Celiac Disease and Systemic Lupus Erythematosus in Children

Celiac disease (CD) and systemic lupus erythematosus (SLE) are two diseases intensively studied in all age groups, with an increasing incidence at the global level, possibly due to the increased awareness of the diseases and their accurate diagnosis and as a consequence of the new research and innovation technologies that have appeared in medicine. The first is a controllable condition found in approximately 1% of the entire population in the form of a reaction to environmental stimuli affecting individuals with genetic susceptibility, causing gluten intolerance, gastrointestinal and extradigestive symptoms, starting from subclinical stages and culminating in severe malabsorption. On the other hand, lupus is an autoimmune disease with chameleon-like symptoms and found mainly in the female sex, which leaves its clinical mark on most organs, from the skin, eyes, and kidneys to the cardiovascular, pulmonary, neurological, osteoarticular, and hematological systems. Celiac disease (CD) and systemic lupus erythematosus (SLE) are two diseases intensively studied in all age groups, with an increasing incidence at the global level, possibly due to the increased awareness of the diseases and their accurate diagnosis and as a consequence of the new research and innovation technologies that have appeared in medicine. The first is a controllable condition found in approximately 1% of the entire population in the form of a reaction to environmental stimuli affecting individuals with genetic susceptibility, causing gluten intolerance, gastrointestinal and extradigestive symptoms, starting from subclinical stages and culminating in severe malabsorption. On the other hand, lupus is an autoimmune disease with chameleon-like symptoms and found mainly in the female sex, which leaves its clinical mark on most organs, from the skin, eyes, and kidneys to the cardiovascular, pulmonary, neurological, osteoarticular, and hematological systems.

celiac disease
systemic lupus erythematosus
children
nutrition

1. Introduction

Celiac disease, also called gluten-sensitive enteropathy, is characterized by a disturbance of the internal environment associated with histological changes in the small intestine, the most important of which is the subtotal atrophy of the villi with hyperplasia of the crypts. Clinically, it is manifested by a wide spectrum of symptoms, from gastrointestinal disorders (diarrhea, bloating, weight loss, and abdominal pain) to extra-intestinal symptoms (iron deficiency anemia, delayed puberty, and oral ulcers), centered on variable degrees of malabsorption [1,2]. With an estimated prevalence of 1:100, serological screening is performed by titrating anti-tissue transglutaminase antibodies (TGAs) considered positive at values over two times the normal limit, doubled by genetic testing for human leukocyte antigen (HLA)-DQ2 or HLA-DQ8 and total immunoglobulin A dosing. Regarding duodenal biopsy, the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommends its use in cases with positive TGA-IgA < 10 times the upper limit of normal values, with the possibility of abstaining if TGA-IgA is over 10 × the upper limit of normal values, in association with the positivity of endomysial antibodies in two blood samples. In the literature, however, there are authors adept at confirming the diagnosis through digestive endoscopy with biopsy in those with equivocal screening results but with strong clinical suspicion after a period of time in which the child follows a normal diet (with gluten content) [2,3,4,5].

Juvenile systemic lupus erythematosus is a multisystemic autoimmune/inflammatory disease that usually starts before the age of 18 (in approximately 15–25% of all SLE patients) where, unlike the adult form, it shows increased activity depending on aspects such as gender, ethnicity, and the age of onset, which results in significant damage and requires aggressive therapy. The incidence varies between 0.36 and 2.5 per 100,000 children, with a prevalence of 1.89–34.1 per 100,000, a peak incidence around the age of 12.6 years, and a physiopathological basis centered on the involvement of the genetic component, with >7% of patients developing the disease as a result of single mutations, while 5-year survival has improved from 30–40% in the 1950s to >90% in the 1980s. The diagnosis and therapy can be complex, being influenced by the polymorphism of the injuries (more aggressive in terms of the renal, hematological, and neuropsychic components), the need for individualized treatment, and drug interactions or associated comorbidities that can, in some cases, endanger lives. Also worth mentioning are the possible atypical forms of lupus, characterized by the absence of autoantibodies, a severe evolution, and a reserved prognosis, especially under the age of 5 [6,7,8].

