Expert view: Is NAFLD a ticking time bomb?

25th April 2019

• Non-Alcoholic Fatty Liver (NAFL) which is a broad, mostly benign liver disease
• Non-Alcoholic Steato-Hepatitis (NASH) an inflammatory and progressive condition.

• De Novo Lipognese, fat deposition and metabolic syndrome directly (aramchol) or via the PPAR α β δ (pioglitazone, elafibranor) and FXRE receptors (obeticholic acid)

• Oxidative stress (Vitamin E), inflammation (Cenicriviroc) and apotosis (Emricasan)

• Fibrosis (selonsertib).

1. Public Health England Guidance: Childhood obesity: applying all our Health. April 2015.
2. Williams R et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet 2014:29;384(9958):1953-9.
3. EASL-EASD-EASO. Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388-402.
4. Younussi et al. AASL The globalization of nonalcoholic fatty liver disease: Prevalence and impact on world health. Hepatology 2016;64:73-84.
5. Eckstedt M et al. Fibrosis stage is the strongest predictor for disease specific mortality in NAFLD after up to 33 years of follow up. Hepatology 2015;61(5):1547-54.
6. Lazo M et al. Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults With type 2 diabetes. Diab Care 2010;33:2156-63.
7. Cobbold J Piloting a multidisciplinary clinic for the management of non-alcoholic fatty liver disease: initial 5-year experience. BMJ Frontline Gastroenterol 2013;4(4):263-9.
8. Dunn W. Therapies for non-alcoholic steatohepatitis. Liver Res 2017;1:214-220 
9. Allied Market Research. www.alliedmarketresearch.com/nonalcoholic-steatohepatitis-NASH-market (accessed April 2019). 

Raising awareness of brachytherapy: a case study

Study suggests scratching the skin primes the gut for allergic reactions to food

24th April 2019

Scratching the skin triggers a series of immune responses culminating in an increased number of activated mast cells in the small intestine, according to research conducted in mice.

This newly identified skin-gut communication helps illuminate the relationship between food allergy and atopic dermatitis. The study was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, and led by researchers at Boston Children’s Hospital.¹

Atopic dermatitis is a strong risk factor for developing food allergy, but the precise relationship between the two conditions remains unclear. The current study proposes that scratching the skin instigates mast-cell expansion in the intestine.

The researchers found that some cells in the skin respond to scratching – simulated by applying and removing small strips of tape on the skin of mice – by producing interleukin-33 (IL-33), which enters the bloodstream. When IL-33 reaches the gut, it works in concert with IL-25 to activate type 2 innate lymphoid cells (ILC2s). Activated ILC2s also make IL-13 and IL-4, which were found to be responsible for the expansion of intestinal mast cells.

The researchers also found that as mast cells expanded, the intestinal lining became more permeable, making it easier for allergens to enter the tissues. Notably, mice that underwent tape stripping had more severe reactions to food allergen than mice that did not. Finally, the researchers found that intestinal biopsies from four children with atopic dermatitis contained more mast cells than those from four children without the condition.

Although additional work is needed to determine the relevance of the findings to humans, the researchers suggest that interventions to limit itching potentially could lessen the severity of food allergy among people with atopic dermatitis.

Reference

1. Leyva-Castillo J-M et al. Mechanical skin injury promotes food anaphylaxis by driving intestinal mast cell expansion. Immunity 2019;DOI: 10.1016/j.immuni.2019.03.023.

Blood samples to help select the right early phase clinical trials for cancer patients

23rd April 2019

Scientists could help match cancer patients with no other treatment options to clinical trials with experimental medicines, by analysing the genetic faults in a sample of their blood, according to research published in Nature Medicine.

The researchers, funded by Cancer Research UK, The Christie Charity, AstraZeneca and the NIHR Manchester Biomedical Research Centre (BRC), demonstrated in their feasibility study that a blood test can be carried out and analysed in a timeframe that can help clinicians select a matched, targeted treatment.

Currently, enrolment to trials depends on a patient’s type of cancer or genetic data obtained from an invasive tumour biopsy, which is often months or years old and may not represent a patient’s current disease due to their tumours’ evolutionary changes over time.

Scientists from the Cancer Research UK Manchester Institute at The University of Manchester, showed that a small volume of blood can contain up-to-date genetic information about a patient’s cancer to inform treatment choices. In this feasibility study of the first 100 patients, 11 were enrolled onto an available and molecularly matched clinical trial.

Dr Matthew Krebs, the lead clinician of the study from The University of Manchester and The Christie Hospital NHS Foundation Trust, said: “This study is bringing clinicians and scientists together to develop a new approach to treating patients with advanced cancers.

