Category: Knee Arthritis

You Don’t Look Sick – Living with Rheumatoid Arthritis: DAY 5 HAWAI’I

I woke up early so I could go to the farmers market. I like looking at the crafts. This time I bought a ring. It is a stainless steel brushed silver ring with very thin rainbow colors along each edge. I had the word ‘resilience’ engraved on it. I like it very much. I also gave my niece a birthday present.

Then I went to the Hawaii Tropical Bioreserve and Garden. It is very beautiful. Jungle and flowers and ocean.

I bought some vegan gelato before heading to an outdoor area with live music and dancing.

When I got back to my hotel and opened my door, the hotel cat ran into my room. He wouldn’t leave. I tried to ignore him, use a cord to play with him and feed him. Nothing worked. It took more than an hour before he could leave. I used a paper bag! He wanted to climb in. After I got him out, he climbed onto a table outside my door and tried to knock over a vase. I told him to stop and then he lay down in front of my door and scratched it.

It was a long night.

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November 12, 2023
RA patients in remission should continue taking TNF inhibitors to prevent flare-ups, the study found

New research at ACR Convergence 2023, the annual meeting of the American College of Rheumatology (ACR), found that patients with rheumatoid arthritis (RA) in sustained remission who stopped taking TNF inhibitors (TNFi) had significantly more flares and lower Boolean 2.0 remission rates compared to those who continued treatment. Boolean 2.0 is a revised definition for evaluating disease activity in RA, classifying more patients as achieving remission than Boolean 1.0. It is endorsed by the American College of Rheumatology and the European Alliance for Associations in Rheumatology (EULAR) (Abstract #L07).

As more RA patients achieve durable remission, questions remain about the long-term effectiveness of tapering and stopping TNFi treatment. In the randomized, multicenter, noninferiority ARCTIC REWIND trial, Siri Lillegraven, MD, MPH, PhD at Diakonhjemmet Hospital, Oslo, Norway, and colleagues compared the three-year effect of tapering versus stable treatment in RA patients in sustained remission. It follows a trial last year.

The current study included 92 patients from Norwegian rheumatology centers who were randomized 1:1 to taper off TNF inhibitors until discontinuation or continuation of treatment. During the three-year study period, all received study visits every four months. Patients restarted treatment at the full dose if they experienced a flare, which was defined as loss of remission plus an increase in disease activity score of 0.6 units or more and two or more swollen joints. In lieu of these criteria, a doctor and a patient might agree that a significant flare had occurred. The study also looked at remission status, medication use and serious side effects or complications.

Of the original 92 patients, 80 (87%) completed three-year follow-up. At the end of the study, 75% of patients in the tapering group experienced a flare, compared to 15% in the stable group. Most of those who experienced a flare were in remission by their next office visit (81% in the taper group and 67% in the stable group), although the taper group had significantly lower Boolean 2.0 remission rates throughout the study.

Lillegraven says the researchers were “somewhat surprised by the difference in the proportion of patients in ACR/EULAR Boolean remission in the two groups,” noting that “although most patients in the taper group experienced a flare within the first year and the earlier resume treatment at full dose Boolean 2.0 remission rates were significantly lower in the tapering TNFi group than in the stable group throughout the study period.”

The risk difference for flares observed in this data [-24% over three years] is quite similar to what was observed in the one-year study. That’s a bit surprising, because we might have expected that more patients receiving stable treatment would develop a flare over time, narrowing the difference between the two groups.”

Siri Lillegraven, MD, MPH, PhD at Diakonhjemmet Hospital, Oslo, Norway

Lillegraven notes that the study’s open-label design could influence the evaluation of flares, but says that study staff “were continuously instructed on the importance of recording flares similarly in both groups, a pragmatic approach that will improve clinical care reflects, where patients know which treatment they are receiving. received.”

Lillegraven says her team has many studies planned to better understand how to personalize treatment for RA patients in remission. This includes factors that can help determine which patients should and should not taper off their treatment.

“We have begun planning a 10-year follow-up of the study to better understand the long-term outcomes of different treatment strategies in RA remission. We are [also] consider studies to better understand patient preferences regarding medication tapering.”

Shared decision-making is central to any consideration of tapering, she says.

“The patient should be informed of the risks and benefits of tapering, and the patient’s overall situation should be taken into account before the decision is made. Although the data do not support tapering off TNFi at a group level, factors such as side effects related to the treatment or the patient having a strong preference for tapering will obviously influence such a decision.”

Source:

American College of Rheumatology

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November 11, 2023
More than 314,000 cells analyzed for precise treatment strategies

Rheumatoid arthritis (RA) is one of the first autoimmune diseases to be identified and remains incurable. Despite the discovery of several disease-modifying treatments, the response to each treatment remains unpredictable. This indicates a difference in the pathophysiology of RA between patients.

