Arthritis in Children with Psychiatric Deteriorations: A Case Series

Pediatric acute-onset neuropsychiatric syndrome (PANS), pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections, Sydenham chorea, and other postinfectious psychiatric deteriorations are thought to be caused by inflammatory/autoimmune mechanisms, likely involving the basal ganglia based on imaging studies. Patients have a relapsing-remitting course and some develop severe refractory psychiatric disease. We found that 55/193 (28%) of consecutive patients meeting PANS criteria developed chronic arthritis and 25/121 (21%) of those with related psychiatric deteriorations developed chronic arthritis. Here we describe 7 of these patients in detail and one sibling. Many of our patients often have “dry” arthritis (no effusions found on physical exam) but subtle effusions detected by imaging and features of spondyloarthritis, enthesitis, and synovitis. Joint capsule thickening, not previously reported in children, is a common finding in the presented cases and in psoriatic arthritis in adults. Due to the severity of psychiatric symptoms in some cases, which often overshadow joint symptoms, and concomitant sensory dysregulation (making the physical exam unreliable in the absence of effusions), we rely on imaging to improve sensitivity and specificity of the arthritis classification. We also report the immunomodulatory treatments of these 7 patients (initially nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs with escalation to biologic medications) and note any coincidental changes to their arthritis and psychiatric symptoms while on immunomodulation. Patients with overlapping psychiatric syndromes and arthritis may have a unifying cause and pose unique challenges; a multi-disciplinary team can utilize imaging to tailor and coordinate treatment for this patient population.


Introduction
Pediatric acute-onset neuropsychiatric syndrome (PANS) is characterized by the sudden onset (≤48 h) of severe obsessive compulsive symptoms and/or eating restriction in addition to other sudden-onset neuropsychiatric symptoms causing tremendous mental anguish, disability, and significant caregiver burden [1,2].A related condition, pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS), likely has overlapping pathophysiology with Sydenham chorea (SC).See online supplementary 1 (for all online suppl.material, see https://doi.org/10.1159/000530854)for classification criteria for PANS/PANDAS.Like SC (which has strong psychiatric comorbidities), PANS/PANDAS are thought to be triggered by infection [3,4], causing basal ganglia inflammation/ dysfunction based on four imaging studies and studies of autoantibodies binding to cells within the basal ganglia, causing cholinergic interneuron signal changes [5,6] and activation of CAM kinase II in an in vitro model of neuronal activation [7].We previously reported a high rate of inflammatory back pain, enthesitis, and arthritis in patients presenting to our clinic [2].We aimed to describe these complex cases in detail to emphasize the overlap of psychiatric symptoms and arthritis, both of which we suspect result from a systemic inflammatory response secondary to infection as is being described in post-COVID autoimmunity [8,9].
Evaluations for arthritis were performed by pediatric rheumatologists (J.F. and M.M.).A patient met criteria for chronic arthritis if arthritis signs and symptoms lasted >6 weeks and there was objective evidence of arthritis (imaging evidence of arthritis or joint effusion or two or more of the following: limited or painful range of motion, tenderness, and warmth).To confirm the diagnosis of arthritis, we used objective imaging data: magnetic resonance imaging (MRI) and/or musculoskeletal (MSK) ultrasound.Classification of arthritis was based on International League of Associations for Rheumatology (ILAR) and Assessment of SpondyloArthritis International Society (ASAS) criteria [10,11].
The MSK ultrasound examinations were performed on a GE LOGIQ E9 ultrasound machine utilizing a 6-15 MHz linear transducer or a Siemens ACUSON Sequoia ultrasound machine utilizing an 18 MHz linear transducer.Settings were optimized for superficial MSK examinations.Both grayscale and color Doppler images of the target joints were acquired and saved on our institution's Picture Archiving and Communication System.Standard approaches were used for MRIs of joints.All imaging was read by fellowship-trained pediatric MSK imaging specialists (J.S.).

Results
Of the 193 consecutive patients who met strict PANS criteria, 55 (28%) developed arthritis following PANS onset.Of the 121 consecutive patients presenting with severe psychiatric deteriorations not meeting PANS criteria, 25 (21%) developed arthritis.We report 7 of these cases in detail (and one sibling).

