Clinical Consultations™: Finding Opportunities to Improve the Management of Patients with Connective Tissue Disease-associated Pulmonary Arterial Hypertension (CTD-PAH)

Clinical Consulations CTD/PAH 

Read the most up-to-date information about the latest developments in psoriatic arthritis

Clinical Updates in Psoriatic Arthritis

The impact of psoriatic arthritis on patients’ quality of life and importance of an early, accurate diagnosis.

Expert Perspective on the Management of Psoriatic Arthritis

Rheumatoid Arthritis Quiz

Learn more about the latest developments in rheumatoid arthritis

Focus on Rheumatoid Arthritis

Lana Dykes is the Editor of Rheumatology Network. She is an experienced editor and technical writer with a demonstrated history of working in the banking and publishing industries. She enjoys cooking, yoga, and drawing. 

A nationally representative race- and sex-specific study of adult patients in the United States reported that gout was more prevalent in those self-reporting Black race when compared with White participants. Investigators believe these differences may be explained by sex-specific differences in diet, as well as social determinants of health and clinical factors, according to results published in 

“Gout has historically been considered a disease of White men who overindulge in gamey meats and other rich foods,” investigators explained. “However, emerging data suggest gout and hyperuricemia (its causal precursor) impart an even larger burden on other demographic groups, including Black men, Black women, and White women. Indeed, the global frequency and disability burden of gout among women have been rising disproportionately relative to gout among men, with gout among women characterized by a higher frequency of obesity and related cardiometabolic sequalae.”

The cross-sectional analysis used data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2007 and 2016. During in-person interviews, demographics, including race and ethnicity, education level, medical history, income, body mass index, alcohol consumption, and use of diuretics were collected. The main outcome was the prevalence of any race- and sex-specific of gout diagnosis and hyperuricemia and differences before and after adjusting for socioclinical risk factors. Risk factors included lower educational levels, poverty, higher BMI, poor diet, chronic kidney disease (CKD), diuretic use, and a higher number of alcoholic beverages consumed per week.

In total, 18693 participants were included in the analysis, with a total of 3304 Black women (mean age 44.8 years), 6195 White women (mean age 49.8 years), 3085 Black men (mean age 43.6 years), and 6109 White men (mean age 48.2 years). The age-standardized prevalence of gout was 3.5% (95% CI, 2.7%-4.3%) in Black women and 2.0% (95% CI, 1.5%-2.5%) in White women (age-adjusted odds ratio [OR], 1.81 [95% CI, 1.29-2.53]). Prevalence was higher in Black men (7.0% [95% CI, 6.2%-7.9%]) when compared with White men (5.4% [95% CI, 4.7%-6.2%]; age-adjusted OR, 1.26 [95% CI, 1.02-1.55]).

Associations attenuated after adjusting for factors such as diet, body mass index, CKD, and poverty among women and for diet and CKD among men. Hyperuricemia prevalence was consistent among men and women with gout, with the greatest attenuations associated with hyperuricemia among women after adjusting for poverty (OR, 1.71 [95% CI, 1.36-2.15]), BMI (OR, 1.22 [95% CI, 0.96-1.57]), diet (OR, 1.52 [95% CI, 1.19-1.93]), and CKD (OR, 1.01 [95% CI, 0.76-1.35]). In men with gout, the greatest attenuations were reported after adjusting for diuretic use (OR, 1.24 [95% CI, 0.96-1.61]) and CKD (OR, 1.08 [95% CI, 0.81-1.42]).

Results are generalizable to the population of White and Black individuals living in the United States as NHANES data are collected from community-based samples and weighted to the population. The findings for gout were consistent with hyperuricemia. However, the cross-sectional, observational design limited the study and the analyses may have been subject to residual or unmeasured confounding. Lastly, racial differences may be subject to other factors, such as stress, physical activity, and poorer access to health care. Racial differences among men and women are likely associated with these contributors.

“Differences may be explained by racial differences in key socioclinical factors, including excess BMI, poverty, and poor diet as well as CKD in women and by CKD, poor diet, and diuretic use in men,” investigators concluded. “Culturally informed interventions designed to address adiposity and kidney disease and improve diet quality while recognizing the role of poverty in gout among women could help reduce these disparities.”

McCormick N, Lu N, Yokose C. Racial and sex disparities in gout prevalence among us adults. JAMA Network Open. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2795143?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=081522. Published August 15, 2022. Accessed August 15, 2022.

Articles

Despite gout being largely associated with White men, new data suggest gout and hyperuricemia impart a larger burden on other demographic groups, including Black men, Black women, and White women.

Prevalence of Gout Reportedly Higher in Black Patients  

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

In patients with psoriatic arthritis (PsA), serum calprotectin levels are associated with the presence of carotid plaques, according to a study published in 

“In PsA patients, serum calprotectin level was independently associated with the presence of carotid plaques, probably involving platelet and endothelial cells activation,” Isaac Cheng, PhD, of The Chinese University of Hong Kong in Shatin, China, and colleagues, wrote. “Moreover, subclinical carotid atherosclerosis was associated with the inflammatory burden (as reflected by the disease duration) in these patients.”

While the association between PsA and increased cardiovascular (CV) disease risk is well established, only limited data is available on the underlying mechanisms.