“Historically, patients who have exhausted other options but are still reasonably well might access a clinical trial based on their cancer type, but without that new therapy being targeted to their tumour’s particular genetic profile. Now, that paradigm is shifting toward personalised medicine. By understanding the genetic faults underpinning a patient’s cancer from a blood test, as demonstrated in this study, this raises the hope of matching more patients to a specific targeted clinical trial treatment with better chance of benefit.”

In the first of the two-part trial, called TARGET, the researchers were able to collect, process and analyse blood samples from 100 patients in the Manchester area.

Professor Caroline Dive, the laboratory lead author of the study from the Cancer Research UK Manchester Institute, said: “Now that we have demonstrated the feasibility of matching clinical trials for patients who have not responded to previous treatments by analysing the tumour DNA in their blood, we are working to improve our blood testing approach. We are making the test more sensitive and adding new elements to it in order to understand more about a patient’s disease. We are also taking several blood samples over time to see if a faulty gene(s) is disappearing with treatment, or if there is emergence of a new genetic fault that could lead to treatment resistance. This would allow us to stop a failing treatment and consider new options to stay a step ahead of the disease.”

The authors caution that while this study is promising, not every patient will have identifiable and ‘druggable’ faulty genes in their blood, nor will every patient have the opportunity to receive a treatment tailored to their cancer.

The researchers now hope the second part of TARGET, which is already underway, will show how often the blood test is successful at matching patients to early phase clinical trials and the impact this has on their overall survival. There is also an option of referring patients to other clinical trial sites, if suitable matched trials are available in other parts of the country.

Getting closer to finding out why the immune system attacks itself

15th April 2019

1. Mahendra A et al. Beyond autoantibodies: Biologic roles of human autoreactive B cells in rheumatoid arthritis revealed by RNA‐sequencing. Arthritis & Rheumatology 2019;71(4):529 DOI: 10.1002/art.40772

Organisations join forces to create global alliance against antibiotic resistance

Expert analysis: The importance of confirming allergic triggers in rhinitis

Rhinitis is an inflammatory disorder of the nasal mucosa clinically defined by two or more symptoms of nasal itching, sneezing, anterior or posterior rhinorrhoea and nasal blockage.¹

Rhinitis is considered chronic when the symptoms are present for at least one hour daily and last longer than two weeks.² The lifetime prevalence rates of acute rhinitis and chronic rhinitis are 100% and >20%, respectively, which explains the considerable financial burden that the condition imposes to health care systems, in terms of consultations and medications prescribed.³

Moreover, chronic rhinitis negatively affects work and school performance and has been related to learning disabilities in children,⁴ and to an impairment in quality of life greater than that of chronic conditions such as arterial hypertension.⁵

Chronic rhinitis is often associated to other inflammatory disorders of the mucous membranes such as sinusitis, conjunctivitis and asthma, which further amplifies its impact.⁶ Nevertheless, the condition has been historically trivialised and has been regarded as a relevant health problem only in recent years.

Classifications

Several classifications have been proposed for chronic rhinitis based on different parameters such as pathophysiology, frequency and pattern of symptoms or trigger(s) eliciting rhinitis.²

One easy classification divides the disorder into allergic rhinitis (AR) and non-allergic rhinitis (NAR). AR is the most frequent form of chronic rhinitis,⁷ and constitutes a relatively homogenous phenotype with known pathophysiology defined by IgE-sensitisation to environmental allergens.⁶

Conversely, NAR comprises a highly heterogeneous group of diseases where immune-mediated inflammation is not always apparent.⁸ NAR patients are defined by rhinitis symptoms and negativity of classical IgE-sensitisation tests, namely the skin prick test (SPT) and serum allergen-specific IgE⁷ (Figure 1).

Figure 1: Diagnostic biomarkers in the allergic phenotypes of rhinitis. Allergic rhinitis (AR) is characterised by the positivity of skin prick (SPT) test and serum specific (s)IgE. These two biomarkers are sufficient for diagnosis in many cases of AR. In AR individuals, the clinical relevance of an IgE-sensitisation can be accurately established by a nasal allergen challenge (NAC). The basophil activation test (BAT) and the nasal sIgE are positive in most cases of AR, even though they do not use to be necessary for diagnostic purposes. By definition local allergic rhinitis (LAR) patients test negative for both SPT and serum sIgE. The diagnosis of LAR is routinely established by the positivity of the NAC. Some LAR individuals have detectable nasal sIgE or positive BAT responses, and these tests can assist to reach the diagnosis.

Symptoms of AR are driven by re-exposure to seasonal or perennial allergens in IgE-sensitised individuals,¹ and AR patients are by definition positive for at least one of the two tests to measure IgE sensitisation: SPT and/or serum allergen-specific IgE.⁶

Nevertheless, a significant proportion of healthy subjects also display positivity for either test, demonstrating that the correlation of symptoms with allergen exposure is crucial for the interpretation of IgE-sensitisation tests.⁹

A nasal allergen challenge (NAC) can help determine the clinical relevance of IgE-sensitisation in this setting¹⁰ (Figure 2).

