rheumatoid arthritis

Posted on Arthritis

Surprise rheumatoid arthritis discovery points to new treatment

 

Researchers Kodi S. Ravichandran (left) and Sanja Arandjelovic of the UVA School of Medicine have identified an unexpected contributor to rheumatoid arthritis that may lead to a new treatment for the painful condition. Dan Addison | University Communications

Researchers at the University of Virginia School of Medicine have identified an unexpected contributor to rheumatoid arthritis that may help explain the painful flare-ups associated with the disease. The discovery points to a potential new treatment for the autoimmune disorder and may also allow the use of a simple blood test to detect people at elevated risk for developing the condition.

The promising discovery is among the first to emerge from the School of Medicine’s new affiliation with Inova Health, a collaboration that aims to make medical breakthroughs and advance the battle against disease. In this case, the arthritis discovery originated in the lab of UVA’s Kodi Ravichandran, PhD, and was facilitated by combining his team’s resources and expertise with that of Inova researcher Thomas Conrads, PhD, through a THRIV UVA-Inova seed grant.

Understanding Rheumatoid Arthritis

The new findings about rheumatoid arthritis came in an unexpected fashion. Sanja Arandjelovic, PhD, a research scientist in the Ravichandran group, was seeking to better understand what causes the inflammation associated with inflammatory arthritis when she noted that deleting a gene called ELMO1 alleviated arthritis symptoms in mice. This was particularly surprising because Arandjelovic and Ravichandran initially thought that loss of ELMO1 would result in increased inflammation.

“This was a complete surprise to us initially,” recalled Ravichandran, chairman of UVA’s Department of Microbiology, Immunology and Cancer Biology. “I love those kinds of results, because they tell us that, first, we did not fully comprehend the scientific problem when we began exploring it, and, second, such unexpected results challenge us to think in a different way. Given that rheumatoid arthritis affects millions of people worldwide, we felt the need to understand this observation better.”

Digging deeper into the unusual outcome, the researchers determined that ELMO1 promotes inflammation via their function in white blood cells called neutrophils. Ravichandran described neutrophils as the body’s “first line of defense” because they sense and respond to potential threats. “Normally they are good for us, against many bacterial infections,” he said. “But also there are many times when they produce a lot of friendly fire that is quite damaging to the tissues – when they hang around too long or there are too many neutrophils coming in – in this case, infiltrating into the joints during arthritis.”

The researchers also discovered that there is a natural variation in the ELMO1 gene that can prompt neutrophils to become more mobile and have the potential to invade the joints in greater numbers and induce inflammation. (The potential blood test would detect this variation.)

Here things take a particularly cool turn: Normally, doctors are reluctant to try to block the effect of genes like ELMO1 in people, because such genes can play diverse roles in the body. But Ravichandran believes that ELMO1 is different. “ELMO1 partners with very specific set of proteins only in the neutrophils but not in other cells types we tested,” he said. “So, presumably, you may be able to affect only a select cell type.” This latter result came about from a collaborative study where Conrads’ group at Inova performed sophisticated analysis of ELMO1 proteomic partners in neutrophils, many of which also have previously known links to human arthritis. This provided further validation for the role of ELMO1 in rheumatoid arthritis.

Encouragingly, blocking ELMO1 in lab mice alleviated arthritis inflammation without causing other problems, Ravichandran noted. His laboratory is now seeking to identify drugs that could inhibit the function of ELMO1 and is also designing a test for the variation (also called polymorphism) in the ELMO1 gene.

“This is another example of how fundamental basic research can lead to novel discoveries on clinically relevant problems that affect a large number of people,” Ravichandran said.

 

Posted on Rheumatoid arthritis

Prospect of a new treatment for rheumatoid arthritis

Rheumatoid arthritis (RA) affects 1.3 million Americans

Rheumatoid arthritis (RA) affects 1.3 million Americans

An international research group led by Charité – Universitätsmedizin Berlin has completed testing a new drug to treat rheumatoid arthritis. The drug is effective in patients with moderate to severe forms of the disease who have shown an inadequate response to conventional disease modifying drugs. Results from this research have been published in The Lancet*.

Rheumatoid arthritis is a painful inflammatory condition affecting the joints and tendons, which is typically characterized by periods of increased disease activity. Prof. Dr. Gerd-Rüdiger Burmester, Head of Charité’s Medical Department, Division of Rheumatology and Clinical Immunology, conducted a study to assess the efficacy of upadacitinib in patients with an inadequate response to ‘conventional synthetic disease-modifying antirheumatic drugs’. Upadacitinib is a selective inhibitor of the enzyme Janus kinase 1 (JAK1) and has been shown to be efficacious in this patient group in earlier phase II clinical trials. By inhibiting JAK1, upadacitinib disrupts an important signaling pathway that is responsible for triggering inflammatory responses.

