Hydroxychloroquine suppresses ‘trained immunity’

A new study published on the preprint server medRxiv* in June 2020 shows that the drug hydroxychloroquine (HCQ) suppresses a form of immunity called ‘trained immunity,’ with repercussions for its potential use to treat COVID-19.

HCQ is an anti-malarial and a disease-modifying anti-rheumatic drug (DMARD), which was observed to inhibit the replication of SARS-CoV-2 in vitro. However, its antiviral effect in humans in vitro has not been confirmed. It may have an immunomodulatory effect as well. However, the lack of evidence of its efficacy and how they act has roused controversy surrounding its use.

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HCQ Suppresses Trained Immunity

The current study aimed to understand how HCQ acts on the immune response in COVID-19. Using techniques that unravel the function of immune cells, as well as transcriptomic analyses, the researchers found marked changes in the expression of molecular markers and functionalities of monocytes in COVID-19 patients. They also found that interferon-stimulated genes (ISG) play a role in disease severity.

With metabolomic and epigenetic studies, the researchers found that HCQ suppresses trained immunity. Trained immunity refers to a change in the way that monocytes function in response to epigenetic changes that reprogram their antiviral responses. These findings suggest that HCQ may not be suitable for the therapy or prevention of COVID-19.

The Study of Monocytes and Associated Cytokines

The study included 13 patients hospitalized with SARS-CoV-2, all above 18 years of age. The median age was 68 years. They had various coexisting maladies such as pulmonary disease, cardiovascular disease, and malignancy.

Most patients were admitted to hospital with fever, cough, or breathlessness. Seven of the patients required oxygen at admission. All showed signs of pneumonitis on chest imaging, but none were critically ill. All patients were started on chloroquine (CQ) at admission, for five days.

Increase in Monocyte Count and Activation

On blood analysis, the T cell count was slightly lower than normal, and monocyte counts were markedly higher, mostly because of a rise in classical monocytes. Nonclassical monocytes were almost undetectable, and their markers, such as CX3CR1, were reduced.

HLA-DR expression on monocytes was reduced, which has been associated in recent studies with the hyperactivation of monocytes and the excessive release of the pro-inflammatory cytokine IL-6 in COVID-19. CD11b, a monocyte activation marker, is also upregulated. These markers remained constant over five days in those who were still hospitalized at the end of the study.

The researchers then examined the functional status of peripheral blood mononuclear cells (PBMCs) by stimulating them and then measuring the release of cytokines IL-1β, IL-6, and TNFα. They found that excessive cytokine release occurred in COVID-19 patients when lipopolysaccharides and other antigens were used to activate Toll-like receptor (TLR) 4 and other similar receptors.

Polarization of Adaptive Immunity

Next, they looked at whether adaptive immunity was also altered, by stimulating PBMCs for 7 days with Staphylococcal aureus antigens, and measuring Th1 and Th17 cell activation via IFNγ and IL-17 levels respectively. Healthy controls showed increases in the former alone, but in COVID-19 patients, the latter was raised. This indicates a shift towards Th17 cell activation rather than the normal Th1 dominance.  

Predictors of Outcome

When they compared the 9 patients who recovered without intensive care unit (ICU) admission with the 4 who required ICU care or died (3 and 1, respectively), they found no clear markers at presentation to predict favorable or poor outcomes. However, immune markers showed differences such as a reduced monocyte HLA-DR expression in those who went on to poor outcomes, indicating a more severe inflammatory phenotype in monocytes for these patients.

Transcriptome analysis of monocytes from COVID-19 patients showed a higher level of transcription of ISG, which plays a significant role in antiviral responses. Excessively high ISG expression was linked to poor outcomes.

Six and seven patients were discharged within five days and remained hospitalized, respectively. PBMCs from this group at 5 days from admission showed a clear demarcation between findings indicating a good vs. poor outcome.

Specifically, the inflammatory response is characterized by marked innate immune changes, in agreement with previous reports, in the form of increased monocyte activation, increased ISG expression, and elevated monocyte-derived cytokine release.

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The researchers comment, “This enhanced responsiveness is reminiscent of the inflammatory phenotype previously reported in sepsis and influenza. While inflammation early in the infection contributes to improved antiviral mechanisms and elimination of infection, if exacerbated late during the course of the disease it may play a role in the development of the severe complications of COVID-19.”

How HCQ Suppresses Trained Immunity

This led to an investigation into whether HCQ affects trained immunity. This molecule moves passively into the lysosomes and disrupts its function. Since the lysosomes are central to the regulation of immune metabolism with innate immunity via the mTOR receptor on its membrane, trained macrophages are characterized by the activation of key regulators of lysosome genes.

To understand how HCQ affects trained immunity, they repeatedly stimulated human PBMCs with bacterial antigens. They found that the cells produced much more cytokines with repeated stimulation, but this effect disappeared when the cells were treated with HCQ simultaneously.

On restimulation of monocytes with IFNγ, there was a rise in IL-6 and TNFα production, which also vanished with HCQ treatment. The researchers analyzed the change in terms of lysosomal function and found that the inhibition of vacuolar ATPase (V-ATPase) led to blocking the development of trained immunity, which is similar to the effect of HCQ treatment.

