators utilized the French national registry of NLS and CHB to determine the prevalence of maternal diagnosis of RA, which included both fetuses and children born to mothers with anti-SSA and/or anti-SSB antibodies. Eligible patients were over the age of 18 and gave their consent.

Blood was collected at each visit. The presence and levels of anti-SSA and anti-SSB was analyzed using fluorescence-enzyme immunoassay (FEIA) and the normal range was considered <7 units/mL.

Out of 647 patients with RA, 26 had anti-SSA and/or anti-SSB antibodies; 25 patients had anti-SSA (3.9%) and 7 had anti-SSB (1.1%). Only 13 participants had an anti-SSA level of >240 units/mL. The presence of these antibodies was more common in rheumatoid factor (RF)-positive patients (5.1%) when compared with RF-negative patients (1.6%). There were no cases of CHB or NLS in either cohort.

In the French national registry, 51 out of 195 mothers (26.3%) with CHB had an autoimmune disease. Only 3 (1.5% of the total population) had RA and no cases of NLS were born to mothers with RA.

Investigators note that due to the small number of patients with detectable antibodies, they were not able to perform a multivariate analysis. Additionally, they could not determine cut-off points for anti-SSA titers due to the lack of CHB cases in the 2 cohorts.

“Anti-SSA and anti-SSB have a low prevalence in patients with RA with a wish to conceive. Moreover, in the French national registry of NLS and CHB maternal diagnosis of RA was infrequent,” concluded investigators. “If our findings could be replicated in other studies, it is justified to critically review the current guidelines. Especially since the practical consequences of finding these antibodies is currently questioned.”

Smeele HTW, Schreurs MWJ, Costedoat-Chalumeau N, Cornette JMJ, Dolhain RJEM. Low prevalence of anti-SSA (anti-Ro) and anti-SSB (anti-La) autoantibodies in female patients with rheumatoid arthritis with a wish to conceive. 

. 2021;7(2):e001727. doi:10.1136/rmdopen-2021-001727

Given the low prevalence of anti-Sjögren's-syndrome-related antigen A (anti-SSA) and anti–Sjögren's-syndrome-related antigen B (anti-SSB) in women with rheumatoid arthritis who would like to conceive, intensive echocardiographic screening may not be necessary. 

Low Prevalence of Anti-SSA/B in Women With Rheumatoid Arthritis Wishing to Conceive

The COVID-19 pandemic has profoundly impacted the behaviors and clinical practice of rheumatologists in the non-English-speaking countries of Latin America from a professional, economic, and occupational standpoint, according to a study published in the 

“Considering that rheumatic patients are a potentially vulnerable population, changes in behavior patterns are expected both in patients and their physicians,” stated investigators. “The emergence of COVID-19 led to unprecedented changes to rheumatology clinical practice worldwide, including the restructuring of hospitals and the rapid transition to virtual care.”

While social distancing is an effective strategy to prevent the spread of COVID-19, these new practices have had implications for patients with rheumatic diseases, including a reduction in in-person doctor visits and new difficulties in disease management.

In this observational cross-sectional study, investigators created an online survey designed to understand the management and follow-up of patients during the pandemic. The questionnaire was sent to all rheumatologists living in Latin America who were members of the Pan American League of Rheumatology Associations (PANLAR). Data was collected for 30 days during June and July 2020.

The survey included 1097 rheumatologists from 19 Latin American countries. The countries with the most respondents were Brazil (25.2%), Mexico (20.9%), and Colombia (12.8%). The median age was 48 years, 56.3% of participants were female, and 69.5% (n = 730) had over 10 years of experience in rheumatology. A total of 1052 (96%) managed adult patients and 81.8% worked in private practice.

Pre-pandemic, weekly hours of face-to-face practice totaled 27 (15-40), and while 598 (54.5%) of rheumatologists continued to offer in-person care, the survey indicated that those hours were reduced to 10 (5-20) in recent months. Additionally, poor adherence to medication was noted by almost 50% of respondents.

While (78.9%) of rheumatologists employed telehealth practices during the pandemic, they only averaged 5 (2-10) hours per week. Rheumatologists also utilized video calls, WhatsApp, phone calls, and emails to communicate with their patients. Follow-up visits were the most common virtual visit (478; 55.2%). While the majority of respondents believed telehealth was a valid strategy (85.7%), only 49.8% considered continuing it post-pandemic.

A wage reduction was reported by 86.2% of respondents. Further, approximately 50% reduced consultation fees, with an average of a 40% discount.

