Category: Knee Arthritis

Novel nanoparticle-based system developed for the comprehensive treatment of rheumatoid arthritis

A team of scientists led by KOO Sagang of Seoul National University and the Center for Nanoparticle Research within the Institue for Basic Science Center (IBS), in collaboration with researchers from the Korea Institute of Science and Technology (KIST) and the Seoul National University, developed a new solution for the treatment of rheumatoid arthritis (RA).

RA is a chronic disease that unfortunately cannot be cured. The disease causes a mix of troublesome symptoms, such as inflamed joints, harmful cytokines, and immune system imbalances, which work together to create a relentless cycle of worsening symptoms. While addressing some of these factors can provide short-term relief, others remain unresolved, leading to a frustrating cycle of remission and flare-ups.

One of the biggest hurdles in treating RA is the inability to restore the immune system to a healthy state. This leaves the body unable to control the continued production of harmful substances such as reactive oxygen species (ROS) and inflammatory cytokines, leading to persistent inflammation and discomfort.

Essentially, the ideal treatment for RA should not only provide immediate relief from inflammation and symptoms, but also address the cause by restoring the immune system to its normal, balanced state.

New nanoparticle-based system as a solution

The novel platform involves immobilizing ceria nanoparticles (Ce NPs) on mesenchymal stem cell-derived nanovesicles (MSCNVs). Both components can hinder various pathogenic factors, allowing them to work individually and together to achieve comprehensive treatment.

Ce NPs – can scavenge the overproduction of ROS in RA-induced knee joints. They also cause polarization of M1 macrophages into M2, immediately relieving inflammation and symptoms.

MSCNVs – deliver immunomodulatory cytokines, which convert dendritic cells (DC) into tolerogenic dendritic cells (tDCs). This consequently generates regulatory T cells for long-term immune tolerance.

In short, this approach aims to bridge both innate and adaptive immunity to achieve short-term pain relief, and to convert the tissue environment into an immune-tolerant state to prevent recurrence of symptoms.

Researchers confirmed the efficacy of this approach using a collagen-induced arthritis mouse model. The Ce-MSCNV system was able to comprehensively treat and prevent RA by simultaneously easing and restoring immediate T cell immunity. Supporting data suggests that improvement in conditions can be achieved after only a single dose treatment.

The mice treated with the Ce-MSCNV combination did much better compared to the mice treated with the Ce NP or MSCNV group alone. This clearly demonstrates the synergy between anti-inflammatory agents and immunomodulation and underlines the importance of the combined therapy for effective treatment of RA. Furthermore, administration of Ce-MSCNV prior to booster injection significantly reduced the incidence and severity of symptoms, supporting the prophylactic potential of these nanoparticles.

One of the most difficult decisions in the treatment of intractable diseases is determining how long to continue treatment. For RA, it would not be appropriate to stop treatment just because the target marker has stabilized. A safer indicator should be that the innate and adaptive components of the collapsed immune system are normalized to protect the body.”

Koo Sagang, first author

Koo believes that Ce-MSCNVs’ strategy of working together with different treatment mechanisms offers a unique advantage in this regard. Furthermore, she predicts that a similar approach for this purpose would also be applicable to other refractory, inflammatory and autoimmune diseases. The components within the system can also be changed. For example, depending on the type of disease, other catalysts can be used to generate ROS or other cell-derived nanovesicles. Overall, this study proves the potential of a hybrid nanoparticle system for the comprehensive treatment of autoimmune diseases and modulation of the immune system.

Source:

Institute for Basic Sciences

Magazine reference:

Koo, S., et al. (2023). Ceria-vesicle nanohybrid therapeutic agent for modulation of innate and adaptive immunity in a collagen-induced arthritis model. Nature Nanotechnology. doi.org/10.1038/s41565-023-01523-y.

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October 26, 2023
Carriers of HLA-DRB1*04:05 have a better clinical response to abatacept in rheumatoid arthritis

In this study, we showed that among the SE alleles, HLA-DRB1*04:05 in particular was strongly associated with the prognosis of ABT treatment. The allele frequency of HLA-DRB1*04:05 in Japanese patients with ACPA-positive RA is reported to be approximately 28%. Because each individual carries two HLA-DRB1 alleles, approximately half of ACPA-positive RA patients have at least one copy of HLA-DRB1*04:05. And HLA-DRB1*04:05 is strongly associated with the development of ACPA-positive RA, with an odds ratio of 5.0²³. HLA, which is innate and unchangeable throughout a person’s life, suggests that the association between HLA and treatment prognosis is not merely coincidental. In other words, the HLA genotype is the cause, which leads to favorable treatment results. Although several associations between the efficacy of SE and ABT have been reported^9,10,11details at the allele level are limited, even though the significance of the specific alleles as potential biomarkers is promising.

In this study, it was found that only HLA-DRB1*04:05 showed an association with response to ABT treatment, while HLA-DRB1*01:01 and 04:10, which share similar SE, showed no significant association. with treatment responsiveness. In addition to the effect of small sample size, the following reasons can be considered. Amino acids at positions 11, 13 and 67 of HLA-DRB1, which are different amino acid sequences than SE, are also involved in the risk of developing RA. Specifically, it was found that in DRB1*04:05 and 04:10, the valine at position 11 is the amino acid most strongly associated with RA sensitivity, while DRB1*01:01 has another amino acid, leucine, at position 11.²⁵. Furthermore, in a study on the risk of developing RA in the Japanese population, it was shown that the risk of RA differs based on the variant of HLA-DRB1, even sharing the same HLA SE allele. It is suggested that HLA-DRB1*01:01, 04:05 and 04:10 are not bioequivalent²³. Furthermore, HLA risk alleles for autoimmune diseases have been reported to significantly influence the pattern of CDR3 sequences in T cell receptors. Furthermore, CDR3 sequences modified by HLA risk alleles have been associated with the recognition of citrullinated antigens. Therefore, sequences other than SE are also believed to be associated with the development and progression of RA and other diseases²⁶.

