The principal findings are: 1) mucosal recovery did not occur in a substantial portion of adults with CD for years following diagnosis (rate of confirmed mucosal recovery only 34% at 2 years; 95% CI: 27%–40%), 2) there was a borderline significant association between confirmed mucosal recovery (vs. persistent damage) and reduced mortality (HR= 0.13; 95% CI, 0.02–1.06; p = .06) independent of age and gender, and 3) poor compliance to GFD, total villous atrophy at diagnosis of CD, and severe clinical presentation were associated with persistence of intestinal damage in adults with treated CD.
A novel finding of this study is the fact that persons with mucosal recovery after treatment with a GFD may have a clinically relevant lower risk of all-cause mortality than patients with persistent mucosal damage. Moreover, the causes of death in most patients with persistent mucosal damage were CD-related complications such as refractory CD,16
Thus, histological documentation of mucosal recovery by systematic follow-up with duodenal biopsies appears to be a relevant clinical end-point in adults with CD.
The reason(s) that may explain the higher rate of persistent mucosal damage in this cohort are unknown. Most patients in this cohort had good clinical response to GFD, but persistent mucosal damage. However, it is possible that the well-known causes of symptomatic, non-responsive treated CD (e.g., gluten contamination) may also underlie persistent mucosal damage in some of our patients.40, 41
The overall rate of good adherence to GFD in our cohort (66%) is consistent with the rate observed in other adult populations;42–45
poor adherence to a GFD appears to be an obvious factor for persistent damage in a minority of our patients (13%). However, the fact that only 67 (43%) of 156 patients with good adherence to a GFD, as determined by the dietitian interview, achieved mucosal recovery suggests that occult gluten sources (either cross-contamination or inadvertent gluten ingestion that are difficult to identify) or other yet unknown factors (e.g., genetics, age-related, duration of gluten exposure before treatment) may play a role in persistence of mucosal injury in adults with treated CD. These findings further support the urgent necessity of standard labeling for gluten-free foods in the United States.46, 47
Inappropriate food labeling, poor awareness and education about CD, high rate of undetected CD, late intervention, American lifestyle (e.g., culture of “dining out” and easy access to fast-food restaurants), and the limited availability or high cost of gluten-free foods (without compensation for additional cost of maintaining a GFD) might be some factors that explain discrepancies in rate of mucosal recovery after treatment with a GFD among United States and countries with excellent rates of mucosal recovery in adults such as Finland.48, 49 13, 46, 50
Thus, good adherence to GFD is necessary for mucosal recovery, but does not guarantee mucosal recovery in all. Currently, there is not consensus on either the role of intestinal biopsy to monitor intestinal recovery or the most appropriate time of repeat the intestinal biopsy after treatment with a GFD in adults with CD. Our data suggests that the time to mucosal recovery in adults with treated CD is longer than 6 months. Accordingly, a follow-up biopsy, 12–24 months after the onset of treatment with a GFD may be advisable in adults with CD. In this cohort, clinical response after GFD was not associated with mucosal recovery, consistent with other previous reports.9, 15 51
Serological responses (either negative EMA or negative tTGA) were significantly associated with mucosal recovery, however, persistent mucosal damage may be present in the absence of EMA or tTGA in the serum. Thus, biopsy remains the best tool to evaluate mucosal response in adults with CD, although limited only to the proximal small-intestine, where healing seems to lag behind healing more distally.52
Interestingly, 4 patients with poor adherence to GFD achieved mucosal recovery, suggesting that the development of tolerance to gluten may be possible in some adults with biopsy-proven CD; 53–55
however, clinical or histological relapse of the disease (in some cases with a different phenotype) or complications may still occur over time.54, 56
Mucosal recovery in adults with CD may be obtainable after strict adherence to GFD but may require a longer time,13
especially in patients with total villous atrophy at diagnosis as suggested by the evidence of histological improvement (from total to partial villous atrophy) after treatment with a GFD in 44% of our patients with total villous atrophy at baseline. Thus, it is possible that a longer time on a strict GFD may result in mucosal recovery in some patients consistent with our finding that 59% patients with a second or subsequent follow-up biopsies achieved mucosal recovery. However, cautious interpretation of these data is recommended because second (or subsequent) follow-up biopsies were obtained in only one-third of our cohort. Lastly, our results, obtained in a specialized center for celiac disease care may not be applicable to patients who do not have access to expert dietary instruction.
Intraepithelial lymphocytosis improved after treatment with a GFD in 92% of patients with concomitant mucosal recovery. The reason for persistence of intraepithelial lymphocytosis in 7 of our patients with mucosal recovery is unknown, but may be related to gluten-independent factors.34 33, 57
On the contrary, intraepithelial lymphocytosis was observed in up to 49% of patients without mucosal recovery. The fact that 51% patients without mucosal recovery had normal IEL numbers, suggests that intraepithelial lymphocytosis may improve before complete mucosal recovery is achieved, consistent with the model of stages of spectrum of severity. 31
All patients who died within 10 years of follow-up without mucosal recovery had concurrent intraepithelial lymphocytosis in the last follow-up biopsy. Taken together, these findings further support previous reports on the clinical benefit that a GFD may have in the treatment of both mild enteropathy CD or severe CD.1, 9, 58
Potential limitations of this study are those related to a retrospective design--not all patients underwent follow up biopsies at uniform intervals, missing data, drop-outs, and potential of referral or selection bias. Analysis of both the rate of mucosal recovery and potential interventions to improve histological outcome in adults with CD in referral and population-based cohorts by a prospective study design appears to be justified.
In conclusion, we demonstrated that mucosal recovery is absent in a substantial portion of adults with CD after treatment with a GFD. Achievement of mucosal recovery after treatment with a GFD in adults with CD may be associated with a better survival as compared to patients with persistent mucosal damage. Systematic follow-up with intestinal biopsies may be advisable in patients diagnosed with celiac disease as adults.
What is current knowledge?
- Lifelong GFD is the only effective treatment to alleviate the symptoms, normalize antibodies and the intestinal mucosa in patients with CD.
- Up to 95% of children with CD may achieve mucosal recovery within 2 years after starting treatment with a GFD. The rate of mucosal recovery after treatment with a GFD in adults with CD is less certain.
- Persistent mucosal damage after treatment with a GFD may increase the risk of complications in adults with CD. However, the effect that persistent mucosal damage after treatment with a GFD may have on survival of adults with CD is unknown.
What is new here?
- Mucosal recovery was absent in a substantial portion of adults with CD years after diagnosis (Kaplan-Meier 2-year mucosal recovery rate of 34%; median time to confirmed mucosal recovery of about 3.8 years).
- There is a borderline significant association between confirmed mucosal recovery (vs. persistent damage) and reduced mortality (HR= 0.13; 95% CI, 0.02–1.06; p = .06) independent of age and gender
- Systematic follow-up with intestinal biopsies may be advisable in patients diagnosed with CD as adults.