Patients with a IBD (Inflammatory Bowel Disease) moderate to severe phenotype and/or with risk factors for a worse prognosis, once elected for advanced therapy with biologics, should undergo preparation for the start of treatment safely.

This stage involves the evaluation of 3 pillars:

• Check if there is a relative or absolute contraindication to the use of such medications;
• Screening for active or latent infections;
• Updating vaccination status

Regarding contraindications or signs of greater attention to the use of biologics, we have:

• Severe ongoing infection, including perianal abscess;
• Untreated latent tuberculosis (a period from the start of treatment should be awaited to start the biologic, preferably a non-anti-TNF);
• Decompensated CHF or EF ? 35% (absolute contraindication to anti-TNF);
• History of severe previous infusion reaction to biologics;
• Multiple sclerosis or other demyelinating diseases; optic neuritis; previous lymphoma (in these conditions anti-TNF has an absolute contraindication, the others weigh risk x benefit);
• Current malignancy;
• Decompensated liver disease (cirrhosis Child B or C);
• Untreated chronic infection by the hepatitis B virus;
• Uncontrolled HIV infection;
• History of melanoma (absolute contraindication to anti-TNF) or recurrent cervical dysplasia (relative contraindication to anti-TNF)

The next step is to carry out the infectious screening, which includes:

• Chest X-ray;
• PPD and/or IGRA (interferon gamma release test);
• Serologies for hepatitis B, C and HIV (also consider adding screening for measles, CMV, varicella zoster and Epstein-Barr – note that primary EBV infection in immunosuppressed patients increases the risk of lymphoproliferative diseases, in this scenario caution should be exercised when prescribing associated thiopurines);
• In the presence of diarrhea, exclude the presence of Clostridium difficile as a mimicking agent;
• In the female population, colpocytology is also recommended for HPV infection screening.

The screening for latent TB should be renewed annually while the patient is using the biologic, especially if it is of the anti-TNF class, as we know how much TNF-alpha is crucial for granuloma stability.

In the case of patients with PPD ? 5mm, or IGRA + or sequelae on chest X-ray suggestive, first the treatment of latent TB should be started and only start the biologic after 30 days from the start of treatment.

Patients with HBsAg + or with isolated anti-HBc + should receive antiviral therapy during the use of biologics or oral immunosuppressants. In the first case, the treatment time will be guided by liver disease. In the second case (hidden infection), for at least 6 months after the end of treatment (if applicable).

Vaccination status

Regarding the vaccination schedule, inactivated vaccines are extremely safe and indicated for all patients with IBD, and ideally should be administered at least 2 weeks before the biologic, so as not to compromise the vaccine response. The attenuated vaccines are contraindicated for patients who are already using immunosuppressants or biologics, or who are planning to start such medications in the next 4 to 6 weeks. They can only use attenuated vaccines after 3 months of suspension of such medications (if applicable).

The inactivated vaccines to be considered in patients with IBD are: Influenza, Pneumococcal, Tetanus/Diphtheria (Adult Double), Meningococcal, Hepatitis A, Hepatitis B (including possibly making 4 double doses aiming for anti-HBs >10), HPV, COVID-19. Recently, the recombinant inactivated herpes zoster vaccine was also launched, allowing use to patients in immunosuppression or planning to start biologics, unlike the vaccine available until then which was attenuated virus.

Reinforcing, the attenuated vaccines that should not be done in the scenario of immunosuppressed patients are: MMR (measles, mumps and rubella), varicella, yellow fever and the older version of the herpes zoster vaccine composed of live attenuated virus.

References:

1. T. Kucharzik et al. ECCO Guidelines on the Prevention, Diagnosis, and Management of Infections in Inflammatory Bowel Disease. Journal of Crohn’s and Colitis, 2021, 879–913
2. Chebli JMF et al. Preparing Patients With Inflammatory Bowel Diseases For Biological Therapies In Clinical Practice. Journal of Gastroenterology and Hepatology Research 2018; 7(2): 2535-2554
3. Beaugerie et al. Predicting, Preventing, and Managing Treatment-Related Complications in Patients With Inflammatory Bowel Diseases. Clinical Gastroenterology and Hepatology 2020;18:1324–1335
4. S. Riestra et al. Recommendations of the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) on screening and treatment of tuberculosis infection in patients with inflammatory bowel disease. Gastroenterología y Hepatología 44 2021 51—66
5. R. Ferreiro-Iglesias et al. Recommendations of the Spanish Group on Crohn’s Disease and Ulcerative Colitis on the importance, screening and vaccination in inflammatory bowel disease patients. Gastroenterología y Hepatología 45 (2022) 805—818

How to cite this article

Vilela PBM, Check-list to start biological therapy in IBD Gastropedia 2023, Vol 2. Available at: gastropedia.com.br/sem-categoria/check-list-para-iniciar-terapia-biologica-na-dii/

It is well known that serology is an important tool in the diagnosis of Celiac Disease (CD), but the best way to use it is still a recurring doubt in the outpatient routine.