SE and ACPA-positive RA are strongly associated, and ACPA is also associated with the prognosis of ABT treatment^27,28. Previous reports have also shown that SE is associated with ABT outcomes, even after adjusting for the effect of ACPA^9,10. In this study, both multiple regression analysis and mediation analysis suggested that the effect of the HLA-DRB1*04:05 allele was not an indirect effect mediated by ACPA (Table 4, Figure 2). The impact of SE has been reported to be stronger in ACPA-positive RA than in ACPA-positive non-RA controls^29.30. In other words, SE may be involved in the pathogenesis of RA through mechanisms other than direct effects on ACPA positivity. RA risk HLA is robustly associated with CD4 T cell receptor repertoire⁺ T cells^26.31. RA-sensitive HLA alleles, such as HLA-DRB1*04:05, are associated with autoreactive CD4⁺ T cells, which may be therapeutic targets for ABT.

In this study, methotrexate use was low in the abatacept group. Because in general it has been reported that concurrent use of MTX may not increase the effectiveness of ABT. For example, in a phase III study, ABT did not induce immunogenicity associated with loss of safety or efficacy either with or without MTX³². Also in a retrospective cohort study of RA patients with similar background characteristics who underwent treatment with abatacept, concurrent MTX did not appear to influence clinical outcomes.³³. Based on these findings, we believe that ABT would be a suitable treatment option in daily clinical practice in patients with contraindications to MTX.

In this study, the association between the HLA-DRB1*04:05 allele, an SE allele, and favorable treatment outcomes was significant only in ABT-treated patients, but not in those treated with the IL-6 receptor inhibitor TCZ or a TNF drug. inhibitors. This is consistent with the association between the better prognosis with ABT and SE reported in the Early-AMPLE trial comparing ABT with the TNF inhibitor adalimumab.¹¹. SE was also not strongly associated with the efficacy of the JAK inhibitor tofacitinib¹⁰. These findings may reflect the difference in mechanism of action between ABT, which inhibits costimulation of antigen-presenting cells, and CD4.⁺ T cells and IL-6 receptor inhibitors, TNF inhibitors and JAK inhibitors, which are drugs that block inflammatory cytokine signaling.

There are several limitations to this study. First, due to the retrospective nature of this analysis, we cannot exclude the possibility of selection bias. Second, the number in each treatment group is small, so the effect of HLA alleles with small frequency or small effect size may not have been fully realized. Third, since this study was conducted in a single Japanese cohort and there are ethnic differences in the frequencies of the HLA-DRB1 allele, it is necessary to verify whether the results can be generalized to other cohorts, including other ethnic groups.

In conclusion, we analyzed the association between HLA-DRB1 alleles and prognosis in Japanese patients with RA who initiated treatment with ABT, TCZ, and TNF inhibitors, and we showed that among SE alleles, the HLA-DRB1*04 :05 allele was associated with better outcomes with ABT. This study demonstrates the feasibility of stratifying RA patients based on disease risk HLA alleles and supports the need for a larger prospective study.

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October 26, 2023
Ginger shows promise as a natural defense against autoimmune diseases
This is evident from a recent study published in the journal JCI Insight, the authors built on their previous work examining the anti-autoimmune disease effects of 6-gingerol, the most abundant phytochemical produced by the roots of the ginger herb. Because their previous work showed that this plant extract could reverse the effects of neutrophil hyperactivity in mouse model systems, the researchers herein evaluated whether oral consumption of whole ginger extracts could have similar effects both in mouse models and in human pilot trials. Their results show that ginger consumption for just seven days neutralizes hyperactivity in neutrophils in both in vivo systems. When taken by healthy individuals, it increases their resistance to developing conditions, including lupus and antiphospholipid syndrome (APS).

Study: Ginger intake suppresses extracellular neutrophil formation in autoimmune mice and healthy humans. Image credits: Nataly Studio / Shutterstock

Neutrophilic autoimmune diseases and the untapped potential of herbs

Antiphospholipid antibody syndrome (APS) is an autoimmune disease that mainly affects women between the ages of 30 and 40. APS results in the formation of abnormal proteins that promote clot formation in veins and arteries and is especially harmful to both mother and her fetus during pregnancy. APS and lupus, a frequent comorbidity characterized by circulating immune complexes that damage organs after their deposition, are lifelong, incurable conditions resulting from genetics, environmental exposure, or a combination of these. Both diseases result in significant mortality, morbidity and healthcare costs.

Previous research has shown that, despite having very different clinical profiles, both APS and lupus are pathologically caused by the exaggerated and abnormal formation of extracellular neutrophils, medically termed ‘NETosis’. During NETosis, neutrophils overexpress and secrete their nuclear chromatin in the form of web-like structures with pro-inflammatory properties and potentially harmful granule-derived proteins that, despite being localized in organs and the circulatory system, have serious consequences on the health.

Recent studies have shown that excessive NETosis, in addition to its own negative consequences, can result in sustained formation of autoantibodies, resulting in other autoimmune diseases that would otherwise have been suppressed by the body’s adaptive immune tolerance. Considering that most of these autoimmune diseases are incurable, require constant and usually expensive medical interventions, and carry significant mortality costs, finding a low-cost therapy for NETosis is imperative.

In recent years, scientific attention has shifted to the potential of herb-derived phytochemicals with anti-inflammatory properties as a wealth of safe and natural remedies against autoimmune diseases in general, and NETosis in particular. In a previous study, the authors of the current work showed that a purified ginger extract, 6-gingerol, shows promise in stimulating intracellular cyclic adenosine monophosphate (cAMP) and attenuating neutrophil phosphodiesterase (PDE) activity, both of which are important mechanistic results are from NETose.

