Research ArticlePediatric Rheumatology

Association of Infant Breastfeeding and Juvenile Spondyloarthritis: A Case-Control Study

Katelyn H. Baggett, Timothy G. Brandon, Rui Xiao and Pamela F. Weiss
The Journal of Rheumatology July 2024, 51 (7) 708-714; DOI: https://doi.org/10.3899/jrheum.2023-1203

Abstract

Objective Given the multifactorial pathogenesis of juvenile spondyloarthritis (JSpA) and evidence of a protective effect in phenotypically similar diseases, we aimed to test whether breastfeeding is associated with the development and disease activity of JSpA.

Methods This single-center retrospective case-control study included children with JSpA and age- and sex-matched controls with a 1:1 ratio. Univariable and multivariable conditional logistic regression modeling for matched pairs was used to test the association of infant factors with the development of JSpA, including infant nutrition and form of delivery. Linear regression was used to assess the association of JSpA disease activity (JSpA Disease Activity Index with 6 elements [JSpADA6]) at presentation with breastfeeding exposure, form of delivery, and antibiotic exposure.

Results For the 195 case-control matched pairs, the mean age was 13.0 years and 47.7% were female. For breastfeeding, 88.7% of controls and 69.2% of JSpA cases were exposed to breastfeeding of any duration, respectively (P < 0.001). In the multivariable model, exclusive breastfeeding > 6 months was independently and significantly associated with a lower chance of JSpA development (odds ratio 0.47, 95% CI 0.30-0.72; P < 0.001). The median JSpADA6 was not significantly associated with breastfeeding for > 6 months. However, vaginal delivery was significantly associated with a lower JSpADA6 (B = −0.65, 95% CI −1.13 to −0.17; P = 0.008).

Conclusion This study suggests that infant factors that affect the microbiome may be associated with the occurrence and disease activity of JSpA at presentation.

Key Indexing Terms:

Juvenile spondyloarthritis (JSpA) encompasses a heterogenous group of childhood rheumatic diseases associated with HLA-B27 positivity and varying symptoms of peripheral and axial arthritis, enthesitis, bowel inflammation, psoriasis, and uveitis. JSpA accounts for 20% of juvenile arthritis and includes conditions such as enthesitis-related arthritis (ERA), juvenile psoriatic arthritis (PsA), juvenile ankylosing spondylitis (AS), reactive arthritis (ReA), and inflammatory bowel disease (IBD)-related arthritis.1,2 When compared to other categories of juvenile idiopathic arthritis (JIA), children with JSpA are reported to have a poorer overall health status and are less likely to achieve remission.3-6 The pathogenesis of JSpA is thought to be multifactorial, with a genetic predisposition of the HLA-B27 allele seen in 38% to 68% of individuals and environmental exposures, such as the gut microbiome.7,8

The microbiome is an increasingly pertinent area of research for autoimmune inflammatory conditions because of growing evidence supporting the effect of the early gut microbiota on immune system modulation.9 There is growing evidence to support an environmental component in the pathogenesis of JSpA, given that individuals without a genetic predisposition of the HLA-B27 allele can develop JSpA and only 5% of HLA-B27–positive individuals develop spondyloarthritis (SpA).10-12 Studies suggest that the microbiome of children with JSpA differs markedly from that of children without the disease and that the microbiome in JSpA is altered by factors other than HLA-B27 positivity.8,13,14

Breastfeeding during infancy is one of the richest sources of microbiota colonization for the newborn, with estimates of 101 to 107 colony-forming units of probiotic bacteria per micro-liter.15 The early microbiome and exposure to maternal antigens in breastmilk are vital to the development of the immune system and immune tolerance to self, which has gone awry in autoimmune disease.16,17,18 As such, exposure and duration of breastfeeding has been previously linked with a protective effect in several types of autoimmune disease. Studies also suggest that birth by cesarean section (C-section) and antibiotic exposure serve as environmental risk factors for autoimmune disease, through a similar effect on microbiome composition.19,20