Next, the effects of hydroxychloroquine on the transcription of trained monocytes were analyzed. They found that this led to a substantial reduction in the expression of genes related to inflammatory responses, including ISG. This was accompanied by the increased expression of metabolic pathways involved in inflammation. Altogether, this implies the role of HCQ in suppressing the development of trained immunity and the expression of ISG.

HCQ also affects cellular lipid metabolism, as part of its suppressive effect on trained immunity. The stimulation of the monocytes by bacterial antigens, with and without HCQ exposure followed by lipidomic analysis, showed that the normal wide-ranging and deep changes in the monocyte lipids that accompanies trained immunity was suppressed by HCQ. This may affect the structure and function of the cellular membranes, disrupting the activity of membrane-bound genes, including the all-important mTOR on the lysosomal membrane, as well as inhibiting lipid-dependent activation enzymes required for the normal immune response.

HCQ also prevents the normal epigenetic modifications that are required for trained immunity, shutting down normal changes in epigenetic markers associated with immune and inflammatory responses.

Implications and Future Applications

The authors say this data provides crucial new information about how HCQ acts in COVID-19. Though HCQ has been used for decades as an immunomodulator to benefit rheumatoid arthritis and systemic lupus erythematosus because it inhibits pro-inflammatory cytokines like IL-6 and TNFα. It is known that this effect is partly mediated by its inhibition of lysosomal processes like autophagy, antigen processing, and TLR7 processing.

However, the current study adds to this knowledge via the findings that HCQ prevents the development of trained immunity via epigenetic regulation. This may be via its effect on mTOR signaling since this is a lysosome-associated enzyme transmitting information from the lysosome to the cell, and thus mediates inflammation. The data on the changes in lipids that play a key role in mTOR activation supports this reading.

Since trained immunity is required to upregulate the innate immune response and so prevent infection, HCQ is less likely to be of use in preventing or clearing SARS-CoV-2 infection. This agrees with the findings of a recent randomized controlled trial that HCQ given post-exposure does not help prevent symptomatic COVID-19.

The question remains whether the immunomodulatory effects of HCQ could mediate its effectiveness in severe COVID-19 by muting the cytokine storm. The researchers say this is likely to be less useful than IL-6 receptor antibodies or IL-1 receptor antagonists, and an observational study lends some support to this prediction. More research is required to test this hypothesis. They sum up: “Our findings suggest that hydroxychloroquine may not have a beneficial effect on the antiviral immune response in SARS-CoV-2 infection.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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Tocilizumab in Critical COVID-19 Patients

A new study by scientists at Metro Infectious Disease Consultants and published on the preprint server medRxiv* in June 2020 reports that the cytokine blocker tocilizumab is a useful adjunct to supportive medical care in severe COVID-19, with increased survival and a lower requirement for mechanical ventilation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged in China towards the end of the year 2019 but rapidly spread worldwide to become a pandemic. As many as 20% of patients progress to severe disease, and up to 10% may die of terminal respiratory failure secondary to acute respiratory distress syndrome (ARDS). This percentage varies with the population segment affected, with the highest risk being seen among older adults and those with other medical conditions such as type 2 diabetes, obesity, and hypertension.

Study: Tocilizumab as a Therapeutic Agent for Critically Ill Patients Infected with SARS-CoV-2. Image Credit: Wirestock Images / Shutterstock

Wide Range of Symptoms

The spectrum of illness with COVID-19 varies from asymptomatic or mild symptomatic infection in the majority of cases to progressive pulmonary impairment with a pneumonia-like picture, and finally to rapid multi-organ dysfunction with ARDS and cardiovascular collapse. During this stage, the levels of multiple inflammatory cytokines and markers are raised, including IL-2, IL-6, C-reactive protein (CRP), ferritin, D-dimer, and lactate dehydrogenase (LDH).

Tocilizumab – Possible Immunomodulator in COVID-19

There is no specific treatment or vaccine strategy as of now that is effective against SARS-CoV-2. However, the IL-6 blocker tocilizumab has been explored as a possible therapy for immunomodulation, to mute the so-called cytokine storm, the excessive and damaging rise in pro-inflammatory cytokines, in the final stage of severe COVID-19.

This drug is already approved for the treatment of rheumatoid arthritis and the cytokine release syndrome associated with the CAR-T cell treatment of cancer patients. This last condition is very similar to the pathogenesis of the cytokine storm in severe COVID-19 and justifies the experimental use of tocilizumab in the latter stage.

At present, tocilizumab is used at 4-8 mg/kg (max: 800mg per dose) intravenous infusion, repeated once if necessary. The current study was designed to find the actual benefit and the optimal regimen for this drug in COVID-19 patients with the most severe illness.

Study on Tocilizumab Timing and Benefits

The study was made up of 157 patients who were admitted to hospital between March 13, 2020, and April 16, 2020. A retrospective study was done using medical records from multiple practices to retrieve the age, sex, duration of hospital stay, need for mechanical ventilation, the use of steroids and other drugs, and remdesivir. The presence and type of comorbidity were also analyzed, including risk factors like age above 60 years, diabetes, chronic obstructive pulmonary disease, bronchospasm, chronic cardiac or renal disease, immunodeficiency, and cancer.

The dose of tocilizumab was registered as early or late, depending on whether it was given before or within a day after intubation, or later than this, respectively. If the patient was not intubated, the dose was related to the date of admission. The patient outcomes included discharge from hospital, death, or continued hospitalization.