2. Epidemiology

Celiac disease is associated with several autoimmune diseases, of which thyroid disease and type 1 diabetes are defined as “associated conditions” or conditions with increased prevalence but not directly related to gluten ingestion. Loci in the HLA region common to those identified in SLE have been observed, SLE being among the top three autoimmune diseases developed by first-degree relatives of patients with celiac disease. In addition, there is evidence of non-celiac autoimmune diseases in the spouses of patients with celiac disease, which contradicts the claim that the involvement of genetics is the only predisposing cause, since the partners do not share genetic characteristics with each other, but only environmental factors and possibly the microbiome, with an impact on the risk of developing autoimmunity [9,10]. About 30% of all patients with celiac disease have one or more autoimmune conditions, while in the general population, there is a prevalence of 3% to 9.4%.

3. Clinical and Paraclinical Aspects

SLE and CD are two complex diseases, encountered in all age groups (including in pediatric practice), with diverse clinical manifestations involving multiple organ systems and an evolution marked by relapses and remissions, dependent on both environmental factors and individual response to therapy.

The pathogenesis of CD can be attributed to a combination of inflammation, nutrient deficiency caused by malabsorption, and enzyme-mediated autoimmune response. The clinical picture provides an evolutionary description over the years, starting from presentation in the form of diarrhea with malabsorption syndrome and reaching that is nowadays a systemic disease with a serious clinical and histological picture. It can appear at any age and is not limited to the digestive tract, involving almost every organ, including the nervous system, liver, skin, reproductive system, cardiovascular system, and musculoskeletal system. It is usually associated with a more severe clinical and histological picture [13,14].

Regarding the symptoms reported by pediatric age groups, the following were identified, in this order:

very young children (under 3 years old): diarrhea, delay in physical development, abdominal distention; asymptomatic—6.8%
preschoolers (3–6 years): abdominal pain, iron deficiency, delay in physical development; asymptomatic—18.9%
school age (≥6 years): abdominal pain, delay in physical development, diarrhea; asymptomatic—23.7% [13]

As a multisystemic disease with a variable clinical picture in terms of severity, SLE in pre-pubescent children rarely shows positivity of anti-nuclear antibodies (ANAs) at diagnosis, along with a smaller titer of antibodies against double quaternary DNA (anti-dsDNA), and fewer renal and musculoskeletal manifestations. However, there is a greater neuropsychiatric, hematological, and complement system involvement (hypocomplementemia) in contrast to SLE in adolescents, which tends to present as an adult form [15].

The most frequent clinical manifestations described in the literature are represented by constitutional symptoms (fever, fatigue, weight loss), skin damage (malar rash, oral ulcers, vasculitic eruptions, photosensitivity, alopecia, discoid lesions, Raynaud’s phenomenon), muscle-skeletal (often symmetrical, non-erosive polyarthritis of large and small joints, myalgia, rarely myositis), hematological (autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, leukopenia, granulocytopenia, positive Combs test), cardiac (pericarditis, myocarditis, valvular damage, coronary damage due to arteritis or arteriosclerosis), neuropsychological (from headaches, memory loss to global cerebral dysfunction manifested by paralysis or convulsions), pulmonary (pleurisy, pneumonia, pneumothorax, diffuse interstitial damage, hypertension, and pulmonary hemorrhage) and renal (lupus nephritis, classified in six stages, starting from the mild form and culminating in end-stage renal disease) [16].

4. Pathogenic Correlation

Innate immunity represents the first line of defense, determining a rapid response that occurs a few minutes after infection. It is non-specific and does not confer immune memory, being based on the complement system of myeloid cells (neutrophils, monocytes, dendritic cells, and macrophages), natural killer cells (NKs). or innate lymphoid cells (ILCs) responsible for molecular recognition and antigen presentation, phagocytosis, and elimination of pathogens. In contrast, adaptive immunity is provided by B and T lymphocytes and has been described as slow and specific. The origin and development of autoimmune diseases are mainly attributed to an excessive and sustained response to autoantigens mediated by B and T cells. It is well known that autoinflammation driven by dysregulation of innate immune signaling contributes to the establishment of adaptive immune responses that lead to the development of autoimmunity [30,31]. Women have a stronger immune response to infections and vaccination than men, an aspect from which arises their increased susceptibility to the development of autoimmune diseases, possibly because of the influence of sex hormones on the activity of the immune system [32].

CD and SLE are two conditions known to be interconnected, and their association has been intensively studied by dosing anti-transglutaminase and anti-endomysial antibodies, followed by duodenal biopsy performed on those with positive IgA-TGA/EMA. There are studies that aim to identify the primary condition between the two, the results on both sides, identifying a prevalence of 1.38% of celiac disease among lupus patients, as well as an apparent three times higher risk of SLE in people with CD (>20% presenting anti-ds-DNA, an aspect that raises the suspicion of the involvement of the microbiome in systemic autoimmune diseases) compared to the general population [33,34].

