In patients with new-onset rheumatoid arthritis (RA), what is the risk for ischemic and nonischemic heart failure (HF)?

Clinical Impact Ratings

In patients with new-onset rheumatoid arthritis (RA), what is the risk for ischemic and nonischemic heart failure (HF)?


Inception cohort followed for a median of approximately 5 years.




 12 943 patients ≥ 18 years of age (mean age 58 y, 69% women) with new-onset RA (< 12 mo of symptoms) were identified from the Swedish Rheumatology Quality Register. The control group comprised 113 884 people from the general population who were matched on birth year, sex, and area of residency. Exclusion criteria were heart failure before start of follow-up.

Prognostic factors

New-onset RA, sex, age, and area of residency.


First-ever diagnosis of HF during inpatient or specialized outpatient care, categorized as ischemic HF (previous history of ischemic heart disease or diagnostic code for ischemic HF) or nonischemic HF (data obtained by linkage with National Patient Registry).

Main results

 The main results are in the Table. 332 (2.6%) patients with new-onset RA developed HF during follow-up.


Adults in Sweden with new-onset rheumatoid arthritis had increased risk for ischemic and nonischemic heart failure over 5 years of follow-up.

Risk for heart failure in Swedish adults with new-onset rheumatoid arthritis (RA)*

Outcomes Subgroup Event rate/1000 person-y At a median 5 y
Rheumatoid arthritis Control† Hazard ratio (95% CI)‡
HF All 4.1 3.2 1.2 (1.1 to 1.4)
Ischemic HF All 1.9 1.4 1.3 (1.1 to 1.5)
Nonischemic HF All 2.5 2.0 1.2 (1.0 to 1.4)
HF RF positive 4.0 3.2 1.4 (1.2 to 1.6)§
Ischemic HF RF positive 1.9 1.4 1.5 (1.2 to 1.8)§
Nonischemic HF RF positive 2.4 2.0 1.3 (1.1 to 1.6)§
HF RF negative 4.2 3.2 1.0 (0.83 to 1.2)§
Ischemic HF RF negative 1.8 1.4 0.97 (0.73 to 1.3)§
Nonischemic HF RF negative 2.6 2.0 1.0 (0.79 to 1.3)§

*HF = heart failure; RF = rheumatoid factor; other abbreviations defined in Glossary.

†113 884 people from the general population were matched on birth year, sex, and area of residency.

‡Adjusted for sex, age, and area of residency.

§Compared with the entire control group.

Source of funding: No external funding.
For correspondence: Dr. A. Mantel, Karolinska Institutet, Stockholm, Sweden. E-mail


Cardiovascular disease is a major extraarticular comorbidity and a leading cause of premature mortality in RA (1). Traditional risk factors are prevalent and mediate ischemic events and HF, but nonischemic, RA-associated inflammatory mechanisms may have an independent role in the pathogenesis of HF (2).
Mantel and colleagues used an impressive large-scale contemporary cohort study to confirm an increased risk for both ischemic and nonischemic HF (hazard ratio 1.33 to 1.45, narrow CI) in RF-positive patients recently diagnosed with RA. This is a new observation, which suggests inflammation-induced myocardial damage, possibly mediated by cytokines, such as tumor necrosis factor-α (TNF) (2).
At RA onset, risk for HF was not increased, and notably, incident nonischemic HF peaked in the first year of RA (hazard ratio 2.06) in correlation with markers of disease severity. In contrast, ischemic HF risk took > 10 years to evolve. Although 2.6% of patients in the cohort had HF, incidence is probably higher in patients with more severe disease and when asymptomatic HF (detected by screening echocardiography or B-type natriuretic peptide) is included.
The findings of Mantel and colleagues highlight that HF prevention is an additional compelling reason to diagnose and treat RA as early as possible, monitoring markers to ensure optimal disease suppression. In addition, strict attention to identifying and aggressively treating traditional ischemic risk factors seems essential; this may include use of corticosteroids as adjunctive therapy while trying to avoid high cumulative doses that may worsen atherosclerosis (3).
Biologic treatments, primarily TNF inhibitors, should be avoided in patients with previous HF; however, together with methotrexate, they are effective for treatment of patients with more severe new-onset RA where TNF may contribute to the cause of HF (2). Future studies may confirm a reduction in HF with the use of TNF inhibitors, in addition to the reduced risk for cardiovascular events.