Study: Deconstruction of the synovium of rheumatoid arthritis defines inflammatory subtypes. Image credits: Oporty786/Shutterstock.com

A new article recently appeared in Nature, reported the examination of synovial tissue from the joints of nearly 80 people with RA, combined with RNA sequencing and surface protein analyses. This allowed the researchers to assemble an atlas of RA synovial changes from more than 314,000 individual cells. This could help develop targeted therapies that recognize the diversity of RA disease processes.

Background

RA affects about 1 in 100 people worldwide. The main feature is the painful swelling of synovial joints that ultimately culminates in joint damage and disability. Recognition of the immunological origins of RA has led to the deployment of therapies that target inflammatory cytokines and pathways, including tumor necrosis factor (TNF), IL-6, stimulation of T and B cells together, and the pro-inflammatory JAK -STAT transcription. regulatory process.

Genetic differences have been identified, as well as diverse clinical features, but these do not fully predict or explain why treatment response varies between patients, nor do they help identify therapeutic targets. The need for a more detailed picture of RA synovial disease activity motivated the current study.

Multiple effector cells participate in RA activity at the synovial level. Previous research suggests that the synovial cellular profile could predict response to treatment. Furthermore, the presence of common cell state compounds could extend the utility of this study to other autoimmune or inflammatory conditions.

What does the research show?

The study was based on 82 synovial tissue samples taken from patients with a spectrum of RA activity from moderate to high. This is measured by the CDAI (clinical disease activity index), which was ten or higher for all participants. The samples came from those who had not yet started treatment, some with a poor response to methotrexate (which stops the proliferation of inflammatory cells), those who responded poorly to anti-TNF agents (to stop pro-inflammatory signaling) and some who had osteoarthritis.

The scientists were able to divide the RA synovium into six groups based on the cell types that were selectively enriched in each group. Each group is accordingly called a cell type abundance phenotype (CTAP) and is defined by specific cell states.

While some samples showed very low levels of lymphocytes, others were abundant in T and B cells, indicating clear synovial differences. Each cell state reflects different disease stages and types, as well as varying cytokine profiles, and the risk genes were differentially expressed between groups.

The researchers created an atlas of RA synovial cell states, consisting of 77 cell states, including 24 T cell clusters, 9 B cell clusters, 14 natural killer (NK) cell clusters, and 15 myeloid clusters. There were also ten stromal cells and five endothelial clusters. This confirmed RA-associated cell states identified in a previous study from more than 5,000 synovial cells.

For example, the CTAP-TB was enriched in T_PHand T_FHcells, perhaps because these promote the differentiation of B cells into plasmablasts and ABC cells, as opposed to non-T_FH/T_PH memory CD4+ T cells that only do the latter. Both T_FH and T_PH cells are enriched in the synovial tissue of all CTAPs, but extra-follicular activation pathways also appear to be present in CTAP-TB.

Conversely, the CTAP-TF mainly involves cytotoxic together with naive CD4 and CD8 T cells, with selective NK cells that can share their transcriptional profile promoted by the tissue microenvironment. Fibroblast subsets were differentially enriched in this CTAP versus CTAP-M. The latter also showed enrichment of myeloid cells, perhaps because inflammatory monocytes were recruited to transform into macrophages as a result of exposure to the specific cell types and soluble factors present in each CTAP.

These cell neighborhoods did not show consistent associations with aggregated RA scores from histology, which are based on the extent and type of inflammatory cell infiltration. This is probably because the former are so diverse. However, the CTAPs each contribute one-fifth of the variance of the histological density and total scores and are associated with inflammation scores.

Interestingly, the CTAPs showed a close relationship with clinical parameters such as the commonly used autoantibodies against cyclic citrullinated peptide (CCP), reflecting increased lymphocyte infiltration into CCP-positive synovial tissue. CTAP-M was associated with CCP-negative synovial tissue. There was no clear association with the strongest genetic risk predictor, HLA–DRB1.

The CTAPs showed distinct cytokine profiles. For example, the T cell neighborhood of CTAP-TB expressed the TFH/TPH highlight genes CXCL13 as expected, while for CTAP-TF the T and NK cell neighborhood was associated with the expression of the genes IFNG And TNF.

As expected, there was little correlation between disease activity and CTAP or treatment response. This supports the theory that inflammatory phenotypes in different types of RA are reflected in the CTAPs and not in clinical disease activity, as reflected by CDAI and other clinical scores.

However, CTAPs change over time, usually to CTAP-F, after anti-inflammatory therapies such as rituximab and the anti-IL-6 agent tocilizumab. CTAP-F is a predictor of poor response to treatment.

