7 Autoimmunity in gastrointestinal disease

Achalasia

Eosinophilic gastroenteritis (including oesophagitis)

Crohn’s disease

Ulcerative colitis (UC)

Whipple’s disease

Coeliac disease

Sclerosing mesenteritis

Autoimmune pancreatitis

Irritable bowel syndrome (IBS)

IPEX syndrome (see Chapters 1 and 4).

Post stem cell transplantation.

Eventual massive dilatation of the oesophagus occurs.

Occurs in early to middle adult life.

Marked increase in the risk of subsequent oesophageal carcinoma.

Similar features occurs in the trypanosomal infection Chagas’ disease.

Autoantibodies have been described that recognize the neurons of Auerbach’s plexus in the oesophageal wall in the idiopathic form of the disease; these are probably an epiphenomenon, and not disease-inducing.

25% of patients with achalasia have autoimmune thyroid disease.

Drugs to relax smooth muscle are also used (calcium-channel blockers and nitrates).

Botulinum toxin type A (Botox) injections may give temporary relief.

Associated with cholangitis, appendicitis, pancreatitis, giant duodenal ulcer, and eosinophilic infiltration of spleen.

iincidence associated atopic disease and urticaria, and coeliac disease.

Any age/race/sex; higher incidence in later life. Incidence appears to be increasing.

May be seasonal variation in presentation (higher in summer).

Association with hypereosinophilic syndromes (see Chapter 3).

↑IL-5, IL-13, IL-15, fibroblast growth factor 9, and eotaxin.

Bowel wall may be thickened on scans.

Exclude other systemic and local diseases where bowel eosinophilia may be seen (Crohn’s disease, polyarteritis nodosa, Churg–Strauss syndrome, malignancy, parasites).

Trial of elimination diet if specific IgE to foods identified (rarely successful).

Sodium cromoglicate, ketotifen, and montelukast can be tried.

Omalizumab and anti-IL5 Mab have been tried in a small number of cases.

Presents with diarrhoea and abdominal pain, or with evidence of the extra-GI complications.

Inflammation is transmural and granulomata are present.

There is superficial ulceration and crypt abscesses.

Skin lesions are common, and the deep penetrating ulceration frequently gives rise to fistulae.

Associated with seronegative arthritis, uveitis, and sclerosing cholangitis.

Malabsorption (especially of vitamin B₁₂, as the terminal ileum is frequently affected) may occur.

Strong association with NOD-2 (CARD15) gene on chromosome 16 that senses bacterial peptidoglycan and regulates NF-κB expression.

Over 30 genes which contribute directly or indirectly have been identified including:

Measles has also been suggested as a possible trigger.

There is evidence of both a cell-mediated response and defective T-cell suppressor function.

Excess T_H17 cells are critical to disease development.

Increased B-cell activity with immunoglobulin and complement deposition in damaged bowel.

Activated macrophages are present and mast-cell numbers are increased.

Excessive inflammatory cytokines are present (TNFα).

Crohn’s disease should be considered to be a form of host-defence disease with impairment of the ability to handle intestinal bacteria correctly.

Other antibodies found in Crohn’s disease include:

Monitoring is best done with acute-phase markers ESR/CRP.

α₁-acid glycoprotein (orosomucoid) was said to be more sensitive as an acute-phase marker for inflammatory bowel disease, but it really adds nothing to CRP.

Thalidomide is also used for its anti-TNF effect.

Resistant disease is treated with anti-TNF agents: infliximab (5mg/kg), etanercept, adalimumab (Humira^®), or certolizumab (Cimzia^®) (pegylated Fab fragment of humanized anti-TNF).

Natalizumab (Tysabri^®), a humanized mAb against the α4 integrin, has been licensed in the USA for remission induction and maintenance of severe Crohn’s disease. A major risk is development of progressive multifocal leucoencephalopathy (PML).

Presentation is usually with bloody diarrhoea.

Extra-intestinal manifestations include:

Pancolitis may cause a toxic megacolon, a medical/surgical emergency.

Also associated with allele 2 of the IL-1 receptor antagonist.

Multiple genetic loci associated with UC.

Increase in activated T cells (CD4⁺, DR⁺, CD45RO⁺) and also inflammatory cells, including neutrophils.

Atypical P-ANCA (non-MPO) are also seen; a number of candidate antigens have been suggested as the target for this atypical P-ANCA, including lactoferrin and cathepsin G (?related to reactions to enteric bacteria).