Interestingly, some patients with seasonal or perennial rhinitis symptoms display positive NAC with negative SPT and serum allergen-specific IgE. Our group and others have studied this disease phenotype, which is usually termed local allergic rhinitis (LAR).^11,12

This disorder does not properly fit into the above mentioned AR/NAR dichotomy. Similar to AR, LAR patients have a type 2-dominated nasal inflammation, including activation of resident mast cells and recruitment and activation of eosinophils.^13,14

Moreover, LAR patients share many clinical features and in vitrofindings with AR individuals, importantly the positivity of the NAC,¹⁵ and the presence of allergen-specific IgE in the nasal secretions.¹⁶

Epidemiological studies have demonstrated that LAR is a moderate-to-severe condition that might affect up to 25% of non-atopic patients with rhinitis, and that tends to worsen over time,¹⁷ with associated onset of asthma and conjunctivitis.¹⁸ LAR is not an initial state of AR, as studies from our group show that the long-term conversion rate to systemic atopy is comparable between LAR subjects and the general population.¹⁷

Figure 2: Diagnostic algorithm of the allergic forms of rhinitis. BAT: basophil activation test; NAC: nasal allergen challenge; NsIgE: allergen-specific IgE in the nasal secretions.

Identification of triggers is crucial

Identification of the allergic triggers of rhinitis is crucial in order to implement adequate avoidance measures in both atopic and non-atopic patients. Moreover, this identification can help administer specific therapies, such as allergen immunotherapy (AIT). Several controlled trials from different groups have demonstrated the capacity of AIT (with house dust mites, grass and tree pollens) to control the symptoms, reduce the need for rescue medication, improve quality of life and increase the nasal tolerance to the allergen in LAR individuals^19–21 (Table 1).

Table 1: Studies that have investigated the performance of AIT in LAR patients. In all cases similar results and conclusions were obtained: AIT is able to control the symptoms of LAR patients, to reduce the need for rescue medication, to improve quality of life, and to increase the amount of allergen tolerated in the NAC. The red square highlights the three randomised, double-blind, placebo-controlled clinical trials (RDBPCCT) published to date.

In AR patients, AIT is able to prevent the progression of the disease, especially the onset of asthma.²² It is currently under investigation whether AIT has the same capacity in the LAR phenotype. Importantly, there is a rapid evolution towards the clinical worsening during the first five years after LAR onset,¹⁷ implying that this initial period represents a window of opportunity to establish specific therapies aiming to prevent the progression of the disease.

All the above mentioned aspects highlight the relevance of identifying the allergic triggers of nasal reactivity, regardless of the atopic status of the rhinitis patient. In this regard, the NAC is the key tool for the diagnosis of LAR and it can confirm the clinical relevance of IgE-sensitisations in AR individuals.²³

Moreover, the NAC can help design the composition of AIT in patients with multiple sensitisations, or monitor its effect.²³ The NAC displays the optimal features for an in vivo test, as it is very safe and reproducible.²⁴ The NAC for LAR diagnosis significantly outperforms the detection of nasal allergen-specific IgE and the basophil activation test in terms of both sensitivity and specificity.^23,24 

Conclusions

In summary, there is a significant proportion of non-atopic rhinitis patients who display nasal reactivity to environmental allergens. Therefore, the inclusion of the NAC in the diagnostic algorithm is necessary to accurately identify the allergic triggers of rhinitis. This identification is crucial for the early prescription of specific therapies such as AIT which has the potential to prevent the progression of the disease, including the onset of asthma.

Authors

Ibon Eguiluz-Gracia MD PhD

Adriana Ariza PhD

Alba Rodríguez-Nogales PhD

Carmen Rondon MD PhD

References

1 Greiner AN et al. Allergic rhinitis. Lancet 2011;378(9809):2112–22.

2 Papadopoulos NG, Guibas GV. Rhinitis subtypes, endotypes, and definitions. Immunol Allergy Clin NAm 2016;36(2):215–33.

3 Canonica GW et al. A survey of the burden of allergic rhinitis in Europe. Allergy. 2007;62 Suppl 85:17–25.

4 Muraro A et al. The management of the allergic child at school: EAACI/GA2LEN Task Force on the allergic child at school. Allergy 2010;65(6):681–9.

5 de la Hoz Caballer B et al. Allergic rhinitis and its impact on work productivity in primary care practice and a comparison with other common diseases: the Cross-sectional study to evAluate work Productivity in allergic Rhinitis compared with other common dIseases (CAPRI) study. Am J Rhinology Allergy 2012;26(5):390–4.