This cross-sectional study included 78patients (52.6% male, mean age 52 years) with PsA but without CV disease. Calprotectin levels in serum were quantified and high-resolution ultrasound was used to determine carotid intima-media thickness and the presence of plaque.

Of the patients, 37.2% had carotid plaques. Serum calprotectin level was significantly higher in the group with carotid plaques compared with those without carotid plaques (721.3 ng/ml vs 564.6 ng/ml, P = 0.005). Serum calprotectin level correlated with PsA disease duration and mean carotid intima-media thickness.

Least absolute shrinkage and selection operator regression was performed to screen out 19 predictive variables including age, gender, traditional CV risk factors, medication use, clinical features and disease activity. Ln-calprotectin (OR: 3.38, 95% CI [1.37, 9.47]; P = 0.026) and PsA disease duration (1.09, 95% CI [1.01, 1.18]; P = 0.013) were statistically significant in predicting carotid plaque.

Investigators developed a nomogram for discriminating the presence of carotid plaque, which they said was an “easy reference for clinical practice, with good accuracy, sensitivity and specificity (AUC 0.744, sensitivity 65%, specificity 79%).” They concluded that “serum calprotectin level may be a useful biomarker associated with a high inflammatory burden and the presence of subclinical carotid atherosclerosis in patients with PsA.”

A limitation of the study was that most of the patients had low disease activity, thus the results may not be applicable to patients with moderate or high disease activity.

Serum Calprotectin Level Is Independently Associated With Carotid Plaque Presence in Patients With Psoriatic Arthritis

. 2022;9:932696. Published 2022 Jul 8. doi:10.3389/fmed.2022.932696

Serum calprotectin level may be a useful biomarker associated with a high inflammatory burden and the presence of carotid plaque.

Serum Calprotectin Levels Linked to Subclinical Carotid Atherosclerosis in Patients With Psoriatic Arthritis 

Rheumatoid Arthritis Quiz: RA and Flu Vaccination

With seasonal flu vaccinations fast approaching, how much do you know about how rheumatoid arthritis and its treatment affects administration of this vaccine? Test your knowledge with this quiz.

Rheumatoid Arthritis Quiz: Vaccinating Patients Taking Immunosuppressive Medications

Immunosuppressive medication can interfere with the immune response to vaccines, so treatment may need to be held or the timing or type of vaccinations amended. Test your knowledge of vaccinating rheumatoid arthritis patients taking immunosuppressive therapies in this quiz.

Risankizumab Improves Skin, Joint Symptoms in Psoriatic Arthritis

Over the course of 16 weeks, patients with psoriatic arthritis (PsA) receiving risankizumab reported improved joint and skin symptoms when compared with placebo. Improvements were maintained long-term, and the drug was well tolerated with no new safety issues. 

Exercise and Behavioral Approaches Reduce Fatigue in Rheumatic Diseases

Exercise and behavioral techniques can be helpful, but they are not often implemented because their effectiveness is unknown and regular face-to-face sessions are undesirable.

Osteoclasts in Patients With PsA, RA Show Functional Differences

Results from a small study suggest that psoriatic arthritis and rheumatoid arthritis osteoclasts might retain some of their immune cell functions during differentiation.

Take 5 minutes to catch up on Rheumatology Network's highlights from the week ending August 13, 2022.

Rheumatology Network's Top 5: August 13, 2022

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.

The human epidermal growth factor receptor 2 (HER2) and tumor necrosis factor-like weak inducer of apoptosis (TWEAK) biomarkers were associated with new onset proteinuria. Additionally, an increased vascular cell adhesion molecule-1 (VCAM-1) may also predict impending proteinuria. These biomarkers may be useful as potential non-invasive measures for predicting impending flare, according to a study published in 

“Lupus nephritis is a key driver of morbidity and mortality in systemic lupus erythematosus (SLE),” investigators stated. “Detecting active nephritis on a background of pre-existing renal damage is difficult, leading to potential undertreatment and accumulating injury. An unmet need is a biomarker that distinguishes active lupus nephritis, particularly important in pediatrics where minimizing invasive procedures is desirable.”

This multicenter, prospective study included 113 pediatric patients with biopsy-proven lupus nephritis. Urine samples and other clinical data were collected every 3 to 4 months with an average of 7 time points over a 2-year span. Urine was evaluated for HER2, TWEAK, and VCAM-1 by ELISA. Active disease was defined as either a rise in serum creatine ≥ 0.3 mg/dL from baseline or a rise in the renal Systemic Lupus Erythematosus Disease Activity Index (R-SLEDAI) score when compared with the previous visit. Biomarkers were also assessed in patients with juvenile idiopathic arthritis (JIA), amplified pain syndrome, acute kidney injury, and healthy controls.

The mean age of patients was 15 years, 81% were female, 35% were Black, and 25% were White. The rate of active disease was 56% over the 2-year follow-up period. HER2 and VCAM-1 were significantly higher during times of active disease as defined by an increased serum creatine when compared with patients who did not flare and those with inactive disease. All 3 biomarkers were associated with new-onset proteinuria. VCAM-1 was elevated during the time points preceding new-onset proteinuria.

