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Future treatment modalities in Celiac Disease



Celiac Disease (CD) is an immune-mediated systemic disorder elicited by gluten and related prolamines in genetically susceptible individuals and characterized by the presence of a variable combination ofgluten-dependent clinical manifestations, CD-specific antibodies, HLA-DQ2 or HLA-DQ8 haplotypes, and enteropathy. CD-specific antibodies comprise autoantibodies against TG2, including endomysial antibodies (EMA), and antibodies against deamidated forms of gliadin peptides (DGP).

This is a serious issue in children, as undiagnosed celiac disease can lead to growth retardation, anaemia, etc. Moreover, people with celiac disease have genes that also predispose them to other autoimmune disorders, like autoimmune thyroiditis. Having one autoimmune condition increases the chances of having another autoimmune condition. Furthermore, it has been suggested that the chance of developing other autoimmune disorders is increased, when diagnosis of coeliac disease is delayed, hence all children with CD are screened on an annual basis for other autoimmune diseases.

Pathogenesis
Gluten is a general term used to describe a mixture of wheat storage proteins (prolamins and glutenins). However other cereals have proteins that exert a toxic effect for CD patients; toxic prolamins include gliadin in wheat, secalin in rye and hordein in barley. These protein domains are resistant to degradation by gastric, pancreatic and proteases in the human intestinal brush border membrane thereby allowing them to remain intact within the intestinal lumen after ingestion. In individuals with CD, these peptides then enter the lamina propria, triggering chronic inflammatory changes. Gliadin peptides cross the intestinal barrier by both active transport (transcellular) processes and via paracellular mechanisms.It is notable that gliadin peptides in their native form are not toxic. In order for gluten peptides to cause inflammation, they must first be altered by the enzyme tissue transglutaminase (tTG) which is normally present in nearly all organs and is increased in areas of inflammation. In the submusosa of the intestine, tTG deamidates gluten peptides, changing peptide shape and charge. These altered gluten peptides are then able to bind tightly to HLA-DQ2 and HLA-DQ8 molecules on antigen-presenting cells. This binding triggers an inflammatory reaction causing lymphocyte infiltration, villous atrophy and the production of antibodies to gliadin and tTG.

Symptoms
CD is a multi-organ autoimmune disease. The symptoms are variable and can be classified into the following:

  • The Gastrointestinal symptoms include chronic or intermittent diarrhoea, failure to thrive, weight loss, stunted growth, chronic abdominal pain, chronic constipation, chronic fatigue, recurrent aphthous ulcers, abnormal liver tests, etc.
  • Extra intestinal symptoms include- nonspecific poor appetite, growth failure, iron deficiency anaemia Central nervous system: ataxia, seizures, depression. Heart: Carditis
  • Skin: dermatitis herpetiformis, hair loss
  • Reproductive system: miscarriage infertility
  • Bone: osteoporosis, fractures, arthritis
  • Dental anomalies One should have a low threshold to screen for CD in children because of the various presentations.

Treatment
Standard current treatment is a gluten free diet for life. However, approximately 7-30% of patients fail to respond to a gluten- free diet. This may result from either inadvertent or intentional eating of foods containing gluten. Moreover, nonglutencontaining grains are not fortified as wheat flour is. As a result, patients on a glutenfree diet for 10 years or more were shown to be deficient in vitamins. This has ledto research in new non-dietary treatment modalities for patient with CD.

New possible future treatment modalities
Emerging research for the treatment of celiac disease has focused on three areas: To decrease gluten exposure, to modify intestinal permeability and to modulate immune activation

1. To decrease gluten exposure This could be achieved with genetically engineering grains by eliminating immunogenic gluten fragments. However, the large number of peptide epitopes located in different genetic loci of the wheat genome makes this approach challenging. Moreover, potential challenges exist since the genetic modification of food is controversial and is not regarded favourably by the public. Another approach is the use of synthetic polymers that bind and neutralize gliadin. These have recently been studied and experimentally eliminate gliadin.

Enzymatic degradation of the large, immunogenic gliadin peptides into small nontoxic fragments.

This can be performed by prolyl endopeptidases. These are proteases, found primarily in plants and microorganisms, able to degrade the Proline-rich gluten peptides into smaller, less immunogenic fragments. Alternatively, in recent trial in Italy, selected Probiotic Lactobacilli have the capacity to hydrolyse Gluten Peptides during simulated gastrointestinal digestion.

Enzyme therapy is attractive; however, it is complicated because gluten must be completely prevented from interacting with the mucosa. Any remaining gluten peptides may lead to intestinal inflammation

2. To modify intestinal permeability
Intercellular tight junctions are altered in celiac disease. This could be another therapeutic target used to prevent the migration of luminal gluten peptides across the intestinal epithelium. Zonulin, an endogenous peptide involved in tight junction regulation, is amplified in celiac disease and increases intestinal permeability. AT- 1001 is a peptide that inhibits the action of zonulin. Clinical trials have shown no increase in GI symptoms when challenged with gluten in patients given AT-1001. Further phase II studies are currently underway.