6 Bousquet J et al. Allergic rhinitis and its impact on asthma. J Allergy Clin Immunol 2001;108(5 Suppl):S147–334.

7 Dykewicz MS, Hamilos DL. Rhinitis and sinusitis. J Allergy Clin Immunol 2010;125(2 Suppl 2):S103–15.

8 Rondon C et al. Nonallergic rhinitis and lower airway disease. Allergy 2017;72(1):24–34.

9 Roberts G et al. A new framework for the interpretation of IgE sensitization tests. Allergy 2016;71(11):1540–51.

10 Dordal MT et al. Allergen-specific nasal provocation testing: review by the rhinoconjunctivitis committee of the Spanish Society of Allergy and Clinical Immunology. J Invest Allergol Clin Immunol 2011;21(1):1–12; quiz follow Epub 2011/03/05.

11 Krajewska-Wojtys A, Jarzab J, Gawlik R, Bozek A. Local allergic rhinitis to pollens is underdiagnosed in young patients. Am J Rhinol Allergy 2016;30(6):198–201.

12 Rondon C, Canto G, Blanca M. Local allergic rhinitis: a new entity, characterization and further studies. Curr Opin Allergy Immunol 2010;10(1):1–7.

13 Rondon C et al. Nasal inflammatory mediators and specific IgE production after nasal challenge with grass pollen in local allergic rhinitis. J Allergy Clin Immunol 2009;124(5):1005–11 e1.

14 Rondon C et al. Local IgE production and positive nasal provocation test in patients with persistent nonallergic rhinitis. J Allergy Clin Immunol 2007;119(4):899–905.

15 Rondon C et al. Nasal allergen provocation test with multiple aeroallergens detects polysensitization in local allergic rhinitis. J Allergy Clin Immunol 2011;128(6):1192–7.

16 Campo P et al. Local IgE in non-allergic rhinitis. Clin Exp Allergy Immunol 2015;45(5):872–81.

17 Rondon C et al. Follow-up study in local allergic rhinitis shows a consistent entity not evolving to systemic allergic rhinitis. J Allergy Clin Immunol 2014;133(4):1026–31.

18 Rondon C et al. Prevalence and clinical relevance of local allergic rhinitis. Allergy 2012;67(10):1282–8.

19 Rondon C et al. Efficacy and safety of D. pteronyssinus immunotherapy in local allergic rhinitis: a double-blind placebo-controlled clinical trial. Allergy 2016 Jul;71(7):1057–61.

20 Rondon C et al. Specific immunotherapy in local allergic rhinitis: A randomized, double-blind placebo-controlled trial with Phleum pratense subcutaneous allergen immunotherapy. Allergy 2018 Apr;73(4):905–15.

21 Bożek A, Kołodziejczyk K, Jarząb J. Efficacy and safety of birch pollen immunotherapy for local allergic rhinitis. Ann Allergy Asthma Immunol 2018;120(1):53–8.

22 Durham SR et al. SQ-standardized sublingual grass immunotherapy: confirmation of disease modification 2 years after 3 years of treatment in a randomized trial. J Allergy Clin Immunol 2012;129(3):717–25.e5.

23 Augé J et al. EAACI Position paper on the standardization of nasal allergen challenges. Allergy 2018;73(8):1597–608.

24 Eguiluz-Gracia I et al. Safety and reproducibility of nasal allergen challenge. Allergy 2019; in press.

High-tech tissue study reveals which cells drive a painful food allergy

12th April 2019

1. Eight types of immune system T cells were found in the oesophageal tissue. That’s more than had been previously expected.
2. Two cell types (T7 and T8) show up in higher numbers in the diseased tissue. The study finds that one of these two cell types responds to allergens by cranking out massive amounts of inflammation-causing type 2 cytokines.
3. One of these cell types (T8) is nearly non-existent in healthy tissue, making it especially worth targeting for treatment. “These cells are bad actors that should not be in this type of tissue. Inhibiting these cells is now a central goal of our research,” Wen says.
4. So how did these bad players get there? Studying this question led the co-authors to a surprising finding. One of the overactive genes that helps trigger the inflammation response – a gene called FFAR3 – also encodes a receptor for the dietary supplement butyrate.

1. Wen T et al. Single-cell RNA sequencing identifies inflammatory tissue T cells in eosinophilic esophagitis. J Clin Invest 2019;DOI: 10.1172/JCI125917

First results of a major three-year project to analyse airborne grass pollen

1. Brennan GL et al. Temperate airborne grass pollen defined by spatio-temporal shifts in community composition. Nature Ecol Evolution 2019;DOI: 10.1038/s41559-019-0849-7

Researchers develop first functional targeted inhibitors of peanut allergens

1. Deak PE et al. Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen. PNAS 2019;April 8:DOI: 10.1073/pnas.1820417116