50–70% of UC patients will be atypical P-ANCA⁺.

P-ANCA positivity is associated with pancolitis and primary sclerosing cholangitis.

10–15% of patients may have anti-Saccharomyces cerevisiae antibodies (ASCA)—diagnostic utility is low.

Inflammatory markers (ESR/CRP) are elevated and provide a useful way of monitoring disease.

Anti-TNF agents appear to be less effective in UC than in Crohn’s disease.

Significantly increased risk of carcinoma of the colon, so those with pancolitis will usually have a totally colectomy, which is curative. Regular surveillance by colonoscopy may be sufficient for milder disease.

Features of a significant protein-losing enteropathy may occur.

Dementia occurs as late complication.

More common in men.

T.whippelii is a common mouth commensal, and therefore rarely causes the disease, suggesting a subtle immunodeficiency in those who do develop it.

Treatment courses <1 year are associated with 40% relapse rate.

Particularly common in western Ireland (prevalence 1 in 300).

In the UK occurs in 1 in 1500 people.

The symptoms can appear at any age.

In childhood there is failure to thrive, while in adults the disease often comes to light during the investigation of unexplained anaemia (usually iron-deficient anaemia).

Malabsorption may be obvious, but many patients do not have significant steatorrhoea.

Many adult patients may have a normal or increased weight (due to compensatory hyperphagia).

Strong associations with the blistering skin rash dermatitis herpetiformis (see Chapter 10) and with autoimmune diseases particularly diabetes, thyroid disease, Addison’s disease, and SLE.

Gluten sensitivity has been associated with an encephalopathy and a cerebellar syndrome, which respond to gluten withdrawal.

95% of patients are DQ2 positive, but only a minority of people with DQ2 develop coeliac disease.

10% of patients will have selective IgA deficiency.

Subtotal villous atrophy and an increase in intra-epithelial lymphocytes in the early stages are also compatible with the diagnosis.

Total villous atrophy is not required to make the diagnosis.

The amount of gluten being consumed by the patient at the time of biopsy will have a significant bearing on the biopsy findings.

As IgA deficiency may occur, testing for IgA deficiency as part of screening has been recommended, although some centres have dropped this.

In IgA deficiency IgG anti-EMA or tTG have the same significance.

There is no place for the use of R1 reticulin antibodies or IgA and IgG anti-gliadin antibodies, which have low sensitivity and specificity.

The gold standard for diagnosis is still biopsy of the jejunum, although endoscopic biopsy of the duodenum usually gives satisfactory and equivalent results.

Serological tests are now recognized to have high sensitivity and specificity, and many patients, particularly children, will not be biopsied, although best practice indicates that patients should still be biopsied if possible.

Positive antibodies with normal biopsy may represent a prodromal state.

Children with type I diabetes should be screened annually for coeliac disease.

Abnormal bowel returns to normal when gluten is withdrawn from the diet.

Antibodies gradually disappear with gluten avoidance and reappear on gluten challenge.

Compliance is important, as continued exposure to gluten increases the risk of intestinal lymphoma (T-cell).

Secondary splenic atrophy may occur (Howell–Jolly bodies on blood film).

Dermatitis herpetiformis usually responds to gluten withdrawal, but may require treatment with dapsone (care in G6PD-deficient patients).

CRP may be elevated; CT scans may be helpful.

May include mesenteric panniculitis.

Biopsy will be required for confirmation.

May be associated with other autoimmune conditions (thyroid, sclerosing cholangitis, SLE) and autoimmune pancreatitis (see below).

Treatment may include corticosteroids, tamoxifen (to reduce production of TGF-β), colchine, cyclophosphamide, and thalidomide.

Characterized by IgG4 plasma cell infiltrate in pancreas.

Raised serum IgG4.

Autoantibodies to plasminogen-binding protein (PBP) may be a marker, but can be found also in patients with pancreatic cancer.

Other autoantibodies may be found (ANA, AMA, ASMA, ANCA).

Responds to corticosteroids; steroid-sparing agents may be required (mycophenolate mofetil, cyclophosphamide).

Evidence supporting the role of IgG antibodies to foods is weak:

NICE–BDA Guidelines advise the avoidance of ‘resistant starches’ (starchy foods that have been cooked or reprocessed more than once).

All patients claiming that wheat exacerbates symptoms must have coeliac disease excluded (see above).

There is a strong association with CFS/ME, fibromyalgia, depression, and anxiety. Stress invariably exacerbates symptoms.