Previous studies suggest there is an association between the duration of breastfeeding and risk of various autoimmune diseases, though this has yet to be investigated in JSpA. The association between type 1 diabetes mellitus (DM) and breastfeeding is well-known, with 1 study revealing a 2-fold increase in the risk of type 1 DM in children who were never breastfed.21 Studies related to rheumatic disease also suggest a protective effect of breastfeeding, with a study focused on adult patients showing that individuals with AS were breastfed less often than healthy siblings and an unrelated control population.22 Studies similarly suggest that patients with JIA are less likely to be exposed to exclusive breastfeeding beyond 4 months of age compared to healthy controls (HCs).23

Given the multifactorial pathogenesis of JSpA and evidence of a protective effect in phenotypically similar diseases, we aimed to test whether an association exists between breastfeeding and the development of JSpA given the suggested effect on the microbiome.24 Findings from the present study may help to inform perinatal counseling when promoting the importance of breastfeeding in early nutrition and preventing the onset of inflammatory conditions like JSpA in genetically susceptible individuals.

METHODS

This study was determined exempt and granted a waiver of informed consent by the Children’s Hospital of Philadelphia (CHOP) institutional review board (IRB 19-016796). The IRB determined that this study meets the exemption criteria per 45 Code of Federal Regulations (CFR) 46.104(d) 2(ii), 4(iii). A waiver of Health Insurance Portability and Accountability Act (HIPAA) authorization per 45 CFR 164.512(i)(2)(ii) was granted for review of medical and research records for cases. Verbal HIPAA authorization was obtained from parents of controls for completion of the survey.

Participants and data collection. This retrospective case-control study was carried out at CHOP. Children with JSpA were seen at 1 of 3 outpatient rheumatology locations, with 1 large urban and 2 suburban centers. Data related to the JSpA population were retrieved from a preexisting disease registry composed of children with JSpA who met inclusion criteria under any of the following categories: IBD-associated arthritis, magnetic resonance imaging (MRI)-defined sacroiliitis, ERA, PsA, or undifferentiated arthritis (if fulfilled ERA criteria but also had a first-degree relative with PsA). Children with ERA, PsA, or undifferentiated arthritis were classified according to the International League of Associations for Rheumatology (ILAR) classification criteria for juvenile arthritis.25 Criteria used to classify a child with IBD-associated arthritis included children with ulcerative colitis or Crohn disease diagnosed by a gastroenterologist who presented to rheumatology with either concomitant arthritis or enthesitis or was diagnosed with sacroiliitis using MRI. The diagnosis of MRI-defined sacroiliitis was ascertained based on the imaging report. HC subjects were identified and recruited from outside of the Division of Rheumatology as approved by the Pediatric Research Consortium (PeRC) at CHOP between June 2022 and August 2022 at 1 suburban clinic.

Inclusion criteria for the control population consisted of healthy, normally developing subjects, male or female, aged 2 to 18 years. Children with a significant medical history (endocrine, oncologic, rheumatologic, gastrointestinal, or dermatologic disorders) were excluded. Parents of the HC population completed an anonymous 1-time questionnaire pertaining to the child’s demographics (age, biological sex, and race), early nutrition (type and duration of feeding), and birth history (vaginal delivery or C-section) through the use of a handheld passcode-protected research tablet. Those who did not recall their child’s early nutrition or did not complete the entirety of the questionnaire were excluded from analysis. The type of feeding was limited to the first 6 months of life and included the options of breastmilk only, breast and formula, formula only, breast and cereal or other food, or other. If breastfed, the length of time fed exclusively with breastmilk was queried and included the time intervals of < 1 week, ≥ 1 to < 2 weeks, ≥ 2 to < 4 weeks, ≥ 1 to < 3 months, ≥ 3 to ≤ 6 months, or > 6 months as a categorical variable. Race was self-selected, with categories of African American, American Indian/Alaskan Native, Asian American, multiracial, Native Hawaiian or other Pacific Islander, White, or other/unknown.

