SIN ameliorates RA-associated inflammation and immune response by regulating the Lactobacillus-Try-M-AhR axis, improving intestinal barrier dysfunction and restoring Th17/Treg balance ©Science China Press

Since the concept of “gut-joint” axis was proposed, increasing evidence has shown that the imbalance of gut microbiota may play a key role in the occurrence and development of rheumatoid arthritis (RA). Sinomenine (SIN) has been developed as a marketed anti-RA drug in China due to its noticeable anti-inflammatory and immunosuppressive effects. Mounting evidence proves the protective effect of SIN on RA is achieved mainly through the regulation of immunocytes, inflammatory cytokines, and inflammation-related signaling pathways. SIN was poorly absorbed into the systemic circulation, while it could modulate the gut microbiota composition to prevent chronic inflammation-associated diseases. Thus, the beneficial effects of SIN on RA might be due in part to the actions of gut microbiota. However, the key gut microbial species and critical microbial signaling metabolites associated with the anti-RA of SIN remain elusive.

Firstly, Zheng-Meng Jiang et al. demonstrated that SIN could significantly relieve the joint damage and inflammation of collagen-induced arthritis (CIA) in a gut microbiota-dependent manner.

Subsequently, 16S rRNA gene sequencing and metabolomics analysis indicated that SIN relieves microbial imbalance and intestinal barrier dysfunction by mainly modulating the abundance of Lactobacillus, and significantly enrich gut microbiota-derived tryptophan metabolites.

By further exploring the underlying mechanism of SIN-mediated gut microbiota regulation, the team found that tryptophan metabolites (indole-3-acrylic acid, indole-3-propionic acid, and indole-3-acetic acid) supplementation could improve RA-associated inflammation and Th17/Treg imbalance by activating aryl hydrocarbon receptor (AhR) to modulate NF-κB and MAPK phosphorylation.

Intriguingly, both in vitro screening and in vivo mono-colonization studies confirmed that SIN relieved the arthritis symptoms involving the enrichment of two beneficial anti-CIA Lactobacillus species, L. paracasei and L. casei.

Janus kinase inhibitors (JAKi) and biologics are the cornerstones of modern treatment for rheumatoid arthritis (RA). But there have been concerns over long-term side effects. New data from a national healthcare database offer reassuring findings for overall cancers and cardiovascular disease (CVD).

Patients with inflammatory rheumatic diseases have an increased risk of CVD compared to the general population.1 In acknowledgement of this, EULAR – the European Alliance of Associations for Rheumatology – has published recommendations for cardiovascular risk management in patients with a range of rheumatic and musculoskeletal diseases, including RA.2,3

At the 2023 EULAR annual congress, Ahn and colleagues present data on the risks of cancer and CVD in people with seropositive RA (SPRA) who had been treated with JAKi or biologics. Information was collected for over 100,000 people who had a case of new-onset SPRA logged between 2010–2020 in the national healthcare database of the Republic of South Korea.

The research then looked for events of overall and site-specific cancers and CVD outcomes, including deep vein thrombosis, pulmonary embolism, and composite cardiovascular events.

The results showed that – compared with people who received only conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) – the incidence rate ratio of overall cancers and CVD in those receiving JAKi or biologics were 0.88 and 0.91, respectively. JAKi did not confer a greater risk of overall CVD or cancer compared with other biologics or csDMARDs. This means overall cancer and CVD incidence were not increased in people with SPRA treated with JAKi/biologics, and were relatively lower than in csDMARD-only patients, underscoring the need for optimal control of disease activity in order to mitigate risks.

However, the authors note that site-specific lung, liver, prostate, and skin cancers were more frequent in people using JAKi/biologics – a finding which requires further investigation. “Overall, this work is reassuring with regards to overall cancers and CVD, but there is a need to keep collecting data in order to support risk management in clinical practice,” says lead author Sung Soo Ahn.

Immunoglobulin G antibodies (IgB) play an important role as drivers of inflammation in infectious diseases and autoimmune diseases. However, if the same immunoglobulin antibodies from the blood plasma of healthy donors are cleansed and injected into a patient’s bloodstream, they exhibit anti-inflammatory effects and have a positive effect on the immune system. The cause of this was unknown to a large extent up to now. An interdisciplinary team of researchers from Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) and the universities of Ulm and Würzburg led by Prof. Falk Nimmerjahn (Chair of Genetics at FAU) has now unlocked the mechanism that causes these intravenous immunoglobulin antibodies to resolve joint inflammation in rheumatoid arthritis. The researchers have published their findings in the journal Immunity.