The longitudinal nature, evaluating diverse racial and ethnic backgrounds, and being the largest prospective assessment within this specific patient population strengthened the study. Additionally, the biomarkers met ideal requirements for the predictive value because they rose alongside an elevation in R-SLEDAI, demonstrating specificity. It should be noted, however, that a single biomarker is not likely to be enough to determine lupus nephritis activity and a combination, comprised of several aspects of pathogenesis, is ideal. Larger studies, identifying biomarkers at the time of flare and before a flare, would be helpful. Further, the samples analyzed for prior visits were comparatively low. More frequent sampling might aid in additional insights regarding the kinetics of these biomarkers. Patients with known lupus nephritis were not included and, therefore, investigators were not able to evaluate the utility of these biomarkers in new-onset cases.

“This prospective pediatric study demonstrates that it is possible to identify biomarkers to predict disease activity in children,” investigators concluded. “Early detection, prior to accumulation of renal damage, is central to improved treatment that minimizes long-term accrual of damage and the evolution of end-stage renal disease.”

Costa-Reis P, Maurer K, Petri MA, et al. Urinary HER2, TWEAK and VCAM-1 levels are associated with new-onset proteinuria in paediatric lupus nephritis. 

. 2022;9(1):e000719. doi:10.1136/lupus-2022-000719

"An unmet need is a biomarker that distinguishes active lupus nephritis, particularly important in pediatrics where minimizing invasive procedures is desirable.”

Biomarkers Linked to New Onset Proteinuria in Pediatric Lupus Nephritis 

Patients with gout who received a COVID-19 vaccination, particularly the adenovirus vector ChAdOx1 nCov-19 (ChAd) vaccination, reported a slight increase in gout flares on the second day after vaccination. These findings emphasize the safety of the vaccination within this patient population, according to a study published in 

“The COVID-19 pandemic has had tremendous social and economic impacts, especially for people living with inflammatory disorders like gout,” investigators explained. “COVID-19 vaccines are effective against severity of SARS-COV-2 infection, such as hospitalization and death, but there has been a concern regarding their effect on the risk of flares in patients with gout, which are associated with health-related quality of life, healthcare resource utilization, and work productivity.”

A time-stratified case-crossover study included patients with gout who experienced flares between December 2020 (when public vaccination began) and September 2021. Data was pulled from The Health Improvement Network (THIN), which includes medical records from 17 million patients in the United Kingdom. Risk of gout flare was assessed for the first 7 days on and after the vaccination and compared with patients who did not receive vaccination during that time using conditional logistic regression. Subgroup analyses were performed based on different COVID-19 vaccines (ChAd and BNT162b2 [BNT]).

Of the 5904 patients with gout included in the study, 63.5% (n = 3748) experienced 1 flare, 19.1% (n = 1125) experienced 2 flares, and 17.4% (n = 1031) had 3 or more flares. The mean age was 63.1 years and more than 80% of those who had disease flare were men. Approximately 2/3 of patients received the ChAd vaccine.

The risk of gout flares slightly increased on the second day after the vaccination (odds ratio [OR]: 1·44; 95% CI: 1·02 to 2·07) and remained slightly increased, although not statistically significant, on the other remaining days as well (ORs ranged from 1·03 to 1·22). Those receiving the ChAd vaccine were more likely to experience a gout flare vaccine (OR: 1·44; 95% CI: 1·00 to 2·05).

Self-matching of patients on the same day of the week minimized confounding bias from the time constant risk factors for gout, like body mass index, as well as lifestyle factors, such as alcohol consumption. However, investigators were not able to adjust for short-term, time-varying confounding risk factors, such as medications taken during the past 7 days. Another limitation is the potential of misclassification of gout flares, which may have biased results towards the null. Lastly, the date of flare diagnosis may not have been on the same day that the flare occurred. However, patients are not likely to receive a COVID-19 vaccination during the time of flare.

“Previous study found that ChAd vaccines induce a more pronounced increase in several inflammatory markers than mRNA vaccine, which may explain why ChAd vaccine was a trigger of gout flares,” investigators concluded. “Moreover, both ChAd and BNT vaccines could generate interferon... Future studies are needed to understand the potential mechanisms.”

Li H, Dalbeth N, Wallace ZS, et al. Risk of gout flares after COVID-19 vaccination: A case-crossover study [published online ahead of print, 2022 Jun 28]. Semin Arthritis Rheum. 2022;56:152059. doi:10.1016/j.semarthrit.2022.152059

"COVID-19 vaccines are effective against severity of SARS-COV-2 infection, but there has been a concern regarding their effect on the risk of flares in patients with gout, which are associated with health-related quality of life, healthcare resource utilization, and work productivity."

COVID-19 Vaccine Minimally Impacts Risk of Gout Flares 

Over the course of 16 weeks, patients with psoriatic arthritis (PsA) receiving risankizumab reported improved joint and skin symptoms when compared with placebo. Improvements were maintained long-term, and the drug was well tolerated with no new safety issues, according to a study published in 

“Interleukin-23 (IL-23), a key regulator of multiple effector cytokines, has been implicated in the pathogenesis of psoriatic skin lesions, synovitis, enthesitis, and bone erosion, making IL-23 inhibitors candidates for the treatment of PsA,” investigators stated. “Risankizumab, a humanized immunoglobulin G1 monoclonal antibody that inhibits IL-23 by binding to its p19 subunit, has been approved for the treatment of moderate-to-severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.”