During the pandemic, 338 (30.8%) rheumatologists had been required to care for someone with COVID-19. In total, 7.4% (n = 81) of rheumatologists surveyed developed COVID-19 and of the 81 physicians, 8.6% were hospitalized.

The study was limited by subjectivity and recall bias, as the data was self-reported by the rheumatologists surveyed. However, the vast number of respondents from a variety of countries lead investigators to confidently state that the study reflects the impact of COVID-19 in these non-English-speaking countries. Selection bias may be another limitation, as it was distributed by PANLAR chairs, however, investigators note that each chair is elected on a democratic basis.

“During the pandemic, telehealth has had an important role in healthcare delivery, allowing for ongoing medical care while ensuring the safety of patients and physicians as well. Careful planning, outcome assessment, and adaptation of existing virtual care methods are future steps needed to achieve a successful integration of telehealth into routine rheumatology practice,” concluded investigators. “The COVID-19 pandemic has reshaped rheumatology practice in Latin America through a wide impact on rheumatologists’ clinical practice.”

Fernández-Ávila, DG, et al. Impact of COVID-19 pandemic on rheumatology practice in Latin America. https://www.jrheum.org/content/jrheum/early/2021/06/10/jrheum.201623.full.pdf. Published June 2021. Accessed July 14, 2021.

In this observational cross-sectional study, investigators created a survey designed to understand the management and follow-up of patients during the COVID-19 pandemic in Latin American countries. 

How COVID-19 Reshaped Rheumatology in Latin America 

Despite suspicions that patients with autoimmune rheumatic diseases (AIRD) may have worse immune responses against COVID-19, research indicates that this patient population did not differ from the general population in terms of protective antibody responses, according to a study published in 

Protective antibodies support a robust immune system response. Most notably, spike protein (S) and nucleocapsid protein (N) have been shown to protect from reinfection and symptomatic disease. Alternatively, non-neutralizing antibodies may be able to predict more severe reactions.

“The present study shows that patients with AIRD, despite their underlying immune defects and current immunosuppression, mount adequate antibody responses similar to those of healthy controls,” explained investigators. “This is very reassuring considering that there was a widespread fear that patients on immunosuppressants may not mount an adequate immune response and may be vulnerable to reinfection with COVID-19.”

A sample of 50 patients with AIRD (mean age 45.9 ± 13; 76% females) who developed COVID-19 were matched with 50 controls (mean age 45.9 ± 13; 76% females) with COVID-19. Investigators matched for age, sex, and COVID-19 severity, which was determined using the National Institutes of Health’s Coronavirus Disease (COVID-19) Treatment Guidelines. In the AIRD cohort, patients were included if they were on disease-modifying anti-rheumatic drugs (DMARDs) or immunosuppressants for a minimum of 3 months and had reverse transcription polymerase chain reaction (RT-PCR) or rapid antigen positivity for SARS-CoV-2. The most common AIRDs were rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and spondyloarthritis. Comorbidities were balanced between the 2 groups.

Approximately 30 days after the RT-PCR test, serum was collected and kept at -80°. Immunoglobulin G (IgG) antibodies were assessed using electrochemiluminescence immunoassay (ECLIA).

Anti-N IgG was positive in 80% (40) of patients with AIRD and 90% (45) of controls and anti-S IgG was positive in 82% (41) patients with AIRD and 86% (43) of COVID-19 cases in the control cohort. Neutralizing antibodies were negative in 14% (7) of patients in the AIRD cohort and 10% (5) in the control group. Patients with AIRD displayed adequate protective antibody responses to COVID-19 at 30 days post-infection. Female participants in both groups had the highest proportion of the protective antibody.

Investigators also hypothesized that if patients had an adequate response to natural infection while on immunosuppressants, they would most likely have a similar response to the COVID-19 vaccination.

The study was minorly limited by only including antibody responses, a limited sample size, and the mixture of AIRD patients on a variety of drugs. However, the one-to-one control group removes many confounders, such as age, sex, and disease severity. Further, the antibody responses studied were not inferior to the control group and anti-N and anti-S antibodies in fact protect from severe COVID-19. While sample size was limited, it was the largest cohort to date in which investigators determined the correlation between rheumatic disease and specific protective antibodies.

“Though patients were heterogeneous with different diagnoses, what was common was that all patients had a systemic inflammatory disease and were on some form of immunosuppression,” concluded investigators. “Thus, this data has important implication for rheumatologists in a real-life scenario to provide them with the confidence that such patients still have adequate humoral immune responses to SARS-CoV-2 despite the immunosuppressant drugs.”