Children with JSpA had an initial evaluation by a rheumatologist between February 2016 and January 2022. Index visit was defined as the first visit in the JSpA registry that occurred within 6 months of diagnosis or prior to the initiation of conventional synthetic disease-modifying antirheumatic drugs or biologic therapy to obtain an accurate baseline disease activity score. Parents of children with JSpA completed the same questionnaires related to their children’s demographics, early nutrition, and birth history as part of an ongoing disease registry. Data related to antibiotic exposure 6 months prior to index visit were available for analysis within the JSpA population, though not collected within the HC population. JSpA disease activity was quantified by the modified JSpA Disease Activity Index with 6 elements (JSpADA6), a validated tool consisting of parent-, patient-, and physician-reported measures, with a score range of 0 to 6 (with 6 indicating the highest baseline disease activity).26,27 JSpADA6 elements include active joint count, active enthesitis count, patient-reported pain over the past week recorded on a visual analog scale, morning stiffness for > 15 minutes, clinical sacroiliitis (defined as the presence of ≥ 2 of the following: tenderness on examination, positive FABER test [flexion, abduction, external rotation; Patrick test], and inflammatory back pain as determined by the adult Assessment of SpondyloArthritis international Society criteria28), and history of uveitis including acute/symptomatic and chronic/asymptomatic disease.26

Statistical analysis. Healthy subjects were age- and sex-matched to children with JSpA at a 1:1 ratio for a total population of 390 children. Demographic information and baseline characteristics were summarized by frequencies and percentages for categorical variables (eg, sex, race) and by mean (SD) or median (IQR) for continuous or count variables. Race was dichotomized as White or non-White for the purposes of statistical analysis, because of the small counts for several racial groups, including American Indian or Alaska Native and Native Hawaiian or other Pacific Islander. Between-group comparisons of categorical variables were made using the Pearson chi-square or Fisher exact test, as appropriate. Univariable and multivariable conditional logistic regression modeling for matched pairs was used to test the association of infant factors (breastfeeding history and form of delivery [vaginal or C-section]) that may be associated with the development of JSpA. For the purposes of regression analyses, breastfeeding history was defined as > 6 months of breastfeeding and ≤ 6 months of breastfeeding including never breastfed.

A sensitivity analysis was performed to exclude subjects with a family history of a SpA-related condition (ankylosing SpA, iritis or uveitis, PsA, ReA or Reiter syndrome, ulcerative colitis, or Crohn disease) to account for the possibility that mothers with an autoimmune condition may be less likely to breastfeed their children if the mother is treated with medications that are considered pregnancy category D or X, signifying increased risk to the fetus or teratogenicity, respectively.29

To assess our secondary objective, the association of infancy factors with JSpA disease activity at presentation, we performed a cross-sectional analysis of 103 children with JSpA using data from the index visit with available data related to the child’s demographics, early nutrition, birth history, and antibiotic exposure 6 months prior to index visit. Multiple linear regression was used to assess the association of disease activity, as measured by the JSpADA6, at the index visit, and infancy factors including breastfeeding exposure defined as > 6 months of breastfeeding, form of delivery, and antibiotic exposure, each as a categorical variable.

For a 1:1 matched case-control study, assuming a probability of exposure to be 0.5 among controls and the odds ratio (OR) between cases and control to be 1.5, a total of 388 subjects (ie, 194 cases and 194 controls) was needed to achieve 80% power at a significance level of 0.05.

All analyses were performed using Stata 17 (StataCorp 2021, Stata Statistical Software: Release 17). A 2-sided P < 0.05 was considered statistically significant for all analyses.