In the phase 2, double-blind, dose-ranging study, eligible patients with active PsA (≥ 5 tender joints and ≥ 5 swollen joints) for 6 or more months were randomized 2:2:2:1:2 to receive risankizumab 150 mg at weeks 0, 4, 8, 12, and 16, 150 mg at weeks 0, 4, and 16, 150 mg at weeks 0 and 12, 75 mg at week 0, or placebo. Those who completed week 24 were able to receive risankizumab 150 mg every 12 weeks for 36 weeks as a part of a 52-week open-label extension study. The extension study also included follow-up visits at week 48 and week 52. The primary endpoint was efficacy as determined by American College of Rheumatology (ACR) responses. Secondary endpoints included ACR20/50/70 responses at week 16, Psoriasis Area Severity Index (PASI) responses, 28-joint Disease Activity Score base don C-reactive protein (DAS289[CRP]), and minimal disease activity (MDA).

Most (93.5%) patients (n = 173/185) completed week 16 and 78.5% (n = 145) were able to enter the open-label extension. Demographics were similar between the participants in the core study. The mean age was 49 years, PsA disease duration was 6.7 years, and 42.9% of patients were female in the group receiving the placebo.

A significant number of patients in arm 1 and 2 of the risankizumab cohorts achieved ACR20 at week 16 when compared with placebo (50/84 [59.5%; 90% CI 50.0–68.6]; treatment difference [90% CI] 24.0 [9.3, 38.7]; 

 = 0.007). Further, significantly more patients in the risankizumab groups were able to achieve ACR20/50/70, PASI75/90/100, MDA, and greater improvements in DAS28(CRP) when compared with placebo at week 16. ACR20/50/70 response rates increased throughout the open-label extension, with 75.2%, 43.6%, and 24.8% achieving these goals, respectively. PASI75/90/100 responses increased from 82.9%, 73.2%, and 61.0%, respectively. Benefits of risankizumab were able to be sustained long-term. Risankizumab 150 mg was well tolerated over the course of the 76-week open-label extension trial.

The small patient population limited the precision of the outcomes and accuracy of the translation of the results. The 2:2:2:1:2 randomization method included the smallest number of patients in the low-dose cohort. Additionally, the study did not test differences across the treatment arms. However, assessing the key domains of PsA and confirmed efficacy of IL-23 inhibitors strengthened the study.

“Improvements were maintained over the long term among patients who enrolled in the open-label extension study,” investigators concluded. “Overall, the findings of this study demonstrated that risankizumab was well tolerated, reduced the signs and symptoms of psoriasis and arthritis, and inhibited the progression of joint damage over the long term in patients with active PsA. These results supported further evaluation of risankizumab for the treatment of PsA in a phase 3 program.”

Mease PJ, Kellner H, Morita A, et al. Long-Term Efficacy and Safety of Risankizumab in Patients with Active Psoriatic Arthritis: Results from a 76-Week Phase 2 Randomized Trial [published online ahead of print, 2022 Aug 5]. 

. 2022;10.1007/s40744-022-00474-5. doi:10.1007/s40744-022-00474-5

Patients with psoriatic arthritis receiving risankizumab reported improved joint and skin symptoms when compared with placebo.

Risankizumab Improves Skin, Joint Symptoms in Psoriatic Arthritis  

A telephone-delivered approach including cognitive behavioral approaches (CBA) and personalized exercise programs (PEP) was shown to produce and maintain both statistically and clinically significant reductions in the severity and impact of fatigue for patients with rheumatic diseases. Investigators urge rheumatologists to utilize this treatment method in routine clinical practice, according to a study published in 

“Chronic fatigue is a poorly managed problem in people with inflammatory rheumatic diseases,” investigators stated. “CBA and PEP can be effective, but they are not often implemented because their effectiveness across the different inflammatory rheumatic diseases are unknown and regular face-to-face sessions are often undesirable, especially during a pandemic. We hypothesized that remotely delivered CBA and PEP would effectively alleviate fatigue severity and life impact across inflammatory rheumatic diseases.”

) was a multicenter, controlled, open-label, parallel-group trial that evaluated usual care alongside a telephone-delivered CBA or PEP against a usual care approach in hospitals in the United Kingdom (England and Scotland). Eligible patients, randomized 1:1:1, had a stable inflammatory rheumatic disease and reported clinically significant, persistent fatigue. A web-based randomization system was used to assign treatment allocation and CBA and PEP sessions were delivered over a 6-month period by trained health professionals. Primary outcomes included fatigue severity, as assessed by the Chalder Fatigue Scare, and impact (Fatigue Severity Scale) at week 56.

Between September 2017 and September 2019, 367 patients were randomly assigned to either PEP (n = 124), CBA (n = 121), or usual care (n = 122). The mean age was 57.5 years and 75% (n = 274) of participants were women. Most patients (n = 202, 55%) had a diagnosis of rheumatoid arthritis, 78 (21%) had connective tissue disease, 72 (20%) had axial spondyloarthritis, and 14 (4%) had another inflammatory rheumatic disease.