What are the implications?

“The CTAP paradigm has the potential to serve as a powerful prototype to classify other types of tissue inflammation.” The subtypes of enriched inflammatory cells in different CTAPs also reveal new research questions about how these interact to produce a range of inflammatory phenotypes in such diseases.

“CTAPs are dynamic and can predict response to treatment, highlighting the clinical utility of classifying synovial phenotypes of rheumatoid arthritis.” It was possible to predict the CTAP using RNA sequencing with different methods. This offers potential therapeutic targets for the future.

Meanwhile, the spectrum of inflammatory changes in RA explains why treatment responses vary so widely among patients treated with anti-TNF agents. This may imply that specific therapies that target the cells and pathways enriched in each CTAP could induce better responses, and advance drug development and precision medicine.

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November 10, 2023
You Don’t Look Sick – Living with Rheumatoid Arthritis: DAY 2 HAWAII

I woke up super early. I had difficulty sleeping. At first it was a bit warm and the fan is very noisy, but the main problems were 1) another guest was snoring and 2) someone was blaring pop music at 3am. It was one song from Judy, but it woke me up. Now back to the snoring. All quests have the windows open because it is hot and there is no air conditioning. A guest snores or snores so loudly that we can all hear it! It kept waking me up. It was loud! It sounded like someone said “ew.” I don’t know, but I hope it’s milder tonight.

Then I drove to the farmers market and met my friend. It started to rain very hard. I never found my umbrella, so all I had was my windbreaker. We walked around and saw all the little stalls. I bought someone a Christmas present. Then we got in our cars and went to another small market. Between the two markets I was given lettuce, a red pepper and a tomato so I can make sandwiches. The only thing I don’t have is vegan Mayo, but I’ll have to suffer through it.

Family drove to my friend’s house. It’s the first time I’ve seen it in real life and it’s beautiful. It’s the kind of house I’d like to live in. He’s doing some renovations and additions, but he gave me a full tour. We sat outside on his lanai for a few hours and talked.

Then I drove back to Hilo where I stopped at a vegan restaurant to get a sandwich. It started raining really hard and I wanted to eat outside, so I took my sandwich back to my hotel room. Since it was almost four in the afternoon, that’s both my lunch and dinner. I’m so tired and I’m not going to get up very late tonight.

See you tomorrow…

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November 10, 2023
You Don’t Look Sick – Living with Rheumatoid Arthritis: HAWAII DAY 3

I woke up early this morning and headed to Rainbow Falls. I should have seen a rainbow, but I didn’t. I walked up the rock steps to get to the top and see the hot pools. (I think that’s what they’re called). Walking down was a bit slow.

I returned to find that my friend’s cat wouldn’t be seen at the vet until later that day and our outing was postponed. I went shopping for items like t-shirts and a dream catcher.

I came back to my room for lunch. I have a kitchen in my room so I can make my own food.

After lunch I wrote out some postcards. I was smart to put them in the car because on my next trip I stopped by a post office and was able to mail them. I drove to another waterfall called ‘Akaka. It was so beautiful.

When I got there, the employee told me to take the shortcut. I hate when people tell me what to do, so I did the whole walk. It was a total of half a mile with a lot of stairs. I took a detour to drive along the scenic route.

I got back to my hotel room just in time to meditate with the other members. When I was done, I drove to a restaurant that had vegan food for takeout.

See you tomorrow…

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November 10, 2023
National trends in the prevalence of rheumatoid arthritis and osteoarthritis in South Korea, 1998–2021

Patient selection and data collection

This study used data from the Korea National Health and Nutrition Examination Survey (KNHANES), conducted between 1998 and 2021 by the Korea Centers for Disease Control and Prevention Agency (KDCA).^10,11. The study population included adults aged ≥ 19 years and data collected included information on age, gender, place of residence, body mass index (BMI), education level, income, alcohol consumption, smoking status and history of RA and OA.¹². We focused our research on the adult population, which is over 19 years old in South Korea. A nationally representative sample of 163,221 participants was used to examine the prevalence of RA and OA before and during the COVID-19 pandemic. The survey was conducted over 24 years and the number of participants surveyed in each year group was as follows: 51,515 in 1998-2001; 26,996 in 2005-2007; 20,070 in 2008–2010; 17,601 in 2011–2013; 17,129 in 2014–2016; 18,469 in 2017–2019; 5839 in 2020; and 5,602 in 2021.

The study protocol was approved by the Institutional Review Board of Kyung Hee University (KHUH 2022-06-042) and KDCA, and all participants provided written informed consent. Furthermore, the KNHANES provides accessible public access to its data, which can be used as a valuable resource for various epidemiological studies. This study followed the ethical guidelines established by relevant national and institutional review boards for human research and adhered to the 1975 Declaration of Helsinki, as amended in 2008.