In the phase III study presented, patients treated with upadacitinib showed significant improvements in joint swelling when compared to patients receiving placebo. Patients also experienced less pain and showed improvements in joint function. Prof. Burmester is very pleased to see this new tablet-based treatment produce such significant improvements in clinical symptoms. “Our results prove that JAK inhibitors represent an effective treatment alternative in patients with long-term conditions who do not respond adequately to conventional drugs, and in those for whom biologics are not a good treatment option. JAK inhibitors could help these patients achieve a quick response to treatment, allowing them to gain control over their illness. The trial sponsor AbbVie is currently in the process of collating all trial results and submitting them to the European and US regulatory authorities for review.”

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Posted on Multiple Sclerosis

Researchers study the mechanisms that prevent autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis after an infection




 

Andre Ballesteros-Tato. UAB




The key weapon against viruses and bacteria that invade the body is production of antibodies, which act like guided missiles to attack and neutralize pathogens.

But as the body throws its effort into making ever-better antibodies during an infection, the random mutations that create those ever-stronger antibodies may also produce antibody-producing B cells that attack one’s own body, mistakenly triggering autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus or multiple sclerosis.

André Ballesteros-Tato, Ph.D., assistant professor, University of Alabama at Birmingham Department of Medicine, likens those mistaken autoimmune attacks to the collateral damage that can happen in a wartime battle.




In research published in Nature Immunology, Ballesteros-Tato and colleagues used mice to study regulatory mechanisms in the immune system that prevent autoimmune disease. Using an influenza infection model in mice, they have found that a particular population of immune cells developed during the later stages of the immune response to the influenza infection. These cells, called T follicular regulatory cells, or TFR cells, subsequently prevented the generation of self-reactive antibody responses. At the same time, they did not affect the influenza-specific immune reaction.

“This research gives us clues of what to look for when we look at how autoimmune disease develops,” Ballesteros-Tato said.

Study details

TFR cells are poorly understood compared with the more common T regulatory, or Treg, cells, which act to shut down or suppress immunity at the end of an immune reaction. The UAB team found that the two types behaved differently during influenza infections of mice.

As is well-known, the signaling molecule interleukin 2, or IL-2, has elevated levels as the immune response begins, and IL-2 stimulates the development of the conventional Treg cells. In the mice, these cells reached their peak one week after infection. In contrast, the UAB researchers found that IL-2 signaling inhibited, rather than promoted, the development of TFR cells during the peak of the immune response in mice. This inhibition used a mechanism that depended on the Blimp1 transcriptional repressor. Blimp1 prevented expression of the Bcl-6 master transcription factor, precluding TFR cell development.

When the influenza virus was eliminated and IL-2 levels were falling, some Treg cells downregulated the expression of CD25, which is part of the IL-2 receptor on the surface of Treg cells. Those cells upregulated the Bcl-6 master transcription factor and differentiated into TFR cells, reaching their peak numbers 30 days after infection. The TFR cells migrated to follicles of the lymph nodes, where antibody-producing B cells are known to proliferate and mutate their antibody genes to create ever-stronger antibodies.

In the follicles, the TFR cells prevented the accumulation of B cell variants that had mistakenly mutated to make antibodies that could attack the body’s own cells. The TFR cells did not reduce the immune response against the influenza virus. Experimental methods that removed the TFR cells or prevented their development allowed expansion of B cells that made anti-self antibodies, as measured by anti-nuclear antibodies.

“In summary,” Ballesteros-Tato and colleagues wrote in the paper, “our data demonstrate that IL-2 signaling temporarily inhibits TFR cell responses during influenza infection. However, once the immune response is resolved, TFR cells differentiate and migrate to B cell follicles, where they are required for maintaining B cell tolerance after infection. Thus, the same mechanism that promotes conventional Treg cell responses, namely IL-2 signaling, also prevents TFR cell formation.

 

Posted on autoimmune conditions

Purdue developing new treatment options for millions with autoimmune diseases

Autoimmune disease awareness

Autoimmune disease awareness




Living with an autoimmune disease can feel like an insider is attacking your body. An estimated 24 million people in the United States are affected by autoimmune diseases, a group of diseases in which the person’s immune system attacks part of the person’s own body.

Now, Purdue University researchers have developed a series of molecules that may provide more reliable relief with fewer side effects for people with any of several autoimmune diseases. The new molecules overcome difficulties with current drugs in targeting, for purposes of inhibiting, the appropriate form of Janus kinase, which has four forms affecting cell signaling and gene expression.