Cases Presentations Case 1 (PANDAS)
A previously healthy 7-year-old white female developed abrupt onset of separation anxiety, tics, and enuresis following group A streptococcal (GAS) pharyngitis and was diagnosed with PANDAS by a pediatric neurologist.She had a relapsing-remitting course of tics and psychiatric symptoms with subsequent episodes presenting with severe obsessive compulsive disorder (OCD), anxiety, mood lability, tics, and eventual irritable bowel syndrome, small intestinal bacterial overgrowth, depression, and suicidality.She was not evaluated for GAS at her relapses and never received antibiotics or anti-inflammatories (except to treat her initial strep pharyngitis at the age of 7 years and small intestinal bacterial overgrowth in her twenties).She had insidious onset of back pain (starting in early adolescence) which was diagnosed as "mechanical back pain." During her initial clinic visit (age 20 years), she reported pain and stiffness in her back, hips, and fingers, worse in mornings and with prolonged stationary positions.On physical examination, she had tenderness in her fingers, toes, and overlying her sacroiliac joints (online suppl.3).X-rays showed bilateral sacroiliitis.Two years later, MRI of the pelvis (while on methotrexate and adalimumab for 1 year) showed severe enthesitis of the bilateral iliofemoral ligament and proximal hamstring insertion onto the bone (shown in Fig. 1), but inactive sacroiliitis and MSK ultrasound of the fingers showed trace fluid in the fingers.
Based on the physical examination and imaging, the patient met criteria for 3 forms of arthritis: enthesitisrelated arthritis, axial spondyloarthritis, and peripheral spondyloarthritis.She is HLA-B27 negative.One year prior to the MRI, she was started on methotrexate and adalimumab and had coincident improvement that year both in psychiatric and joint symptoms.However, adalimumab was selfdiscontinued due to concern over debilitating pelvic pain (eventually diagnosed as endometriosis).Due to fear/wariness of medication, the patient has not taken methotrexate consistently nor allowed us to advance her arthritis treatment; thus, her arthritis has worsened coincidentally with worsening mood/anxiety.Her fear/wariness of medication stems from a long history of failed psychotropic medication trials.

Case 2 (PANS)
A previously healthy 10-year-old white male with history of transient tic disorder (3-week episode of mild coughing tic a year prior to onset of PANS) developed abrupt/severe-onset OCD, anxiety, rage, sleep disturbance with persistent nightmares, developmental regression, sensory dysregulation, urinary frequency, and worsening tics with eventual development of severe pain amplification syndrome involving the abdomen and joints.Three months prior to the onset of his initial psychiatric symptoms, he developed pseudomonas folliculitis after being in a hot tub.He tested positive for Mycoplasma pneumoniae by serology 2 weeks after onset of symptoms, although he had been having recurrent sore throats and nasal drainage during the 3 months prior to the onset of symptoms.He was eventually diagnosed with thyroiditis (age 11 years) and type I diabetes (age 13 years).Due to persistent joint pain and two cooccurring autoimmune conditions, we re-evaluated his joints.
On physical examination at clinic presentation (age 11 years), he had tenderness in his fingers and toes and subsequent ankle swelling and warmth (online suppl.3).Ankle ultrasound at the age of 15 years revealed synovial proliferation, capsular thickening, and effusions (shown in Fig. 2).
The patient met criteria for enthesitis-related arthritis and subsequently started on methotrexate (age 13 years).Rituximab was then added for 2 years (age 14-16 years) given the presence of three autoimmune diseases, severe evolving psychiatric symptoms (disabling OCD, tics, mood instability, school refusal, and eventual development of psychosis).His neuropsychiatric symptoms coincidentally resolved over an 18-month period on rituximab/methotrexate, but he continued to have severe ankle arthritis, limiting mobility.On follow-up ultrasound, in addition to ankle arthritis, he also had arthritis in his fingers and wrists.Given progression of arthritis while on methotrexate and rituximab, we sequentially added in other arthritis medications: sulfasalazine, apremilast, adalimumab, and abatacept.These medications were discontinued due to side effects or poor efficacy.He was then transitioned to leflunomide and secukinumab (IL-17 inhibitor) and his arthritis improved.Follow-up ultrasound demonstrated stable/improved findings.The patient recently had multiple infections including pneumonia, toenail paronychia (treated with antibiotics), and CO-VID, with no worsening joint pain or neuropsychiatric changes.His psychiatric symptoms have remained in remission for almost 3 years.