4.1. Genome-Wide Association

Although it is known that environmental stimuli can predispose individuals to the development of autoimmune diseases, studies focusing on related individuals and twins have shown that genetic factors as well as non-random inheritance of alleles (linkage disequilibrium) also play an important role in influencing the risk of their appearance [35,36]. The hypothesis that the presence of CD positively imprints the risk of SLE was confirmed by studying two samples with the help of Mendelian randomization (MR) based on the datasets related to the association at the genome level (GWAS) of different diseases involving the immune system [34].

Many of the recently identified autoimmunity genetic locations (loci) at the chromosome level are shared between various autoimmune diseases, suggesting that subgroups of them are prone to showing similarities regarding the etiology and pathogenic mechanisms implicated. The degrees to which autoimmune disorders are characterized by shared (rather than unique) susceptibility loci vary substantially, from the entire number of shared loci (for RA) to 50% or more shared for CD, psoriasis, MS, SLE, T1D, ankylosing spondylitis, and autoimmune thyroid disease. Regarding the SLE-CD relationship, they seem to share loci such as TRAF1, IL12A, KIAA1109, and TNFAIP3, an aspect identified within two groups (out of a total of four identified) of associations of autoimmune diseases: group two that includes CD, RA and SLE and group four in which associations between T1D, RA, CD, Crohn’s disease and SLE are described [38].

Other genetic variations intensively studied regarding their association with autoimmune diseases, in particular, SLE, were the R620W polymorphism of the protein tyrosine phosphatase non-receptor type 22 gene (PTPN22), MYO9B, and CLEC16A (chromosomal position 16p13) [39,40,41]. Regarding the first one, there is contradictory evidence with reference to the increase in the genetic risk for CD [39,42,43]. Variations of the latter have also proven their involvement in the development of autoimmunity in celiac disease, CLEC16A being recognized for its impact on the phenomenon of immune tolerance resulting from thymic selection through autophagy of epithelial cells [41].

4.2. The Impact of Viral Infection

Infections with enteric viruses (Coxsackie B and Rotavirus), influenza A, and herpesviruses can modulate the induction and development of autoimmune diseases while also playing a protective role, depending on several factors such as the genetic background, the host’s immune responses, the type of virus strain, viral load, and time of onset of infection. Viral-induced autoimmunity can be activated by several mechanisms, including molecular mimicry, epitope spreading, bystander activation, and immortalization of infected B cells, while protective effects can be achieved by activating regulatory immune responses, thus suppressing the development of autoimmune reactions. An important detail regarding herpesviruses is their persistence in the form of a latent infection that contributes to the pathogenesis of the systemic autoimmune disease at the time of reactivation [45].

The Epstein–Barr virus (EBV) is suspected of having a central role in autoimmune diseases, increasing the risk of SLE by up to 50% in children, an aspect supported by the increase in EBV DNA, mRNA, and titers of anti-early antigens IgG and IgA detected in their blood. The mode of action is based on molecular mimicry, inflammation, activation of innate immunity and production of type I IFN and pro-inflammatory cytokines, with immune evasion and anti-apoptosis. At the genetic level, the protein implicated in anchoring to loci with susceptibility to SLE, CD, or other autoimmunities is represented by EBNA2, together with transcription factors (numbering 20, of which at least 4 are therapeutic targets of current medication).

4.3. The Influence of the Internal and External Environment

4.3.1. The Microbiome

In humans, the intestinal microbiota tends to stabilize and reach a greater diversity around the age of three years, influencing a multitude of physiological or pathological processes of the host either directly (at the digestive level) or remotely by creating links with vital organs such as the heart, working together to maintain homeostasis. In evolution, until adulthood, Gram-positive bacteria such as Clostridium, Bifidobacterium, Lactobacillus, Ruminococcus, Streptococcus, and Gram-negative bacteria such as Bacteroides and Escherichia appear in the intestine. Intestinal dysbiosis observed in autoimmune diseases is associated with a decrease in both bacterial function and diversity, damage to the intestinal barrier function, increased inflammation, and a decrease in regulatory T cells in the intestine, as well as, possibly, with molecular mimicry and T-cell activation, favoring a pro-inflammatory or posttranslational modification of luminal proteins. Worthy of discussion is the variable course of autoimmune diseases in each individual, including monozygotic twins, an observation that reiterates the contribution of environmental factors to the pathogenesis of the disease [47,48,49,50].

