Sex Differences in Response to TNF-Inhibiting Drugs in Patients With Spondyloarthropathies or Inflammatory Bowel Diseases

Laganà, Bruno; Zullo, Angelo; Scribano, Maria Lia; Chimenti, Maria Sole; Migliore, Alberto; Diamanti, Andrea Picchianti; Lorenzetti, Roberto; Scolieri, Palma; Ortona, Elena; Pierdominici, Marina; Bruzzese, Vincenzo

doi:10.3389/fphar.2019.00047

Cited by 16 publications

(10 citation statements)

References 27 publications

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“…Furthermore, we found that innate cellular niches were unchanged during therapy, whereas adaptive immune cell niches were signi cantly rewired. Females in our study were enriched in these responsive adaptive immune CNs compared to males, providing a potential biological underpinning to previously observed and unaccounted for sex differences in response to TNFi inhibitors 37,38 .…”

Section: Discussionsupporting

confidence: 65%

A tissue atlas of ulcerative colitis to guide TNF inhibitor therapy

Mayer¹,

Holman²,

Tandon³

et al. 2021

Preprint

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Ulcerative colitis is a chronic-relapsing inflammatory disease of the large intestine with a complex, multifactorial pathogenesis. TNF inhibitors are widely used to suppress immune-mediated tissue damage in ulcerative colitis patients; however, therapy failures are common. Predicting TNF inhibitor response requires an understanding of the architectural features that underlie mucosal inflammation and those responsible for resistance. Here, we used highly multiplexed immunofluorescence to uncover the spatially resolved tissue architectures underlying disease progression and treatment response in 42 tissue regions from 34 individuals. We created a tissue atlas and performed spatial analysis to identify cell-cell contacts and cellular neighborhoods. We observed that cellular functional states depend on cellular neighborhood and that a subset of inflammatory cell types and cellular neighborhoods in ulcerative colitis patients persisted even during treatment with TNF inhibitor, indicating resistant niches. A computer vision model, with no a priori assumptions regarding cellular architectural features, was able to predict TNF inhibitor resistance. This spatial model significantly outperformed classification models based on single-cell data alone. Our results demonstrate the value of a spatial tissue atlas as a precision medicine tool to guide treatment of patients suffering from autoimmune diseases.

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Section: Discussionsupporting

confidence: 65%

A tissue atlas of ulcerative colitis to guide TNF inhibitor therapy

Mayer¹,

Holman²,

Tandon³

et al. 2021

Preprint

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ Regarding TNF-α, it was found that chronic inflammatory diseases may have different outcomes linked to the gender. Women present higher disease activity markers due to hormonal, genetic and environmental factors [32][33][34] .…”

Section: Discussionmentioning

confidence: 99%

Sodium pentobarbital dosages for exsanguination affect biochemical, molecular and histological measurements in rats