Case 3a (PANS)
A previously healthy 5-year-old white female with recurrent allergies developed abrupt onset of OCD with contamination fears, eating restriction, anxiety, mood disorder, and sleep disturbance following a gastrointestinal infection, then a subsequent relapse at age 6 years coinciding with streptococcal infections.She developed joint pain 3 years later (age 8 years) and presented to our clinic (age 11 years) with ongoing joint pain and severe psychiatric symptoms.Along with the joint pain, she had recurrent oral and genital sores, pseudofolliculitis (Behcet's pustulosis), and pathergy, meeting criteria for Behçet's disease.She is HLA-B51 positive, an allele associated with Behçet's disease.On physical examination, she initially did not have findings but eventually developed warmth and swelling in her ankles and tenderness and swelling in her toes (online suppl.3).She also had enthesitis in the upper and lower pole of her patella.Ultrasound confirmed arthritis in her ankles and toes (synovial thickening and effusion) (online suppl.5).
She was treated with naproxen and eventually colchicine and methotrexate were added with a coincidental robust improvement in neuropsychiatric function.She was eventually diagnosed with psoriasis at age of 14 years, thus changing her diagnosis to psoriatic arthritis.She continued to have joint pain while on methotrexate and developed intolerance, so sulfasalazine was started.Both her psychiatric symptoms and arthritis are quiescent on sulfasalazine.Her sister eventually presented to our clinic due to inflammatory back pain, multiple joint pains, and eventual depression and tics.She is also HLA-B51 positive and was diagnosed with psoriatic arthritis (online suppl.4).
Case 4 (Abrupt-Onset Neuropsychiatric Disorder) A previously healthy 9-year-old white male with preexisting anxiety developed abrupt onset of separation anxiety along with other significant behavioral concerns including abrupt onset of depression, mood swings, panic attacks, cognitive decline with loss of reading and math skills, loss of motor coordination, polyuria, and restlessness/hyperactivity following a febrile illness around the time of a close contact streptococcal exposure (patient with elevated anti-DNase B).Upon review of systems, he endorsed ankle pain.On neurologic exam, he had wormian tongue movement, mild milkmaid grip, arm wavering, and piano playing movement of the fingers, suspicious for SC.Two other peers from their small community developed similar deteriorations around the same time.
On physical examination at initial presentation (age 9 years), he had joint tenderness in finger and toe joints, wrists, knees, and Achilles insertion point tenderness (online suppl.3).Initial ultrasound indicated synovitis with follow-up indicating capsular thickening and effusion (online suppl.6).
The patient was diagnosed with enthesitis-related arthritis.The arthritis was initially not treated aggressively as his psychiatric symptoms were the focus of treatment.The arthritis progressed and he developed more chronic psychiatric symptoms.This case demonstrates that the psychiatric symptoms often receive more attention than the arthritis due to the relative adverse impact of the symptoms.This patient has been treated with methotrexate, sulfasalazine, and apremilast.They were eventually discontinued due to either no significant benefit or medication intolerance.He recently started leflunomide.
Case 5 (Subacute, Relapsing-Remitting, Severe Psychiatric Disorder) A previously healthy 6-year-old white female developed subacute OCD, severe anxiety, auditory hallucinations, nightmares, mood disorder, defiance, irritability, aggression, severe oppositional behavior, dysgraphia, and school refusal.A preceding illness was not noted in the medical record.A few years later (age 10 years), she had another psychiatric deterioration (superimposed on chronic symptoms) which was preceded by recurrent GAS pharyngitis.Behavioral change was noted 2-3 weeks after her second GAS pharyngitis and she also tested positive for mononucleosis (positive screen).She concurrently developed joint pain in her feet with this second deterioration.
On physical examination at clinic presentation (age 10 years), she had severe Raynaud's, tenderness over her toe joints, and dactylitis (online suppl.3).She also had a rash that was suspicious for psoriasis.Ultrasound confirmed arthritis in her toes (synovial, capsular thickening, effusion, and bone erosions) (shown in Fig. 3).She was diagnosed with psoriatic arthritis.Due to her arthritis, psoriasis, and severe impairing psychiatric symptoms, coupled with the suspicion that there was a unifying underlying inflammatory/ autoimmune driver for all three of these conditions, aggressive immunomodulation with corticosteroids, IVIG, and mycophenolate mofetil was introduced.Significant foot and back pain did not improve, but notably, her psychiatric symptoms coincidentally improved.She was subsequently treated with sulfasalazine, apremilast, adalimumab, and eventually a trial of azathioprine.These medications were discontinued due to lack of significant benefit to her arthritis.Her arthritis is now improving on methotrexate and secukinumab.A recent ultrasound demonstrated an overall decrease in effusion and synovitis of the fingers and toes, and her psychiatric symptoms remain largely resolved.

