REFRACTORY CELIAC DISEASE
Patients with late-onset CD, especially those not diagnosed until after age 50, may have a diminished or absent response to dietary therapy. In some patients, histologic signs and clinical symptoms persist or relapse after a prior positive response to a strict GFD, despite continued adherence to the diet for longer than 12 months.44 Once other causes have been carefully excluded, these patients are considered to have refractory celiac disease (RCD). Exact prevalence of RCD is unknown, but Tack et al8 estimate it at 5% of all cases of CD. Relapsing CD resulting from poor adherence to the GFD is not considered true RCD.8,16,37,38
According to researchers for the European Celiac Disease working group,8,45 RCD can be divided into types I and II:
• RCD I, in which normal polyclonal T cells are present in the intestinal lumen
• RCD II, in which abnormal clonal T cells infiltrate the intestinal mucosa, representing premalignancy.45
The histologic picture of RCD mimics that of severe CD. Malabsorption complications, lesions in the intestinal mucosa, and inflammatory lymphocytosis are present.44 Some patients, like those with classical CD, have serology test results that are consistent with CD and an initial response to GFD therapy; after months or years, however, this response subsides. Other patients are immediately unresponsive to GFD and lack the serologic markers for CD.8
A differential diagnosis including other explanations for the manifestations of RCD must be carefully reviewed, with each excluded, through the strategies shown in Table 2. This review is essential, as patients with RCD II have a much worse prognosis than those with RCD I; the associated five-year survival rates are 44% to 58%, versus 85% or greater, respectively.36,46
Additionally, the continued autoimmune expansion of aberrant T cells in patients with RCD II causes early conversion to malignancy, usually within four to six years after diagnosis. Enteropathy-associated T-cell lymphoma is the most common malignancy, occurring in more than 50% of patients with RCD II, and a likely cause of death.3,8,46,47
Treatment for Refractory Celiac Disease
In addition to the GFD, patients with RCD I generally respond well to corticosteroids or other immunosuppressive treatment.8 Use of budesonide, a corticosteroid given in a once-daily, 9-mg dose, has led to almost complete recovery in most patients. Duration of therapy is response-dependent.37
Systemic corticosteroids or other immunosuppressant agents, such as azathioprine, should be reserved for patients with RCD I or RCD II who do not respond to budesonide, as lengthy treatment regimens are required, with considerable risk for adverse effects.35,48
Recently, promising results have been reported in a small, open-label cohort study involving patients with RCD II who underwent five days of treatment with IV cladribine (0.1 mg/kg/d).49
PREVENTION OF CD
A good nutritional start from birth could be the best means of preventing symptomatic CD. According to findings from a meta-analysis of data from four studies, children being breastfed at the time gluten was introduced had a 52% reduction in risk for CD, compared with their peers who were not being breastfed at that time.50
The protection breast milk appears to provide against CD is not clearly understood. One possible mechanism is that breast milk may protect an infant against CD by preventing gastrointestinal infections, as is the case with other infections. The presence of GI infections (eg, rotavirus) in early life could lead to increased permeability of the intestinal mucosa, allowing the passage of gluten into the lamina propria.3,8,50
Extended duration of breastfeeding is also associated with a reduced risk for CD.8,41,50 Long-term studies are needed, however, to determine whether breastfeeding delays CD onset or provides permanent protection against the disorder.
RECENT DEVELOPMENTS
A recently marketed OTC testing kit for CD is now available in Canada and other countries outside the US; this may be an indication of the growing awareness of the numbers of patients with undiagnosed CD. The test parallels the tTG serum test, which in the US is evaluated only in laboratories; it has comparable specificity and sensitivity, with results within 10 minutes. In the US, the FDA has not yet approved the kit, but domestic testing of the product may soon be under way.51
Alternative treatment modalities are currently focusing on the detoxification of wheat components, rapid enzymatic degradation to reduce exposure to gluten, inducing gluten tolerance, inhibiting permeability of the small intestine to gluten (which, it is thought, may prevent many of the systemic manifestations of CD), and finally, development of an immunomodulatory vaccine.8,33 None of these therapies is yet approved.
IMPLICATIONS OF DELAYED DIAGNOSIS
The unrecognized prevalence of CD is a growing issue, as many symptomatic but unscreened patients are frequently misdiagnosed with IBS, chronic fatigue, or other idiopathic disorders. The silent and latent forms of CD are of the greatest concern, as they show minimal signs and can lead to multiple organ system damage and are implicated in other autoimmune disorders. The longer diagnosis is delayed, the greater is patients’ resistance to dietary therapy, and the less likely that established intestinal and/or neurologic damage can be reversed.10,20,51