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The average patient age was 58 years, and 65% were male. About 40% and 30% were White and Black, respectively, with 22% being Hispanic and a small percentage of Asians. 69% had other illnesses. All patients had raised inflammatory markers on admission.

Steroids were given to 60%, and 99% received hydroxychloroquine and azithromycin. About 85% of patients were given one dose of tocilizumab, and 15% had two doses 12 hours apart. The majority received 4 mg/kg, up to 400 mg in total, while nine patients received 600 or 800 mg.

56% of patients required mechanical ventilation, with 37 receiving tocilizumab early and 44 late.

Among discharged patients (48%), the hospital stay lasted about 15 days. In those who died (28%), it was 16 days and 29 days for those still in hospital at the end of the study period (24%). The highest mortality was among Blacks, at about 44%.

Early Tocilizumab Helps More Patients Recover Faster

Analysis of the use of ventilators in relation to the timing of tocilizumab from the date of admission, the use of steroids, and demographic factors, showed that with each day of delay from the day of admission, the chances of requiring mechanical ventilation went up by a fifth.

In patients who required mechanical ventilation, the timing of tocilizumab was related to the mortality, with a lower mortality rate among those who received the tocilizumab earlier, compared to later dosing (14% v 868%) after accounting for demographic differences. The rate of discharge was also significantly higher in the early-tocilizumab group, at 60%, compared to 18% in the late tocilizumab group of patients.

Among the 81 patients who were put on mechanical ventilation and then discharged, tocilizumab was given early, about 4.2 days from admission, and within a day of intubation. Those who died received the drug about 4 days from intubation and about 5.5 days from admission.

The time from intubation to dosing was the only predictor for discharge following intubation. Again, later tocilizumab administration increased the odds of death in mechanically ventilated patients by 18-fold compared to earlier administration. Among early-tocilizumab patients, non-whites were 6 times more likely to die than whites.

Among those on steroids, 44% were discharged, and 35% expired. There were 25 patients on steroids and mechanical ventilation who died, compared to 15 who were discharged.

Among those who had two doses of tocilizumab, half were intubated. Half were discharged, 23% died, and 32% were still in hospital at the time of analysis. When those who chose not to be put on ventilation via living wills, about 14% of whites and 32% of non-whites died, focusing attention on the continuing but little understood tendency for non-whites to have higher mortality.

Implications

Despite the observational nature of the study, some conclusions were arrived at. Severe drug reactions were rare. However, the use of multiple drugs made it almost impossible to disentangle the effects of any individual drug. This mandates further research with randomized studies.

The study sums up: “While the optimal time to dose tocilizumab has not been previously established, our data strongly support a mortality benefit of dosing tocilizumab early and within 1 day of intubation. Accordingly, we strongly encourage the use of this agent earlier in the COVID-19 treatment spectrum.”

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:

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Immuno-oncology may accelerate the development of treatments for COVID-19

Researchers at Roswell Park Comprehensive Cancer Center have been actively engaged in the effort to develop treatments or other control strategies that can help communities worldwide to address the impacts of the COVID-19 pandemic.

Because viruses such as SARS-CoV-2 and tumors both interact with the immune system, trying to evade both innate and adaptive immunity, expertise in immunotherapy of cancer is deeply relevant in fighting COVID-19.

“For decades, some of the most important and influential advances in treating cancer came from our understanding of infectious diseases and in particular from virology, the study of viruses,” notes Roswell Park’s Pawel Kalinski, MD, Ph.D., Vice-Chair for Translational Research and Rustum Family Professor for Molecular Therapeutics and Translational Research, lead developer of one of these new COVID-19 treatment strategies.

“Now, those of us working in immuno-oncology may have the opportunity to return the favor and to accelerate the development of treatments for COVID-19 and other infectious diseases.”

The opportunity to apply what we know about cancer as we seek a way to treat COVID-19 hinges on the tools that help our bodies to find and destroy cancer.

“The defense mechanisms that allow cancer cells to go undetected sometimes are similar to how viruses hide from the immune system. So applying what we know from virology can help us to identify and exploit weaknesses in SARS CoV-2, the virus that causes COVID-19,” says Igor Puzanov, MD, MSci, FACP, Professor of Medicine, Director of Early Phase Clinical Trials, Co-Leader of the Developmental Therapeutics Program and Chief of the Melanoma Section in the Department of Medicine.

Dr. Puzanov, who has been working closely with doctors from Catholic Health and the University at Buffalo (UB) as well as colleagues from Italy and China to make some of the most promising COVID-19 therapies available to patients in and around Western New York, catches us up on these various research efforts.

Sarilumab: New role for anti-inflammatory?

The first investigational treatment for COVID-19 to become available in the Buffalo area was the anti-inflammatory agent sarilumab (also known as Kevzara).

Doctors believe the drug, approved for use by the FDA for moderate to severe rheumatoid arthritis and also as a treatment for lupus, might also help fight inflammation in the lungs -; like that experienced by people suffering from COVID-19 infections.

Dr. Puzanov is the Principal Investigator of a local collaborative group of Roswell Park and UB researchers participating in a national phase 2/3 trial with sarilumab, enrolling close to 2,000 patients to determine how effective sarilumab may be as a treatment for patients with severe or critical COVID-19.