In particular, their research found that NETs and neutrophils in manifestations of thromboinflammatory diseases not only influence APS, lupus and similar autoimmune diseases, but also promote adverse outcomes in communicable diseases such as coronavirus disease 2019 (COVID-19).

About the study

The current study aimed to determine whether whole ginger extracts have similar NETosis-reversing effects as 6-gingerol and have beneficial effects on consumption even for healthy individuals who do not exhibit autoimmune symptoms. This study represents a pilot study that may form the basis for future clinical testing of ginger’s beneficial proteins in the treatment of a spectrum of NETosis-related autoimmune diseases, including APS, lupus, vasculitis, rheumatoid arthritis, and even COVID-19.

Researchers began testing the efficacy of powdered whole ginger obtained from Aurea Biolabs (Kerala, India) in in vitro testing. Immunoglobulin G (IgG) was obtained from both APS and lupus patients (cases) and healthy controls and purified using the Protein G Agarose Kit (Pierce). The purity and concentration of IgG were estimated using Coomassie staining and BCA protein assay, respectively. For NETosis assays in human neutrophils, blood was collected from healthy human volunteers, purified via density gradient centrifugation, and neutrophils were isolated using dextran sedimentation and red blood cell (RBC) lysis. Flow cytometry and nuclear morphology microscopy were used to verify purity.

For NETosis assays, the above purified neutrophils were mixed with neutrophils derived from APS and lupus patients (three volunteers, respectively). In vitro assays consisting of immunofluorescence microscopy, measurements of phosphodiesterase (PDE) activity, and calculations of intracellular cAMP levels.

In vivo APS models included venous thrombosis experiments performed on male C57BL/6 mice (10-13 weeks). Female BALB/c mice (9 weeks old) were used for lupus testing. The venous thrombosis testing was performed using an electrolytic inferior vena cava (IVC) model. Circulating myeloperoxidase (MPO)-DNA complexes were then quantified and isolated thrombi were processed via thrombus section and immunohistochemistry.

Finally, the pilot study was conducted in humans. Participants older than 18 years and without NETosis-associated autoimmune diseases were recruited. Female participants had to be fertile to allow the evaluation of ginger consumption in combination with contraception. Women who were pregnant, lactating, or suffering from cardiovascular disease, diabetes, or cancer were excluded to avoid confusion due to their illness or the medications they were taking. All statistics performed in this study were 1-way analysis of variance (ANOVA) corrections based on multiple corrections.

Findings of the study

The main findings of this study were that ginger consumption significantly inhibited NETosis in healthy study participants, even after stimulation (mixing) of neutrophils from APS or lupus patients. This was expected given that their previous research reported the same findings on the use of purified 6-gingerol supplementation, and whole ginger extracts contained approximately 20% 6-gingerol. Similarly, this study presents that consumption of whole ginger inhibited cAMP-specific PDE activity, confirming previous findings.

In in vivo mouse models, consumption of whole ginger APS was shown to attenuate IgG-mediated venous thrombosis and NETosis. Remarkably, consumption of whole ginger attenuates lupus-relevant disease activity even in lupus-positive female BALB/c mice.

Pilot human experiments confirm that ginger is an important focus in future clinical trials, as it was found to stimulate neutrophil cAMP and reduce NETosis in healthy human volunteers, even after just seven days of ginger diet supplementation. To verify these results and confirm that the findings were not a byproduct of the small sample size (N = 9; 3 men, 6 women), the study was repeated with an unrelated volunteer cohort (N = 8). findings consistent across replications. Furthermore, the second cohort study revealed a reduction in plasma NET levels (measured by the MPO-DNA complexes).

Conclusion

The current study highlights the potential of whole ginger consumption as a safe and natural intervention, both to treat existing cases of APS, lupus and other NETosis-associated diseases and to prevent the development of these conditions in previously healthy people . They combined in vitro testing with in vivo mouse and human models and found that consumption of whole ginger attenuates venous thrombosis (APS) and significantly reduces the clinical features of lupus in mouse models.

In healthy human volunteers, ginger consumption for just seven days was associated with a notable reduction in NETosis and cAMP, confirming its potential against autoimmune diseases in future clinical trials.

“…we found that the dissolved ginger extract counteracted the PDE activity of neutrophils. The result was increased neutrophil intracellular cAMP levels, which were associated with blunted NETosis by human neutrophils in vitro. Such data complement recent studies that have reported a role for ginger extracts, and in particular 6-gingerol, as inhibitors of cAMP-specific PDE activity. Importantly, the suppressive effects of ginger on NETosis can be attenuated by blocking PKA activity, a key downstream cAMP-dependent kinase. The fact that increasing neutrophil cAMP and activating PKA would be beneficial for disease activity in mice is in good agreement with our previous work demonstrating the potential therapeutic target of this pathway in APS and lupus models with synthetic PDE4 inhibitors. ”
Magazine reference:

Ramadan A. Ali, Valerie C. Minarchick, Miela Zahavi, Christine E. Rysenga, Kristin A. Sturm, Claire K. Hoy, Cyrus Sarosh, Jason S. Knight, M. Kristen Demoruelle. Ginger intake suppresses extracellular neutrophil formation in autoimmune mice and healthy humans. JCI Insight. 2023;8(18):e172011, DOI – https://doi.org/10.1172/jci.insight.172011, https://insight.jci.org/articles/view/172011
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October 26, 2023
Patient-centered assessment of rheumatoid arthritis using a smartwatch and customized mobile app in a clinical setting
Study design

This was a prospective study among participants with moderate to severe RA and 28 controls, matched for age (± 3 years), gender, and race. A sample size of 60 was chosen to facilitate one-on-one follow-ups. RA and control participants were recruited from the rheumatology clinic and general medical clinic of the Reliant Medical Group (Worcester, Massachusetts). All participants were provided with an Apple Watch Series 4 and an iPhone 7 with a pre-loaded, customized, study-specific mobile application. Personal training was provided by an on-site study coordinator on how to use the devices and application, perform the guided testing, and complete the PRO measures. Participants were required to complete PRO measurements weekly, daily, or twice daily, and guided testing twice daily for 14 days (Fig. 2; Supplementary Table S3). The data was transmitted in near real time to monitor compliance and to allow study coordinators to contact participants to encourage task completion if necessary.

