JAK Inhibition in Down Syndrome Regression Disorder

Abstract

Down Syndrome Regression Disorder (DRSD) is an uncommon but devastating condition affecting primarily adolescents and young adults with Down syndrome (DS). Individuals with DS display a dysregulated immune system associated with hyperactive interferon signaling, which is associated with a high incidence of autoimmune conditions. While the cause of DSRD is unknown, increasing evidence indicates that it may have an immune basis, and some individuals with DSRD have responded to intravenous immunoglobulin therapy. This case series describes three individuals with probable DSRD who received the JAK inhibitor tofacitinib and saw improvement in DSRD symptoms across multiple domains of neurological function.

1. INTRODUCTION

Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is a leading cause of intellectual and developmental disability (de Graaf et al., 2015). Over the last decade, reports have documented an increasing number of adolescents and young adults with DS displaying developmental regression associated with neuropsychiatric features (Mircher et al., 2017, Hart et al., 2021, Ghaziuddin et al., 2015, Stein et al., 2017, Worley et al., 2015, Cardinale et al., 2019, Santoro et al., 2020). This condition, referred to as Down Syndrome Regression Disorder (DSRD), includes symptoms such as catatonia, mutism, depersonalization, loss of ability to perform activities of daily living, hallucinations, delusions, and aggression (Mircher et al., 2017, Worley et al., 2015, Santoro et al., 2020). The dramatic decline in functioning is devastating not only for the individual with DSRD, but also for their caregivers and community. The etiology of DSRD is unclear, and only recently have practitioners been able to recommend a cohesive diagnostic approach and criteria for diagnosis (Santoro et al., 2022b).

Individuals with DS display consistent activation of the interferon (IFN) response (Sullivan et al., 2016), hyperactive JAK/STAT signaling (Waugh et al., 2019), and chronic dysregulation of the immune system (Waugh et al., 2019, Araya et al., 2019), which could be explained by triplication of four IFN receptors encoded on chromosome 21 (Galbraith, 2023, Waugh et al., 2023). This dysregulation may explain the increased incidence of autoimmune conditions in DS, including autoimmune thyroid disease (Amr, 2018), celiac disease (Liu et al., 2020), and immune-mediated skin conditions (Sureshbabu et al., 2011), and could potentially underlie some DSRD cases. Notably, the JAK1/3 inhibitor tofacitinib, which is approved for the treatment of diverse autoimmune conditions (Schwartz et al., 2017), was found to attenuate IFN hyperactivity with therapeutic benefit for alopecia areata and psoriatic arthritis in DS (Galbraith, 2023, Rachubinski et al., 2019, Pham et al., 2021). Here, we report three cases of tofacitinib use for the treatment of DSRD.

2. METHODS

This case series describes observations from two participants with DS in an open-label, Phase 2 clinical trial for tofacitinib for immune skin conditions (NCT04246372) who had a previous diagnosis of DSRD, and an individual who received tofacitinib clinically off-label for DSRD symptoms. All research procedures were approved by the local Institutional Review Boards. All individuals described received 5 mg tofacitinib twice daily for up to 40 weeks with a cognitive assessment at baseline, 16 weeks, and 40 weeks as applicable. The cognitive tests performed include the Cambridge Neuropsychological Test Automated Battery (CANTAB) Paired Associates Learning and Spatial Span Forward subtests for assessment of visual memory and learning; the NEuroPSYchological Assessment II (NEPSY-II) Visuomotor Car and Motorcycle subtests for assessment of visuomotor function; the Kaufman Brief Intelligence Test 2 (KBIT-2) for assessment of verbal and non-verbal intelligence; and the Peabody Picture Vocabulary Test 5^th edition (PPVT-5) for assessment of receptive vocabulary.

3. RESULTS

3.1. CASE 1

Case 1 is a 28-year-old female with DS who qualified for the trial with a dermatologic diagnosis of hidradenitis suppurativa. This participant was an articulate and independent young adult who experienced her first regressive episode at 20 years old, shortly after moving away from family for college. She experienced a dramatic loss of adaptive daily living skills over approximately 8 weeks (feeding, toileting, self-care), and was unable to follow basic directions or verbally communicate. She also had difficulty with forming short-term memories, experienced delusions, auditory, visual, and olfactory hallucinations, and catatonic behavior for a period of 18 months. She was treated with sertraline and risperidone with weekly psychotherapy, slowly returning to her baseline level of functioning but with continuing anxiety and obsessive-compulsive symptoms. Two years after the onset of the initial regression, she experienced another significant regressive episode that did not respond to multiple psychiatric medications, including lorazepam. Electroconvulsive therapy (ECT) was initiated, and she regained her abilities to almost her baseline functioning after 12 ECT sessions. Maintenance ECT of at least once every 3 weeks was required to prevent worsening of anxiety and obsessive-compulsive symptoms. The treatment and recovery process during this period have been described in detail (Patel and Sannar, 2017). After four years of maintenance ECT, and eight months prior to enrollment in the tofacitinib trial, a third significant regressive episode occurred with loss of skills and speech, hallucinations, catatonia, and incontinence.

