Children with PANS Are at Risk of Developing Arthritis or Other Autoimmune Diseases

A study found children with pediatric acute-onset neuropsychiatric syndrome (PANS) show signs of an underlying inflammatory process and are at risk of developing arthritis and other autoimmune diseases.¹

“We observed an unexpectedly high frequency of immune activation signs, arthritis, and autoimmune disease, suggesting that PANS itself is part of an inflammatory diathesis, akin to neuropsychiatric lupus or Sydenham chorea, where neuroinflammation is comorbid with arthritis and other inflammatory sign,” wrote investigators, led by Meiquian Ma, MD, from the department of pediatrics at Stanford University School of Medicine.

Epidemiologic studies suggest patients with obsessive-compulsive disorder (OCD) and other psychiatric conditions have a high rate of autoimmune conditions. A previous study found one-third of patients with PANS developed arthritis, but the analysis did not determine the type of arthritis or examine other autoimmune conditions.²

Investigators wanted to better understand the inflammatory processes during psychiatric symptom flares.¹ Therefore, they conducted a retrospective cohort study of 193 patients with PANS to assess whether PANS is associated with an inflammatory diathesis.

More than half of the sample were male (58%), and the mean age was 7.5 years. Most of the participants were White (82.9%), followed by multiracial (14.5%), Hispanic or Latino (11.4%), and Asian (2.6%).

Patients were followed up for a mean of 4 years at Stanford Immune Behavioral Health Clinic between September 1, 2012 and December 31, 2021. The team reviewed medical records, a pre-defined set of immune markers that were measured during a psychiatric symptom flare, and the imaging findings of arthritis and other autoimmune diseases. Immune markers included autoimmunity signs, immune dysregulation or inflammation signs, and vasculopathy signs.

Immune Markers

1. Autoimmunity signs: Antinuclear antibody, antihistone antibody, antithyroglobulin antibody, C1q binding assay, and complement levels [C3 and C4])
2. Immune dysregulation or inflammation signs: leukopenia, thrombocytosis, C-reactive protein, and erythrocyte sedimentation rate
3. Vasculopathy signs: livedo reticularis, periungual redness and swelling, abnormally prominent onychodermal band, palatal petechiae, high von Willebrand factor antigen, and high d-dimer

The team estimated the cumulative risk of developing arthritis and autoimmune diseases through product limit (Kaplan-Meier) survival probability.

Most patients (77.2%) had ≥ 1 sign of autoimmunity, immune dysregulation or inflammation, or vasculopathy during a psychiatric symptom flare. More than half of the patients (54.2%) had nonspecific markers of autoimmunity. Additionally, 35.8% had signs of vasculopathy and 12% had nonspecific signs of immune dysregulation or inflammation.

“The high level of antihistone antibodies are another remarkable finding,” investigators wrote. “We proactively evaluated this autoantibody given concern for drug-induced lupus.”

The subset of patients who were tested for all immune markers had greater estimates of autoimmunity (69.2%), vasculopathy (96.3%), and immune dysregulation or inflammation (20.5%). About a third of patients with ≥ 1 sign of autoimmunity, immune dysregulation or inflammation, or vasculopathy showed signs of having markers consistent with ≥ 2 of the arthritis subcategories.

The mean age for an arthritis diagnosis and another autoimmune diagnosis was 12.7 and 12.4 years, respectively. Only 4 patients had an autoimmune disorder before PANS onset. By 14 years old, the estimated cumulative incidence of arthritis was 28.3% (95% confidence interval [CI], 20.8% - 36.3%), and the estimated cumulative incidence of another autoimmune disease was 7.5% (95% CI, 4% - 12.4%).

Among those with arthritis, 55% had joint capsule thickening, 81.8% had distal interphalangeal joint tenderness, and 80% had spinous process tenderness. The most common types of arthritis were enthesitis-related arthritis (67.3%), spondylarthritis (49.1%), and psoriatic arthritis (18.2%).

“Inflammation in this cohort does not provoke a significant acute phase response because PANS-related inflammation is likely associated with ERA and juvenile SpA,” investigators wrote.

Investigators wrote the study was limited by having no control sample, not studying medications that may be linked to an arthritis risk, and missing data.

“Our findings demonstrate that a significant proportion of patients with PANS have evidence of subtle systemic inflammation and raise the possibility that the psychiatric symptoms reflect a brain response to a global process,” investigators concluded. “Addressing inflammation may be critical in preventing the development of arthritis and other autoimmune diseases, but clinical trials are needed to determine the association of anti-inflammatories with psychiatric symptoms in this patient population.”

References

1. ^{Ma M, Masterson EE, Gao J, et al. Development of Autoimmune Diseases Among Children With Pediatric Acute-Onset Neuropsychiatric Syndrome. JAMA Netw Open. 2024;7(7):e2421688. Published 2024 Jul 1. doi:10.1001/jamanetworkopen.2024.21688}
2. ^{Rahman S, Gaertner F, Houghton J, Macaubas C, Chan A, Columbo L, Frankovich J, Mellins E. Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) Is Characterized by a Novel Subset of Monocytes with Markers Associated with Crossing the Blood Brain Barrier (BBB) [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 4). https://acrabstracts.org/abstract/pediatric-acute-onset-neuropsychiatric-syndrome-pans-is-characterized-by-a-novel-subset-of-monocytes-with-markers-associated-with-crossing-the-blood-brain-barrier-bbb/. Accessed August 16, 2024.}