Determination of RA and OA

The aim of our study was to investigate the risk factors associated with the two most common forms of arthritis, RA and OA, over a 24-year period, from 1998 to 2021. To achieve our research objective, we collected a large number surveyed participants and asked them the question, “Have you ever been diagnosed with RA or OA by a doctor?” Based on their answers, we divided the participants into three groups: RA, OA, and both¹³. We collected data on several potential risk factors associated with the development of RA and OA, such as age, gender, lifestyle habits and socio-economic status. We conducted statistical analyzes to examine the associations between these risk factors and the development of RA and OA and to identify patterns or trends that have emerged over 24 years.

Covariates

Covariates included age (19–29, 30–39, 40–49, 50–59, 60–69, 70–79, and ≥ 80 years), gender, region of residence (urban and rural)^14,15,16, BMI group, household income (lowest, second, third, and highest quartiles), education level (primary school or less, middle school, high school, and college or higher education), alcohol consumption (1–5 days/month, ≥ 6 days/month, and non-drinker) and smoking status (non-smoker, ex-smoker and smoker). BMI was subdivided into underweight (< 18.5 kg/m2).²), normal weight (18.5–22.9 kg/m²), overweight (23–25 kg/m2²), and obese (≥ 25.0 kg/m²) according to Asia-Pacific guidelines^17,18.

static analysis

The results of this study were presented using qualitative data, expressed in proportions or percentages. Weighted multivariate regression model analyzes were conducted to compare the estimates of each related factor before and during the COVID-19 pandemic, using weighted odds ratios (ORs) with 95% confidence intervals (CIs).¹⁹. The prevalence of RA and OA was calculated using data from the KNHANES, spanning the period 1998 to 2021, stratified by year group. A weighted complex sampling analysis was performed to ensure accurate estimation. Binomial or linear logistic regression models were used to calculate the ORs with 95% CIs or β coefficients with 95% CIs. To ensure the robustness of the main findings, a stratification analysis was performed in all regression models using variables such as gender, education level, region of residence and income. Furthermore, the ratio of ORs was calculated to estimate the interaction duration of each risk factor and identify groups that were more vulnerable to the patient with RA and OA during the pandemic. Overall, this study aimed to provide a comprehensive analysis of the impact of the COVID-19 pandemic on the prevalence of RA and OA and to identify the factors contributing to vulnerability to these conditions. The SAS software (version 9.4; SAS Institute, Cary, NC, USA) was used for statistical analyses, with a two-sided test, and a p-value ≤ 0.05 was considered statistically significant¹⁹.

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November 9, 2023
Research links lower testosterone levels to an increased risk of arthritis

In a recent study published in Scientific Reports, researchers determined the relationship between serological testosterone levels and arthritis in adults in the United States (US).

Study: Lower serum testosterone is associated with an increased risk of arthritis. Image credits: airdone/Shutterstock.com

Background

Arthritis is a joint disease that affects the hyaline articular cartilage, surrounding tissues and subchondral bone. Hormonal variables, such as testosterone, have been linked to the growth and development of knee osteoarthritis (KOA).

Studies have shown that androgens activate non-genetic and non-genetic mechanisms, with the most rapid evidence being a rapid increase in intercellular calcium concentration.

Physiological testosterone doses have been shown to improve cartilage production in men with advanced osteoarthritis, and treatment with testosterone replacement improves articular cartilage regeneration in affected individuals.

According to research, androgens are also involved in the formation and development of osteoblasts. However, there is minimal evidence for sex-specific relationships between serological testosterone expression and OA, and the association between plasma testosterone in arthritic individuals and disease progression is not clear.

About the study

In the current study, researchers examined the influence of serological testosterone levels on the pathophysiology of arthritis.

Data from 10,439 adults who participated in the 2013–2016 National Health and Nutrition Examination Survey (NHANES) were analyzed using multivariable logistic regression modeling, performed to determine odds ratios (ORs).

The model estimates are adjusted for covariates such as age, gender, race, education level, marital status, income, alcohol consumption, smoking status, test reports, laboratory findings, survey responses, and comorbidities (such as diabetes, cardiovascular disease, and hypertension). ).

In addition, generalized additivity modeling and smoothed curve fitting were performed. The database samples were selected using stratified multistage sampling.

Data collection methods include home interviews to collect demographic, nutritional and health-related data, and medical examinations to collect laboratory data [including sex hormone binding globulin (SHBG) and estradiol] and physical assessment data [including body mass index (BMI) and waistline].