Figure 2

Study design. JMAP joint pain card, BALL patient reported outcome measure, RA Rheumatoid arthritis, VAS visual analogue scale.

Prior to the start of the study, an advisory board of patients with RA (who did not participate in the study) provided input on the study design and mobile app; This was followed by a beta test over a period of five days, involving five participants with RA, to gather feedback on the usability of the app, the clarity of the instructions and the feasibility of the assessment scheme. Feedback from the beta test included issues remembering how to charge the devices, inconsistent syncing of data with the backend server, and limitations of the iPhone leg strap. In response to this feedback, the training was updated with more specific instructions on when to charge the devices, the software was updated to improve data synchronization, and the leg strap was redesigned, along with a detailed pictorial guide on how to attach it.

Study objectives

The following research objectives were investigated:
1. 1.
  
  Construct validity: correlations between guided test performance and PRO measure severity.
2. 2.
  
  Clinical utility: differences in guided test performance and PRO measure scores between RA and control cohorts.
3. 3.
  
  Feasibility: Survey assessment completion rates and Apple Watch wear rates in RA and control cohorts.
4. 4.
  
  Repeatability and reproducibility: Changes in guided test performance and PRO measures over time in RA and control cohorts.
Ethics

All documentation, including the study protocol, any amendments, and informed consent procedures, was reviewed and approved by the Reliant Medical Group Institutional Review Board. All participants provided written informed consent before any research procedures were undertaken. The study was conducted in accordance with the principles of Good Clinical Practice of the International Committee for Harmonization and the Declaration of Helsinki.

Selection of participants

The full list of inclusion and exclusion criteria for participants is included in Supplementary Table S4. Briefly, participants with RA were recruited by physicians from the Reliant Medical Group during a clinical visit if they had a clinically verified diagnosis of moderate to severe RA, with severity assessed using Routine Assessment of Patient Index Data 3 (RAPID- 3; score ≤ 12). : moderate RA; score > 12: severe RA). Controls were outpatients of the Reliant Medical Group and were excluded if they had a previous or current diagnosis of a rheumatologic disease, inflammatory disease, malignancy, or other relevant diseases.

Study assessments

The rating scheme and example screenshots of the custom mobile application used to collect the statistics of these ratings are provided in Supplementary Table S3 and Supplementary Figure S3, respectively.

For the guided tests, the iPhone was used to collect accelerometer and gyroscope data while participants performed predefined guided tests of physical function. The guided exercises are designed using clinical and patient feedback to test aspects of participants’ functionality that are likely to be affected by the symptoms most important to patients with RA (i.e. joint pain, stiffness, fatigue and sleep ).². Participants were instructed to perform each guided test daily, once in the morning (immediately after waking) and once in the afternoon, to assess change in stiffness throughout the day. The wrist ROM test is described in detail in the PARADE study⁵. Briefly, while holding the iPhone pointed upward over the edge of a table, participants flexed and extended their wrist joint to the maximum angle (without going outside the comfort zone), repeating the movement for 10 seconds. The test was performed once with both hands. For the sit-to-stand test, participants sat on a chair with the iPhone strapped to their right thigh and their arms crossed over their chest. Then they stood up and sat down five times at their own pace. The average time taken to go from sitting to standing and from standing to sitting was extracted from accelerometer and gyroscope data. For the lie-to-stand test, participants lay on a bed with their legs extended and the iPhone strapped to their right thigh, then stood up on the floor twice at their own pace. The average time taken to transition from lying down to standing and from standing to lying down was extracted from accelerometer and gyroscope data. Other guided tests included the walking test and the 9-hole peg test (ResearchKit; Apple Inc., CA, USA)⁵. In the walking test, participants were asked to attach the iPhone to their right thigh and walk in a straight line for 30 seconds. In the 9-hole peg test, which measures manual dexterity, participants are asked to use two fingers of their left hand to drag a circular “peg” on the iPhone screen to a “hole” elsewhere on the screen and then two Use fingers of their right hand to remove the pin from the hole. The Apple Watch was also used to continuously collect background accelerometer data to passively measure daily and nightly activity counts, the data of which are not reported in this article.

PROs were assessed on days 1, 7, and 14 and included the following: Functional Assessment of Chronic Disease Therapy – Fatigue (FACIT Fatigue) to assess fatigue²⁸; HAQ-DI and SF-36²⁹ questionnaires to indicate the impact on the participant’s quality of life^24,30,31; Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference to assess how pain disrupts participants’ daily well-being, and PROMIS Sleep Disturbance to assess sleep quality³²; RASIQ to quantify the severity of symptoms and their impact on the participant⁴. RA-specific assessments (RASIQ, PGA, stiffness) were not performed in controls.

Short questionnaires were administered every day, except for morning stiffness, which was administered on days 2–6 and 8–13. Morning stiffness and stiffness severity were assessed based on responses to questions 11, 12, and 13 of RASIQ⁴. The JMAP recorded the number and severity of painful joints experienced at a given time, from 55 pre-specified joints, displayed on a body map; pain was scored as no pain, mild pain, moderate pain, or severe pain¹¹. Pain VAS assessed the severity of pain on a scale ranging from 0 mm (no pain) to 100 mm (worst pain)³³. PGA generally measures how RA affects participants and/or disease activity, using a single-item question and the VAS score³⁴. A global assessment of fatigue over the past 24 hours was measured on a 10-point scale ranging from ‘no fatigue’ (0) to ‘as bad as you can imagine’ (10).