Rheumatoid arthritis: increased inflammation among smokers and toxic drug-induced liver failure

I wish to comment on the following topics, Rheumatoid Arthritis, inflammation and liver.  Rheumatoid Arthritis brings pain to sufferers and is exacerbated by smoking and over medication, taxing the liver. When pain happens, the liver is giving a signal that it can no longer detox the body.  The best route is to clean the body from inflammation starting with the liver. I always tell my mom and other seniors to eat whole foods that are anti-inflammatory, cleansing such as yellow , sulfur rich foods (e.g., garlic, onions, lemon grass, citrus, greens, turmeric, ginger and other veggies).


Toxic drug-induced liver failure during therapy of rheumatoid arthritis with tocilizumab subcutaneously: a case report
Friedrich Anger; Armin Wiegering; Johanna Wagner; Johan Lock ; Johannes Baur
Should Rheumatology be a core discipline of a chronic pain multi-disciplinary team?: Rheumatology and chronic pain
Matthew Palethorpe ; Natalie Latcham; Suresh Selvaraj; Marwan Bukhari
Intercentre variance in patient reported outcomes is lower than objective rheumatoid arthritis activity measures: a cross-sectional study
Nasim Ahmed Khan; Horace Jack Spencer; Elena Nikiphorou; Antonio Naranjo ; Rieki Alten
Comment on: Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans: reply
Jeremy Sokolove; Harlan Sayles; Ted Mikuls
Comment on: Increased inflammation and disease activity among current cigarette smokers with rheumatoid arthritis: a cross-sectional analysis of US veterans
William S. Wilke
Unsubscribe       Manage email alerts
Written requests to unsubscribe can be sent to: Journals Marketing, Oxford University Press, Great Clarendon Street, Oxford, OX2 6DP, UK.

Carnosine And Raw Veganism

Posted by Andrea Lewis

 Carnosine is an important nutrient that is gaining greater attention, due to dozens of research studies that have demonstrated its wide range of health benefits. There’s just one caveat: carnosine is only found as carnosine in fish, beef, poultry and pork. And yet, ironically, the animals that are considered the best sources of this nutrient do not themselves consume animals. So, where are they getting their carnosine from? The same place that vegans are getting theirs: whole foods.

Carnosine, which is concentrated in the brain and muscle tissues, is a dipeptide of the amino acids beta-alanine and histidine. And while carnosine, in its whole dipeptide form, is only found in meat, both of its constituents are found in a wide variety of plant foods. This is the most logical explanation for how animals like cows, turkeys, chickens and pigs come to have so much in their tissues, especially when one considers how carnosine in meat is broken down and used in the body.

Carnosine Digestion and Synthesis

Upon digestion, carnosine is broken down in the gastrointestinal tract into its constituents. Yes, some intact carnosine does escape the GI tract freely but that small amount is quickly broken down in the blood by the enzyme carnosinase. Carnosinase hydrolyzes carnosine and other dipeptides containing histidine into their constituent amino acids. In other words, after consuming meat, all of the carnosine that was ingested is converted to beta-alanine and histidine. Then, oddly enough, the amino acids are converted back to carnosine in the muscles and used or transported where needed. The entire process of carnosine synthesis is not entirely understood, but it’s worth noting that consuming carnosine from meat is unnecessary, as it will be converted into beta-alanine and histidine anyway, both of which are available in many raw whole foods.