Shenoy P, Ahmed S, Shanoj KC, et al. Antibody responses after documented COVID-19 disease in patients with autoimmune rheumatic disease [published online ahead of print, 2021 Jun 22]. 

. 2021;1-6. doi:10.1007/s10067-021-05801-9

Research indicates that patients with autoimmune rheumatic diseases (AIRD) did not differ from the general population in terms of protective antibody responses against COVID-19. 

Autoimmune Rheumatic Disease Does Not Influence Immune Response Against COVID-19

When compared with patients with rheumatoid arthritis (RA) alone, those with RA and erectile dysfunction (ED) had a decreased risk of certain cardiovascular (CV) events such as heart failure, myocardial infarction, and death, according to a study published in the 

 Additionally, the rate of ED was not significantly increased in patients with RA.

Developing ED is generally an indicator that a patient will eventually have CV disease (2-3 years before CV symptoms and 2-5 years before CV events). When compared with the general population, patients with RA have an increased risk of developing CV disease, due in part to inflammation, which is responsible for 30-50% of deaths in this patient population. Common CV-related conditions include coronary artery disease, myocardial infarction (MI), heart failure (HF), cerebrovascular events, venous thromboembolism, and sudden death.

“Due to the association of ED with CV events in the general population, we hypothesized that men with RA would have an increased rate of most CV events when also diagnosed with ED,” stated investigators. “Interestingly, this was not the case. Most CV events were not statistically associated with ED diagnosis, potentially indicating that risk from ED and RA are redundant. Peripheral arterial disease was the only CV condition that was increased by the presence of ED, with potential interaction between RA and ED diagnosis.”

In this retrospective study, a total of 260 men with RA from Olmsted County, Minnesota, as well as an age-matched male cohort (n = 260), were analyzed using the Rochester Epidemiology Project (REP). Eligible patients were aged ≥ 18 years and were diagnosed with RA between January 1, 1980, and December 31, 2007. Patients needed to meet at least 4 of the 7 American College of Rheumatology (ACR) 1987 classification criteria for RA.

Data collected from the medical records included ED diagnosis information, risk factors for ED (such as alcohol concerns, thyroid disease, depression, anxiety, penile or spinal trauma, and pelvic radiation), treatments for ED, and medications that may impact ED (aspirin, antihypertensives, antidepressants, and antiandrogens). CV disease collected included MI, revascularization procedures, angina, and HF. Smoking status and BMI were obtained, as well as noncardiac vascular diseases, including venous thromboembolism, cerebrovascular events, and peripheral arterial events.

Prevalence of ED at incidence/index rate (HR 0.80, 95% CI 0.55–1.16), as well as baseline CV characteristics and predisposing factors were similar in both cohorts. Throughout the study, men aged < 50 years (P = 0.74; Table 2) and men aged ≥ 50 years (P = 0.17) had no significant difference in ED diagnosis rates. For those with an ED diagnosis, both the comparator group and patients with RA were treated in a similar manner.

Surprisingly, patients with RA and ED had a significantly decreased rate of myocardial infarction (HR 0.26, 95% CI 0.07–0.90), heart failure (HR 0.49, 95% CI 0.25–0.94), and death (HR 0.56; 95% CI 0.36–0.87). Investigators associated those taking phosphodiesterase-5 (PDE5) inhibitors with a decreased risk of death and certain CV diagnoses.

Men with RA and ED were shown to have an increase in peripheral arterial disease (HR 2.22, 95% CI 0.98–5.03), however, it did not reach a level of statistical significance.

The study was hindered by a demographic composition that was disproportionately White as well as the limited sample size, thus limiting generalizability. As it was a retrospective study, the availability of medical record information may have created an unintentional bias. As investigators believed frequent underdiagnosis of ED was an issue, they would like future studies to ascertain an accurate ED risk.

However, strengths include the thorough medical data provided by REP, which allows for a population-based assessment and long-term longitudinal follow-up over decades. Access to medical records confirmed International Classification of Diseases (ICD) code-based physician diagnosis. Lastly, the ability to age-match males from the general population secured a geographically based comparator cohort.

“The incidence of ED in patients with RA is similar to that of age-matched comparators. Although ED did not affect the overall rate of CV events in RA, it was associated with an increased risk of peripheral arterial disease and a decreased risk of MI and HF,” concluded investigators. “While these trends require further study, they may be explained by common pathologic mechanisms, healthcare-related confounding variables, or the use of vasoactive pharmacologic therapy for ED.”