Guided testing algorithms

Details of the algorithms for the wrist ROM test, sit-to-stand test, and lie-to-stand test are given in Supplementary Methods S1. An illustrative flowchart of the algorithm for the lie-to-stand test is shown in Supplementary Figure S4 and has been previously reported for the wrist ROM test¹¹.

Data quality assessment

Automated and manual data quality assessments were performed throughout the study to ensure that the data analyzed came only from properly conducted tests. The quality control of the wrist test was performed manually, and both manual and algorithmic quality controls were performed for the walking test, the sit-to-stand test, and the lie-to-stand test. Tests that were clearly performed incorrectly were removed from the sample.

static analysis

Descriptive statistics were used for demographic and clinical characteristics, PRO measures, and guided testing. Wilcoxon signed-rank tests were used for matched (i.e., participants with RA vs. controls and morning vs. afternoon) and rank-sum tests for unmatched (i.e., participants with moderate vs. severe RA) comparisons. Nonparametric tests were used because a normal distribution could not be assumed due to the small sample size. Trends over time were assessed using univariate mixed effects models, with study day as fixed effect and individual differences as random effects. ICCs were calculated to measure the consistency of guided testing over time for each participant using a two-way mixed effect, single rater, consistency convention; a higher ICC indicated more regular test performance over the study period than a lower ICC. Correlations between PROs and supervised tests were assessed using Pearson correlation coefficients, and one-way ANOVA was performed using the Kruskal-Wallis test by rank, with Mann-Whitney U tests for post-hoc pairwise comparisons. There was no adjustment for multiplicity in this study, and the study was not suitable for hypothesis testing; therefore, Pvalues were used for quantification/descriptive purposes only.
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October 26, 2023
Scientists achieve breakthrough in the treatment of ‘neglected’ polymyalgia rheumatica

Scientists have had success treating a ‘neglected’ inflammatory disease, polymyalgia rheumatica, with a drug that could offer patients an alternative to steroids.

The study, conducted by Anglia Ruskin University (ARU) and published in the New England Journal of Medicine, describes a successful trial of sarilumab. The drug, approved in Britain to treat rheumatoid arthritis, blocked the protein interleukin-6, which can cause inflammation.

Polymyalgia rheumatica (PMR) is characterized by pain and morning stiffness in the shoulder and hips and affects people over the age of 50. It can significantly affect quality of life and is currently mainly treated with the steroids glucocorticoids.

Although glucocorticoids can control the condition, more than half of PMR patients experience a relapse of their condition when they reduce their steroid medication. Interleukin-6 has been implicated in the pathophysiology of PMR because circulating elevated levels and increased tissue expression of interleukin-6 have been found in PMR patients.

During the year-long clinical trial conducted by researchers, 118 patients received either twice-monthly injections of sarilumab or a placebo. The sarilumab group received a tapering dose of glucocorticoid for 14 weeks in combination with bimonthly injections of sarilumab, while the placebo group received a tapering dose of glucocorticoid for 52 weeks.

The primary outcome at the end of the study was sustained remission of the condition. This happened in 28% of people taking sarilumab, compared to 10% of people taking the placebo. After achieving remission at 12 weeks, there were more disease flares in the placebo group (57%) compared to those who received sarilumab (24%).

Lead PMR expert and senior author of the study, Professor Bhaskar Dasgupta, from the Medical Technology Research Center at Anglia Ruskin University (ARU), said: “Polymyalgia rheumatica is a poorly managed and neglected condition for which current treatment is unsatisfactory and can have long-term side effects. Patients can relapse while tapering their medications, and these relapses currently have very limited treatment options.

“Our findings show promise that sarilumab can be used to treat PMR and improve outcomes for people coming off steroid medications.

“This is an exciting development that has the potential to improve treatment options for a condition common in older people. PMR is the most common reason for long-term steroid prescriptions. Any effective drug that can spare the use of steroids would be a should have a major impact.” on reducing the serious side effects of such steroids, including diabetes, osteoporotic fractures and infections.”

The research was funded by Sanofi and Regeneron Pharmaceuticals.

Earlier this year, a review paper was published in the journal Nature reviews by Professor Dasgupta and colleagues highlighted the emerging view that relapsed PMR patients also have underlying giant cell arteritis, in which the main blood vessel aorta and its branches become inflamed. Researchers suggested that the two should be treated as linked conditions under the term GCA-PMR Spectrum Disease (GPSD).

Source:

Magazine reference:

Tomelleri, A., et al. (2023). Disease stratification in GCA and PMR: state of the art and future perspectives. Nature Reviews Rheumatology. doi.org/10.1038/s41584-023-00976-8.

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October 25, 2023
Tips for Parenting with Rheumatoid Arthritis

Parenting is hard at first – but rewarding. Add a chronic condition like RA to the mix, and that delicate balance between your self-care and your role as a parent can easily get lost. These tips and strategies can help you get through difficult days, manage your energy, and make meaningful memories with your family.

I was recently interviewed for the WebMD article below, which provides tips for parenting while living with rheumatoid arthritis. Although the article focuses on RA, many of the tips mentioned would apply to other chronic diseases as well!

I’ve always believed that parents with chronic illness deserved more recognition and support – that’s why I started Mamas Facing Forward in the first place! So it’s exciting to see this topic being addressed in a more mainstream health publication. Hopefully this article will help other parents realize they are not alone – and find their way to us where we can continue to support them!