The Chalder Fatigue Scale included a total of 101 participants in the PEP cohort, 107 in the CBA cohort, and 107 in the usual care group. Those in the PEP and CBA groups had both significantly better improved fatigue severity (Chalder Fatigue Scale; PEP: adjusted mean difference −3·03 [97·5% CI −5·05 to −1·02], p=0·0007; CBA: −2·36 [–4·28 to −0·44], p=0·0058) and fatigue impact (Fatigue Severity Scale; PEP: −0·64 [–0·95 to −0·33], p<0·0001; CBA: −0·58 [–0·87 to −0·28], p<0·0001) when compared with those who received usual care alone. No serious adverse events were reported.

Limitations included the lack of full masking due to the need to engage people in behavioral changes. Further, the comparison group was usual care because the intention was to determine whether interventions made an impact on current practice. However, detection bias was minimized by masking investigators and analysts to allocation. Potential nocebo effects in relation to the usual care cohort were not substantial. Patients in the usual care group were given educational materials that were previously linked to positive impacts and were currently related to improved outcomes when compared with the baseline score and equivalent attrition rates. Lastly, while 12% of participants discontinued therapies, these stats were in line with previous data.

“CBA and PEP delivered by telephone provided statistically and clinically significant reductions in fatigue severity and impact for a wide range of patients whose disease was otherwise stable,” investigators concluded. “The treatments were well tolerated, their benefits were maintained 6 months after treatment completion, and they were successfully delivered by members of the rheumatology multidisciplinary teams after specialist training.”

Martin KR, Bachmair EM, Aucott L, et al. Protocol for a multicentre randomised controlled parallel-group trial to compare the effectiveness of remotely delivered cognitive-behavioural and graded exercise interventions with usual care alone to lessen the impact of fatigue in inflammatory rheumatic diseases (LIFT). 

. 2019;9(1):e026793. Published 2019 Jan 30. doi:10.1136/bmjopen-2018-026793

Exercise and behavioral techniques can be helpful, but they are not often implemented because their effectiveness is unknown and regular face-to-face sessions are undesirable. 

Exercise and Behavioral Approaches Reduce Fatigue in Rheumatic Diseases 

All patients aged ≥ 65 years who are on immunosuppressive medication

All patients aged >18 and <65 years who are on immunosuppressive medication

Hold methotrexate for 2 weeks before and after vaccination

Hold methotrexate for 2 weeks before vaccination

Hold methotrexate for 2 weeks after vaccination

Any dose of glucocorticoids, but vaccination should be deferred in those taking high doses until the dose is tapered to the equivalent of prednisone < 20 mg daily

Low dose glucocorticoids, equivalent to prednisone ≤ 10 mg daily

Low and moderate doses of glucocorticoids, equivalent to prednisone ≤ 20 mg daily

With seasonal flu vaccinations fast approaching, how much do you know about how rheumatoid arthritis and its treatment affects administration of this vaccine? Test your knowledge with this quiz. 

Psoriatic arthritis (PsA) and rheumatoid arthritis (RA) osteoclasts show immune and other functional differences, according to the first human study that examined the detailed proteomic changes during human osteoclast differentiation. The results were published in 

“Our results shed light on the characteristic proteomic changes during human osteoclast differentiation and expression differences in RA and PsA, which reveal important pathophysiological insights in both diseases,” Orsolya Tünde Kovács, of Semmelweis University in Budapest, Hungary, and colleagues, explained.

PsA and RA are associated with increased activity of osteoclasts, which play an essential role in bone maintenance, repair, and remodeling. Inflammation may accelerate bone resorption via osteoclast activation and is associated with local and systemic bone loss in these inflammatory arthropathies. Little is understood about the molecular changes during human blood-derived osteoclast differentiation and there is no information about the differences in protein expression in osteoclasts derived from patients with PsA or RA.

Blood samples were collected from 6 healthy donors, 6 patients with PsA, and 6 patients with RA. Monocytes were isolated and differentiated into osteoclasts in vitro to analyze proteomic changes during osteoclast differentiation.

In healthy donor-derived monocytes, expression of the proteins involved in metabolic activity, secretory function, and cell polarity was increased during the differentiation of the osteoclasts, while signaling pathways involved in the immune functions were downregulated. The differences between cells of healthy donors and patients with PsA or PA were most pronounced after the final steps of differentiation to osteoclasts. Proteins involved in metabolic processes were decreased in PsA and RA osteoclasts compared with healthy samples. In PsA and RA osteoclasts, the expression of proteins involved in immunological processes and proteins of the major histocompatibility complex were increased compared with healthy osteoclasts. The processes involved in protein synthesis were downregulated in PsA osteoclasts, and the expression of proteins involved in ATP synthesis were decreased in RA samples.

In PsA and RA, the “differentiation to osteoclasts was characterized by decreased metabolic activity, associated with various immune pathway activities,” along with “accelerated cytokine production in RA,” the authors stated.

Further studies with a higher number of patients including different disease stages are needed to provide data regarding osteoclastogenesis in inflammatory arthropathies.