Wilton KM, Achenbach SJ, Davis JM 3rd, Myasoedova E, Matteson EL, Crowson CS. Erectile Dysfunction and Cardiovascular Risk in Men with Rheumatoid Arthritis: A Population- Based Cohort Study [published online ahead of print, 2021 Jan 15]. 

. 2021;jrheum.201226. doi:10.3899/jrheum.201226

Surprisingly, patients with rheumatoid arthritis and erectile dysfunction had a significantly decreased rate of myocardial infarction, heart failure, and death when compared with patients with rheumatoid arthritis alone.

Erectile Dysfunction Decreases Risk of Cardiovascular Events in Patients With Rheumatoid Arthritis

Patients with psoriatic arthritis (PsA) receiving tofacitinib, an oral Janus kinase (JAK) inhibitor, and adalimumab experienced more pain improvements, more rapidly, than those receiving the placebo, according to a study published in 

Further, investigators discovered that patients in the tofacitinib arm with higher baseline pain had quicker pain improvements.

“This analysis provides information on when clinically meaningful improvements in pain may be expected in patients with PsA receiving tofacitinib or adalimumab, and how baseline pain severity may impact response to tofacitinib, which is of value in clinical practice,” stated investigators.

Pain, a core domain of PsA, has been historically linked to poor quality of life and a predictor of disability. In patients with PsA, pain is commonly measured on a Visual Analogue Scale (VAS), a painDETECT questionnaire for neuropathic pain, the Widespread Pain Index, and the Symptom Severity Scale, which assesses pain due to central sensitization. Investigators utilized the notion that improvements in VAS pain scores of ≥30% and ≥50% mean pain is either “much improved” or “very much improved,” respectively. It should be noted that these thresholds have not yet been validated in patients with PsA.

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In this post hoc study, investigators utilized data from 2 trials: OPAL Broaden (

), in which patients received tofacitinib 5 mg twice daily, placebo for 3 months before switching to tofacitinib 5 mg twice daily (OPAL Beyond), or adalimumab (OPAL Broaden). The patient populations from both trials were analyzed separately. Participants were excluded if they had a history of autoimmune diseases other than PsA or were diagnosed with fibromyalgia.

In addition to ≥30% and ≥50% improvement in baseline pain, median time to initial pain improvement was also estimated. Finally, a parametric model was created to understand the relationship between pain severity and time to pain response for the tofacitinib group. Any significant differences in the time to initial and continued pain improvement between the tofacitinib 5 mg twice daily versus placebo-to-tofacitinib cohorts, and the adalimumab versus placebo-to-tofacitinib cohorts were noted.

A total of 238 patients received tofacitinib 5 mb twice daily, 118 were in the placebo-to-tofacitinib group, and 106 patients received adalimumab 40 mg once every 2 weeks. Patients in OPAL Broaden (adalimumab) had generally lower pain scores, fewer swollen and tender joint counts, and shorter PsA durations when compared with the tofacitinib groups.

Results indicated that, at month 3, there were greater improvements in VAS pain scores in patients receiving either tofacitinib or adalimumab when compared with the placebo group. Additionally, the median days (95% CI) to initial/continued pain improvements were, respectively, 55/60 and 85/171 for tofacitinib, versus 106/126 and 169/NE for placebo-to-tofacitinib. Improvements in VAS pain scores were quicker in the adalimumab group versus the placebo group. In the tofacitinib cohort, pain improvement time was shorter in participants with a higher baseline pain. Data showed that 25% of patients in the tofacitinib 5 mg twice daily group could reach ≥30% pain improvements by the 2-week mark. Pain improvements of ≥30% or ≥50% were similar in both groups. In the tofacitinib 5 mg twice daily cohort, the parametric model designed to study median time to improvements from baseline showed that pain decreased more rapidly in those with higher baseline pain. Predicted median times to ≥50% improvement were 101.3 days for patients with a VAS pain score of 30 mm and only 81.1 days for patients with a VAS pain score of 80 mm.

The post hoc analysis was limited by incorporating comparisons with the placebo-only group. Further, comparisons between adalimumab and tofacitinib were not performed. Continued improvement was defined as the initial improvement over 2 visits, it was not always possible to determine when patients received clinically important and maintained pain relief. Investigators noted that, as pain is complex, the VAS may not completely capture all pain components for patients with PsA. Lastly, the inclusion/exclusion criteria from the 2 clinical trials ruled out other comorbidities that could affect the pain experienced by the patient.