Tips for Parenting with Rheumatoid Arthritis

WebMD

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October 25, 2023
Tapering and discontinuation of glucocorticoids in patients with rheumatoid arthritis treated with tofacitinib

This study aimed to evaluate the steroid-sparing effect of tofacitinib in patients with RA. To the best of our knowledge, this is the first prospective study that evaluated the feasibility of a predetermined schedule for GCs discontinuation in patients initiating tofacitinib treatment. This showed that already 12 weeks after starting treatment, 30% of patients were able to stop their daily dose of GCs. The most recent recommendations for the treatment of RA suggest that the dosage of GCs should be reduced to discontinuation as soon as possible¹. In fact, the dose and duration of steroid treatment influence the safety profile and there is no agreement on the definition of the ‘safe’ dose.¹⁷. The optimal dose and duration of GC therapy and the best strategy to taper off and withdraw GCs are still scarce. A recent systematic literature review reported 14 different regimens proposed to reduce and/or stop oral GCs¹⁸. Randomized clinical trials with RA drugs do not provide sufficient information on GC therapy during treatment with biologics and do not allow to displace definitive conclusions on GC discontinuation, also considering that the steroid-sparing effect never appears as a secondary endpoint¹⁹.

A subanalysis of the ACTION (AbataCepT In rOutiNe Clinical Practice) study showed that over a 24-month period from the start of abatacept, approximately 40% of the 734 patients taking GCs at the start of the study were able to control their prednisone levels to lower. dose, usually within the first 3 months of treatment, and that the median GC dose decreased from 7.5 mg/day to 5 mg/day after 24 months of treatment²⁰. The need to evaluate the steroid-sparing effect of RA medications is real and relevant, as evidenced by real-world studies. Most real-world evidence comes from retrospective studies evaluating the effect of bDMARDs on GC therapy in patients with long-standing RA, such as those enrolled in our study. Many years ago, Naumann et al. described dose reduction of GCs that was associated with reduced disease activity as early as 3 months after starting a TNF inhibitor in 87 patients with RA; during 5 years of follow-up, 81% of patients reduced the dose of GCs and 32% of patients discontinued treatment²¹.

In a French retrospective study published in 2009, the authors noted an overall 30% reduction in the dose of oral GCs in the first year of treatment with TNF inhibitors, starting as early as 3 months; on the other hand, 61% of patients were still using low-dose prednisone after 1 year⁷. More recently, analysis of the TReasure database found that after a median of 59 months, 28.4% of 1936 patients receiving GCs at registry entry discontinued concomitant steroid treatment.²². The retrospective nature of the study explains the lack of prespecified criteria for GC tapering. The SPARE-1 study included RA patients treated with tocilizumab (TCZ) and an oral prednisone dose > 5 mg/day and aimed to evaluate the percentage of patients who reduced their GC dose to less than 5 mg/day after 12 months of TCZ²². At the end of follow-up, 40% of patients reached the target dose; RA duration not more than 5 years, daily prednisone dose <7.5 mg, and low baseline ESR were predictive of PDN reduction to less than 5 mg/day²³.

Fernandez-Nebro et al. prospectively followed for 24 months 161 patients starting infliximab, etanercept, or adalimumab, showing that almost 60% of patients taking GCs at baseline were able to discontinue and the remaining patients significantly reduced the daily dose²⁴. In a previous paper published by our group, we demonstrated a 56% reduction in the percentage of RA patients treated with baricitinib who were taking glucocorticoids after 24 weeks; In addition, we registered a significant reduction in the daily dose of prednisone from an average of 5 mg/day to 0 mg/day, simultaneously with a significant reduction in pain after just 4 weeks.²⁵. Similarly, in the current study, the rapid effect of tofacitinib on pain and disease activity certainly contributed to the rapid reduction of the dose of GCs, to complete discontinuation; Indeed, approximately one-third of included patients discontinued daily GCs within 12 weeks of starting tofacitinib.

The initial adjunctive GCs therapy on a DMARD background would allow rapid control of disease activity, also guaranteeing long-term structural benefits, which persist even after GCs withdrawal; doses ranging from 5 to 10 prednisone per day appear to be associated with significantly slower radiographic progression². A post hoc analysis of 6 randomized, controlled phase III trials of tofacitinib suggested that concomitant use of GCs did not affect either the clinical or radiographic efficacy of the drug.²⁶. In a prospective evaluation of the efficacy of tofacitinib according to discontinuation of GCs, we observed no difference in the reduction of disease activity as assessed by DAS28_CRP, CDAI and SDAI; furthermore, low disease activity or remission was achieved regardless of the concomitant use of GCs. In contrast, data from a Turkish registry showed a significantly higher DAS28_CRP score and a significantly lower proportion of patients achieving low disease activity or remission in patients who continued GCs concurrently with bDMARDs or tsDMARDs.²⁰. Data on the effect of GCs on clinical response to TNF inhibitors are also conflicting and have shown that a higher or lower percentage of patients achieve the treatment goal.^27,28. In the SEMIRA (The Steroid EliMination In Rheumatoid Arthritis) trial, patients were randomly assigned to the regimen of continued prednisone or tapered prednisone; two-thirds of patients who achieved low disease activity with tocilizumab tapered the steroid dose in the 24-week study, but contrary to what we observed in our patients, patients who continued with prednisone had better control of disease activity²⁹.

In our study, age at enrollment and disease duration were negatively associated with GC discontinuation. This is not surprising, as results from a recent double-blind, placebo-controlled study showed that elderly patients (over 70 years at baseline) with established and severe RA had long-term beneficial effects in both disease and disease activity. and joint damage resulting from taking a low dose of prednisolone as an addition to basic treatment³⁰. However, this study did not include patients taking tsDMARDs. Recently, data from the Veterans Affairs Rheumatoid Arthritis Registry showed that 54% of patients tapered and 33% discontinued oral GCs; younger age, positive rheumatoid factor, higher ESR at enrollment, a greater number of prior csDMARDs, and a higher mean glucocorticoid dose during the 30 days before the index date were all significantly associated with GC tapering and discontinuation³¹.