3. To modulate immune activation This may be achieved by preventing gliadin deamination through the inhibition of tissue transglutaminase, by preventing HLA presentation through blocking the HLA DQ2 or DQ8 molecules, or by modulating cytokine production.

(i) BL-7010 is a non-absorbable, orally available polymer which has a high affinity for gliadins and by sequestering gliadins, it effectively masks them from enzymatic degradation and prevents the formation of immunogenic peptides that trigger the immune system. This significantly reduces the immune response triggered by gluten. BL-7010 is excreted with gliadin from the digestive tract and does not get absorbed into the blood. A Phase I/II study with BL-7010 was successfully completed in 2014. When taken orally, it was demonstrated that it prevents the degradation of gliadin, which causes the over-reactive immune response. With gliadin still intact, immune cells are not triggered to form, which prevents the harmful immune response those with celiac disease would usually experience.

(ii) AMG 714 is an investigational anti-IL-15 monoclonal antibody being studied for the treatment of glutenfree diet non-responsive celiac disease (NRCD) and refractory celiac disease. IL-15 is considered to have a central role in celiac disease and to be a key driver of the generation of aberrant and malignant intraepithelial lymphocytes (IELs).

Vaccine
Nexvax2, a therapeutic vaccine currently in clinical trials, is intended to protect against the effects of gluten exposure in HLA-DQ2.5+ patients with celiac disease.

Approximately 90% of celiac disease patients carry the HLA-DQ2.5 gene. ImmusanT, the biotech company that developed the vaccine says, currently, there is no pharmaceutical treatment for celiac disease and the only method of management is to maintain a gluten-free diet (GFD). Effective implementation of a GFD is onerous and often impractical. Persistent intestinal injury and frequent digestive symptoms in many patients are evidence of ongoing gluten exposure. ImmusanT is developing Nexvax2, an epitope-specific immuno-therapy (ESIT) that consists of three immunodominant peptides, designed to protect against gluten exposure.

Phase 1b trials of Nexvax2 were completed in February this year. Phase 2 trials are planned by ImmusanT.

Conclusion
With these and other therapies currently being researched, patients with celiac disease should have a positive outlook on the future of celiac disease treatment.

The Author
Dr Rajeev Tomar is Medical Director of KCH Clinics Abu Dhabi, Head of Paediatrics, Consultant Paediatrician and Paediatric Hepatologist at KCH Clinics Abu Dhabi.

References

  1. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease, S. Husby etal. (JPGN 2012; 54: 136160)
  2. Selected Probiotic Lactobacilli Have the Capacity to Hydrolyze Gluten Peptides During Simulated Gastro- Intestinal Digestion.
  3. Francavilla R, Appl Environ Microbiol. 2017 May 12
  4. New and developing therapies for celiac disease; Christina A. Ther Adv Gastroenterol (2009) 2(5) 303_309
  5. Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, doubleblind, placebo-controlled phase 1 studies.
  6. Mesenchymal stem cells as potential therapeutic approaches in celiac disease, Ali Moheb-Alian; Gastroenterol Hepatol Bed Bench. 2016 Dec; 9 (Suppl1):S1-S7.

Smartphones: small size, big problem

Research has shown that when children watch too much television, their risk of obesity increases. However, more and more screen time is coming from other devices, like tablets and smartphones, and the impact of these devices has not been researched as much. In a new study published in The Journal of Pediatrics, researchers found that children who reported spending more time on screen devices and watching television engaged in behaviours that can lead to obesity.

Dr Erica L. Kenney and Dr Steven L. Gortmaker from the Harvard T.H. Chan School of Public Health studied data from the 2013 and 2015 waves of the Youth Risk Behavior Surveillance System, which included 24,800 adolescents in grades 9-12. The survey gathered data on the following: hours spent on screen devices (including smartphones, tablets, computers, and videogames) and watching television, hours of sleep on an average school night, number of sugar-sweetened beverages consumed in the previous 7 days, and frequency of physical activity (at least 60 minutes per day) for the past 7 days.

The researchers found that almost 20% of US adolescents spent more than 5 hours a day on smartphones, tablets, computers, and videogames compared with only 8% watching more than 5 hours a day of television. Watching too much television continued to be associated with obesity and poor diet among adolescents. However, the researchers also found that adolescents who spent more than 5 hours a day on screen devices were twice as likely to drink a sugary drink each day and not get enough sleep or physical activity, and were about 43% more likely to have obesity compared with adolescents who did not spend time on these devices.