The new inhibitors may provide relief for people suffering from rheumatoid arthritis, psoriasis, myelofibrosis and other autoimmune diseases with a reduction in side effects compared with current therapies. The research appears in the November edition of the Journal of Medicinal Chemistry.

“Our new molecules fit within the emerging field of therapeutically useful Janus kinase inhibitors that have attracted a lot of attention and excitement within the medicinal chemistry community and the general field of medicine,” said Mark Cushman, a distinguished professor of medicinal chemistry in Purdue’s College of Pharmacy, who leads the research team. “Our compounds contribute a new structural chemotype that is expected to have unique pharmacological properties relative to the other known Janus kinase inhibitors.”

Cushman, a member of the Purdue University Center for Cancer Research, said the new molecules also show potential to allow for more treatment options for people with autoimmune diseases. Abnormalities of the immune system often lead to autoimmune diseases or cancer.




The work aligns with Purdue’s Giant Leaps celebration, celebrating the university’s global advancements in health as part of Purdue’s 150th anniversary. This is one of the four themes of the yearlong celebration’s Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world issues.

Researchers filed a patent with the Purdue Office of Technology Commercialization and the technology is available for licensing.

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Posted on Arthritis

Study lists foods for fighting rheumatoid arthritis symptoms and progression






 






This is a list of foods and their possible effects on rheumatoid arthritis symptoms and progression
Khanna, S., Jaiswal, K.S., and Gupta, B. Front. Nutr. | doi: 10.3389/fnut.2017.00052

Blueberries, canary seed, ginger, olive oil and green tea are just some of the foods recommended for managing rheumatoid arthritis.

 

A list of food items with proven beneficial effects on the progression and symptoms of rheumatoid arthritis is provided in a new study published today in Frontiers in Nutrition. The authors suggest incorporating these foods into the diet to support the management of this debilitating autoimmune disease.

“Regular consumption of specific dietary fibers, vegetables, fruits and spices, as well as the elimination of components that cause inflammation and damage, can help patients to manage the effects of rheumatoid arthritis,” says Dr. Bhawna Gupta, who completed this study together with Ms. Shweta Khanna and Mr. Kumar Sagar Jaiswal at the Disease Biology Lab, School of Biotechnology, KIIT University, India. “Incorporating probiotics into the diet can also reduce the progression and symptoms of this disease.”




She continues, “Patients suffering from rheumatoid arthritis should switch from omnivorous diets, drinking alcohol and smoking to Mediterranean, vegan, elemental or elimination diets, as advised by their doctor or dietician.”

Rheumatoid arthritis causes pain, swelling and stiffness in the joints, severely impacting quality of life. It is difficult to detect the early onset of the disease and if undetected or misdiagnosed has a rapid rate of progression in the first few years. The first line of treatment includes disease-modifying anti-rheumatic drugs, but these can be expensive.

“Supporting disease management through food and diet does not pose any harmful side effects and is relatively cheap and easy,” Dr. Gupta explains. “Doctors, physicians and dieticians can use our study to summarize current proven knowledge on the links between certain foods and rheumatoid arthritis. Knowing the nutritional and medicinal requirements of their patients they can then tailor this information for the betterment of their health.”

Various dietary plans for rheumatoid arthritis, such as vegan, 7-10 days fasting and Mediterranean, have long been recommended. This study — only the second overall assessment of diet and food on this disease — provides a very thorough evaluation of current scientific knowledge and makes a point of only reporting dietary interventions and specific foods that clearly show proven long-term effects.

Foods highlighted as reducing the progression and symptoms of rheumatoid arthritis range from fruits such as dried plums, blueberries and pomegranates, to whole grains, the spices ginger and turmeric, as well as specific oils and teas. They can provide a range of beneficial effects, such as lowering inflammatory cytokines (chemicals released by the immune system that can cause problems in rheumatoid arthritis patients), reducing joint stiffness and pain, as well as lowering oxidative stress — the ability of the body to counteract or detoxify harmful chemicals.

The authors hope the study can also be used as a reference for the development of new medicines.

“Our review focused on specific dietary components and phytochemicals from foods that have a proven beneficial effect on rheumatoid arthritis,” says Dr. Gupta. “Pharmaceutical companies may use this information to formulate ‘nutraceuticals’. Nutraceuticals have an advantage over chemically-tailored medicines as they are not associated with any side effects, originate from natural sources and are cheaper.”

Dr. Gupta concludes by offering some advice for those hoping to use the findings of their study.

“We reviewed research from several laboratory experiments under different conditions. Dietary components vary according to geography and weather conditions, so patients should be aware of their nutritional requirements, allergies and any other food-related disease history. We strongly suggest the general public consult doctors and dieticians before following any diet program or food compounds discussed in the study.”