“The findings from the current analysis could guide physicians in their management of patient expectations with respect to pain reduction and, in particular, when patients with PsA may expect to notice meaningful improvements with tofacitinib.”

de Vlam K, Ogdie A, Bushmakin AG, et al. Median time to pain improvement and the impact of baseline pain severity on pain response in patients with psoriatic arthritis treated with tofacitinib. RMD Open. 2021;7(2):e001609. doi:10.1136/rmdopen-2021-001609

“This analysis provides information on when clinically meaningful improvements in pain may be expected in patients with psoriatic arthritis receiving tofacitinib or adalimumab, and how baseline pain severity may impact response to tofacitinib, which is of value in clinical practice,” stated investigators.

Tofacitinib and Adalimumab Significantly Improved Pain for Patients With Psoriatic Arthritis 

 What are the benefits of value-based care and how does it allow for personalized patient care?

 There are several benefits in a successful value-based care program. You could say that there's the opportunity to lower costs of care, and you could say that there's the opportunity to improve outcomes. And really, that's where I would focus. It really puts a premium on delivering outcomes for individual patients. And this is what precision medicine is all about. When I go to see the doctor, I care about how I am going to end up doing. I don't care about the average patient; I don't care about the typical patient. And I don't particularly care about the doctor seeing a ton of other patients. I want my care to be excellent and my outcomes to be excellent. And that's really what these value-based care programs are about. It's about assessing the individual and assessing the individual's journey and the individual's response. And in rheumatology, we're still in the process of adapting this treat-to-target model where we're assessing patients before and after an intervention and response and how they respond on an individual level to guide changes in their care. Unfortunately, this has not been as widely adopted yet in the United States, because we know that it yields better outcomes and lower costs for the system. And right now, I think a critical thing to understand about this is that those doctors that are doing a great job are not getting paid for doing a great job they're doing. They're getting paid the same if they do a great job or not. You could say that word of mouth can increase how busy they are in their practice, but at least formally, the way that they're being compensated is not about the quality of care they deliver. Any doctor that's doing a great job out there is doing it because they believe in that because of the good graces of their heart. And because it's generally good for business, this value-based care approach directly compensates doctors for generating good outcomes.

 How does a collaborative approach to working with payers benefit practices and patients?

 I worked in a sort of adversarial relationships for 20 years with payers before I came to this value-based approach and got more and more enamored with it. Now that's what I do all day. It used to be that it was sort of like the Hatfields and the McCoys in my clinic where we felt like the insurance companies were doing it to us again. The problem was that that wasn't a very productive way of interacting and it didn't actually work when you think of it as a zero-sum game. That is, every dollar that I make is $1 that the insurance company isn't making. That's sort of the way that we looked at. The fact of the matter is in our healthcare system, there's a different role that a health plan has and that clinicians have and the priorities are different. What these value-based care programs allow is to create a Venn diagram of our needs on the clinician side, on the health plan needs, and overlap those and create programs that bring the best of the intentions of both sides to bear on the patient care and brings patients along. And so the opportunity is to build relationships and build understanding between clinicians, or clinician groups like United Rheumatology, where I work, that creates these linkages between health plans and clinicians. And the more that we work together, the more that we understand one another, the more that we recognize opportunities to work together. You can think of, for instance, in this fragmented healthcare landscape- the United States, unlike a lot of European countries, I'd like to think of these value-based programs as a data bridge, that on the one side of the river we have the clinicians building a bridge, and the data is the steel they use to build that bridge. What kind of data is that disease specific activity measures, for instance like a CDAI, in rheumatoid arthritis? And we know how active the patient's disease is at a given time, but the payer has no idea about how a patient is doing. And then there's this big gap in the middle of a river on the other side. They're building a bridge toward us in these programs, and their data, their steel, that they're building that bridge from his medical claims data, that they have these other forms of information that we don't have access to. And in our healthcare system, typically, there's been a huge gap in between those 2 data sets. And what these programs do is they link them together like a bridge, and we share information. On the other side of the fence, the health plan shares information. And only by sharing that information and bringing that data together, can we determine what the best approaches are from an outcome perspective for the patients and from a cost of care perspective for the system.

Podcasts

On the latest episode of Overdrive, we sat down with Andrew L Concoff MD, FACR, CAQSM, to discuss value-based care, including the benefits, collaborate approach to working with payers, the revenue and cost savings, and how value-based care can support routine and consistent health visits.

Overdrive Podcast: Value-Based Care in Rheumatology

Katie Robinson is a medical writer. She covers various health and medical topics for a professional audience.