The 2013 EULAR recommendations on the treatment of moderate to high doses of glucocorticoids in rheumatic diseases state that “When deciding to initiate glucocorticoid treatment, comorbidities and risk factors for adverse effects should be evaluated and treated where indicated […]”³². Particularly at medium to high doses, GCs are often associated with the occurrence of adverse events, including osteoporosis, diabetes, hypertension, cardiovascular events, and recurrent infections. Sparing GCs – as suggested by our results – may be beneficial in terms of short-term safety (risk of infection, especially reactivation of herpes Zoster) and long-term safety (metabolic and cardiovascular events, as well as osteoporotic fractures ). A large study of RA patients from the CorEvitas registry showed that GCs increased the risk of cardiovascular events after just six months of treatment, at a daily dose of more than 5 mg³³.

Some of these side effects – mainly infections and cardio-metabolic effects – raise concerns in patients treated with both bDMARDs and tsDMARDs; in particular, the results of the ORAL Surveillance study raised a warning about cardiovascular safety in patients treated with tofacitinib³⁴.

The current study has some limitations. The small sample size did not allow stratification of patients based on concurrently administered MTX. However, the MTX dose remained stable and the logistic regression did not identify the co-medication as a factor influencing the ability to discontinue GCs. The long disease duration and failure of previous treatments probably caused the steroid-sparing effect of tofacitinib to be underestimated. Still, 30% of patients stopping GCs after just three months is an impressive result.

The strength of the study lies in its prospective nature and interventional design, which allowed the GC dose reduction schedule to be predefined to homogenize the outcome.

In conclusion, in our cohort of patients with long-standing RA treated with tofacitinib, discontinuation of glucocorticoids was feasible in up to 30% of patients. The results of the study should encourage rheumatologists to consider GC tapering and withdrawal as a possible goal in the daily management of RA patients on long-term treatment with oral GC.

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October 25, 2023
Genetic markers can help women with rheumatoid arthritis make informed decisions about pregnancy

When women with rheumatoid arthritis (RA) plan to become pregnant, many worry about whether they should stop their medications, risking a flare-up of their disease, or continue taking medications and risk possible damage to the baby.

About 50% to 75% will see their disease improve naturally during pregnancy for reasons yet unknown, while others may see a worsening of their RA. But they couldn’t have known what would happen to them.

Now, for the first time, Northwestern Medicine scientists have identified pre-pregnancy genetic markers that can predict who will get better and who will get worse.

The research was published this week in Research and therapy for arthritis.

RA is an incurable disease that affects 1% of the world’s adult population and is three times more common in women. It leads to significant disability due to inflammation of the joints and destruction of cartilage and bones.

“When women with RA become pregnant, there is often a natural improvement,” said lead researcher Damini Jawaheer, associate professor of medicine in rheumatology at Northwestern University Feinberg School of Medicine. “They describe it as ‘a miracle.’ They say, “I’ve never felt better with the medicine I’ve been taking.” But the cause of this improvement is a complete mystery.

“If women with RA can know in advance whether their disease is likely to resolve during pregnancy, they know they can stop taking their medications. Some RA medications are toxic and affect the fetus, while others are considered safe. But some women with RA don’t want to take RA medications during pregnancy, even those that are considered safe.”

Being able to predict who will get better and who will get worse will help women in their pregnancy planning and will also help ensure that treatment during pregnancy is targeted only to those women who are predicted to get worse, Jawaheer said . In addition, women who are predicted to improve, and their fetuses, will not be unnecessarily exposed to medications.

Jawaheer and her team found that before pregnancy, a group of white blood cells called neutrophils were highly expressed among the women who improved during pregnancy, and that some genes related to B cells were highly expressed among women who deteriorated.

This field hasn’t been well studied, in part because it’s difficult to find women for pregnancy screenings before they become pregnant, Jawaheer said.

She and colleagues were able to conduct the study because they had previously established a unique pregnancy cohort in Denmark, which enrolled women with RA and healthy women before pregnancy and followed them over time to determine who improved and who deteriorated. Using blood samples taken from these women before pregnancy, they examined the levels of several genes expressed in the blood. Blood samples were collected before pregnancy from 19 women with RA and 13 healthy women participating in the prospective pregnancy cohort.

Next, Jawaheer plans to conduct a study on a larger cohort of women to validate these findings. Additionally, her lab is trying to figure out why RA improves during pregnancy.

How does nature ensure that an incurable disease disappears? If we can understand how pregnancy produces natural improvement, we can use that as a model to develop a new drug that would be safer and could improve the lives of women and men living with this terrible disease.”

Damini Jawaheer, associate professor of medicine in rheumatology at Northwestern University Feinberg School of Medicine

The name of the paper is: “Pre-pregnancy gene expression traits are associated with subsequent improvement/worsening of rheumatoid arthritis during pregnancy.”

The other Northwestern author is Matthew Wright.

The study was funded by grants R21AR057931 and R01AR073111 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the National Institutes of Health and by Gigtforeningen and Juliane Marie Center in Denmark.

Source:

Magazine reference:

Wright, M., et al. (2023). Pre-pregnancy gene expression signatures are associated with subsequent improvement/worsening of rheumatoid arthritis during pregnancy. Research and therapy for arthritis. doi.org/10.1186/s13075-023-03169-6.

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October 25, 2023
From this moment on. Ahead.: Rheumatoid Arthritis and Sex: Tips to Improve Intimacy

Rheumatoid arthritis (RA) can find its way into every aspect of your life, including your sex life… You can still have a healthy sex life if you have RA… But you may need to find other ways that work best for you and your partner .

