IgG4-related disease (IgG4-RD) is caused by the abnormal accumulation of immune cells in the body’s tissues, especially plasma cells that produce high amounts of IgG4 antibodies. Patients are typically amazed and relieved once the diagnosis of IgG4-RD has been established. Once they become convinced that they do NOT have cancer, an infection, or some other inflammatory disease, they naturally want to take charge of their medical issues and partner with their medical team to do as much as they can to get their disease under control, to avoid organ damage, and to prevent disease flares.
Can Diet Control IgG4-RD?
A highly relevant question, and certainly among those that IgG4-RD experts hear most! The short answer is that although diet often plays an important role in managing IgG4-RD and is particularly critical in patients with some types of organ involvement (especially pancreas or kidney disease), dietary alterations do not offer a way of impacting disease activity in a predictably positive way. The longer answer, which is important, is as follows: And they begin to wonder about something they can certainly affect: diet. Has something that I’ve been eating caused this? Is there something I can eat more of (such as a vitamin) to keep this from getting worse?
There are examples of conditions in which diet plays a direct role in causing a disease or making it worse. The classic example is gluten enteropathy (celiac disease or sprue), a condition that is caused by gluten ingestion in the diet and treated effectively if gluten (a substance found in bread, beer, and other foods) is removed. Another is high blood pressure, in which excessive sodium consumption can make the condition worse.
This is not the case for IgG4-RD. (As a clinician, I wish it were that simple!) Unfortunately, there is no evidence and little reason to suspect that any element in the diet causes or contributes to IgG4-RD. There is also no basis for believing that eating more of any particular food or ingesting any particular types of vitamins or supplements will fundamentally alter the underlying inflammatory process. For these reasons, it’s wise not to put too much faith in the idea that dietary alterations or the ingestion of certain supplements will have a lasting, impactful effect on the basic immunology of IgG4-RD.
The Role of Diet in Managing IgG4-RD
That is NOT to say, however, that diet is not important in IgG4-RD. While there’s no solid evidence that a particular diet will fundamentally alter the course of IgG4-RD, and managing IgG4-RD with food alone is not feasible, chronic inflammation is a hallmark of IgG4-RD, and there is a link between diet and inflammation. There is one major setting in which diet plays an important role in effective IgG4-RD management and helps patients minimize the disruption that IgG4-RD can cause in their lives. This is the setting of pancreatic disease (exocrine pancreatic insufficiency). There is a range of different clinical profiles of IgG4-RD, and diet plays a particularly key role for people with involvement of the pancreas. This organ is important for digestion and blood sugar regulation.
Read also: Managing Stage 3 Kidney Disease with Diet
Pancreatic Involvement and Dietary Adjustments
Some patients with histories of pancreatic involvement benefit from pancreatic enzyme replacement in their diets - supplementing their meals and snacks with tablets that replace the body’s pancreatic enzymes normally produced by a healthy pancreas. Patients with pancreatic involvement may also have negatively impacted micronutrients. The potentially impacted micronutrients are the fat-soluble Vitamins A, D, E, and K, along with Zinc, B12, folic acid and Iron. While clinical deficiency is uncommon, sub-clinical depletion of certain micronutrients may be present and patients may be unaware. A daily multivitamin with minerals may help, but testing blood levels when starting pancreatic enzymes, and yearly thereafter, would be recommended. Collaboration with a Registered Dietitian may also be helpful, especially if unexplained changes to skin, hair, nails, or vision are present.
General Dietary Recommendations for IgG4-RD
There’s no evidence that particular foods will definitively cause or contribute to IgG4-RD, so there’s no list of foods to avoid with IgG4-RD that can be universally applied. While there are no set inflammatory foods to avoid with IgG4-RD, it is recommended that most of these foods be limited in any healthy diet. Eliminating or limiting these foods could help ease symptoms for some people. For instance, fatty meals can trigger gastrointestinal problems for some people with pancreatic disease.
Practical Tips for Dietary Management
Make small, sustainable changes. Don’t overwhelm yourself with many big changes at once. Don’t do it alone. It is important not to make dietary changes without first discussing them with your healthcare team. It may be a good idea to consult with a dietitian or nutritionist who has experience with IgG4-RD. Always let your healthcare team know if you notice anything new or unusual.
The Significance of IgG4 in Allergic Diseases
The detection of FS-IgG4 appeared in the 1970s (12) and was soon applied in clinical work. However, the significance of IgG4 in allergic diseases is still controversial. It was not recommended for the diagnosis of food allergy in the most influential guidelines on food allergy, including those from the European Academy of Allergy and Clinical Immunology (EAACI) (13), the National Institute of Allergy and Infectious Diseases (NIAID) (14) and the American Academy of Allergy and Immunology Position Statement (AAAI) (15). These opposing opinions have clearly hindered the development of its application in clinical work until the studies on EOE changed the perception. Subsequent evidence has shown that FS-IgG4 is closely correlated with allergic diseases, including allergic rhinitis, asthma, atopic dermatitis, and chronic rhinosinusitis (16-19).