Throughout her episodes, comprehensive evaluations for systemic, metabolic disorders, and autoimmune encephalitis did not show any alternative treatable etiology (Table 1) and EEGs during the first two episodes of regression were each normal. In evaluation of her third regression episode, an abnormal EEG demonstrated bilateral frontotemporal slowing and epileptiform discharges, and a 24-hour EEG showed diffuse background slowing, lack of a posterior dominant rhythm, temporal intermittent rhythmic delta activity, and abundant bilateral temporal epileptiform discharges lasting up to 3 seconds. Although no clinical or electrographic seizures were noted, she began lamotrigine at the recommendation of an epileptologist.

Table 1: Demographic and Clinical Data.

The characteristics and clinical initial work-up from the three presented cases. Data do not reflect research procedures.

	Case 1	Case 2	Case 3
Age at Onset	20	20	13
Sex	Female	Female	Female
Race	Caucasian	Caucasian	Caucasian
Ethnicity	Non-Hispanic	Non-Hispanic	Hispanic
Medical History
Obstructive Sleep Apnea	+	+	+
Congenital Heart Defect	-	+	-
Autoimmune Disease	+ (HS)	+ (HS, alopecia areata)	+ (Celiac)
Thyroid Disease	-	+ (Grave’s Disease)	-
Potential Preceding Event	• Transition / Change in Environment	• Transition / Change in Environment • Overstimulation	None
Weeks to Symptom Peak	8	12	8
Serum Biomarkers
ANA	-	+ (1:40)	+ (1:320)
Thyroid Dysfunction	-	Resolved at time of enrollment	-
TPO Ab	+	-	-
Thyroglobulin Ab	-	-	-
Vitamin D	Low	n/a	Low
ESR	-	n/a	-
CRP	-	-	-
Cytokines	Elevated sIL2 and sIL10	n/a	Elevated sIL2
EEG	Initially normal for several years, then with progressive diffuse/temporal slowing and bilateral temporal epileptiform spikes	Mild diffuse slowing	Normal
MRI	MRI Brain: Normal	MRI Brain: Cyst of the cavum septum pellucidum et vergae resulting in obstruction to CSF flow at the level of the foramina of Monro. Findings are long-standing and likely compensated for as there is no obvious periventricular interstitial edema or papilledema. MRA: normal	MRI Brain: Bilateral GRE signal abnormality in the globus pallidus MRA: Normal
CSF	Normal*	N/A	Normal*
Prior Immunotherapy	IVIG: No response	None	IVIG: Improvement but incomplete response
Duration of Prior Immunotherapy	10 weeks	N/A	14 months

^*Basic inflammatory CSF, intrathecal IgG synthesis, autoantibody testing, IgG index. HS: hidradenitis suppurativa.

At the start of the tofacitinib trial, the participant was on a stable psychiatric medication regimen including escitalopram, memantine, lorazepam, and ziprasidone, with ECT therapy 2–3 times per week, and had received IVIG therapy every 7–14 days in the 10 weeks prior to enrollment with minimal improvement. IVIG treatment was stopped 3.5 weeks before enrollment. During the trial, measures designed to assess aspects of executive function and visuomotor abilities were administered at baseline and 16 weeks (Table 2). Overall, the participant demonstrated qualitative improvements in engagement in conversation, comprehension, and memory of recent events at her 16-week appointment, which associated with improved scores in the CANTAB Paired Associates Learning test. Improvements in visuomotor abilities are demonstrated by images of the NEPSY-II Visuomotor test (Figure 1). The participant’s recovered language skills are captured in the improved KBIT-II verbal score, although the PPVT-5 raw score decreased. Clinically, her Montreal Cognitive Assessment (MoCA) scores showed sustained improvement while on tofacitinib. Just prior to the 40-week timepoint, the participant developed an upper respiratory illness and short regressive episode associated with lower scores in cognitive tests (Table 2). Nevertheless, the participant has remained on tofacitinib for >3 years to manage her DSRD symptoms. ECT intervals are now reduced to once every 4 weeks. EEG background features of encephalopathy have improved, and the observed temporal lobe seizures are controlled with lamotrigine alone.