“This treatment builds on work conducted in China and Italy, where doctors used a similar drug, tocilizumab, with positive results,” says Dr. Puzanov, co-author of a recent editorial in the journal Translational Medicine on the potential for using tocilizumab and sarliumab as a treatment for COVID-19.

We need more data before we can draw firm conclusions, but we’re hopeful that anti-inflammatory drugs like these can help minimize the possibility of long-term lung damage and reduce the amount of time a person may need to be on a ventilator.”

Igor Puzanov, MD, MSci, FACP, Study Co-Author, Professor of Medicine, Director of Early Phase Clinical Trials

Repurposing cancer drugs in fight against COVID

One of the most innovative approaches being explored as a possible treatment for COVID-19 originated from Roswell Park.

Dr. Kalinski championed the idea of combining two drugs -; rintatolimod (also known as Ampligen) and interferon alfa-2b (also known as interferon A) -; as a combination approach for cancer immunotherapy.

He has several studies of this two-drug combination underway at Roswell Park in some solid-tumor cancers and, working closely with Brahm Segal, MD, got FDA authorization to assess this combination in patients with both cancer and COVID-19.

“This is an exciting idea. We know these two immune modulators can stimulate the immune system in patients with cancer, and now we want to take it a step forward and see if this combination can also stimulate the immune system of people with COVID,” says Dr. Puzanov.

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This study is also notable as one of the relatively few investigational approaches targeted toward patients with mild or moderate COVID-19.

“We are conducting our first study of this approach in patients who have both cancer and COVID-19 because they are at higher risk of severe illness,” he adds.

“The hope is that, given early, this combination could prevent the virus from taking hold and causing long-term damage, decreasing the severity of the infection and how long it takes people to recover.”

Remdesivir Approved for Emergency Use

Antiviral drugs first developed for use in treating other infectious diseases were some of the first therapies to be given to patients with COVID-19.

In early May 2020, the FDA authorized the use of the Ebola drug remdesivir as an emergency option for treating COVID-19 in adults and children hospitalized with severe disease. A small number of patients locally have been treated with this drug.

“Early tests have shown that patients treated with remdesivir spend one-third less time in the hospital for their illnesses. So this is a promising therapy we are eager to see more data on,” notes Dr. Puzanov.

Convalescent plasma: All about the antibodies

Roswell Park has also been a regional collection center supporting several hospitals offering patients with COVID-19 a treatment known as convalescent plasma -; plasma infusions from the blood of people who have been treated and cured of their COVID-19 infections, in the hopes that antibodies in their plasma might help others to fight the virus.

George Chen, MD, and Joanne Becker, MD, have been leading this work. They’re encouraging people who have successfully been treated for the virus to consider donating their plasma to help others.

“Convalescent plasma has actually been used for decades as a treatment for viral infections. It can be very important in helping us to manage a brand-new disease like COVID-19, and early evidence suggests that it is helping many patients to improve,” says Dr. Puzanov.

A search for biomarkers

Roswell Park teams are also hard at work analyzing how the SARS CoV-2 virus affects us in order to give clinical teams and vaccine developers a deeper knowledge of how best to manage and possibly prevent this disease. Kunle Odunsi, MD, Ph.D., FRCOG, FACOG, and Carl Morrison, MD, DVM, are leading an important effort to understand the body’s response to COVID-19 infections.

They’re applying their expertise in cancer immunotherapy and precision medicine to identify biomarkers that would allow us to identify early those patients who are more likely to progress to a severe case and to require more intensive treatment.

It’s a first-of-its-kind effort involving regional and industry partners: Catholic Health, UB, and Thermo Fisher Scientific.

“This is a very creative way to learn more about this virus and this disease using cutting-edge gene-sequencing technology, something that’s never been done before with any previous pandemic,” says Dr. Puzanov.

“And it could ultimately prove very important as a way to not only improve clinical outcomes for those with COVID-19 but also to make sure that we apply precious medical resources where they are most needed.”

Part of ongoing global effort

As the first wave of COVID-19 cases in our region begins to subside, Dr. Puzanov takes stock of the collaborative efforts that have made this diverse collection of research efforts possible.

“We’re proud to contribute our knowledge and our expertise in getting new therapies safely to patients through this global effort,” he says. “We are helping to advance the world’s understanding of this disease and how best to treat it, and we hope that this will translate to greater peace of mind for everyone.”

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Roswell Park Comprehensive Cancer Center

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Deployment of health care professionals can improve inflammatory-rheumatic disorders

Inflammatory-rheumatic disorders are a widespread ailment, affecting at least 1.5 million people in Germany alone. Because there is a shortage of rheumatologists, however, only half of the patients in this country are adequately treated.

The use of other health care professionals, as is the case in Denmark and the UK, could help to improve the situation. A study in Germany has shown for the first time that the care of patients with inflammatory-rheumatic diseases by ‘rheumatological assistants’ (RFA) is just as effective as treatment by specialist rheumatologists.

To reduce waiting times and prevent damage to health, the European League Against Rheumatism (EULAR) strongly recommends the use of RFAs in Germany, which will be announced at a press conference on 3 June 2020 held for its annual congress.

Around two percent of the adult population in Germany is affected by chronic inflammatory rheumatic diseases, such as rheumatoid arthritis (RA), axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA). “These patients have a considerable medical condition,” explains Dr. Kirsten Hoeper from the Clinic for Rheumatology and Immunology at the Hanover Medical School in Germany.