RESULTS

Patient characteristics. Patient characteristics of the JSpA and HC populations are summarized in Table 1. One hundred ninety-five HCs were age- and sex-matched 1:1 to our existing cohort of children with JSpA, for a total population of 390 children. For each group of controls and cases, the mean age was 13.0 (0.2) years and 47.7% were female. There were no significant differences in race or form of delivery between cases and controls. To create nonoverlapping categories for the 195 subjects with JSpA, a classification hierarchy was used, first classifying subjects according to the ILAR criteria and then secondarily assigning a classification of IBD-associated arthritis and then MRI-defined sacroiliitis if the ERA/PsA/undifferentiated JIA criteria were not met; 59.5% met ERA criteria, 22.1% met PsA criteria, 3.6% met undifferentiated JIA criteria, 9.2% had IBD-associated arthritis, and 5.6% had MRI-defined sacroiliitis.

View this table:
Table 1.

Subject characteristics.

Early nutrition practices of HCs vs children with JSpA. Of the subjects, 88.7% of the HCs and 69.2% of the JSpA cases were exposed to breastfeeding of any duration, respectively (P < 0.001). Figure 1 depicts the breastfeeding history of JSpA cases and controls according to never breastfed, breastfed for ≥ 3 months, or breastfed for > 6 months. Overall, 30.8% of JSpA cases and 11.3% of HCs were never breastfed (P < 0.001) and 28.2% of JSpA cases and 46.6% of HCs were breastfed for > 6 months (P = 0.04). Additionally, 29.7% of JSpA cases were introduced to formula feeding before the sixth month of life, compared to 11.3% of HCs (P < 0.001). Results of the univariable and multivariable models are shown in Table 2. In the multivariable model, which included breastfeeding exposure (none or ≤ 6 months as the reference) and form of delivery, the duration of breastfeeding for at least 6 months remained independently and statistically associated with the development of JSpA (OR 0.47, 95% CI 0.30-0.72; P < 0.001). After excluding JSpA subjects with a family history of an autoimmune disease (n = 28) in a sensitivity analysis, the frequency of exclusive breastfeeding for > 6 months remained significantly lower in children with JSpA than in HCs (29.3% of children with JSpA vs 46.6% of HCs; OR 0.45, 95% CI 0.28 to 0.71; P = 0.001).

Figure 1.
Figure 1.

For the 173 controls and 135 patients with JSpA who were exposed to breastfeeding, the percent that were breastfed exclusively for ≥ 3 or > 6 months are shown. The ≥ 3 and > 6-month groups are not mutually exclusive. JSpA: juvenile spondyloarthritis.

View this table:
Table 2.

Univariable and multivariable analyses of the infancy factors associated with the development of JSpA (N = 390).

Infancy factors and JSpA disease activity. For the secondary objective of infancy factors and JSpA disease activity at disease onset, 103 patients with JSpA had an index registry visit a median of 0.3 months after diagnosis (IQR 0-10.5). For subjects with JSpA, the median age at the index visit was 13.3 (0.3) years and 45.6% were female. The median JSpADA6 was 2 (IQR 1.5-3.0, range 0-5) and was not significantly different in children with a history of no breastfeeding and exclusive breastfeeding for ≤ 6 months or exclusive breastfeeding for > 6 months (P = 0.63).

Of the 103 patients with JSpA, 70 (68%), 24 (23.3%), 68 (66%), and 26 (25.2%) patients with JSpA were exposed to breastfeeding of any duration, breastfed for > 6 months, born by vaginal delivery, and/or had antibiotic exposure 6 months prior to index visit, respectively. Table 3 shows the results from the univariable and multivariable linear regression models. In univariable analysis, only vaginal delivery was significantly associated with a lower index visit JSpADA6 score, as shown in Figure 2 (P = 0.01), which remained significant in multivariable analysis after adjusting for breastfeeding and antibiotic exposure (β = −0.65, 95% CI −1.13 to −0.17; P = 0.01). HLA-B27 status was also tested in univariable (P = 0.82) and multivariable (P = 0.99) models but did not reach statistical significance.

View this table:
Table 3.

Univariable and multivariable linear regression model for JSpA disease severity at presentation.