Individuals were asked whether they had been diagnosed with arthritis by doctors or other medical professionals, and if so, they were asked to report the type of condition as rheumatoid arthritis, osteoarthritis, or other.

The Centers for Disease Control and Prevention (CDC) isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS) technique was used to determine TT concentrations.

Results

Initially, 20,146 individuals were identified, of whom 5,380 and 4,327 were excluded due to missing data on serological testosterone levels and development of arthritis, respectively. Of the 10,439 study participants, 48% were male, with an average age of 47 years and an average serum testosterone level of 215. Of the participants, 27% developed arthritis.

Arthritis patients showed lower serum testosterone than their non-arthritic counterparts, in line with previous studies. The findings from linear regression analysis showed a statistically significant negative association between serological testosterone levels and arthritis.

Similarly, the fourth quarter univariable analyzes using the first quarter as reference showed a significantly lower risk of developing arthritis.

Specifically, sensitivity analyzes using quartiles of serum testosterone resulted in odds ratios of 1.0, 0.9, 0.5, and 0.5 for the first quartile, second quartile, third quartile, and fourth quartile, respectively, in the fully adjusted model.

Individuals in the top quartile of serum testosterone levels showed a 51% lower risk of developing arthritis compared to individuals in the lowest quartile.

Smoothed curve fitting showed a non-linear relationship between the development of arthritis and serological testosterone levels. The subgroup analyzes showed that the negative association between serological testosterone and the development of arthritis was statistically more significant in older female smokers with comorbidities and body mass index (BMI) values of 30 kg per m2 and above.

Testosterone and estradiol are natural immunosuppressants that suppress antibody and cell-mediated immunity while acting as anti-inflammatory agents. Because women have more active immunity than men, they play a crucial role in lowering men’s susceptibility to autoimmune diseases.

The primary androgen, testosterone, binds to specialized intracellular receptors to create active forms of testosterone receptor complexes. Androgen and estrogen receptors are present in both male and female osteoblasts, and testosterone binds to both to regulate bone calcium.

Decreased testosterone levels can affect cartilage metabolism via ion channels and androgen receptors, resulting in cartilage and KOA breakdown. The activation of androgen receptors (AR) and estrogen receptors (ER) has a profound influence on bone metabolism.

Testosterone increases the glycosaminoglycan content in the extracellular matrix of the chondrocytes, improves the coverage of type II collagen on the cartilage surface and influences the development of the fibrocartilage structures.

Low testosterone levels may be the cause of obesity rather than its consequence, with BMI having a causal influence on serum testosterone in the hypothalamic-pituitary-gonadal axis.

Conclusion

Overall, the study results indicated that lower levels of serum testosterone were associated with an increased risk of developing arthritis.

The in-depth investigation of the negative and non-linear association between serological testosterone levels and the development of arthritis was related to BMI and sex.

The findings could impact the prevention and treatment of arthritis. However, further research is needed to elucidate the mechanisms underlying the impact of serum testosterone on the development of arthritis.

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November 9, 2023
Study sheds new light on the variety of cellular causes of rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation leading to pain, joint damage and disability, affecting approximately 18 million people worldwide. Although RA therapies targeting specific inflammatory pathways have emerged, only some patients’ symptoms improve with treatment, highlighting the need for multiple treatment approaches tailored to different disease subtypes. To more precisely define the cellular causes of RA, an international research consortium, co-led by researchers from the Broad Institute of MIT and Harvard and Brigham and Women’s Hospital, a founding member of the Mass General Brigham health care system, analyzed tissues from RA donors to the at the single-cell level, integrating multiple forms of analysis to stratify RA based on six subtypes of inflammation. Findings, published in Natureshed new light on the variety of cellular causes of RA, which may lead to more targeted, effective and patient-tailored therapeutic approaches.

“In treating people with rheumatoid arthritis, we struggle to find the right treatment for the right patient,” says corresponding author Soumya Raychaudhuri, MD, PhD, of the Brigham’s Division of Rheumatology, Inflammation and Immunity and the Broad Institute, where he is an institute member. “We wanted to determine why some subgroups of patients do not respond to conventional treatments by looking at the subtypes of inflammation. We did this from many different angles, using multiple advanced, single-cell techniques and by integrating the results in a way that is has not been done before for an inflammatory disease.”

The study findings represent a major milestone in the Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic Lupus Erythematosus program, a public-private partnership launched in 2014 to advance the understanding of autoimmune diseases at the molecular and cellular levels and identify promising drug targets to identify. Working with researchers and physicians in the US and Britain, the researchers analyzed 79 donor samples of synovial tissue, the inflamed tissue in RA that normally helps soften and support joints. In particular, the researchers examined tissue from patients with new disease and from patients who did not respond to treatment to better identify both the initial causes of RA and those of refractory diseases.