Carnosine Benefits

Carnosine’s main claim to fame is its ability to inhibit AGE (Advanced Glycation End) products, which is valuable for treating and preventing a range of diseases. This benefit is largely responsible for carnosine’s other health benefits and uses:

  • Anti-oxidant
  • Heart health
  • Diabetes
  • Kidney health
  • Atherosclerosis
  • Eye health
  • Improved cognitive function
  • Autism Spectrum Disorder

Carnosine has been shown to reduce and protect against oxidative stress in the body, making it an excellent anti-oxidant. This anti-oxidant protection extends to pH buffering and electrolyte support, which is highly beneficial to heart health. The heart is a fast twitch muscle that demands a lot of energy, but it does not get the same amount of rest as the other fast twitch muscles in the body. The heart must always be active or, obviously, we die. As a result, the heart requires more carnosine to engage in faster, efficient muscle contractions. Heart tissue must also have the right electrolyte balance, pH buffers, and plenty of antioxidants to manage daily demands at an optimal level; carnosine helps to provide all of the above. Studies have shown that individuals with myocardial infarction, bundle branch blocks, angina, congestive heart failure (CHF), and other cardiomyopathies may benefit from increasing their intake of carnosine. One such study, ‘β-Alanine and orotate as supplements for cardiac protection’, published in the journal Open Heart, showed that carnosine, synthesized in the body from beta-alanine, is indeed more concentrated in fast twitch muscles, like the heart, and can help protect against cardiac issues, such as congestive heart failure.

Diabetics tend to have elevated levels of oxidative stress stemming from their condition. Diabetics also tend to have pronounced issues with atherosclerosis and kidney disease, because diabetes causes a stiffening of tissues as a result of excess AGEs in the body; that excess has been linked to a lack of carnosine. The same holds true for some optical issues. Carnosine helps protect the eye from oxidative damage of the lens and retina. One animal study, in particular, demonstrated that carnosine protected the retina from restriction in blood supply (oxygenation) when the eye tissue was under increased intraoccular pressure, which reduces the risk for glaucoma. Carnosine is also available in an eye drop solution for those at risk for glaucoma and cataracts. For more information on that topic, Google ‘carnosine eye drops’, there are a lot of blogs and research papers on the topic.

Carnosine has been studied extensively in the muscles and brain tissues, because that’s where it’s concentrated. In regards to brain and neurological health, carnosine has been shown to be of great help in preventing and reversing cognitive decline. And it’s affect on the brain and muscles appears more perceptible in the elderly. One study in particular, ‘Anserine and carnosine supplementation in the elderly: Effects on cognitive functioning and physical capacity’, published in the Archive of Gerontology and Geriatrics, Sept-Oct. 2014, showed that while cognitive function and physical capacity increased, BMI, blood pressure and heart rate improved during the 13-week study, in which fifty-one subjects were given Chicken meat extract containing CRC components (2:1 ration of anserine to carnosine). FYI, anserine is also a dipeptide that contains beta-alanine and histidine. A quote from the study, “After supplementation Body Mass Index (BMI) decreased significantly (p<0.05) in the CRC group performance comparing the placebo group. In two of six Senior Fitness Test the scores increased significantly (p<0.05) in CRC group comparing to the placebo group. The perceived exertion differed significantly (p<0.05) at the baseline and after follow up at the CRC group. The mean values of the Short Test of Mental Status (STMS) scores showed the significant (p<0.04) increase only in CRC group, in the subscores of construction/copying, abstraction and recall. Conducted anserine and carnosine supplementation in the elderly brings promising effects on cognitive functioning and physical capacity of participants. However, further studies are needed.”

Another study, entitled ‘Carnosine Treatment for Gulf War Illness: A Randomized Controlled Trial’, published in the Journal of Health Sciences, Vol. 5, No. 3, 2013, showed that carnosine was also able to treat cognitive and some physical issues in gulf war veterans. “About 25% of 1990-1991 Persian Gulf War veterans experience disabling fatigue, widespread pain, and cognitive dysfunction termed Gulf War illness (GWI) or Chronic Multisymptom Illness (CMI). A leading theory proposes that wartime exposures initiated prolonged production of reactive oxygen species (ROS) and central nervous system injury. The endogenous antioxidant L-carnosine (B-alanyl-L-histidine) is a potential treatment since it is a free radical scavenger in nervous tissue. To determine if nutritional supplementation with L-carnosine would significantly improve pain, cognition and fatigue in GWI, a randomized double blind placebo controlled 12 week dose escalation study involving 25 GWI subjects was employed.