4.3.2. Atopy

The association between allergic diseases and autoimmunity is still being researched; a retrospective cohort study carried out in 1990–2018 that included patients of all age categories, doubled by a transversal study, concluded that the risks of developing of autoimmunity (including CD and SLE), in the long term are increased in subjects with atopic terrain (allergic rhinitis/conjunctivitis, atopic eczema, asthma), being distributed in groups according to age and gender [52].

4.3.3. Vitamin D Deficiency

It has been shown that immune cells, including dendritic cells, macrophages, and T and B cells, express the vitamin D receptor and 1α-hydroxylase, substances with a role in both calcium homeostasis and the mineralization of the collagen matrix, as well as immunomodulators in innate and adaptive immunity (through control of immune cell growth and differentiation), being anti-inflammatory, antioxidant, and anti-fibrotic. Another known effect of vitamin D is maintaining the integrity of the intestinal barrier (essential in preventing dysbiosis) by regulating the colonic mucus, influencing the composition and functions of the intestinal microbiota, and modulating the release of zonulin. Regarding the intake of vitamin D administered daily (in case of minimal exposure to the sun), the consensus was reached that it represents 400 IU/day for ages older than 1 year, 600 IU/day for ages between 1 and 70 years, and 800 IU/day for 71 years and older, while the upper tolerable level varies between 1000 and 4000 IU/day, comprising 1000 IU for infants 0–6 months, 1500 IU infants 6–12 months, 2500 IU for children 1–3 years, 3000 IU for children 4–8 years, and 4000 IU for children 9 years and older. The prevalence of insufficiency (21–29 ng/mL or 52–72 nmol/L) and vitamin D deficiency (below 20 ng/mL or 50 nmol/L) were also studied among children, recording values of 61% and 9%, respectively, in a study group made up of 6275 participants, with data proving that vitamin D supplementation for five years, with or without omega 3 fatty acids, can reduce the risk of autoimmune diseases by 22%. The association between vitamin D and autoimmune disease has also been observed to be subject to seasonal variation (higher prevalence in spring-born children) as well as latitude (higher prevalence in northern countries with less UVB radiation) [53,54,55,56].

4.3.4. Prolactin Level

Prolactin (PLR) is secreted both by the anterior pituitary gland and by various extra-pituitary sites (including immune cells); hyperprolactinemia (>18 ng/mL in boys and >24 ng/mL in girls) is therefore described in the phases of active autoimmune diseases, including SLE and CD, as the stage in which it determines increased synthesis of IFN-gamma and IL-2 by Th1 lymphocytes and the activation of Th2 lymphocytes with consecutive production of autoantibodies, correlating with the age of diagnosis, the duration of symptoms, the degree of villous atrophy, and infiltration of the lamina propria [59,60]. Regarding CD, it seems that hormone levels are directly related to the gluten-free diet, registering a decline in PLR, simultaneously with the anti-transglutaminase antibodies, after six months of a gluten-free diet. In SLE, in addition to the impact on serology, PRL seems to leave a mark on neurological, renal, and hematological function, as well as the involvement of serous cells in the clinic of the disease [61].

4.3.5. The Overwork

Chronic, deep fatigue, defined as periods of debilitating exhaustion that interfere with normal activities by decreasing concentration, orientation, and mental performance, is also one of the frequently encountered symptoms. Given the role played by inflammation through various mechanisms (starting from pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6, and IFN-γ) in inducing fatigue, inflammatory pathways and subsequent physiological changes are considered potential treatable targets in patients with autoimmune disease.

4.3.6. The Psychic Component

In agreement with the previous statements, an important element that contributes to the appearance of fatigue is direct or indirect damage to the central nervous system [64]. Psychological stress, including social stress, also seems to be a risk factor in the alteration of the intestinal barrier (consisting of a layer of mucus, intestinal epithelial cells, tight junctions, immune cells, and intestinal microbiota), outlining a vicious circle together with the psychological impact determined by the disease, which can either trigger or aggravate autoimmune manifestations in children [65,66,67].