Missed opportunities for treating patients due to long waiting times

Severe pain, extreme fatigue, lack of strength, stiffness and physical deformity can have a significant impact on activities, education and career, partnership and family and can lead to occupational disability. Early diagnosis and therapy are essential to prevent as far as possible such serious consequences of damage to the joints.

But the existing medical resources do not suffice to provide early, patient-centred and guideline-based care. The waiting times are far too long,this is despite the fact that new drugs could almost completely force the disease back into so-called remission for the majority of patients – provided that treatment is administered in good time.”

Dr Kirsten Hoeper, Clinic for Rheumatology and Immunology, Hanover Medical School, European League Against Rheumatism

The deployment of RFAs could improve the situation, as is already well-established in some Northern European countries.

RFAs are members of related medical professions such as paramedic, nurse, student nurse or road traffic/motor traffic accidents, who have acquired additional theoretical and practical knowledge about the care of patients suffering from rheumatic and musculoskeletal diseases (RMDs). Such a delegation of medical care in rheumatology is recommended worldwide.

“The legal framework for this also exists in Germany,” says Hoeper. “In addition, the curriculum for the RFA degree exists since 2006, which is currently available to the German Medical Association for certification in an extended form.

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In order to examine whether and how RFAs can also be used in the German health care system, a prospective, randomised, controlled and multi-centre study was conducted, which was completed in December 2019.

“A total of 236 patients from eight German centres participated in the study, where a blood test had confirmed the diagnosis of rheumatoid arthritis,” explains the author of the study Hoeper.

Study involvement of RFAs produces the same treatment results

On average, the patients were 58 years of age, over 70 percent were female and suffered from rheumatic complaints for a period of 130 (ranging from 12 to 144) months on average.

While one study group was exclusively treated by rheumatologists during the twelve-month study period, the other study group RFAs temporarily took over the care at three fixed intervals with only brief contact to the physicians.

The patients’ condition was measured using the standard assessment form DAS28 (Disease Activity Score at 28 joints), which assesses the activity of the disease on an ascending scale from 2.0 to 10.0. Values between 3.2 and 5.1 are considered moderate.

Result of the study: The structured delegation of medical tasks to an RFA does not undermine the current standard of care. While the disease activity for the group co-treated by RFAs was on average DAS28 2.43, the value for the group with continuous rheumatologist consultation was on average DAS28 2.29.

“This difference is not clinically or statistically significant”, concludes EULAR President Professor Dr. Iain B. McInnes from Glasgow, Scotland, UK. “For the first time it can be shown for Germany that an RFA consultation is a safe way to complement the care of patients suffering from rheumatoid arthritis”, says Professor Dr. med. John Isaacs from Newcastle, Great Britain, EULAR Scientific Programme Committee Chair.

Better care in a cost-efficient way

“Integrating a team approach comprising rheumatologists with other health professionals into the treatment of patients with inflammatory rheumatic diseases presents great opportunities,” emphasises McInnes.

“RFAs can complement a physician’s workload, who in turn can use freed-up resources for more complex or new patients,” Hoeper adds. The long waiting times for an appointment with a rheumatologist could thus be cut shorter. Hoeper concludes, “by following the international EULAR Recommendations regarding RFAs, Germany will lead to better patient care in a cost-efficient way”.

Source:

European League Against Rheumatism

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Georgia State researcher receives $1.95 million NIH grant to study cause of autoimmunity

Reviewed by Emily Henderson, B.Sc.Jun 8 2020

Dr. Leszek Ignatowicz, a professor in the Institute for Biomedical Sciences at Georgia State University, has received a five-year, $1.95 million federal grant to study what causes autoimmunity in the human body.

Autoimmune diseases, which occur when the immune system mistakenly attacks the body’s own organs, tissues and cells, are the third most common group of diseases in the United States after cancer and heart disease. More than 100 types of autoimmune diseases have been identified, including Type 1 diabetes, rheumatoid arthritis, multiple sclerosis, lupus, psoriasis, thyroid diseases and inflammatory bowel disease.

Most autoimmune diseases have no cure, which results in debilitating symptoms, organ function loss and even death. Despite how common and increasingly prevalent autoimmune diseases have become, they largely remain a mystery.

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This grant from the National Institutes of Health’s National Institute of Allergy and Infectious Diseases will fund research to understand why the immune system attacks its own body, referred to as compromised tolerance, and how autoimmunity develops.

All vertebrates, including humans, have two levels of immunity. The first is the innate immune system, which is activated by molecules common in bacteria, parasites or viruses. The second layer of defense is the adaptive immune system, which depends on lymphocytes (B cells or T cells), one of the body’s main types of immune cells. Autoimmunity takes place when lymphocytes become activated by peptides derived from the body’s own proteins rather than those from pathogens, activating an immune response.

Most people don’t get autoimmune diseases because tolerance works properly in their body. With central tolerance, T cells that have a capacity to be pathogenic and autoreactive, or activated by self-antigens, are supposed to be eliminated and die in the thymus gland where they originally developed. This process is not 100 percent reliable, and an unknown percent of potentially autoreactive T cells escape and may cause autoimmunity. Then, a second line of security called peripheral tolerance identifies these remaining T cells that have the potential to be autoreactive and inhibits them.