The combination of effusion and hemarthrosis at the time of acute knee injury is associated with adverse outcomes at 2 years post-injury, according to a study published in 

 The study also found that measurable acute joint injury inflammatory response was associated with worse patient-reported outcomes, but to a lesser degree than these clinical factors.

In this Q&A, corresponding investigator, Fiona Watt, MBBS, PhD, FRCP, Centre for Inflammatory Disease, Imperial College London, and the Centre for Osteoarthritis Pathogenesis Versus Arthritis, University of Oxford, UK, discusses the research and its findings.

This longitudinal cohort study included 150 patients (82% male, median age 25 years) at a median of 17 days after a clinically significant acute knee injury. Researchers measured several predefined clinical variables at baseline, and 12 synovial fluid and 4 plasma or serum biomarkers at baseline and at 3 months. The primary outcome was Knee Injury and Osteoarthritis Outcome Score (KOOS4) at two years. Of the participants, 77 had all necessary variables available and were included in the analysis.

 We have been studying the links between tissue injury and osteoarthritis for a long time. This looks at this association at a molecular level in laboratory projects, but increasingly we wanted to test what we were finding in a “real life” situation, and this was when the KICK study was set up. Very simply, we wanted to test if the molecules in joint tissues that we found in pre-clinical models to be up-regulated by injury were also seen in the acute joint injury response in humans, and whether this immediate response predicted subsequent osteoarthritis development at 2 years after the injury.

What were the surprises from the findings?

 As in other settings, it's probably no surprise that clinical factors when measured carefully might predict outcome as much as measurement of biomarkers, but that these can be complementary/additive. The presence of blood in the joint (not something we typically quantitate) as a strong predictor of outcome is perhaps not a surprise, but has not been described as a predictive factor in this setting before. That symptomatic outcomes and structural outcomes on X-ray had little association with each other, at least when we looked at the 2-year time point, was not something we were expecting and needs to be better understood. Again, this may not be a surprise for those familiar with the related literature in established osteoarthritis.

 We desperately need better understanding of this whole area, both to understand osteoarthritis pathogenesis as a whole and also to try to predict and intervene specifically in post-traumatic osteoarthritis (which often affects individuals at a younger age). So, in developing our knowledge, the findings in that way are significant. For those trying to build a picture of important predictive factors which might feed into prognostic models. And those trying to find new therapeutic targets or mechanisms, I think this study generates lots of important avenues to pursue.

What is the current practice and how could the findings possibly change things?

 It is important to state that the study was not designed to test current practice or to change it. However, our findings do throw a spotlight on the fact that many people with significant structural injuries and hemarthrosis are managed conservatively, sometimes with a lack of clear pathways of care. In the UK and increasingly globally, practice has moved away from arthroscopic or even arthrocentesis procedures. One question that this study’s findings pose is whether more could be done early, at the time of injury, and whether this might modify symptomatic outcomes and later disease risk. But this needs to be tested.

What are the key takeaway points for clinicians who may be reading this article?

 Post-traumatic osteoarthritis, whether defined symptomatically or radiographically, was seen to be relatively common at 2 years after structural clinically significant knee injury in this group of predominantly young male sporting adults.

We found some predictors of worse outcome after acute knee injury. These were having a worse baseline Patient-Reported Outcome Measures (PROMs) score, the presence of moderate to large effusion or presence of substantial synovial fluid blood staining/ hemarthrosis at the time of the injury and an elevated inflammatory response measured in synovial fluid (specifically interleukin 6 [IL-6] and monocyte chemoattractant protein-1 [MCP-1] levels) at the time of the injury.

 These findings have not yet been replicated in other cohorts. We need to consider in our future studies and care of people with knee injuries whether an acute knee injury is a “joint attack” akin to a “heart attack;” an opportunity for early intervention aiming for prevention of future disease. Whether we can reliably identify those at higher risk in whom to intervene is an area of further work.

The work was funded by Versus Arthritis and Watt is funded by a UKRI Future Leaders Fellowship.

Clinical and molecular associations with outcomes at 2 years after acute knee injury: a longitudinal study in the Knee Injury Cohort at the Kennedy (KICK)

 [published online ahead of print, 2021 Jun 24]. 

. doi: https://doi.org/10.1016/S2665-9913(21)00116-8

In this Q&A, corresponding author, Fiona Watt, MBBS, PhD, FRCP, discusses her study that found the combination of effusion and hemarthrosis at the time of acute knee injury is associated with adverse outcomes at 2 years post-injury.