Although this study cannot conclude definitively that using screen devices is causing higher rates of obesity, the findings are cause for concern. According to Dr Kenney: This study would suggest that limiting childrens and adolescents engagement with other screen devices may be as important for health as limiting television time.

Until more research is done, clinicians may want to encourage families to set limits for both television and other screen devices.


The next 7 great achievements from paediatric research

Advances in pediatric research have significantly reduced deaths and improved the quality of life for families worldwide over prior decades. Researchers are now poised to achieve even greater medical accomplishments, buoyed by the use of new technology-based tools, including electronic health records that will assist in longitudinal data collection, according to an article published by the American Academy of Pediatrics (AAP).

The Next Seven Achievements in Pediatric Research, published in the May 2017 Pediatrics, reflects on the progress that has been made and predicts the next great research breakthroughs for childrens health. The article emphasizes the need for continued federal support and focus on child health research. Emerging new risks such as the Zika virus, obesity epidemic and exposure to adverse childhood experiences threaten to shorten the lifespans of the next generation without a sciencebased approach, the authors state.

We must continue the momentum thathas brought us life-saving immunizations, reduced infant deaths and increased life expectancy for children because of newly discovered treatments and preventive measures, said Tina Cheng, MD, MPH, FAAP, lead author. We are on the edge of exciting new initiatives that can move forward only with support for research, physician training and data collection improvements.

In 2015, the AAP Committee on Pediatric Research highlighted seven great achievements in paediatric research, which were chosen from responses to a survey of paediatric professional organization board members. The seven success stories cited were: preventing disease with life-saving immunizations; reducing sudden infant death with a Back to Sleep campaign; finding a cure for Acute Lymphoblastic Leukemia; helping premature babies breathe with a specific therapy called surfactant; preventing Human Immunodeficiency Virus transmission from mother to baby; increasing the life expectancy for children with Sickle Cell Anaemia and Cystic Fibrosis; and saving lives with car seats and seat belts.

The next seven great achievements, the authors predict, will be:

  • More paediatric immunizations to prevent emerging and persistent diseases
  • Cancer immunotherapy
  • Genomic discoveries to predict, prevent and more effectively treat disease
  • Recognizing foetal and childhood origins of adult disease before effective early intervention
  • Understanding how social and environmental conditions affect health to guide population health efforts
  • Quality improvement initiatives in medical care
  • Implementation of research knowledge to reduce global poverty Yet the paediatric research field faces challenges, such as the unique effort needed to include children and teens in clinical research.
  • doi: 10.1542/peds.2016-3803

Treatment for Erbs Palsy birth injuries of the brachial plexus

Mr Tom Quick of the Royal National Orthopaedic Hospital is an expert in the treatment of Erbs Palsy or Birth Brachial Plexus Palsy (BBPP)

By Mr Tom Quick, FRCS

The surgeons at the Royal National Orthopaedic Hospital (RNOH) Peripheral Nerve Injury Unit (PNI), Mr Tom Quick and his colleagues, Dr Marco Sinisi and Mr Mike Fox, offer a full range of treatment options for the injury known as Erbs Palsy or Birth Brachial Plexus Palsy (BBPP). Their service is focused on a functional improvement for the patient from birth, through adolescence to adulthood.

Wilhelm Heinrich Erb was a Bavarian nerve doctor of the late 19th Century. He gave his name to an injury of the nerves of the brachial plexus which happens at the time of birth: Erbs Palsy. There is much we have learnt about this injury since then.

The nerves of the arm leave the spine at fi ve levels (like fl oors of a building). These nerve roots are made up of hundreds of thousands of nerve cells which then all intermingle at a major junction called the brachial plexus. The injury of a Birth Brachial Plexus Palsy (BBPP) is one of the stretching forces of the delivery. Nerves can cope with some stretch but too much damages them. The damage can be quite mild (conduction block) which can recover completely and quite quickly, or be partially or completely snapped (rupture) or pulled clean from the spinal cord (avulsion).

The nerve injury in BBPP
Alongside precise and expert examination of the child I also use neurophysiology to make this assessment. Neurophysiology is medical circuit testing. This study is able to provide information not just on the condition of the nerves but also on how likely they are to recover.

Primary Brachial Plexus surgery
This is an operation on the nerves of the brachial plexus in the neck to free them from the scar tissue which forms after the nerves are damaged. Then if necessary I might have to take spare nerves from the childfs arm or leg and splice them (nerve grafting) into the brachial plexus or reroute (nerve transfer) some other undamaged nerves from nearby.