WebMD

I was recently interviewed for the WebMD article below, which provides tips for improving intimacy while living with rheumatoid arthritis. I speak from personal experience when I say that this is a topic where it used to be impossible to find positive, uplifting advice. That’s why I started speaking out on this very personal topic in the first place! It’s exciting to see this topic covered in a more mainstream health publication! Hopefully the article will help raise awareness that couples facing these challenges are not alone or unusual – and encourage people to contact their doctor for help if necessary.

Rheumatoid Arthritis and Sex: Tips to Improve Intimacy

WebMD

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October 25, 2023
Is there a connection between the onset of psoriasis and the risk of autoimmune diseases?

In a recent study published in the Scientific Reports Journal, researchers evaluated the risk of new autoimmune diseases in individuals with early psoriatic disease.

Study: Risk of incident autoimmune diseases in patients with newly diagnosed psoriatic disease: a national population-based study. Image credits: Flystock/Shutterstock.com

Background

Psoriatic disease, which often includes psoriasis and psoriatic arthritis, is a systemic inflammation-related disease with serious clinical consequences.

Autoreactive T lymphocytes, which express proinflammatory cytokines such as interleukins (ILs)-17 and 22, and interferon-gamma (INF-γ) characterize psoriatic diseases.

Studies have linked the autoimmune component of psoriasis to several autoimmune diseases, including autoimmune thyroid diseases, inflammatory bowel disease, alopecia areata, and autoimmune rheumatic diseases.

About the study

In the national population study, researchers evaluated the link between autoimmune diseases and psoriatic diseases.

Patients with newly diagnosed psoriatic disease between January 2007 and December 2019 were included in the study, using the Korean National Health Insurance Service (NHIS) database.

The team used previously established diagnostic algorithms for psoriatic disease in Korea to identify people with the condition. Patients with psoriatic disease had one or more recorded visits with psoriatic diseases such as psoriasis and psoriatic arthritis as their primary diagnostic code and vitamin D prescriptions.

Autoimmune diseases such as CD, UC, Graves’ disease, Hashimoto’s disease, SLE, RA, Sjögren’s syndrome, systemic sclerosis, AS, type 1 diabetes and alopecia areata were studied.

Comparators who had no diagnostic code for psoriatic diseases between January 2005 and December 2019 and no diagnostic code for autoimmune diseases during the washout were randomly selected and matched on sex and age at a 1:1 ratio.

In addition to the diagnostic codes, the researchers also added relevant prescription information for medications and RID codes for all diseases to the diagnostic algorithms for outcomes.

The team added follow-up information on newly identified autoimmune diseases from 2007 to 2020. Multivariate Cox regression modeling was performed to determine adjusted risk ratios (aHRs).

The Charlson Comorbidity Index (CCI) values for comorbidities such as hypertension, diabetes, dyslipidemia, chronic obstructive pulmonary disease (COPD), liver cirrhosis, chronic kidney disease, alcoholic liver disease, and heart failure were determined. The team conducted subgroup analyzes based on gender, age and severity of psoriatic disease.

Patients who received diagnostic codes for psoriatic disease between January 2005 and December 2006 were excluded from the study.

Additionally, the team excluded individuals diagnosed with autoimmune diseases [Crohn’s disease (CD), ulcerative colitis (UC), Graves’ disease, Hashimoto’s disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome, ankylosing spondylitis (AS), systemic sclerosis, alopecia areata, and diabetes type 1] before diagnosis of psoriatic disease and those followed for less than one year.

Results

The study included 321,354 individuals in the psoriatic and control groups with a mean age of 43 years, and 59% were men.

Patients with psoriasis showed a significantly increased risk of ankylosing spondylitis, systemic lupus erythematosus, ulcerative colitis, Crohn’s disease, alopecia areata, type 1 diabetes and rheumatoid arthritis, with aHR values of 2.3, 1.9, 1.7 , 2.0, 1.4, 1.2 and 1.6. respectively.

On the other hand, the risks for Hashimoto’s disease, Graves’ disease, systemic sclerosis and Sjögren’s syndrome did not differ significantly between the groups. Type 1 diabetes, alopecia areata, AS, RA, SLE, UC, and CS had NNH values of 9,567, 1,295, 9,946, 3,256, 47,987, 17,899, and 39,988 individual years, respectively.

With the exception of type 1 diabetes, all autoimmune diseases showed a significantly increased risk in psoriatic subjects compared to controls after controlling for CCI and insurance type. After controlling for CCI and insurance type, the risk of type 1 diabetes (aHR, 1.1) was not significant in men with psoriatic disease compared with male controls.

After adjusting for type of insurance and CCI, all autoimmune diseases showed significantly greater risks in younger psoriatic individuals under 40 years of age and in individuals 40 years of age and older compared with controls.

After controlling for insurance type and CCI, CD risk (aHR, 1.4) was not significantly greater in older psoriatic subjects than in controls.

Mild and moderate psoriatic disease occurred in 79% (n=255,285) and 21% (n=66,069) of patients with psoriatic disease, respectively, including the incidence of UC, CD, RA, SLE, alopecia areata, and type diabetes. 1, and AS were greater compared to controls.

After controlling for age, gender, CCI, and insurance type, patients with moderate to severe psoriatic disease showed a significantly increased risk of rheumatoid arthritis, AS, and type 1 diabetes, with aHR values of 1.5, 1.5, and 1.2, respectively.

Conclusion

Based on the study results, patients with psoriatic conditions have a greater chance of developing autoimmune diseases.

This study also found the occurrence of autoimmune diseases unrelated to psoriasis, such as Graves’ disease, Hashimoto’s disease, Sjögren’s syndrome, and systemic sclerosis. Due to the low absolute risk, routine screening for these conditions may not be recommended.

However, appropriate investigations may be necessary in individuals with psoriatic disease to determine the existence of concomitant alopecia areata and provide tailored therapy.

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October 24, 2023