The goal of this work is to better understand how the natural limitations of thymic selection predispose us to autoimmunity. This research will provide a better understanding of cellular and molecular mechanisms driving autoimmunity and help to develop therapeutic strategies targeting autoreactive T cells that escaped central tolerance. From a clinical perspective, identification of dormant, autoreactive T cells is critically important for saving a new category of autoimmune patients with peripheral tolerance deliberately broken by regulatory T cells that silence treatments to enhance immunity to infection or cancer.”

Dr. Leszek Ignatowicz, Professor, Institute for Biomedical Sciences, Georgia State University

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Georgia State University

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People suffering from rheumatoid arthritis with increased disease activity have high thrombosis risk

Reviewed by Emily Henderson, B.Sc.Jun 5 2020

People suffering from rheumatoid arthritis with increased disease activity are more often affected by thrombosis. A current Swedish study came to the result that among patients with high disease activity, one in one hundred will develop venous thromboembolism within one year, a more than twofold increase compared to patients in remission. Data of the German RABBIT1 register published by the European League against Rheumatism (EULAR) show that this increased risk of thrombosis can be reduced by treatment with biological disease-modifying antirheutmatic drugs (bDMARD). This is important information, especially at this time during the COVID-19 pandemic, since thrombosis and pulmonary embolism also play a major role in COVID-19 infection. Vigilance for thrombosis during the treatment of people with arthritis is particularly recommended. Moreover, maintaining therapies to keep disease activity under control is vital.

Thrombosis is a significant medical problem. In the case of venous thromboembolism (VTE), clotting occurs inside a blood vessel and can affect the blood flow. Quick diagnosis and treatment are important as untreated deep vein thrombosis (DVT) in the leg can lead to potentially life-threatening pulmonary embolism: Parts of the thrombus tear off and enter a pulmonary vessel through the blood stream. In up to 30 percent of cases, patients die within 30 days after diagnosis from deep vein thrombosis in the leg or pulmonary embolism.

Due to chronic inflammation in patients suffering from rheumatoid arthritis, the risk of dangerous deep vein and pulmonary thrombosis is two to three times as high. “In the case of autoimmune diseases such as rheumatoid arthritis (RA), the immune system turns against the body and causes inflammation in a number of places. Inflammation may have a disruptive effect on coagulation,” explains EULAR President Professor Dr. med. Iain B. McInnes from The University of Glasgow, UK. In people who are suffering from rheumatoid arthritis, the risk of thrombosis must always be taken into account.

The factors promoting thrombosis in patients suffering from rheumatoid arthritis and the medication that potentially reduces the risk have now been examined in two current studies.

One in one hundred patients with RA increased disease activity will suffer from thrombosis

A Swedish cohort study tried to find an answer to the question of whether the degree of disease activity has an impact on the thrombosis risk (1). The team around Viktor Molander, PhD student at the Karolinska Institutet in Stockholm analysed the data of 46,311 patients suffering from RA taken from the Swedish Rheumatology Quality Register (SRQ) over a period of 12 years. For the measurement of disease activity the “Disease Activity Score 28” (DAS28) was used. The DAS28 assesses the disease activity of rheumatoid arthritis based on the assessment of 28 defined joints.

The study indicates a close connection between the clinical disease activity of RA measured by DAS28 and the risk of VTE: Molander came to the result that “among patients with high disease activity, one in one hundred is going to develop VTE within the following year, a more than twofold increase compared to patients in remission.”

Having regular check-ups by a rheumatologist can be inconvenient. However, it is an important measure to monitor the development of the condition and whether treatment has to be adjusted accordingly.”

Dr. John Isaacs, EULAR Scientific Chair Professor, from The University of Newcastle, UK

Biologics can reduce the risk of thrombosis

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The risk of thrombosis is also influenced by the medication used in rheumatoid arthritis cases. Conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) such as Methotrexate, Sulfasalazine and Leflunomide are part of the basic treatment of RA. A next step are biologics (bDMARD), which also include tumor necrosis factor (TNF) inhibitors like Adalimumab, Certolizumab Pegol, Etanercept, Golimumab and Infliximab.

The question of whether the risk of thrombosis is reduced by application of bDMARDs such as TNF inhibitors in comparison to csDMARDs was addressed in a scientific study including the lead author Dr. rer. nat. Martin Schäfer from the program area of Epidemiology at the German Rheumatism Research Center, Berlin, Germany. For this purpose, the team has analyzed the data of more than 11,000 RA patients in the German RABBIT1 register, who were treated either with another csDMARD after at least one csDMARD failure, or whose treatment was switched to bDMARD.

The result: “By treatment with TNF inhibitors, the risk of major VTE events is reduced by almost half in comparison to csDMARDs,” explains Schäfer. According to the RABBIT data, an increase in inflammatory activity was also associated with a significant increase in the risk of VTE: The risk was approximately twice as high as a CRP value of at least 5mg/l. “For patients with an increased risk of thrombosis, alternative treatment with TNF inhibitors, and possibly other biologic drugs, should be considered instead of standard csDMARD treatment,” concludes PD Dr. med. Anja Strangfeld, study manager at RABBIT register in Berlin and co-author of the study. “Reducing the inflammatory activity is also an important factor to reduce the risk of VTE.”