Mohamed

Hosney

Bassiony

et al. 2020

Sci Rep

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Rodents are widely used for animal research in Egypt. Pentobarbital is the most common anesthetic agent; however overdoses may affect the experimental outcomes and limit the use of tissues. To investigate the effects of sodium pentobarbital overdoses during exsanguination, three groups (6 rats/ group) of male and female rats were injected i.p. with 50, 100 and 150 mg/kg of sodium pentobarbital, then carotid exsanguination was performed immediately after loss of consciousness. Hypoxiainducible factor 1-alpha (Hif1a) and tumor necrosis factor-alpha (Tnfa) mRNA expressions in liver and kidney organs were evaluated. As well as, serum aminotransferase activities (AST&ALT), glucose, urea, creatinine, malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) levels were determined. The histological alterations in liver, kidney and spleen were studied. It was found that Hif1a and Tnfa were significantly overexpressed in the studied organs and serum AST, glucose, creatinine and urea levels were significantly increased after sodium pentobarbital overdoses (100 and 150 mg/kg) compared to 50 mg/kg dose. Similarly, significant increase in MDA and GSH levels of liver, kidney and spleen were noticed. Results showed gender difference where Hif1a and Tnfa levels were significantly overexpressed at high dose of sodium pentobarbital of liver and kidney organs in female more than male rats. Since euthanasia protocol may influence the physiological variables and affect genes' expression, it is recommended to avoid sodium pentobarbital overdose during euthanasia as it may interfere with the biochemical, molecular and histological measurements. In Egypt, rodents are considered the first choice for the majority of animal research and training. Euthanasia of animals is generally performed upon completion of the study or if a humane endpoint has been reached. Last updates of the Canadian Council on Animal Care (CCAC) and American Veterinary Medical Association (AVMA) euthanasia guidelines 1 describe several techniques for successful euthanasia to refine killing methods for rats and other laboratory animals 2. Euthanasia procedures are divided into two main methods; chemical and physical. Ideally, a mechanical method, such as exsanguination, should be implemented after the chemical death. Pentobarbital is an anesthetic agent commonly used in euthanasia. Olsen and Li (2011) reported that sodium pentobarbital is an injectable, fast-acting, central nervous system depressant which acts via GABA receptors to cause a loss of consciousness and cardiovascular depression 3. In the AVMA Guidelines, anesthetic overdose is recommended as an acceptable method of euthanasia. For rodents, overdose of sodium pentobarbital is the most preferable euthanizing agent 4-6. The main reported negative side effects of pentobarbital mono-anesthesia are cardiovascular and respiratory systems depression, decreased arterial blood pressure, peripheral vasodilation, decreased cardiac output and depression of the vasopressor response to hemorrhage 7. Moreover, ...

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“…Together, both sex and gender contribute to differential efficacy of immunotherapies prevalent among females than males (3:1 ratio), with females often having more severe disease with onset at a younger age than males [10]. The first-line therapies, which include steroidal and nonsteroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs, help manage inflammation, pain, and swelling, but biologics, including tumor necrosis factor (TNF) inhibitors (e.g., etanercept, infliximab, and adalimumab), can result in remission, not only of RA but of other inflammatory diseases, including psoriatic arthritis and inflammatory bowel diseases [11]. While diverse biologics are available for the treatment of RA (e.g., anti-CD20 antibody, rituximab or Janus kinase inhibitor, tofacitinib) and psoriatic arthritis, TNF inhibitors have been most widely used, have been on the market for a long time, and are the only body of data pertaining to male-female disparities in treatment outcomes.…”

Section: Male-female Disparities In Immunotherapiesmentioning

confidence: 99%

The impact of sex and gender on immunotherapy outcomes

2020

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Immunotherapies are often used for the treatment, remission, and possible cure of autoimmune diseases, infectious diseases, and cancers. Empirical evidence illustrates that females and males differ in outcomes following the use of biologics for the treatment of autoimmune diseases, e.g., rheumatoid arthritis (RA), infectious diseases, e.g., influenza, and solid tumor cancers. Females tend to experience more adverse reactions than males following the use of a class of biologics referred to as immunotherapies. For immunotherapies aimed at stimulating an immune response, e.g., influenza vaccines, females develop greater responses and may experience greater efficacy than males. In contrast, for immunotherapies that repress an immune response, e.g., tumor necrosis factor (TNF) inhibitors for RA or checkpoint inhibitors for melanoma, the efficacy is reportedly greater for males than females. Despite these differences, discrepancies in reporting differences between females and males exist, with females have been historically excluded from biomedical and clinical studies. There is a critical need for research that addresses the biological (i.e., sex) as well as sociocultural (i.e., gender) causes of male-female disparities in immunotherapy responses, toxicities, and outcomes. One-size-fits-all approaches to immunotherapies will not work, and sex/gender may contribute to variable treatment success, including adherence, in clinical settings.

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Sex Differences in Response to TNF-Inhibiting Drugs in Patients With Spondyloarthropathies or Inflammatory Bowel Diseases

Cited by 16 publications

References 27 publications

A tissue atlas of ulcerative colitis to guide TNF inhibitor therapy

A tissue atlas of ulcerative colitis to guide TNF inhibitor therapy

Sodium pentobarbital dosages for exsanguination affect biochemical, molecular and histological measurements in rats

The impact of sex and gender on immunotherapy outcomes

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