“L-carnosine was given as 500, 1000, and 1500 mg increasing at 4 week intervals. Outcomes included subjective fatigue, pain and psychosocial questionnaires, and instantaneous fatigue and activity levels recorded by ActiWatch Score devices. Cognitive function was evaluated by WAIS-R digit symbol substitution test.

“Carnosine had 2 potentially beneficial effects: WAIS-R scores increased significantly, and there was a decrease in diarrhea associated with irritable bowel syndrome. No other significant incremental changes were found. Therefore, 12 weeks of carnosine (1500 mg) may have beneficial cognitive effects in GWI. Fatigue, pain, hyperalgesia, activity and other outcomes were resistant to treatment.”

Carnosine has the ability to cross the blood-brain barrier, the brain’s security system, which is essentially a network of blood vessels that only permit essential nutrients to enter while blocking other substances. This has been an obstacle to treating many neurological issues, including seizures and Autism Spectrum Disorder. In animal studies, carnosine has been shown to improve management of seizures, acting as an anticonvulsant. One study, published in Brain Research, November 6, 2008, examined the effect of carnosine on epilepsy in rats. The epileptic episodes were induced by penicillin. The scientists ascertained that “These findings indicate that carnosine has an anticonvulsant effect on penicillin-induced epilepsy in rats. Thus, our data support the hypothesis that carnosine may be a potential anticonvulsant drug for clinical therapy of epilepsy in the future.” Later studies supported their findings. An article published in Nutrition Review, April 19, 2013, reported that carnosine improved language skills and behavior in children with ASD (Autistic Spectrum Disorder). “Researchers treated 31 autistic children, ranging from 3 to 12 years in age, with either 400 mg of L-Carnosine, twice a day, or a placebo, for 8 weeks. At the end of the study the children treated with L-Carnosine showed significant improvements in behavior, socialization, and communication, as well as increases in language comprehension based on CARS (Childhood Autism Rating Scale), vocabulary tests (E/ROWPVT) and biweekly parent reports. In the conclusion to their report the researchers state, “Oral supplementation with L-Carnosine resulted in demonstrable improvements in autistic behaviors, as well as increases in language comprehension that reached statistical significance.” … the researchers report that L-Carnosine may improve receptive language, auditory processing, socialization, awareness of surroundings, and even help fine motor planning and expressive language when compared to placebo. Responses are usually seen between one to eight weeks after beginning treatment.” The study referenced in the article is titled ‘Double-blind, placebo-controlled study of L-carnosine supplementation in children with autistic spectrum disorders’, and was published in the Journal of Child Neurology, November 17, 2002.

What About Histidine?

All of the carnosine studies I found (including those mentioned and quoted above) used either beta-alanine supplements, l-carnosine supplements or carnosine extracted directly from poultry, but histidine is also required for synthesis of carnosine in the body. I assume, because the nutrient is so prevalent in such a wide variety of foods, that the researchers saw no need to use a histidine supplement as part of their carnosine research studies when using beta-alanine supplements. Histidine can be found in both animals and plants, as well as every tissue in the human body; even the myelin sheaths that coat nerve cells and ensure the transmission of messages from the brain to various parts of the body contain histidine. So, whether one is a vegan, vegetarian or carnivore, they are sure to get sufficient amounts of histidine in their diet.

Best Whole Food Sources of Beta-Alanine

  • Soy beans / soy nuts
  • Edamame
  • Asparagus
  • Turnip greens
  • White mushrooms
  • Watercress
  • Laver seaweed
  • Spirulina seaweed

Best Whole Food Sources of Histidine

  • Edamame
  • Green peas
  • Asparagus
  • soybean sprouts
  • Broccoli
  • Mustard Greens
  • Spinach
  • Sweet corn
  • Garlic
  • Cabbage
  • Eggplants
  • Celery
  • Onions
  • Carrots
  • Bamboo shoots
  • Cauliflower
  • Daikon (Japanese radish)
  • Pumpkin
  • Okra pods
  • Head lettuce / Butter lettuce
  • Lotus root
  • Chinese chives
  • Green sweet peppers
  • Chinese cabbage
  • Tomatoes
  • Cucumbers