Figure 2.
Figure 2.

The JSpADA6 index and parent-reported form of delivery, according to vaginal delivery or cesarean section, was available for 99 patients with JSpA at the index registry visit, a median of 0.3 months after diagnosis and prior to the initiation of DMARD or biologic therapy. DMARD: disease-modifying antirheumatic drug; JSpA: juvenile spondyloarthritis; JSpADA6: Juvenile Spondyloarthritis Disease Activity Index with 6 elements.

DISCUSSION

This study evaluated the association of infant factors with the development and disease activity of JSpA. Our results suggest that a shorter duration of exclusive breastfeeding or absence of breastfeeding may be associated with greater odds of developing JSpA. Additionally, we found that although breastfeeding was not associated with JSpA disease activity at presentation, vaginal delivery was associated with a lower JSpADA6 score at diagnosis. Both these infant factors are known to affect the microbiome, which in recent years has been hypothesized to play an ever-increasing role in the pathogenesis of autoimmune diseases such as SpA.

Current recommendations from the World Health Organization and American Academy of Pediatrics include exclusive breastfeeding for the first 6 months of life followed by an expanded diet with continued breastfeeding until 2 years of age.30,31 Over the previous several decades, rates of autoimmune disease have increased steadily, with 1 study noting a rise in the prevalence of antinuclear antibodies, the most common biomarker of autoimmunity.32,33

Rates of breastfeeding exposure remain suboptimal, with 16.8% of infants within the general US population34 and 11.3% of the present study’s HCs receiving no breastfeeding exposure, with further decreased breastfeeding exposure seen wherein 30.8% of JSpA cases were never breastfed. This study adds to growing literature supporting the importance of breastfeeding and highlights that education and intervention may be needed to emphasize the benefits of breastfeeding and reduce barriers caregivers are facing when choosing the mode of infant nutrition. As proposed by previous studies of autoimmune disease, this study found that an absence of breastfeeding or shorter duration of breastfeeding was associated with an increased odds of JSpA, supporting the hypothesis that breastfeeding may provide a protective effect against the development of JSpA.17,18

The pathogenesis of JSpA is multifactorial, with a studied genetic predisposition of the HLA-B27 allele and suggested environmental influence of the gut microbiome. Studies suggest that the microbiome of children with JSpA differs markedly compared to HCs, with decreased microbial diversity and abundance seen in children with JSpA.14 Previous authors have also questioned the hypothesis that HLA-B27 positivity alone augments the microbiome, supporting the notion of an environmental rather than genetic shaping of the microbiome.14 Previously, Kindgren et al suggested that microbiome dysregulation in children with JIA is detectable as young as infancy, as determined by stool samples collected an average of 12 years prior to JIA diagnosis.35 These authors suggested that early nutrition and environmental exposures are associated with the bacterial strains that infer the greatest risk for JIA.35 Twin studies similarly suggest a multifactorial interplay between genetic risk and environmental exposures in the development of several autoimmune diseases36; however, further research of the association of environmental exposures and the development of JSpA is lacking.

Previous studies of children with JIA and adults with axial SpA suggest decreased disease activity in individuals who are exposed to breastfeeding37,38 and that vaginal delivery may be protective against the development of autoimmune disease.39,40 Birth history is thought to influence the early gut microbiota through transmission of maternal microbes during fetal transit through the vaginal birth canal. Studies suggest that infants born by C-section have decreased microbial diversity and abundance, leading to decreased modulation of the developing immune system.35 Whereas previous studies suggest that infants born by C-section have an increased risk of developing JIA, our study found no association between the form of infant delivery and occurrence of JSpA. However, vaginal delivery was associated with a lower JSpADA6 after adjusting for breastfeeding exposure and antibiotic exposure.41 Antibiotic exposure is similarly suspected to influence the development of autoimmune disease through alterations of the gut microbiome.20 Residual alterations in microbiome composition are suggested to persist for several years after antibiotic exposure, with gradual normalization of the gut microbiome beginning several months after exposure.42 Whereas previous studies suggest that antibiotic exposure may be most deleterious within the first several months of life,43 our present study examined antibiotic exposure 6 months prior to index visit and found no association between antibiotic exposure and the occurrence of JSpA. Future research is needed to determine the association between time since antibiotic exposure and disease onset and to explore the association of antibiotics during infancy with SpA later in life.