The results indicate that antibodies from healthy donors, also known as intravenous immunglobulin antibodies, or IVIg for short, are able to suppress a central self-destructive process of rheumatoid arthritis – the degeneration and remodeling of bones and cartilage tissue in joints. “This bone degeneration caused by the inflammatory reaction leads to severe damage of the joints in patients of rheumatoid arthritis,” explains Prof. Nimmerjahn. “The results of the study now show for the first time how this process is suppressed on the molecular level by antibodies.” What surprised the interdisciplinary research team most of all was that molecules usually associated with fighting off pathogens such as bacteria and fungi play a central role for the anti-inflammatory effect of intravenous immunoglobulin antibodies. If these receptors were missing, the antibodies could no longer protect against inflammation and bone loss.  These findings are of great importance for the development of new therapies for autoimmune diseases and inflammation triggered by cytokines and autoantibodies.

The amount of environmental exposure to polycyclic aromatic hydrocarbons, or PAH for short, is strongly linked to a person’s risk of developing rheumatoid arthritis, suggests research .

These chemicals, formed from the burning of coal, oil, gas, wood, or tobacco and the flame grilling of meat and other foods, also seem to account for most of smoking’s impact on risk of the disease, the findings indicate.

Mounting evidence links several environmental toxicants with various long term conditions. But few studies have looked at their association with inflammatory conditions, such as rheumatoid arthritis, which is thought to arise from an interplay between genes, sex, and age, and environmental factors, including smoking, nutrition, and lifestyle.

To try and shed some light on the potential role of environmental exposure on rheumatoid arthritis risk, the researchers drew on responses to the nationally representative US National Health and Nutrition Examination Survey (NHANES) between 2007 and 2016.

NHANES evaluates a wide variety of toxicants, including PAH; chemicals used in the manufacture of plastics and various consumer products (PHTHTEs); and volatile organic compounds (VOCs), derived from paints, cleaning agents, and pesticides, among other things; along with data related to health, nutrition, behaviours and the environment.

The study included 21,987 adults, 1418 of whom had rheumatoid arthritis and 20,569 of whom didn’t. Blood and urine samples were taken to measure the total amount of PAH (7090 participants), PHTHTEs (7024), and VOCs (7129) in the body.

The odds of rheumatoid arthritis were highest among those in the top 25% of bodily PAH levels, irrespective of whether or not they were former or current smokers.

After accounting for potentially influential factors, including dietary fibre intake, physical activity, smoking, household income, educational attainment, age, sex, and weight (BMI), only one PAH—1-hydroxynaphthalene—was strongly associated with higher odds (80%) of the disease.

PHTHTE and VOC metabolites weren’t associated with heightened risk after accounting for potentially influential factors.

Somewhat surprisingly, however, smoking wasn’t associated with heightened rheumatoid arthritis risk either, after accounting for PAH levels in the body. 

And further analysis to separate out the influences of PAH and smoking showed that bodily PAH level accounted for 90% of the total effect of smoking on rheumatoid arthritis risk.

This is an observational study, and as such, can’t determine cause. And the researchers acknowledge various limitations to their findings, including that measurements of environmental toxicants in fat (adipose) tissue weren’t available.

Nor did they measure heavy metal levels which have previously been linked to rheumatoid arthritis risk. Cigarettes are a major source of the heavy metal cadmium.

But they write: “To our knowledge, this is the first study to demonstrate that PAH not only underlie the majority of the relationship between smoking and [rheumatoid arthritis], but also independently contribute to [it]. 

“This is important as PAH are ubiquitous in the environment, derived from various sources, and are mechanistically linked by the aryl hydrocarbon receptor to the underlying pathophysiology of [rheumatoid arthritis].”

They add: “While PAH levels tend to be higher in adults who smoke…other sources of PAH exposure include indoor environments, motor vehicle exhaust, natural gas, smoke from wood or coal burning fires, fumes from asphalt roads, and consuming grilled or charred foods.

“This is pertinent as households of lower socioeconomic status generally experience poorer indoor air quality and may reside in urban areas next to major roadways or in high traffic areas.” These people may therefore be particularly vulnerable, they suggest.