In this large population-based cohort study, duration of CD proved to be a strong predictor of future DRP development. The association between T1D and CD is well recognized and may be due to shared risk factors (21
). Research has largely focused on studying the prevalence of CD in T1D (8
), as well as the benefits of starting a gluten-free diet in asymptomatic CD within the T1D population (9
). Few studies have examined the risk of complications in patients with both conditions (10
), and none have thus far been able to determine time-specific risks for T1D complications.
The present findings are consistent with those of our earlier study (U.K. study) (11
) in which advanced retinopathy was seen in 58.3% of patients with T1D and CD versus in 25% of patients with T1D without CD (11
). The high prevalence of DRP, neuropathy, and nephropathy in the U.K. study could mirror different patient characteristics and T1D-management traditions in Sweden and the U.K. Case and control subjects in the U.K. study were selected from a tertiary diabetes center (possibly with higher rates of complications because of selecting patients with severe T1D), whereas the current (Swedish) study was based on all patients with a recorded diagnosis of T1D. The higher prevalence of DRP in the U.K. study could also be due to malnutrition in the CD plus T1D group, since they were thinner than the T1D-only group.
Research evidence suggests that patients with T1D screened for CD and subsequently prescribed a gluten-free diet improve in their clinical parameters, including growth and metabolic control, compared with T1D patients untreated for CD (9
). However, in our U.K. study on retinopathy a 1-year gluten-free diet did not influence the prevalence of retinopathy (11
). Although the majority of young patients with CD seem to adhere well to a gluten-free diet (24
), we cannot rule out that the addition of yet another condition (i.e., T1D) affected dietary adherence negatively. In a random subset of patients with CD in our dataset, 83% adhered to a gluten-free diet (16
). In the current study, we lack individual-based information on gluten-free diet, but one can speculate that the highest degree of dietary adherence was noted just after diagnosis, when the risk of DRP is lower.
In a recent multicenter study (25
), the effect of biopsy-proven CD on metabolic control in patients with T1D was examined over time. After 5 years of follow-up, patients with T1D and CD had lower weight and height than patients with only T1D (25
). However, no differences in BMI and HbA1c
levels were observed between the groups after the 5-year follow-up. If patients with T1D and CD have worse nutritional status than T1D patients without CD, the former's risk of DRP development could be increased (26
One explanation for the lower risk of DRP at baseline in patients with T1D and CD is the lower levels of cholesterol and blood pressure found in CD patients (27
). Hypercholesterolemia and hypertension increase the risk of DRP (3
). Recently, Picarelli et al. (10
) demonstrated that patients with T1D and CD had lower levels of HbA1c
, triglycerides, and cholesterol than patients with only T1D. These researchers (10
) found no signs of retinal or renal abnormalities in patients with T1D and CD (10
), but the study was cross-sectional without follow-up.
Inflammatory and autoimmune mechanisms may be involved in DRP development (4
). In fact, anti-inflammatory drugs have been suggested as potential new therapies against DRP (7
). When the carotid intima-media thickness was examined in Italian patients with T1D and CD (23
) (as a measure of subclinical atherosclerosis), these patients had greater carotid intima-media thickness than patients with only T1D (23
). The positive association between CD and subclinical atherosclerosis could signal microvascular damage (DRP). Patients with CD are at increased risk of cardiovascular death (15
) and incident ischemic heart disease (28
). Another possible mechanism for the increased risk of DRP seen over time is that of persistent low-grade inflammation. The intestinal mucosa in patients with CD can take a long time to fully recover, even after initiation of a gluten-free diet. Studies show that chronic, low-grade inflammation plays an important role in the pathogenesis of DRP (29
). Having low-grade intestinal inflammation or CD with little symptoms might also affect the patient’s adherence to a strict gluten-free diet, which in turn could potentially affect the risk of future DRP.
The pattern of increasing risk of DRP seen over time was also present in our subgroup analyses in which we found lower risk estimates for DRP during <10 years’ duration of CD diagnosis and higher risk during ≥10 years’ CD duration. The nonsignificant differences in DRP risk across calendar periods may be due to longer T1D duration before the end of follow-up in patients diagnosed in earlier calendar periods (many years at risk for DRP in each patient). In contrast, patients diagnosed in the latest calendar period were (for study design reasons) only at risk just after T1D diagnosis, and because the follow-up time was short, most patients did not develop DRP. The number of DRP events after 2000 was low, with a wide 95% CI (0.11–1.80). The differences in calendar period–specific risk estimates may also reflect the changes made in T1D care and management in Sweden over time as well as the diagnostic methods used for identification of CD.
The major strengths of this study are the population-based design, the definition of CD (all cases were biopsy verified), and that our study included all patients with T1D in Sweden. The nationwide identification of CD from all pathology departments in Sweden (16
) minimized the risk of selection bias. Although we did not use positive CD serology for the diagnosis of CD, 88% of those with available data on CD serology had positive antibodies before biopsy (16
). Another strength is the large number of participants and statistical power: because >900 patients had T1D and CD, we could perform stratified analyses. Additional data on pregnancy and medication allowed us to conduct sensitivity analyses and minimize potential misclassification. Even when we restricted our outcome to DRP requiring retinal laser therapy, we found the same pattern of low HR in early CD followed by an increased HR over time (longer duration of CD). Because of fewer positive events in this subanalysis, only the HR in patients with CD for 10–14.99 years was statistically significant.
This study is limited by the absence of information on metabolic control (HbA1c
, insulin dosage, and BMI) in patients with T1D. In addition, the 41,566 patients with T1D were not screened for CD specifically for this study; therefore, the clinical presentation may vary among our CD patients. Today, all Swedish children and adolescents with T1D are screened for CD (routine care), but that may not have been the case in the beginning of the study period. In the 1990s, two-thirds (29 of 44) of all pediatric departments regularly screened all T1D patients for CD, with the remaining departments opting for CD testing on clinical suspicion (30
). Hence, we cannot dismiss the possibility that there are individuals with undiagnosed CD in our T1D-only cohort. Still, their presence will not affect our risk estimate more than marginally because patients with T1D and undiagnosed CD are unlikely to make up more than a small percentage of our reference category (T1D only). Furthermore, if undiagnosed CD would have any effect, it would probably dilute existing associations.
Our results indicate that CD is a strong predictor for simplex and severe laser-treated DRP in patients with T1D. We suggest that the lower effect of DRP in early CD is due to DRP-protective characteristics of patients with CD (lower cholesterol and BMI). Long-standing CD, however, increased the risk of DRP by >200% (aHR 3.01) and thus merits closer monitoring of DRP in patients with T1D.