The most important feature to understand about nerve surgery is that it is not like rewiring a light bulb: But more like planting a vine . it has to grow and it does this slowly. Surgery allows recovery to take place it doesnft actually repair the function of the nerves directly. Following nerve surgery there is often no sign of improvement for many months and full improvement not for a number of years after surgery. The damage of the nerves is one problem, but this problem always leaves imbalance in the function of the muscle, the growth of the bones and muscles and the way the body learns to use the arm, thus it can continue to cause problems throughout all of childhood.

The shoulder in BBPP
The most common problem in BBPP is one that affects the shoulder; the problem of shoulder dysplasia. This condition leads to a series of events that leads to shoulder joint subluxation and then full dislocation of the shoulder joint. At the RNOH the PNI unit is highly experienced in an operation called an anterior release, which corrects and rebalances the early stage of the problem. Later presenting cases (over age 4-6) often require an operation which was developed here at the RNOH called a glenoplasty where the bone of the shoulder joint is reshaped to improve function.

The forearm and hand In BBPP
there is often involvement of the arm further down than the shoulder and elbow. Joint releases, tendon transfers, nerve transfers, osteotomies are all utilised in specific cases.


Precarious beginning leads to promising future

Dr. Christian Pizarro holds baby Curley

Nemours duPont CT Surgeon, Dr. Christian Pizarro, performs lifesaving surgery

At 34 weeks and 1 day, Felice Curley delivered beautiful twin boys. Tyrus (Twin A) and Hezakiah (Twin B) weighed in at 4.7 lbs and 4.9 lbs, respectively. In the neonatal intensive care unit (NICU) at their local community hospital, the preemies received the special care and attention they needed.

However, after a few days, Hezakiah, still in the NICU, began exhibiting breathing difficulty. The clinicians caring for Hezakiah were convinced that he had developed some type of pulmonary condition and began a series of different treatments to ameliorate the symptoms. Unfortunately, these interventions failed and Hezakiah began deteriorating rapidly. He was quickly transferred to a larger medical center for care. Once Hezakiah arrived at the facility, the providers there quickly realized they were not equipped to properly help this very sick infant. Because of this, preparations were made to transfer Hezakiah to Nemours/ Alfred I. duPont Hospital for Children, a tertiary care center. Though 80 miles away, it was clear to medical personnel that transporting Hezakiah there was the only way to save his life.

While in transit, Hezakiah was put on life-sustaining ECMO by the Nemours Transport Team. Upon arriving at Nemours/Alfred I. duPont Hospital for Children, Hezakiah was transferred to the NICU. In the NICU, pulmonary etiology was ruled out. It was determined that Hezakiah had a complex cardiac abnormality. Hezakiah was diagnosed with a rare congenital cardiac condition called Total Anomalous Pulmonary Venous Return/Repair (TAPVR). This heart defect occurs in the fi rst eight weeks of pregnancy and causes the vesselsthat bring oxygen-rich blood back to the heart from the lungs to be improperly connected. Babies with this heart defect cant supply oxygenated blood to the body after birth. Instead, they will have a mixture of oxygenated and de-oxygenated blood in circulation a situation that is fatal. More specifi cally, in TAPVR, the four pulmonary veins do not connect normally to the left atrium. Instead, the pulmonary veins drain abnormally to the right atrium through an abnormal connection.

At approximately 22 days old, Hezakiah needed heart surgery to live. According to the team at Nemours/ Alfred I. duPont Hospital for Children, the chances of Hezakiah surviving the surgery were less than 50%. Despite the odds, Dr. Christian Pizarro, a worldrenowned pediatric cardiothoracic surgeon at Nemours/Alfred I. duPont Hospital for Children, surgically reconnected the pulmonary veins to the left atrium. While Hezakiah recovered in the CICU, the transport team who brought him to Nemours/Alfred I. duPont Hospital for Children, and who kept him alive on that trip, stopped by to check on him.

Felice Curley was astounded by the outpouring of care and concern her family received. She commented: Long after the surgery was done, Dr. Pizarro continued to check in on my son, always taking the time to answer my questions and always genuinely interested in us as a family. Thats what has made my experience great. Its the whole team here. The social worker, psychologist, speech therapist, the transport team, the nutritionist, and child life who consoled and helped my two older children to understand what had happened to their brothers. And, of course, without Dr. Pizarros expertise, my son wouldnt be here. I think this [Nemours/Alfred I. duPont Hospital for Children] is the greatest hospital!

Now at 12 weeks old, Tyrus weighs in at a robust 10 lbs, and Hezakiah isnt far behind at 7 lbs, 14 oz. Hes learning how to suck so that he can gain weight more quickly and get stronger. Felice Curley says he is progressing nicely with the help of a speech therapist and other therapy services experts.

Thanks in large part to the expertise and support of the entire team at Nemours/ Alfred I. duPont Hospital for Children, Hezakiah has a bright future ahead.

 

 
Date of upload: 16th Jul 2017

                                  
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