Source:

European League Against Rheumatism (EULAR)

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WHO resumes hydroxychloroquine drug trial in COVID-19

The coronavirus disease (COVID-19) has rippled across the world with a devastating effect. As scientists raced to find an effective treatment for patients, existing malaria and rheumatoid arthritis drug hydroxychloroquine became one of the most popular candidates.

Then, on May 25, the World Health Organization (WHO) announced that it was temporarily suspending the human trial involving the drug hydroxychloroquine in COVID19. This came after a study published in the journal The Lancet reported that the drug heightened the risk of heart problems and death in patients with COVID-19 disease.

Image Credit: Creativeneko / Shutterstock

Image Credit: Creativeneko / Shutterstock

The Solidarity Trial controversy

The controversy heightened when the journal issued an erratum on the first published study, citing concerns about the reliability of the database.

The journal and the company, Sugisphere, has received a backlash from scientists across the globe. A letter was formulated by more than 200 scientists and health experts asking for a review of the said paper.

The health experts raised doubts about how Surgisphere, whose founder Sapan Desai was a co-author of the study, obtained data from hospitals across the globe. They also pointed out that the data on the paper were inconsistent with government figures.

The Lancet study claimed to have analyzed Surgisphere data collected from nearly 96,000 patients with COVID-19 who were admitted to 671 hospitals from their database of 1,200 hospitals across the globe. The patients received hydroxychloroquine alone or in combination with antibacterial drugs. The data showed that hydroxychloroquine had been tied to cardiac abnormalities, and even death, which prompted the WHO to suspend the trial.

An independent audit of the data’s validity has now been commissioned by the authors who are not part of the Surgisphere.

Resuming trials

Now, the WHO has retracted its decision and announced that the clinical trial would resume as it searches for potential coronavirus treatments.  

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The WHO said it will continue the Solidarity Trial, which aims to see the effect of hydroxychloroquine on COVID-19 patients.

The Data Safety and Monitoring Committee of the Solidarity Trial has been reviewing the data since it was halted.  Based on their findings and evaluation, the members of the committee recommended that there are no reasons to modify the trial data, and all trials should continue.

“The Data Safety and Monitoring Committee will continue to closely monitor the safety of all therapeutics being tested in the Solidarity Trial. So far, more than 3,500 patients have been recruited in 35 countries,” Dr. Tedros Adhanom Ghebreyesus, WHO’s director-general, said.

New data on hydroxychloroquine

A new study has shown that hydroxychloroquine is ineffective in preventing infection in people exposed to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Though the new trial found no serious side effects or heart problems linked to the use of the drug, it did not prevent the development of COVID-19 any better than a placebo.

The trial results, which were published in the New England Journal of Medicine, showed that 40 percent of the trial participants taking the drug developed non-serious side effects, including abdominal pain, diarrhea, and nausea. However, the trial found no severe side effects or any cardiac complications from taking hydroxychloroquine.

Among the participants, 12 percent of those given the drug developed COVID-19, compared to 14 percent in the vitamin placebo (folate) group.

Global figures

The race for finding an effective treatment for COVID-19 is on, as the numbers of infections skyrocket. The global death toll has reached more than 391,000, while there are 6.63 million confirmed cases. The United States still runs as the country with the highest number of infections, surpassing 1.87 million, with at least 108,000 deaths.

Brazil has seen a rapid increase of confirmed cases, now surpassing 614,000 people and at least 34,000 deaths. The South American nation is facing the ordeal of controlling the spread of the virus, as the health system has been overwhelmed.

The United Kingdom has also reported a high fatality rate, with more than 39,000 deaths and a total of 283,079 confirmed cases.

Of the total number of infections, more than 2.85 million people have recovered.

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New research focuses on protein-coding gene’s role in inflammatory bowel disease

Reviewed by Emily Henderson, B.Sc.Jun 4 2020

A protein-coding gene associated with autoimmune diseases such as Crohn’s disease and ulcerative colitis, collectively referred to as inflammatory bowel disease, or IBD, will be the focus of new research in the School of Medicine at the University of California, Riverside.

The work is made possible by a National Institutes of Health grant exceeding $2.5 million.

The gene, called protein tyrosine phosphatase non-receptor Type 2, or PTPN2, is expressed in all the body’s cells but has particularly important roles in immune cells and intestinal epithelial cells. It is also associated with Type 1 diabetes and rheumatoid arthritis.

The research, performed on mice, will aim to identify the mechanisms by which PTPN2 regulates immune interactions between macrophages — a type of white blood cell — and epithelial cells and how this regulation affects the barrier properties of the intestinal epithelium in health and disease.

A single layer of cells that plays a critical role in human health, the intestinal epithelium provides a barrier while also allowing nutrient and water absorption. Intestinal epithelial cells are critical for regulating immune function, communicating with the intestinal microbiota, and protecting the gut from pathogen infection — all of which critically depend on an intact epithelial barrier.

While some studies have partially identified the functions of PTPN2 in macrophages and epithelial cells, the role of PTPN2 in regulating how these cells talk to each other has not been studied. We hope to increase our understanding of the role PTPN2 ultimately plays in maintaining a protective gut barrier and regulating appropriate immune responses.”