Case 6 (PANS)
A previously healthy 5-year-old white male had abrupt-onset OCD and other psychiatric symptoms coincident with his sister having been diagnosed with severe perianal streptococcal dermatitis.This episode was retrospectively diagnosed as a PANS episode by our experienced psychiatrist.He had a relapsing-remitting course with worsening functioning over time.He developed joint and back pains shortly after the initial onset of behavioral changes but was never evaluated for arthritis.He was diagnosed with psoriasis (age 8 years).
Upon presentation to our clinic (age 22 years), he had chronic, severe OCD, depression, cognitive and executive functional issues, and episodic encopresis.On physical examination, he initially did not have any findings and was lost to follow-up for months.When he returned, tenderness was noted in his toe joints.Ultrasound confirmed arthritis in his fingers and toes (capsular thickening, effusions).He also had X-rays of his feet that demonstrated erosions in his toes (shown in Fig. 4).
Based on the physical examination and imaging, the patient met criteria for 2 forms of arthritis: psoriatic arthritis and peripheral spondyloarthritis (HLA-B27 negative).He was initially started on methotrexate, but this was discontinued due to liver abnormalities.Apremilast was then started, but this was discontinued due to lack of benefit and gastrointestinal side effects.We were considering biologic medications but held off given the increased risk for central nervous system inflammatory diseases.Azathioprine was started, which coincided with improvement in joint pain and psychiatric symptoms.He has since moved out of state and is lost to follow-up.

Case 7 (PANS)
A previously healthy 12-year-old white male developed abrupt-onset OCD, anxiety, behavioral regression, oppositionality, writing deterioration, and new-onset enuresis.Over the ensuing 6 months as his psychiatric symptoms partially improved in response to fluvoxamine and cognitive behavioral therapy, he began to report pain in his hands, feet, knees, and back.An infectious illness prior to or at the time of psychiatric presentation was not recorded.
Physical examination at presentation to our clinic (age 13 years) demonstrated tenderness in his fingers, toes, and enthesitis (online suppl.3).The initial MRI of the pelvis demonstrated facet arthritis and enhancement of both sacroiliac joints.Follow-up MRI 2.5 years later demonstrated a new erosion (shown in Fig. 5).Ultrasound demonstrated synovial thickening and effusion in multiple finger joints.
Based on the physical examination and imaging, the patient met criteria for 3 forms of arthritis: enthesitisrelated arthritis, axial spondyloarthritis, and peripheral spondyloarthritis (HLA-B27 negative).He was initially started on nonsteroidal anti-inflammatory drugs (NSAIDs) and had slight improvement in his joint pain.His ongoing OCD and anxiety symptoms coincidentally improved dramatically within a few weeks of starting NSAIDs.Given that the joint pain was not fully resolved on NSAIDs, we are advancing his arthritis treatment.Due to underlying fears/ skepticism about medications, it has been challenging for us to advance his arthritis treatment.