Each patient must be well evaluated before defining the best strategy. In patients with low probability of CD, for example, it is not recommended to combine several autoantibodies. Although this conduct increases sensitivity, it decreases specificity for diagnosis and, for this reason, it is not a good option in this group of patients.

On the other hand, when we are facing a patient with a high probability of the disease, even if the autoantibodies are negative, the investigation should continue with the performance of duodenal biopsies.

If you still do not know the pathophysiology of Celiac Disease, it is worth checking out this post (click here) before studying the related autoantibodies.

Autoantibodies in Celiac Disease

The antigliadin antibody has been used for decades in the diagnosis of CD, but its utility is quite limited today due to its low performance compared to other available tests.

The tissue transglutaminase IgA (anti-tTG IgA) is the first-line autoantibody because it has the highest sensitivity and is widely available. The higher its title, the greater the chance of CD and the greater the duodenal lesion. Titles greater than 5 times the upper limit of normal (ULN) have a high positive predictive value.

Due to the possible association of celiac disease with IgA deficiency, the collection of anti-tTG IgA should preferably be associated with the dosage of total IgA (especially in patients with a high probability of the disease). Another option is to associate the research of an IgG class autoantibody.

The deaminated gliadin or deaminated is an autoantibody against gliadin that came into contact with the tissue transglutaminase enzyme and underwent the process of deamination (release of its amine group). The association of anti-tTG IgA with deaminated gliadin IgG has shown the best performance (sensitivity and specificity) for the diagnosis of CD, but the research of this autoantibody is more expensive and little available in our environment currently. Thus, a good option is the association with anti-transglutaminase IgG, for example.

The anti-endomysium IgA antibody is the antibody with the best specificity (approximately 100%) and therefore has an important role in diagnostic confirmation (especially in patients with anti-tTG IgA with titles less than 2 times the ULN).

Performance of serological tests

The performance of serological tests in clinical practice is worse than in many of the major trials, as studies are usually conducted in a population with a high prevalence of CD. In addition, it is also important to remember that performance depends on the maintenance of a gluten diet. About 80% of patients negate autoantibodies in 6 to 12 months and more than 90% in 5 years. Weakly positive patients may negate their autoantibodies within a few weeks of dieting. It is rare that these autoantibodies do not normalize in the long term with a gluten-free diet. If this happens, it is necessary to rule out that gluten consumption is not happening unconsciously.

In the last decade, many studies have been conducted with POCTs (point-of-care tests). These are quick tests that can be used both in the endoscopy sector and in the office. A meta-analysis published in 2019 found sensitivity and specificity of 94 and 94.4% respectively, considering histology as the gold standard. Despite these results showing high sensitivity and specificity, due to the great variety of work done and conflicting results, more studies are still suggested before using them in clinical practice. For now, the use of POCTs should still be reserved for places with limited access to laboratories.

Studies are also being conducted with research of autoantibodies in saliva for screening in children suspected of CD. Despite the favorable results, showing a non-invasive, cheap and reproducible option, the evidence so far is not sufficient to recommend its use.

On the other hand, the detection of autoantibodies in feces does not seem to be useful in disease screening, with work showing a sensitivity of only 10%.

Given that autoantibodies in CD are produced in the small intestine itself, work is being done with research of autoantibodies in the supernatant of the duodenal biopsy. This research seems to have its importance mainly in the diagnosis of patients in the early stages of the disease, when serum autoantibodies may still be negative. But more studies are still needed to confirm its role in clinical practice.

Conclusion

Autoantibodies are extremely relevant exams for the diagnosis of CD. However, there is no single algorithm to define which autoantibody to request. In addition to knowing the sensitivity and specificity of each of them, it is necessary to evaluate the pre-test probability of the disease in each patient and the accessibility to the different available exams to define the best strategy.