To ‘deconstruct’ RA pathology at the cellular level, the researchers combined surface protein data and histological analysis with multiple forms of single-cell RNA sequencing and bulk RNA sequencing. Despite the variety of methods used to analyze more than 314,000 cells, the researchers consistently found evidence of six major types of inflammation, which they stratified by associated cell type, called cell type abundance phenotypes (CTAPs). Although some CTAPS, such as those enriched in T and B cells, would be expected to be used for an autoimmune disease like RA, the researchers were surprised to see that CTAPs were associated with structural cells such as fibroblasts and endothelial cells, with relatively few inflammatory leukocytes. They also found that patients’ CTAPs were dynamic and could change over time in response to treatment.

In the future, the researchers want to expand their knowledge of the cell types involved in RA by studying how interconnections between cells promote disease states. Furthermore, they hope that this work will advance the analysis of synovial tissues in RA patients, which is not currently standard practice. Although blood tests are more common in RA patients, findings from this study and others emphasize that the cellular profile of synovial tissue differs substantially from that of blood.

What this study shows is that tissue matters. Our findings point to the value of obtaining synovial tissue biopsies to evaluate the nature of the pathological process, which can be so different among patients. Future clinical trials will benefit greatly from assessing tissue characteristics in addition to responses to therapy. By providing this atlas of cell types and pathways involved in RA, we are better able to pursue our goal of precision medicine: being able to select the right drug for the right patient and achieve a high response rate.”

Michael Brenner, MD, co-senior author, Brigham’s Division of Rheumatology, Inflammation and Immunity

Source:

Brigham and Women’s Hospital

Magazine reference:

Zhang, F., et al. (2023). Deconstruction of the synovium of rheumatoid arthritis defines inflammatory subtypes. Nature. doi.org/10.1038/s41586-023-06708-y.

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November 9, 2023
Deconstruction of the synovium of rheumatoid arthritis defines inflammatory subtypes
- Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  
  Fan Zhang, Anna Helena Jonsson, Aparna Nathan, Nghia Millard, Michelle Curtis, Qian Xiao, Maria Gutierrez-Arcelus, Gerald FM Watts, Dana Weisenfeld, Kathryne E. Marks, Joyce B. Kang, Laurie Rumker, Joseph Mears, Kathryn Weinand, Ellen M. Gravallese, Adam Chicoine, Kazuyoshi Ishigaki, Gregory Keras, Ilya Korsunsky, Zhihan J. Li, Yuhong Li, Yakir Reshef, Saori Sakaue, Zhu Zhu, Katherine P. Liao, Kevin Wei, Deepak A. Rao, Michael B. Brenner and Soumya Raychaudhuri
- Center for Data Sciences, Brigham and Women’s Hospital, Boston, MA, USA
  
  Fan Zhang, Aparna Nathan, Nghia Millard, Michelle Curtis, Qian Xiao, Maria Gutierrez-Arcelus, Joyce B. Kang, Laurie Rumker, Joseph Mears, Kathryn Weinand, Kazuyoshi Ishigaki, Ilya Korsunsky, Yakir Reshef, Saori Sakaue & Soumya Raychaudhuri
- Division of Genetics, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  
  Fan Zhang, Aparna Nathan, Nghia Millard, Michelle Curtis, Qian Xiao, Maria Gutierrez-Arcelus, Joyce B. Kang, Laurie Rumker, Joseph Mears, Kathryn Weinand, Kazuyoshi Ishigaki, Ilya Korsunsky, Yakir Reshef, Saori Sakaue & Soumya Raychaudhuri
- Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
  
  Fan Zhang, Aparna Nathan, Nghia Millard, Michelle Curtis, Qian Xiao, Maria Gutierrez-Arcelus, Joyce B. Kang, Laurie Rumker, Joseph Mears, Kamil Slowikowski, Kathryn Weinand, Kazuyoshi Ishigaki, Ilya Korsunsky, Yakir Reshef, Saori Sakaue, Katherine P. Liao & Soumya Raychaudhuri
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
  
  Fan Zhang, Aparna Nathan, Nghia Millard, Michelle Curtis, Qian Xiao, Maria Gutierrez-Arcelus, Joyce B. Kang, Laurie Rumker, Joseph Mears, Kamil Slowikowski, Kathryn Weinand, Kazuyoshi Ishigaki, Ilya Korsunsky, Yakir Reshef, Saori Sakaue & Soumya Raychaudhuri
- Department of Rheumatology and the Center for Health Artificial Intelligence, University of Colorado School of Medicine, Aurora, CO, USA
  
  Fan Zhang
- Division of Immunology, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
  
  Maria Gutierrez-Arcelus
- Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network, Bethesda, MD, USA
  
  William Apruzzese
- Rheumatology Research Group, Institute of Inflammation and Aging, University of Birmingham, Birmingham, UK
  
  Saba Nayar, Mark Maybury, Ilfita Sahbudin, Hayley L. Carr, Karim Raza, Dagmar Scheel-Toellner & Andrew Filer
- Birmingham Tissue Analytics, Institute of Translational Medicine, University of Birmingham, Birmingham, UK
  
  Saba Nayar and Andrew Filer
- Division of Allergy, Immunology and Rheumatology, Department of Medicine, University of Rochester Medical Center, Rochester, NY, USA.
  