Discussion
The above cases are examples of severe psychiatric deteriorations and coincidental or future development of chronic arthritis confirmed by imaging.It is interesting that MSK complications often developed years after the initial onset of psychiatric symptomatology, suggesting a role for genetic or additional acquired triggers to provoke clinically significant arthritis.In contrast to our findings, reflecting a decade-long clinical experience, MSK signs and symptoms were not prominent in earlier descriptive series of children with PANS/PANDAS, which largely focused on presenting features [2,12].We suspect that infections trigger a systemic inflammatory response which impacts the behavior systems and the heightened immune response may also lead to arthritis and other autoimmune/inflammatory conditions in the future.An alternative or additional hypothesis is that these patients are immunogenetically predisposed to autoimmunity, and such genetic loading may predispose to multiple inflammatory conditions.
We rely on imaging to provide objective data about arthritis in patients with psychiatric symptoms.Severe OCD, anxiety, depression, and psychosis often overshadow subtle joint achiness and stiffness.Additionally, this patient population tends to have sensory dysregulation, making the physical exam unreliable with regard to joint tenderness.Patients are often uncooperative with the examination due to their psychiatric symptoms.Imaging provides objective data in these challenging cases.Imaging is also ordered when the family/patient reports a reduction in physical activity, avoidance of previously enjoyed activities, stiffness, or altered gait in the morning or after prolonged stationary positions such as sitting.
Many of these patients had synovial and capsular thickening on their ultrasounds.Capsular thickening is reported in adults with psoriatic arthritis [13] but has not been reported in children.The capsular thickening seen in these patients is likely reflective of the psoriatic arthritis subtype and possibly relates to the connection between GAS and psoriasis [14].NSAIDs are the first line for childhood arthritis and have been shown to reduce PANS flare duration and symptoms [15,16].However, when patients have significant capsular or synovial thickening on imaging and ongoing pain and stiffness despite NSAID therapy, we often escalate treatment to include disease-modifying antirheumatic drugs.In patients with refractory psychiatric symptoms, we have escalated to immunomodulatory approaches that have been used in other disorders which have overlapping arthritis and psychiatric symptoms (neuropsychiatric lupus and Behcet's disease) including azathioprine (case 6), mycophenolate mofetil (case 5), and rituximab (case 2) with coincidental improvement in psychiatric symptoms.Poor efficacy and gastrointestinal side effects have been noted for apremilast in our patient population despite its indication for psoriasis.In patients who have had refractory psoriatic arthritis, we have used IL-17 inhibitors.We have avoided using TNF inhibitors as the first line (since these have been known to trigger demyelinating disease and lupus) given our patient population has an HLA overlap with multiple sclerosis and features of lupus including low complement levels, elevated immune complexes, and leukopenia (publication pending).This patient population also has sensory dysregulation including chemosensitivity and is often intolerant to the usual escalation protocols of disease-modifying antirheumatic drugs, so we often escalate more slowly than in typical childhood arthritis.

Conclusion
We report 7 patients with severe psychiatric deteriorations and objective evidence of arthritis possibly relating to a postinfectious inflammatory response akin to SC and what is being reported as post-COVID autoimmunity.Our patient population is different from those typically seen in the general rheumatology clinic in that their arthritis is often "dry" and can have capsular thickening.When selecting immunomodulation to treat their arthritis, we often incorporate into the decision the possibility that the psychiatric symptoms are (in part) related to a systemic inflammatory response.medical case and any accompanying images.This study protocol was reviewed and approved by the Stanford Panel on Human Subjects Institutional Review Board, approval number 26922.

Fig. 1 .
Fig. 1. (Case 1) Hip imaging of a 21-year-old female with PANDAS who met criteria for enthesitis-related arthritis, axial spondyloarthritis, and peripheral spondyloarthritis.a Initial radiograph demonstrates right greater than left sacroiliac joint sclerosis (solid arrow) and narrowing.b Follow-up MRI 2 years later showed resolved sacroiliitis.However, the T1 fat-saturated post-contrast sequence shows bilateral enthesitis of the hamstring origins (dashed arrow) and iliofemoral ligaments (dotted arrow).

Fig. 2 .
Fig. 2. (Case 2) Ankle ultrasounds of 16-year-old male with PANS, type I diabetes, thyroiditis, and bilateral ankle arthritis.Right (a) and left (b) ankles that demonstrate joint effusions (dashed arrows), synovitis (solid arrow), and capsular thickening (dotted arrow) of the lateral ankle joint recesses.Note that synovitis can appear as thickened synovium or echogenic foci within a joint effusion.Fib, fibula; Tal, talus.