References

1. Green P, Stavropoulos S, Panagi SG, Goldstein S. Characteristics of adult celiac disease in the USA: results of a national survey. Am J Gastroenterol 2001;96:126– 131.
2. Sanders DS. Changing face of adult coeliac disease: experience of a single university hospital in South Yorkshire. Postgrad Med J 2002;78(915):31–33.
3. Al-Toma A , Volta U, Auricchio R, Castillejo G, Sanders D, Cellier C, Mulder C, Lundin K. European Society for the Study of Coeliac Disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United European Gastroenterol J . 2019;7(5):583-613.
4. Singh P, Arora A, Strand T, Leffler D, Mäki M, Kelly C, Ahuja V, Makharia G. Diagnostic Accuracy of Point of Care Tests for Diagnosing Celiac Disease: A Systematic Review and Meta-Analysis. J Clin Gastroenterol 2019;53(7):535-542.
5. De Leo L, Bramuzzo M, Ziberna F, Villanacci V, Martelossi S, Di Leo G, Zanchi C, Giudici F, Pandullo M, Riznik P, Di Mascio A, Ventura A, Not T. Diagnostic accuracy and applicability of intestinal auto-antibodies in the wide clinical spectrum of coeliac disease. EBioMedicine . 2020 Jan;51:102567

How to cite this article

Vilela E. The role of autoantibodies in the diagnosis of celiac disease. Gastropedia 2023, Vol 1. Available at: https://gastropedia.com.br/gastroenterology/the-role-of-autoantibodies-in-the-diagnosis-of-celiac-disease

Celiac disease is an autoimmune disease caused by an abnormal immune response to gluten peptides in the upper small intestine. It is important to understand its pathophysiology to know how to interpret the serological tests that assist in the diagnosis of celiac disease.

Gluten is a protein found in wheat, barley, and rye. In the small intestine, gluten is digested and breaks down into gliadin.

In celiac disease, gliadin manages to cross the epithelial barrier in the small intestine and reach the underlying lamina propria. The cause of gliadin epithelial permeability is uncertain, but it may be due to an underlying pathological process (for example, infection) or changes in intercellular junctions (tight junctions).

Immune response in the mucosa

When gliadin comes into contact with the lamina propria, it is deaminated by tissue transglutaminase (TTG). The deaminated gliadin then reacts with HLA-DQ2 or HLA-DQ8 receptors on antigen-presenting cells that stimulate the activation of T and B cells, leading to the release of cytokines, antibody production, and lymphocyte infiltration. Over time, inflammation causes villous atrophy, crypt hyperplasia in epithelial cells, and intraepithelial lymphocytosis.

Genetic Factors

The familial occurrence of celiac disease suggests that there is a genetic influence in its pathogenesis. Celiac disease does not develop unless a person has alleles that encode for the HLA-DQ2 or HLA-DQ8 proteins, products of two of the HLA genes.

However, many people, most of whom do not have celiac disease, carry these alleles; therefore, their presence is necessary, but not sufficient for the development of the disease.

Studies in siblings and identical twins suggest that the contribution of HLA genes to the genetic component of celiac disease is less than 50%.14 Several non-HLA genes that may influence susceptibility to the disease have been identified, but their influence has not been confirmed.

Environmental Factors

Epidemiological studies have suggested that environmental factors play an important role in the development of celiac disease. These include a protective effect of breastfeeding and the introduction of gluten in relation to weaning. Initial administration of gluten before 4 months of age is associated with an increased risk of developing the disease, and the introduction of gluten after 7 months is associated with a marginal risk. However, the overlap of gluten introduction with breastfeeding may be a more important protective factor in minimizing the risk of celiac disease.

The occurrence of certain gastrointestinal infections, such as rotavirus infection, also increases the risk of celiac disease in childhood.

Now understand how the research of autoantibodies can help in the diagnosis of celiac disease: The role of autoantibodies in the diagnosis of celiac disease

References

1. Green PH, Cellier C. Celiac disease. N Engl J Med. 2007 Oct 25;357(17):1731-43. doi: 10.1056/NEJMra071600. PMID: 17960014.
2. Kaminarskaya Yu?. Celiac disease, wheat allergy, and nonceliac sensitivity to gluten: topical issues of the pathogenesis and diagnosis of gluten-associated diseases. Clinical nutrition and metabolism. 2021;2(3):113–124.

How to Cite this article

Martins BC. Pathogenesis of Celiac Disease. Gastropedia, 2023, vol I. Available at: https://gastropedia.com.br/gastroenterology/intestine/pathogenesis-of-celiac-disease

Fecal microbiota transplantation (FMT) or fecal transplant involves the infusion of feces from a healthy donor into the gastrointestinal tract of a patient who has a disease related to alteration of the intestinal flora.