Still, in both PSA and RA, bone erosions may be present, although in PsA they may appear in both peripheral and axial joints and generally show asymmetric involvement, while in RA they mainly appear in peripheral joints and show symmetric involvement. “These bone erosions are in line with our results that suggest that osteoclasts in these diseases might keep some of their immune cell functions,” investigators concluded.

Kovács OT, Tóth E, Ozohanics O, et al. 

Proteomic Changes of Osteoclast Differentiation in Rheumatoid and Psoriatic Arthritis Reveal Functional Differences

. 2022;13:892970. Published 2022 Jul 4. doi:10.3389/fimmu.2022.892970

FDA Approves Ustekinumab for Pediatric Patients with Psoriatic Arthritis

Patients with pediatric psoriatic arthritis will now have access to the first-in-class treatment option, ustekinumab.

Updated Vaccination Guidance for Patients with Rheumatic and Musculoskeletal Diseases

The American College of Rheumatology announced updated vaccination guidance for patients with rheumatic diseases, including expanding indications for certain vaccines for those receiving immunosuppressive medications, medication management, and vaccination delay.

How can Rheumatologists Prevent and Manage Burnout?

Whether it is leaning on the support of colleagues, mindfulness meditation, or jujitsu, rheumatologists weigh on how they personally prevent and manage symptoms of burnout.

What are the Current Challenges Contributing to Physician Burnout in Rheumatologists?

Besides the obvious stressors regarding the uncertainty of COVID-19 and implementation of telemedicine, other issues include the rheumatologist shortage, referred to as the “great resignation."

Rheumatoid Arthritis Quiz: Disease Activity Score

Assessing disease activity is an important part of a treat-to-target strategy. How much do you know about the different approaches? Take this quiz to find out.

Take 5 minutes to catch up on Rheumatology Network's highlights from the week ending August 6, 2022.

Rheumatology Network's Top 5: August 6, 2022

Results from the ORAL Surveillance study reported that rates of infections were higher in patients with rheumatoid arthritis (RA) receiving tofacitinib, either 5 mg 2 times daily or 10 mg 2 times daily, versus tumor necrosis factor inhibitors (TNFi), according to a study published in 

Investigators noted that these outcomes may help to inform future treatment decisions.

“Analyses of real-world and clinical trial data from patients with RA have shown that the risk of serious and non-serious infections (NSIs) is increased in those receiving biologic disease-modifying antirheumatic drugs (bDMARDs) versus conventional synthetic DMARDs (csDMARDs), and the risk of infections varies across treatments,” investigators stated. “For example, the TNFi, etanercept, has been associated with reduced risk of infections versus other TNFi agentsand the Janus kinase (JAK) inhibitor, tofacitinib.”

The open-label, randomized controlled ORAL Surveillance (

) trial evaluated patients with RA aged 50 years or older with 1 or more additional cardiovascular risk factor who were randomized 1:1:1 to receive either tofacitinib 5 mg twice daily, 10 mg twice daily, or a TNFi. Incidence rates (IRs) and hazard rations (HRs) were used to calculate infections, both overall and by age (50 to 65 years; 65 years and older). Infection probability was assessed by Kaplan-Meier estimates and Cox modelling identified risk factors of infection.

In total, 4362 patients were included in the study (tofacitinib 5 mg two times per day: n=1455; tofacitinib 10 mg two times per day: n=1456; TNFi: n=1451). Rates of serious infection events (SIEs), NSIs, and IRs/HRs (95% CI) for all infections were higher in the group receiving tofacitinib 5 mg 2 times daily and 10 mg 2 times daily when compared with TNFis.

Rates of SIEs in the tofacitinib 5 mg group were 1.17 (0.92 to 1.50) and 1.48 (1.17 to 1.87) in the tofacitinib 10 mg cohort. A total of 31 (2.1%) patients in the tofacitinib 5 mg group and 29 (2.0%) patients in the tofacitinib 10 mg group reported multiple SIEs, compared with 24 (1.7%) of patietns in the TNFi group. IRs/HRs for all infections and SIEs in patients receiving tofacitinib 10 mg twice daily were higher in patients aged older than 65 years. 

The probability of SIE increased from month 18 for those receiving tofacitinib 5 mg twice daily and before month 6 in the tofacitinib 10 mg twice daily group compared with TNFi. However, NSI probability increased before month 6 for both tofacitinib cohorts.

The most common risk factors for SIEs included increased age, baseline opioid use, a history of chronic lung disease, and time-dependent oral corticosteroid use. NSI risk was increased for those with a history of chronic lung disease and/or infections, past smoking, female sex, and time-dependent Disease Activity Score in 28 joints (DAS-28), C-reactive protein (CRP) score.

As the ORAL Surveillance study was designed to evaluate non-inferiority of tofacitinib versus TNFi across safety endpoints, it did not compare infection events across treatment groups. Backward selection may have introduced a biased relationship between covariates and outcomes and the stability of this selection method may have affected the number of events. Results from the Cox regression analyses determining risk factors, such as heart failure, chronic renal disease, and inflammatory bowel disease, should be cautiously interpreted. Finally, risk of SIEs with tofacitinib versus etanercept or adalimumab, or etanercept versus adalimumab, could not be definitively concluded as TNFi drugs were confounded by geographical location.