The results of this study should be interpreted in the context of several limitations. First, this study included a total sample size of 390 for the case-control analysis and 103 for the JSpA disease activity analysis and is relatively small; however, we still found a significant association of breastfeeding with JSpA. This was a single-center study; however, this is a large tertiary care referral center with a wide range of disease spectrums that is similar to what is seen in other large tertiary care centers. Additionally, cases and controls were matched on age and sex but not race or sociodemographics. As such, this study does not identify all potential confounders including sociodemographic, socioeconomic, or psychosocial environments. However, any sampling bias was likely minimal given the case and control populations were recruited within the same care network, and as shown in Table 1, there were no significant differences noted. The retrospective design including the use of a survey makes it inherently susceptible to the effects of recall bias. To minimize this occurrence, parents of both cases and controls who could not easily recall the type and duration of their child’s early nutrition were excluded. Protected health information was not collected on HC subjects or excluded subjects. The possibility cannot be ruled out that parents of children with JSpA may have been more likely to overestimate their child’s duration of breastfeeding when suggested that early nutrition serves as a risk factor for the disease. However, if this occurred, then our findings would be biased toward the null, and the significance of our findings may be even stronger. Additionally, the potential effects of apprehension bias leading to falsification or overestimation of survey responses were minimized by allowing the parent to self-select their questionnaire answers using a handheld tablet. It is also possible that there was a lower prevalence of breastfeeding in children with JSpA vs HCs if the mother had a SpA-related or other autoimmune diagnosis and/or was taking an immunomodulatory medication with potential teratogenicity.29 However, we accounted for this possibility and conducted a sensitivity analysis excluding subjects with a family history of autoimmune condition and our results remained robust. Our findings demonstrate an association between early nutrition practices and the occurrence of JSpA, but do not prove a causation. As we aimed to evaluate for the association of infancy factors with disease activity at index visit in a cross-sectional design, future research efforts can include evaluating whether infancy factors may affect the disease course after diagnosis or the various heterogenous presentations of this disease. Additional investigation should include further analysis using available rheumatic disease registries, prospective birth cohorts, and population health surveillance databases within the JSpA population, as previously performed within the JIA population.23

In conclusion, this study supports the concept that the microbiome is associated with the development and disease activity of JSpA at diagnosis. Breastfeeding and vaginal delivery, both infancy factors known to influence the microbiome, were associated with lower odds of developing JSpA and a lower magnitude of disease activity at JSpA diagnosis, respectively. For families with a history of a SpA-related disease, this information may help to inform infant nutrition decisions.

ACKNOWLEDGMENT

We thank the network of primary care clinicians and their patients and families for their contributions to this project and clinical research facilitated through PeRC at CHOP, where study questionnaires were administered.

Footnotes

  • This project was supported by the Children’s Hospital of Philadelphia. This study was funded by the Rheumatology Research Foundation Student and Resident Research Award and the Finkelstein Memorial Student Research Award for rheumatologic and immunologic diseases at the Penn State College of Medicine (KHB) and the National Institutes of Health (PFW; K24AR078950-01A1).

  • PFW has served as a consultant for Pfizer, Eli Lilly, and Novartis. The remaining authors declare no conflicts of interest relevant to this article.

  • Accepted for publication March 14, 2024.

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Keywords

DIET
JUVENILE IDIOPATHIC ARTHRITIS
pediatric ankylosing spondylitis
PEDIATRIC RHEUMATIC DISEASES
RISK FACTORS
SPONDYLOARTHROPATHY

Keywords