Study Design and Methods
This retrospective observational study aimed to evaluate the clinical significance of serum total IgE, HDM IgE, FS-IgE, and FS-IgG4 antibodies in the treatment of allergic diseases in children. Electronic medical records (EMR) of all patients with allergy diseases treated at the Department of Allergy, the Second Affiliated Hospital of Zhejiang University School of Medicine from January 2018 to December 2020 were collected and evaluated. The inclusion criteria were children aged 0-14 years who fulfilled the ARIA guideline for allergic rhinitis and/or GINA guideline for asthma (20, 21), the International Consensus (ICON) guideline for conjunctivitis (22), the EAACI/GA2 LEN/EDF/WAO guideline for urticaria (23), the diagnostic criteria by Hannifin and Rajka for atopic dermatitis (24), and with the data of serum total IgE, HDM IgE, FS-IgE, and FS-IgG4 tested simultaneously. Patients with autoimmune diseases were excluded. Ultimately, 407 patients were recruited for the analysis. Among them, 67 patients underwent dietary elimination guided by FS-IgG4 and supplemented with/without probiotics. After more than 3 months of treatment, serum total IgE, HDM IgE, FS-IgE, and FS-IgG4 were retested, and clinical manifestations were reevaluated.
Read also: Explore Diet and Disease
Study Groups
According to the system affected, patients were categorized into three groups: the group with involvement of the respiratory system (including rhinitis, asthma, and conjunctivitis), the group with involvement of the skin system (including urticaria and atopic dermatitis), and the group with multiple systems involvement (those with a combination of symptoms from different systems). Furthermore, patients with a follow-up history were divided into two groups based on their treatment regimen: those who underwent FS-IgG4-guided diet elimination for more than 3 months were assigned to the dietary elimination group, and those who underwent diet elimination combined with probiotic were assigned to the probiotic group.
Study Variables and Laboratory Testing
Clinical characteristics and demographic profiles were obtained from the hospital’s EMR system. Peripheral blood samples were taken from patients at the time of the initial presentation and during treatment according to the patients’ condition. All laboratory tests were carried out in our hospital laboratory. All of these were expressed in international units per unit volume (IU/ml). Levels of total IgE value>100IU/ml, HDM IgE and FS-IgE value>0.35 IU/ml were considered positive. The concentration of FS-IgG4 was divided into 4 grades: negative (−, <250 U/ml), weakly positive (+,250-500U/ml), positive (++,500-1000U/ml), strong positive (+++,>1000U/ml).
Diet Elimination and Probiotic Supplement
Sixty-seven patients underwent diet elimination based on the result of FS-IgG4. Foods determined as ++ or +++ were completely forbidden to eat, and + foods were reduced in frequency of intake (eating the food at an interval of more than 4 days). Among them, 36 of the patients were supplemented with probiotics in addition to dietary elimination. The above treatment time was required to last more than 3 months.
Outcome Measure
Demographic data, serum level of total IgE, HDM IgE, FS-IgE, and FS-IgG4 from the three groups involving different systems were analyzed initially and at follow-up visits after varying periods of intervention (3-6 months, 6-9 months, 9-12 months, or over 12 months) with diet elimination, with/without probiotic supplementation. Laboratory-related indicators, such as total IgE and HDM IgE, were numerically compared. Due to the low positive frequency of FS-IgE, only the overall positive rate was used for statistical comparison. For FS-IgG4, the test data may exceed the kit reference range.
The intervention of diet elimination or probiotic supplement caused distinct changes in different FS-IgG4; for example, one may decrease, but another may increase. Therefore, we designed a point system for statistical testing. We used 1 point to stand for one kind of elevated FS-IgG4, so patients’ FS-IgG4 status was scored according to the number of foods with positive FS-IgG4. The total was then used to compare the difference between pre- and post-intervention. The same scoring method was applied to FS-IgE changes before and after treatment. Furthermore, the improvement of clinical symptoms was classified based on the subjective feelings of patients before and after treatment by comparing the numbers in the dietary elimination and probiotic group showing significant improvement (‘better ‘or ‘excellent’), and those with no significant change (‘slightly worse ‘, ‘no change’, or ‘slightly better’). Finally, we explored independent factors influencing the clinical manifestations of allergic diseases through regression analysis.
Read also: A Review of the Mediterranean Diet in Kidney Disease
Statistical Analysis
For all patients, continuous data following a normal distribution were expressed as mean ± standard deviation and compared using single-factor analysis of variance (ANOVA). Non-normally distributed data were expressed as median (interquartile range) and compared using the Kruskal-Wallis test. Categorical variables were expressed as frequencies (percentages) and compared using the Chi-square or Fisher’s exact test. For patients before and after treatment, the paired t-test was used for normally distributed data, and the Wilcoxon signed-rank test was used for non-normally distributed data.