“These findings from ORAL Surveillance may inform treatment decisions for patients with RA,” investigators concluded. “The higher risk of infections with tofacitinib versus TNFi, and risk factors identified for infections, should be considered as part of the shared decision-making between physicians and patients.”

Balanescu AR, Citera G, Pascual-Ramos V, et al. Infections in patients with rheumatoid arthritis receiving tofacitinib versus tumour necrosis factor inhibitors: results from the open-label, randomised controlled ORAL Surveillance trial [published online ahead of print, 2022 Aug 3]. 

. 2022;annrheumdis-2022-222405. doi:10.1136/ard-2022-222405

Rates of serious and non-serious infection events were higher in patients receiving tofacitinib, 5 mg 2 times daily and 10 mg 2 times daily, when compared with TNFis. 

Higher Rates of Infection Reported in Tofacitinib vs TNFi in RA 

The symptoms and burden of pain in patients with both fibromyalgia syndrome (FMS) and chronic widespread musculoskeletal pain (CMP) were reduced for those receiving Vitamin D supplementation, according to a study published in in 

 Results were particularly significant in those who were vitamin D deficient.

“Fibromyalgia syndrome (FMS) and chronic widespread musculoskeletal pain (CMP) are diffuse suffering syndromes that interfere with normal activities,” investigators explained. “Controversy exists over the role of vitamin D in the treatment of these diseases.”

A systematic literature review of randomized controlled trials (RCT) was used to determine whether vitamin D (25OHD) deficiency is more prevalent in CMP patients as well as evaluate the effects of vitamin D supplementation in pain management. In total, 434 studies were identified, 14 of which were ultimately included in the assessment, using data from PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), and Physiotherapy Evidence Database (PEDro) from January 1990 through July 2022.

Of the studies included, 9 RCTs assessed pain symptoms regarding vitamin D supplementation using the visual analogue scale (VAS). Three studies, 2 of which had best-quality evidence, reported a correlation between diffuse muscle pain and 25ODH deficiency. Six studies, 4 of which had best-quality evidence, reported that vitamin D supplementation was beneficial for patients with 25OHD deficiency, and 8 studies, 6 of which had best-quality evidence, showed results in pain reduction in patients receiving vitamin D.

Chronic pain was associated with lower levels of vitamin D. While 1 study showed that the correlation was confirmed in women (Heidari et al), another study (Knutsen et al) concluded that hypovitaminosis D and widespread pain was not only restricted to women. In one study, the relationship between low levels of 25OHD and pain was seen in patients regardless of other factors, such as physical activity, smoking habits, and alcohol use, when comparing patients with FMS and healthy controls (23.9 ng/mL vs. 25.6 ng/mL; 

 = 0.05). 25OHD may also play a role in etiology of chronic pain conditions such as headaches or abdominal pain. Investigators reported that the severity of pain and lack of treatment often lead to self-medication.

There was a “high risk” of bias in 6 of the studies, a “low risk in 6, and “some concerns” in 2 studies. The most notable source of high risk was the “selection of the reported result,” presented in 3 studies (23% of the cases).

“The therapeutic approach to FMS and CMP necessarily involves a multidisciplinary protocol, which should be conducted as a team because of the many facets of the pathologies and the many compromised systems,” investigators concluded. “This review suggests that vitamin D deficiency is frequently observed in FMS and CMP patients, and supplementation with vitamin D can be proposed to reduce musculoskeletal pain and improve the quality of life in vitamin D-deficient subjects with FMS and CMP.”

Lombardo M, Feraco A, Ottaviani M, et al. The Efficacy of Vitamin D Supplementation in the Treatment of Fibromyalgia Syndrome and Chronic Musculoskeletal Pain. 

. 2022;14(15):3010. Published 2022 Jul 22. doi:10.3390/nu14153010

Despite previous evidence showing the benefits of vitamin D supplementation in patients with fibromyalgia and chronic widespread musculoskeletal pain, controversy still exists over the role of 25OHD in the treatment of these diseases. 

Vitamin D Supplementation Linked to Pain Reduction in Fibromyalgia 

The American College of Rheumatology (ACR) 

 updated vaccination guidance for children and adults with rheumatic and musculoskeletal diseases (RMDs), including expanding indications for certain vaccines for those receiving immunosuppresive therapy, medication management at the time of vaccination, and vaccination delay.

“Patients worry about the safety of vaccines and the potential for inducing a disease flare. Providers are concerned whether rheumatic diseases and the medications used to treat them could blunt the effectiveness of vaccines,” Anne R. Bass, MD, Professor of Clinical Medicine, Hospital for Special Surgery and Weill Cornell Medicine in New York stated. “They also want to know whether certain vaccines should be given to protect rheumatology patients who are outside the age range for which they are typically recommended. This guideline was designed to address these issues.”

Expanded indications for specific vaccines in patients on immunosuppression:

For patients with RMD aged 65 years or older who are currently on immunosuppressive medication, the pneumococcal vaccination is strongly recommended. The recombinant zoster vaccine is also strongly recommended for all adult patients on immunosuppressive medication.

An HPV vaccine is conditionally recommended for patients between the ages of 26 and 45 if they were not previously vaccinated. For all patients aged 65 years or older, and adults between the ages of 18 and 65 who are currently receiving immunosuppressive medication, a high-dose or adjuvated influenza vaccination is conditionally recommended over the regular-dose vaccine. Receiving multiple vaccinations on the same day rather than over the span of different days is conditionally recommended.