Declan F. McCole, professor of biomedical sciences and the principal investigator of the five-year grant

Preliminary mouse studies in McCole’s lab strongly indicate PTPN2 plays a crucial role in health and disease by strengthening the gut barrier and preventing the immune system from launching an overly aggressive and damaging immune response.

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IBD affects about 3 million people in the United States. The disease, whose common symptoms include diarrhea, abdominal pain, and weight loss, is characterized by chronic inflammation of the gastrointestinal tract, leading to several serious complications. The cause of the disease remains unknown.

McCole will be joined in the project by grant co-investigator Meera G. Nair, an associate professor of biomedical sciences at UCR, whose lab will help characterize PTPN2 regulation of how macrophages change their properties and functions in the presence or absence of inflammation.

“We hope to identify the mechanisms governing how macrophages regulate functions to maintain gut barrier function and what goes wrong when PTPN2 is not present to regulate these interactions,” McCole said. “We expect this will generate fundamental new insights into how loss-of-function mutations — mutations that result in reduced protein functions — in the PTPN2 gene contribute to the onset of autoimmune diseases such as IBD.”

Postdoctoral researcher Marianne Spalinger, a member of McCole’s lab whose preliminary data helped secure the NIH funding, noted IBD cases are increasing in the United States and globally, including parts of the world that have traditionally not seen high numbers of cases.

“We will aim to identify novel targets for therapeutic intervention in IBD patients in this project,” she said.

Meli’sa Crawford, a postdoctoral researcher and new recruit to the McCole lab, will also take part in the research. The grant will also support the research of one graduate student and one junior specialist. Two undergraduates will receive lab experience working on the project.

Source:

University of California – Riverside

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Health care providers urged to stop hydroxycholoroquine use for COVID-19

The sacred oath taken by physicians during graduation from medical school to “First do no harm,” the first words of the Hippocratic Oath, provides a strong impetus for a commentary just published in The American Journal of Medicine.

Researchers from Florida Atlantic University’s Schmidt College of Medicine and collaborators from the University of Wisconsin School of Medicine and Public Health are urging all health care providers to always prioritize compassion with reliable evidence on efficacy and safety.

They recommend a moratorium on the prescription of chloroquine or hydroxychloroquine, with or without azithromycin, to treat or prevent COVID-19, with the exceptions of obtaining the necessary evidence in randomized trials as well as compassionate use.

Despite the fact, or perhaps due in part to the fact that there are no therapeutic or preventive measures for the COVID-19 pandemic in the United States, which accounts for less than 5 percent of the world’s population and about 30 percent of the cases and deaths, the widespread prescriptions of these drugs are nine times greater than in the last several years.

This widespread use is leading to nationwide shortages in patients with lupus and rheumatoid arthritis, for whom hydroxychloroquine has been an approved indication for decades. These patients are unable to refill their prescriptions.

On March 28, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization for chloroquine and hydroxychloroquine for the treatment of COVID-19. By April 24, however, the FDA issued a drug safety communication warning regarding hydroxychloroquine and heart rhythm disturbances that can lead to sudden cardiac death.

If these drugs need to be prescribed for patients with COVID-19, baseline evaluations and serial monitoring are an absolute necessity.”

Richard D. Shih, M.D, Study First Author and Professor of Emergency Medicine, Florida Atlantic University

Shih is also a division director and founding program director for the emergency medicine residency program in FAU’s Schmidt College of Medicine.

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Further, the authors point out that the reassuring safety profile of hydroxychloroquine may be more apparent than real.

The data on safety derive from decades of prescriptions by health care providers, primarily for their patients with lupus and rheumatoid arthritis, both of which are of greater prevalence in younger and middle age women, whose risks of fatal heart outcomes due to hydroxychloroquine are reassuringly very low.

In contrast, the risks of hydroxychloroquine for patients with COVID-19 are significantly higher because fatal cardiovascular complications due to these drugs are so much higher in older patients and those with existing heart disease or its risk factors, both of whom are predominantly men.

In basic research, hydroxychloroquine and chloroquine are structurally related and have similar mechanisms to inhibit the virus that causes COVID-19. Despite their structural similarities, in vitro, hydroxychloroquine appears to be more effective.

In addition, when used for lupus and rheumatoid arthritis, hydroxychloroquine has fewer side effects, less drug interactions and is less toxic in overdose.

The authors note that the currently available evidence is restricted to eight published studies, five on hydroxychloroquine alone; two on hydroxychloroquine plus azithromycin; and one on both in combination or alone.

Of these only three are randomized trials that enrolled 225, 62, and 30 patients – all too small to provide reliable evidence. All three tested hydroxychloroquine alone versus standard of care in China.

One showed no significant difference in viral clearance at 28 days, the second, no difference in viral clearance at seven days, and the third, some improvements in fever, cough and chest computed tomography findings.

“With respect to hypothesis testing, only large-scale randomized trials of sufficient size, dose and duration can reliably detect the most plausible small-to-moderate effects, which can have enormous clinical and public health impacts,” said Charles H. Hennekens, M.D., Dr.PH, senior author, the first Sir Richard Doll professor and senior academic advisor in FAU’s Schmidt College of Medicine.

Source:

Florida Atlantic University

Journal reference:

Shin, R D., et al. (2020) Hydroxychloroquine for Coronavirus: The Urgent Need for a Moratorium on Prescriptions. American Journal of Medicine. doi.org/10.1016/j.amjmed.2020.05.005.

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