The first reports of FMT are from 1700 years ago when a Chinese doctor administered suspensions of human feces orally to patients with food poisoning and/or severe diarrhea. In 2013, the first well-designed study on the success of FMT in infections by Clostridium difficile was published in the New England Journal of Medicine and has since motivated numerous other works related to the topic.

The formal indication of FMT currently is in recurrent infections by Clostridium difficile with a cure rate of up to 90%.

There are ongoing studies of FMT in other gastrointestinal diseases (inflammatory bowel disease, irritable bowel syndrome) as well as in endocrine (obesity, metabolic syndrome), neurological (Parkinson’s, multiple sclerosis), hematological (ITP, GVHD) and psychiatric (autism) diseases.

For the smooth running of the FMT, a multidisciplinary team (attending physician whether it is the clinician, gastroclinician or geriatrician, infectious disease specialist and the endoscopist) aligned and with a well-established protocol in the service is necessary.

STAGES OF THE PROCEDURE

1. CHOICE OF DONOR

The donor can be related or not. This person will have to go through a rigorous infectious screening and a questionnaire regarding the presence of other diseases that may make donation unfeasible.

2. COLLECTION, PREPARATION AND ADMINISTRATION OF MATERIAL

The donor should arrive at the laboratory on the day of the procedure and the ideal time between the collection of feces and the infusion of the material is 6 hours. The fecal weight should be at least 50g and the total volume of the suspension is 100 to 200ml, which will be infused depending on the chosen route. There is also the option to freeze the material but it is preferable to use fresh feces (see image below).

3. ROUTE OF ADMINISTRATION

According to the articles published so far, all 5 routes studied show similar results. In this way, FMT can be performed by:

• Upper digestive endoscopy with nasogastric/nasoenteral tube
• Anterograde enteroscopy
• Colonoscopy
• Rectosigmoidoscopy
• Enema

What will determine the choice of method will be the clinical condition of the patient and experience of the endoscopist. In the upper route, it is suggested to infuse up to 100ml slowly through the nasoenteral tube or through the accessory channel or by a spray catheter. In the lower route, it is suggested to infuse as much of the material as possible (average of 200ml) in the terminal ileum and right colon.

4. PRE, PERI AND POST FMT CARE

The preparation of the exam is the adequate fasting and in cases where the chosen route is low, intestinal preparation can be performed with mannitol solution or polyethylene glycol.

Some precautions can be taken, however, still nothing consensual, such as:

• Use of proton pump inhibitors
• Use of prokinetics
• Use of antidiarrheals (loperamide)

It is recommended to infuse about 100ml of the fecal material slowly when the upper route is used, while when FMT is done by the lower route, slightly larger volumes are used (about 200ml).

5. ADVERSE EVENTS

Adverse events can occur in up to 30% of cases, usually in the first 48 hours post procedure and treated conservatively. The most common are fever, diarrhea, abdominal cramps and belching. Rare cases of death have been described due to regurgitation with bronchoaspiration of fecal material and perforation due to toxic megacolon.

FINAL CONSIDERATIONS

So far, the only indication of FMT with proven scientific evidence is in severe infections by Clostridium difficile. Due to the increase in incidence and morbidity and mortality related to infection by C difficile, fecal microbiota transplantation has been a good therapeutic option in selected cases. In Brazil, there is still no well-defined regiment for the procedure and there are few centers that have performed FMT. However, with recent discoveries of the influence of intestinal microbiota on immune response, it may be that in the future new indications will emerge and FMT will be a widely used procedure in our country.

HOW TO CITE THIS ARTICLE

Carlos A. Fecal Microbiota Transplantation. Gastropedia 2022. Available at: https://gastropedia.com.br/gastroenterology/intestine/fecal-microbiota-transplantation

BIBLIOGRAPHIC REFERENCES

1. Bennet JD, et al. Lancet. 1989 Jan 21;1(8630):164.
2. Zhang F, et al. Am J Gastroenterol. 2012 Nov;107(11):1755
3. Van Nood E, et al. N Engl J Med. 2013 Jan 31;368(5):407-15
4. Cammarota G, et al. Gut 2017;66:569–580
5. Mullish BH, et al. Gut 2018;0:1–22
6. Choi HH, et al. Clin Endosc. 2016 May;49(3):257-65