4.4. Consequences of IgA Deficiency

Selective IgA deficiency (SIgAD), the most common primary immunodeficiency in the Western world (with a prevalence of approximately 1:600 in the general population and the possibility of progression to variable common immunodeficiency of 23.5% among subjects with autoimmunity), is a disease with polygenic determinants that, in part, can overlap with genes associated with autoimmune diseases. The diagnosis is confirmed by the association of immunoglobulin A (IgA) levels lower than 0.07 g/L manifested among patients over four years old, with immunoglobulin M (IgM) and immunoglobulin G (IgG) within normal limits and without any other cause identified for the immunodeficiency. Because immunoglobulin is strongly expressed at the level of the mucous membranes, its deficiency is marked by recurrent infections, allergic disorders, and autoimmune manifestations; therefore, screening is essential in these circumstances [71,72,73].

4.5. The Place of Nutrients in Pathogenesis

With birth, a complex process is started, a process that affects the mother as well as the fetus (depending on the time and the circumstances in which it was born). The latter goes through an intense period of adaptation to environmental factors during childhood and adolescence, an adaptation that leaves its mark on their health and the balance of later adult life [76]. All of these marks can potentiate the occurrence of autoimmune diseases, a group of diseases which, although considered heterogeneous, have many common aspects from a pathogenic and evolutionary point of view, aspects emphasized with the help of the celiac disease–lupus autoimmune association model. Studies regarding the involvement of diet in the modulation of the immune system are in continuous development. The first argument for this theory is represented by the observation of an increase in the incidence of these types of diseases, especially in Western countries, possibly in association with the great diversity of diets and unhealthy eating habits based on high contents of fat, sugars, and total calories added, in contrast to a low fiber content (which is accentuated by its inclusion in a gluten-free diet for children with CD) and an imbalance in the use of fatty acids. These mistakes can promote the alteration of the intestinal barrier function, together with the decrease in the diversity of the microbiome, directly proportional to the diversity of the diet [77,78,79,80].

The mechanism by which dietary fibers influence the intestinal barrier and the immune system involves their fermentation by intestinal bacteria, with the subsequent production of short-chain fatty acids. These represent both an energy substrate for intestinal cells and a pawn in the development and differentiation of regulatory T cells, thus strengthening beliefs about the diet–microbiota–immunity triad [81].

At the same time, numerous studies present in the literature highlighted the impact played by epigenetic changes such as DNA methylation (hypomethylation) or histone acetylation in the onset and evolution of SLE. The substances with a beneficial role in influencing this process proved to be folic acid, methionine, choline, and some vitamins from the B complex (methyl donor nutrients) [87].

5. Treatment

As two autoimmune diseases that share many overlaps in terms of pathogenesis and clinical practice, SLE and CD also follow similar general lines in therapeutic management that include the avoidance of triggering factors, the use of steroid agents in the treatment of the acute phase, and the induction of symptomatology remission and pharmaceutical preparations directed against the various stages of the pathogenic cascade.

Except for the common model of the development and evaluation of autoimmune diseases, previously developed with the help of the SLE-CD correlation, they seem to be interconnected at the therapeutic level as well. Recent studies are contradictory regarding the identification of the impact obtained by the introduction of a gluten-free diet among patients with autoimmune comorbidities such as thyroiditis and type 1 diabetes, without being able to eliminate the risk of bias. The possible positive causal link between the establishment of a gluten-free diet in the context of celiac disease and the evolutionary course of other associated autoimmunities is therefore emphasized; in order to define it more accurately, further studies are needed [96,97,98].

Continuing the CD-SLE model, a list of foods in the composition of which high concentrations of the most important nutrients in autoimmune diseases are found:

Folic acid: green vegetables, bell peppers, beans, lentils;
Methionine: eggs, yogurt, cheese, red meat;
Choline: beef liver, egg, soy, potatoes, quinoa, peanuts, carrots, apples, broccoli;
B complex vitamins: rice, quinoa, apple, strawberries, bananas, watermelon, walnuts, spinach, onions, tomatoes, chickpeas, beans, potatoes, salmon, tuna, beef liver, milk, yogurt, cheese;
Flavanols: cocoa, red grapes, tea, berries, apples;
Vitamin A: liver, carrots, sweet potatoes;
Vitamin E: quinoa, amaranth;
Omega-3 fatty acids: chia/flax seeds, sardines, milk, beans, salmon, soy [80,82,85,87,99].

This entry is adapted from the peer-reviewed paper 10.3390/nu15112535

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