The Student’s t-test was employed to compare normally distributed data, while the Mann-Whitney U test was used for non-normally distributed data between the two treatment groups. Logistic regression analysis was conducted to determine whether the changes in total IgE, HDM IgE, FS-IgE, and FS-IgG4 before and after treatment were independent predictors for improvement of allergic diseases in children. Variables with an adjusted p value<0.1 in the univariate analysis were subsequently evaluated using a multivariate logistic regression model. A p-value <0.05 was the criterion for statistical significance in this analysis. Statistical analysis of all data was performed using SPSS 26.0 (IBM Corp.) and GraphPad Prism 8.0.1.
Demographic Characteristics
A total of 407 patients, with an average age of 7.2 ± 3.6 years (range 8 months to 14 years), were recruited and divided into three groups as following: 141 patients in the group with respiratory system involvement, 124 in the skin system group and 142 in the group with multiple systems involved. The baseline characteristics of the three groups are shown in Table 1. There were no significant differences in gender, age, family history of allergy, or birth history among the three groups (p> 0.05). Patients with multiple system allergies had the highest serum total IgE level (p < 0.05), and the lowest level of HDM IgE was observed in patients of the skin system (p < 0.01). The positive rate of FS-IgE was only about 30%, and there was no significant difference among the three groups.
The Difference in Total/FS-IgE and FS-IgG4 Positive Rates Among the Three Groups
In the three groups, we measured the proportion of patients who were positive for both total/FS-IgE and FS-IgG4, positive for total/FS-IgE but negative for FS-IgG4, negative for total/FS-IgE but positive for FS-IgG4, and negative for both. From the distribution of each group, the proportion of patients with both total IgE and FS-IgG4 positive was the highest, and the proportion of both negative was the lowest. It is noteworthy that the proportion of patients with FS-IgG4 positive and total IgE negative was higher than that of patients with total IgE positive and FS-IgG4 negative. Meanwhile, we found that the distribution of proportions among the three groups was significantly different (p<0.05) (Table 2). Upon pairwise comparison between groups (according to the multiplicity test criteria), the proportion of patients with both positive results in the multiple system group was significantly higher than that in the skin system group (p=0.012).
Comparison of FS-IgG4 Positive Rates Among the Three Groups
The positive rate of each assayed FS-IgG4 of 10 kinds was analyzed and compared among the three groups. Detailed data are shown in Table 4. In all the groups, eggs had the highest positive rate, followed by milk, while mushrooms were not detected as positive. Meanwhile, we found that children with respiratory allergic diseases had the highest positive rate of milk, which was significantly different from that of the skin system (p<0.01).
Outcome Before and After Treatments
Of the 407 participants, 67 underwent at least one follow-up evaluation and repeated laboratory testing under diet elimination guided by FS-IgG4 with or without probiotic supplements. The follow-up interval of patients in both groups before and after treatment was more than 3 months, with the longest follow-up interval being two and a half years. There were no significant differences in total IgE, HDM IgE, FS-IgE, and FS-IgG4 between the dietary elimination group and the probiotic group before treatment. However, after treatment, there was a significant difference in FS-IgG4 between the two groups, and the decrease was more pronounced in the dietary elimination group. Total IgE, FS-IgE, and HDM IgE remained unchanged (Figure 2). In addition, no significant differences before and after treatment were noted with regard to the changes in the total IgE, FS-IgE, and HDM IgE between the dietary elimination group and probiotic group. Yet, we found a significant decrease in FS-IgG4 before and after treatment in both groups. Comparatively, a more significant decrease was observed in the dietary elimination group.
Dietary Modification Improves Symptoms in Irritable Bowel Syndrome (IBS)
Dietary modification improves symptoms in irritable bowel syndrome (IBS). Identification of offending foods by dietary elimination/re-challenge is cumbersome. IgG4 antibodies to common food antigens are elevated in IBS. The study comprised 25 patients with IBS (3 M, 22 F, mean age 43 years, Rome II criteria). IgG4 titres to 16 foods (milk, eggs, cheese, wheat, rice, potatoes, chicken, beef, pork, lamb, soya bean, fish, shrimps, yeast, tomatoes and peanuts) were measured. Foods with titres >250 microg/l were excluded for 6 months. Symptom severity was assessed with a previously validated questionnaire at baseline, at 3 months and at 6 months. IgG4 antibodies to milk, eggs, wheat, beef, pork and lamb were commonly elevated. Significant improvement was reported in pain severity (p < 0.001), pain frequency (p = 0.034), bloating severity (p = 0.001), satisfaction with bowel habits (p = 0.004) and effect of IBS on life in general (p = 0.008) at 3 months. Symptom improvement was maintained at 6 months.
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