Obviously, there are far more histidine-rich whole foods than beta-alanine-rich whole foods, and I didn’t even list half of the whole foods that contain histidine. Apparently, most foods contain histidine, including those used to feed livestock and, of course, the livestock themselves. And it’s worth noting that histidine, in addition to being half of the peptide bond that forms carnosine and its pivotal role in the formation of protein, has demonstrated a variety of therapeutic properties both anecdotally and in clinical studies; those properties include reducing the effects of stress and chronic conditions like rheumatoid arthritis, treating certain types of sexual dysfunction, fighting fatigue and preventing anemia. In any case, it’s good to know that one can indeed get all of the benefits of carnosine and its constituent elements as a raw vegan.

Rheumatoid Arthritis

This slideshow requires JavaScript.


Serotonin Deficiency Implicated in Rheumatoid Arthritis

Ra symptoms and pathology worse in mice missing enzyme needed for serotonin synthesis, according to report in the American Journal of Pathology.

For the first time, serotonin (5-hydroxytryptamine, 5-HT) has been directly implicated in the pathophysiology of rheumatoid arthritis (RA). Although 5-HT is predominantly known as a neurotransmitter within the central nervous system, new evidence points to additional important functions for serotonin in the periphery. A report in The American Journal of Pathology shows that experimentally-induced RA in serotonin-deficient mice is worse than disease reported in controls and that some effects of RA can be reduced by serotonin or its agonists (compounds that activate serotonin receptors).

These findings may lay the groundwork for new treatment approaches for RA. “Our study highlights that 5-HT has a direct immunoregulatory role in arthritis. The development of treatments targeting 5-HT or 5-HT receptors could represent an exciting prospect to regulate the immune response in RA and open new perspectives to improve the therapeutic options for patients,” explained co-lead investigator Marie-Christine de Vernejoul of BIOSCAR, INSERM UMR_S1132 of the Hôpital Lariboisière, Unité Mixte de Recherche (UMR) 1132, Université Paris Diderot (Paris, France).

The investigators used a mouse model of RA known as collagen-induced arthritis (CIA) that produces features similar to that of human RA. Disease manifestations include cartilage and bone destruction, as well as the activation of cells responsible for bone resorption, known as osteoclasts. They compared the effects of CIA in normal mice to those in mice genetically bred with a deficiency in tryptophan hydroxylase-1, a key enzyme needed for serotonin production in peripheral tissues.

The investigators found that both the number and activity of osteoclasts were higher in 5-HT-deficient mice with arthritis. In addition, more bone resorption was detected both at the affected joints and at remote sites.

The serotonin-deficient mice with arthritis also showed changes in certain cell-signaling molecules known as cytokines (higher IL-17, higher TNF-α, and lower IL-4) in their paws. Specifically, they displayed a shift in the balance between T cell subtypes, especially regulatory T cells and Th17 lymphocytes.

Image shows a ball-and-stick model of the serotonin molecule.

“Altogether, our data show that 5-HT deficient mice are characterized by a relative, dampened expansion of Treg associated with an enhanced shift toward a Th17 phenotype, a situation previously described in patients with arthritis,” noted co-lead investigator Francine Côté of the Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications Institut Imagine INSERM U1163/CNRS ERL 8254, Hôpital Necker (Paris, France).

Subsequent experiments using cell cultures showed that the balance between Th17/Treg cells could be normalized by the addition of 5-HT or 5-HT receptor agonists, revealing a direct regulatory role of serotonin in RA. These novel data suggest a new therapeutic target that could be important for this disabling disease.


Funding: The study was funded by Arthritis Courtin’s Fundation, la Fondation pour la Recherche Medical, le Centre National de la Recherche Scientifique, Paris Descartes.