  Javier Rangel-Moreno, Nida Meednu, Darren Tabechian, Jennifer Albrecht, Jennifer L. Barnas, Debbie Campbell, Christopher Ritchlin & Jennifer H. Anolik
- Hospital for Special Surgery, New York, NY, USA
  
  Ian Mantel, Dana E. Orange, S. Louis Bridges Jr., Lionel B. Ivashkiv, Amit Lakhanpal, Anvita Singaraju, Melanie H. Smith, Susan M. Goodman, Vivian P. Bykerk & Laura T. Donlin
- Weill Cornell Medicine, New York, NY, USA
  
  Ian Mantel, S. Louis Bridges Jr., Lionel B. Ivashkiv, Amit Lakhanpal, Anvita Singaraju, Susan M. Goodman, Vivian P. Bykerk & Laura T. Donlin
- Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital (MGH), Boston, MA, USA.
  
  Kamil Slowikowski
- Laboratory of Molecular Neuro-Oncology, Rockefeller University, New York, NY, USA
  
  Dana E. Orange
- Department of Rheumatology, Columbia University College of Physicians and Surgeons, New York, NY, USA
  
  Laura Geraldino-Pardilla & Joan M. Bathon
- Department of Rheumatology, University of Colorado School of Medicine, Aurora, CO, USA
  
  Kevin D. Deane, Jennifer A. Seifert, Larry W. Moreland, and V. Michael Holers
- Department of Rheumatology, Allergy and Immunology, University of California, San Diego, La Jolla, CA, USA.
  
  Arnoldas Ceponis, Gary S. Firestein, and David L. Boyle
- NIHR Birmingham Biomedical Research Center and Clinical Research Facility, University of Birmingham, Queen Elizabeth Hospital, Birmingham, UK
  
  Mark Maybury, Ilfita Sahbudin, Hayley L. Carr, Karim Raza, Dagmar Scheel-Toellner & Andrew Filer
- Department of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  
  Ami Ben-Artzi, Lindsy Forbess and Michael H. Weisman
- Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  
  Arthur M. Mandelin II & Harris Perlman
- Center for Experimental Medicine and Rheumatology, EULAR Center of Excellence, William Harvey Research Institute, Queen Mary University of London, London, UK
  
  Alessandra Nerviani, Myles J. Lewis, Felice Rivellese & Costantino Pitzalis
- Barts Health NHS Trust, Barts Biomedical Research Center (BRC), National Institute for Health and Care Research (NIHR), London, UK
  
  Alessandra Nerviani, Myles J. Lewis, Felice Rivellese & Costantino Pitzalis
- Department of Biomedical Sciences, Humanitas University and Humanitas Research Hospital, Milan, Italy
  
  Constantine Pitzalis
- Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  
  Laura B. Hughes
- Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York, NY, USA
  
  Diane Horowitz and Peter K. Gregersen
- Department of Pathology and Laboratory Medicine, Hospital for Special Surgery, New York, NY, USA
  
  Edward DiCarlo
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
  
  Brendan F Boyce
- Department of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  
  Mandy J. McGeachy & Larry W. Moreland
- Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
  
  Andrew Cordle and Aaron Wyse
- Division of Allergy, Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  
  Patrick Dunn
- Northrop Grumman Health Solutions, Rockville, MD, USA
  
  Patrick Dunn
- Division of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
  
  Joel M. Guthridge and Judith A. James
- Laboratory of Human Immunogenetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
  
  Kazuyoshi Ishigaki
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  
  James A. Lederer
- Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
  
  Andrew McDavid
- Division of Immunology and Rheumatology, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
  