Medication management during non-live attenuated vaccine administration:

Investigators conditionally recommend deferring live-attenuated vaccines for patients on immunosuppressive medications as well as holding immunosuppressants for a predetermined amount of time before and 4 weeks after. In patients taking glucocorticoids, prednisone ≤ 10 mg daily is strongly recommended for both the influenza vaccination and other non-live attenuated vaccinations, regardless of disease activity. However, it is conditionally recommended to defer other non-live attenuated vaccinations for those receiving a daily dose of prednisone ≥ 20 mg.

Administering live-attenuated rotavirus vaccination to infants exposed to immunosuppressive medications in utero:

Infants exposed to a tumor necrosis factor (TNF) inhibitor in the second or third trimester may receive the rotavirus vaccine within the first 6 months of life; however, infants who were exposed to rituximab should wait to receive the vaccine until after 6 months of age.

“This new guideline recognizes that some patients, particularly very young children with autoinflammatory conditions, simply cannot stay off their medications for very long without having a severe flare of their disease,” Bass explained. “However, those patients still need to get vaccinated.”

Updated Vaccination Guidance for Patients with Rheumatic and Musculoskeletal Diseases 

In the final part of our physician burnout series, 

 interviewed Jack Arnold, MBBS, MRCP, a clinical research fellow at Leeds Centre of Rheumatic and Musculoskeletal Medicine, Massimo Radin, MD, PhD, a researcher at the University of Torino (UNITO), and Andrew Concoff, MD, Executive Vice President and Chief Value Medical Officer at United Rheumatology, to discuss how they personally prevent and manage burnout.

The importance of maintaining wellness is of obvious importance, particularly within the medical community. “You want to have the clarity of thought of being somebody who is well rested [and] who is firing on all cylinders,” Arnold explained. “When you fail to address it, you’ll run into problems sooner or later. The better we get at picking it up earlier, the more effective you can be.”

Radin and Arnold find it helpful to have a strong support system in place among their collogues, as they’re more likely to understand specific issues related to the field. In addition, Radin emphasizes the importance of mental health for both rheumatologists and patients alike. “Everyone should check their mental health from time to time,” he states. “We talk about the stigma of mental health a lot. I see a lot of patients that don't want to go to a psychologist. I’d like to think that we are behind that, but we're really not. And in dealing with a chronic disease, it's something that should be implemented. In the guidelines of managing a patient with chronic disease, mental health should be one of the top spots.”

What are some of the strategies that rheumatologists utilize to prevent and manage burnout?

I think I have got better the longer I've been working at picking up when I'm showing signs of [burnout]. I'll find, for example, that I'll become very fatigued, or my concentration won't be quite there. And, fortunately, my wife is [in the medical field] as well so she will tend to pick it up before I do. But you know, it's very common. And it's important to notice the early signs that you're going that way and try to intervene because it's not something you can leave unaddressed. If you leave it completely unaddressed, you become less effective as a physician and become a fairly unpleasant person to be around.

You need to address that and do things that you would suggest when you're talking to patients. You'd ask them to do certain things or take these things seriously and you need to do that as a physician as well. I see it creeping in every so often, particularly if it's been a busy period.

The first thing that tends to happen is I tend to talk to my wife, my friends, and people I’ve known for a while [to] talk it through and talk through general stresses. The other [aspect] is to take the things that you can modify very seriously. You can't modify the stresses associated with work, but you can modify things like your diet, exercise, etc. For example, I do jujitsu and it's very difficult to worry about what's going on at work when I've got somebody throwing me onto a mat. It's almost mindfulness in that sense.

Another thing that I’ve found helpful is stoic philosophy. It just breeds into this acceptance that there are things you can't modify, and you do what you can with the things you can, but anything that takes you away from this cycle of being at work, and then worrying about decisions you've made or work that's left over from the day before, you need to break that cycle. It’s different between people, but that's what works for me.

Well, one thing that I think is really helpful is to talk about this kind of situation with my colleagues, to unwind, going out of work together, or talking about difficult cases, or if I’ve had a very difficult time during rotation. You feel less alone and understood by your peers.

In the midst of a busy day, there are several things that I do to prevent feeling burnt out. Number one is making sure that time to get work done is built into the day. That we don't have meetings that are solid from the beginning of the day to the end of the day, and there's time to actually take a breath and get some work done, as opposed to going all the way through the day and then having to follow up and do the remainder of the work.

The second thing is paying attention to behavioral health. During lunch breaks, it's a matter of getting out and getting morning sun, getting just a few minutes of exercise, and clearing your head for a moment. [It can be a] powerful approach. Taking that lunch break and not viewing a lunch break as a sign of weakness, but instead as an important part of the way that you rejuvenate and regenerate. And even some very quick behavioral health approaches like mindfulness meditation or just taking a few minutes to take a few breaths. Being in the moment can [also] be a great way to recharge and restart. It’s also important that your weekends are rejuvenating and that when you come back from the weekend you feel as if you've been away, you feel as if you've gotten a break, and that you've recharged your batteries.