Source: Eileen Leahy – Elsevier
Image Source: The image is credited to Ben Mills and is in the public domain.
Original Research: Abstract for “Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption” by Yasmine Chabbi-Achengli, Tereza Coman, Corinne Collet, Jacques Callebert, Michelangelo Corcelli, Hilène Lin, Rachel Rignault, Michel Dy, Marie-Christine de Vernejoul, and Francine Côté in American Journal of Pathology. Published online March 8 2016 doi:10.1016/j.ajpath.2015.11.018


Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption

Rheumatoid arthritis is a chronic disease that results in a disabling and painful condition as it progresses to destruction of the articular cartilage and ankylosis of the joints. Although the cause of the disease is still unknown, evidence argues that autoimmunity plays an important part. There are increasing but contradictory views regarding serotonin being associated with activation of immunoinflammatory pathways and the onset of autoimmune reactions. We studied serotonin’s involvement during collagen-induced arthritis in wild-type and Tph1−/− mice, which have markedly reduced peripheral serotonin levels. In wild-type mice, induction of arthritis triggered a robust increase in serotonin content in the paws combined with less inflammation. In Tph1−/− mice with arthritis, a marked increase in the clinical and pathologic arthritis scores was noticed. Specifically, in Tph1−/− mice with arthritis, a significant increase in osteoclast differentiation and bone resorption was observed with an increase in IL-17 levels in the paws and in Th17 lymphocytes in the draining lymph nodes, whereas T-regulatory cells were dampened. Ex vivo serotonin and agonists of the 5-HT2A and 5-HT2B receptors restored IL-17 secretion from splenocytes and Th17 cell differentiation in Tph1−/− mice. These findings indicate that serotonin plays a fundamental role in arthritis through the regulation of the Th17/T-regulatory cell balance and osteoclastogenesis.

“Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption” by Yasmine Chabbi-Achengli, Tereza Coman, Corinne Collet, Jacques Callebert, Michelangelo Corcelli, Hilène Lin, Rachel Rignault, Michel Dy, Marie-Christine de Vernejoul, and Francine Côté in American Journal of Pathology. Published online March 8 2016 doi:10.1016/j.ajpath.2015.11.018

Treatment gaps in rheumatoid arthritis

By Rita Baron-Faust, MPH

Even with health insurance, some patients with rheumatoid arthritis (RA) may not be adequately treated. This news comes from an analysis of a large nationwide pharmaceutical claims database.

Analysis of claims data from 4.66 million American adults treated for RA between January 2005 and September 2008, finds that only two-thirds of patients with newly diagnosed disease received DMARD therapy during the first year after their diagnosis.

And 28% received no DMARDs at all, just treatment for symptoms.

Those patients receiving only symptomatic relief tended to be older and had more co-morbidities and contraindications to methotrexate, according to the industry-sponsored retrospective cohort study.

At the same time, the authors observe, “this population was arguably underserved because 38% of this inception cohort did not see a rheumatologist in year one, and 15% never saw one over a median of 2.3 years of follow-up.”

Although one-fifth did receive biologics within 12 months, there was extensive medication switching among the group, and a relatively rapid decline over time in patients who stayed on the drugs.

The analysis reveals a somewhat lower incidence of RA than other population studies, but a similar age and gender adjusted prevalence of RA (0.63% overall, and 0.33% in men and 0.92% in women).

While the data lack supporting clinical information, such administrative databases can reflect actual treatment patterns in daily clinical practice. The same patterns of treatment of RA have been seen in other studies, they note.

The study was aimed at determining whether physicians were following current American College of Rheumatology RA treatment guidelines.

There could be a number of reasons for the apparent under-treatment of patients, the study authors speculate: lack of physician awareness of, or disagreement with, treatment guidelines; and determinations that patients were too old, their disease too mild, or there were contraindications for therapy.

Patients may have also wanted to avoid drug treatment due to adverse effects or costs, they add.

Within 12 months after their diagnosis, 65%, 64%, and 20% of the incident cohort (those without an apparent prior diagnosis of arthritis) had been prescribed corticosteroids, non-biologic DMARDs, and TNF-inhibitors, respectively.