  William H. Robinson, Paul J. Utz, and Michael H. Weisman
LG-P., KDD, DT, AC, GSF, MM, IS, AB-A., AMM, A. Nerviani, FR, CP, LBH and DH recruited patients and obtained synovial tissues. LWM, SMG, HP, VMH, AF, VPB, and JHA contributed to sample acquisition and processing and design of the AMP study. ED, EMG and BFB performed histological assessment of tissues. DW, KPL, AF, and VPB compiled and analyzed histological and clinical data. WA provided project management and compiled histological and clinical data. K. Wei, AHJ, GFMW, A. Nathan, and MBB designed and implemented the tissue disaggregation, cell sorting, and single-cell sequencing pipeline. AHJ, K. Wei, and GFMW oversaw and executed the tissue disaggregation pipeline. S.N., J.R.-M. and N. Meednu. performed immunofluorescence microscopy and analyzed these data together with MC and AHJKEM and IM performed and analyzed functional cellular assays. MJL, FR, and CP contributed unpublished clinical trial data. FZ, A. Nathan, N. Millard, MC, QX, MG-A., JBK, K. Weinand, JM, LR, and SR performed computational and statistical analyses. AHJ, K. Wei, MBB, JHA, LTD, DAR, FZ, A. Nathan, SR, DEO, JR-M. and AF provided input on cellular analysis and interpretation. DEO, JR-M., AF and JHA provided input for histological analyses. N. Millard and KS implemented the website. SR, MBB, JHA, LTD, and DAR supervised the study. FZ, AHJ, A. Nathan, N. Millard, QX, and SR wrote the first draft. FZ, AHJ, A. Nathan, K. Wei, N. Millard, DAR, LTD, JHA, MBB, and SR edited the draft. Members of the AMP RA/SLE Network contributed to this work by managing patient recruitment, managing clinical data, obtaining and processing synovial tissue samples, managing biorepositories, performing histological or computational analyses, providing software code, providing website support and/or providing input for data analysis. and interpretation. All authors participated in editing the final manuscript.

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November 8, 2023
The use of TNF inhibitors during pregnancy is not associated with worse fetal or obstetric outcomes

According to new research at ACR Convergence 2023, the annual meeting of the American College of Rheumatology (ACR), use of tumor necrosis factor inhibitors during pregnancy is not associated with worse fetal or obstetric outcomes and may reduce the risk of serious maternal infections during pregnancy ( Abstract #0477).

Tumor necrosis factor (TNF) inhibitors such as adalimumab and infliximab are often prescribed for inflammatory forms of arthritis that have not improved with other treatments. Although research shows the drugs are safe during pregnancy, many women stop taking them for fear of harming the fetus. Unlike other medications used for inflammatory arthritis, such as methotrexate, which can cause serious fetal complications, TNF inhibitors are not known teratogens (an agent that causes abnormalities after fetal exposure during pregnancy).

To further test the safety of persistent TNF inhibitors during pregnancy, Anna Molto, MD, PhD, HDR, a rheumatologist and researcher at Cochin Hospital in Paris, France, and her colleagues used data from a nationwide French health insurance database to create a to emulate a randomized database. clinical trial (RCT). This type of research relies on observational data to conduct a study when a gold standard RCT may not be ethical or feasible.

The researchers identified more than 2,000 women treated with TNF inhibitors for rheumatoid arthritis (579 patients) or spondyloarthritis (1,503 patients) between 2008 and 2017. Each had a singleton pregnancy, with 1,497 (72%) stopping treatment when they learned they were pregnant. The average age of the women at the start of pregnancy was 31 years±5 years and the average duration of illness was 4 ±5 years.

The results showed no statistically significant difference in poor obstetric, fetal or infant outcomes, including spontaneous abortion (a loss of pregnancy naturally before twenty weeks of gestation), medical termination of pregnancy, preeclampsia or eclampsia, gestational diabetes, premature birth, small birth weight or serious birth defects.

Interestingly, women who continued to use TNF inhibitors were less likely to be hospitalized for serious infections during pregnancy during six weeks postpartum compared to those who stopped treatment (0.2 versus 1.3 percent, respectively). Molto says this finding was the most surprising.

“Although we had assumed that pregnancy outcomes would be at least comparable in both groups, we did not expect that there would be a lower risk of maternal infections in patients who continued TNFi, as the risk of infection is known to be higher with these treatments” , she says. She speculates that the finding may be due to lower concomitant use of corticosteroids, but does not yet have results to confirm her theory.

Regarding the overall study results, Molto says: “These data add to the increasingly reassuring data on the use of TNFi during pregnancy. And most importantly, if a rheumatologist is considering stopping a TNFi during pregnancy because of the risk of infection, this study suggests that this may not be justified.”

Molto acknowledges the limitations of relying on claims data, noting that disease activity cannot be measured, but also points out that the use of a national database ensures that “all French participants are included, [thereby avoiding] selection bias.”

The next step, Molto says, is to test the hypothesis in a randomized controlled trial.

This study was carried out thanks to the funding program of the French Ministry of Health.

Source:

American College of Rheumatology

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November 8, 2023