Table 2. Changes in cognitive assessments with tofacitinib treatment.

Improvements were seen in spatial and episodic memory, visuomotor and verbal tasks after 16 weeks of treatment with tofacitinib. Results were variable for two participants followed for 40 weeks of tofacitinib treatment.

	Case 1			Case 2			Case 3
Assessment	Baseline	Week 16	Week 40	Baseline	Week 16	Week 40	Baseline	Week 16
CANTAB: Paired Associates Learning				n/a	n/a	n/a
First Attempt Memory Score	3	8	12				2	7
Max Patterns Reached	4	6	8				3	6
Total Errors (Adjusted)	59	40	20				44	22
CANTAB: Spatial Span Forward
Max Forward Length	n/a	4	5	n/a	n/a	n/a	3	5
Max Forward Reached	2	5	6	n/a	2	2	5	6
NEPSY-II: Car				n/a
Time	180	30	70		96	107	140	30
Errors	100	0	99		40	102	82	0
Pencil Lifts	17	0	11		2	1	12	1
NEPSY-II: Motorcycle
Time	180	47	99	180	107	180	180	24
Errors	194	26	196	192	70	149	114	12
Pencil Lifts	24	2	26	2	5	3	18	0
KBIT-2: Verbal (raw score)	24	45	42	26	32	32	19	41
KBIT-2: Nonverbal (raw score)	15	15	15	8	19	15	9	22
KBIT-2: IQ Composite (standard score)	-	-	-	40	44	40	31	54
PPVT-5	153	137	139	n/a	132	105	70	123
Improvement	• Improvements in CANTAB • Partial improvement in NEPSY-II • Partial improvement in KBIT-2: Verbal • No change in KBIT-2: Nonverbal • No improvements in PPVT-5			• Improvements in CANTAB • Partial improvement in NEPSY-II • Partial improvement in KBIT-2: Verbal • No change in KBIT-2: Nonverbal • No improvements in PPVT-5			Yes, all measures

Figure 1. Visuomotor task improvement with tofacitinib administration.

Dramatic improvement by Case 1 in ability to understand and complete a visuomotor task after 16 weeks of treatment with tofacitinib. Changes were variable with a relapse of some symptoms likely due to a mild acute illness just before Week 40.

3.2. CASE 2

We also describe a second participant with history of DSRD, who is a 26-year-old female with history of hidradenitis suppurativa, alopecia areata, and Grave’s disease. Although previously active and social, she first developed regressive symptoms at 20 years old with a loss of speech and adaptive behavior skills, avolition, and gait disturbances and tremor. These symptoms responded well to a combination of citalopram and carbidopa-levodopa for over two years with no additional regressive episodes noted (Palat et al., 2018). However, the participant began experiencing cognitive changes, including seizures, in the year before entering the tofacitinib trial. Carbidopa-levodopa was discontinued the month prior to enrolling in the trial. At enrollment, she was able to provide assent but only was able to complete parts of the cognitive assessment battery and remained quiet and shy. By week 8 it was noted that she was more engaged in conversation with the providers and study coordinators, and by week 16 was projecting her voice to be heard. The caregiver reported that the participant showed continual improvement in activities of daily living. Further, she showed a marked improvement in ability to understand and complete cognitive assessment tasks, as reflected in improved scores in the NEPSY-II Visuomotor, KBIT-2, and PPVT-5 tests. At week 40, she continued to show improvement in engagement with the study coordinators and her greater community, as reported by the caregiver, although cognitive assessment scores remained unchanged (Table 2).

3.3. CASE 3

The clinical patient was a primarily self-sufficient 13-year-old Hispanic female with DS who developed subacute onset insomnia, disinhibition, slowed processing speed, and bradykinesia over a period of two weeks. The patient had a prior mild upper respiratory tract infection approximately four weeks prior to the onset of symptoms but had recovered in full at the onset of neuropsychiatric disease. The patient subsequently lost the ability to feed herself, toilet independently, and perform other activities of daily living. Three months after the onset of symptoms, the patient was mute, experiencing frequent delusions and bouts of inappropriate laughter and was unresponsive to family members’ attempts to engage. Serum and neurodiagnostic work up is presented in Table 1. The patient was treated with intravenous immunoglobulin (IVIG) which resulted in a partial improvement subjectively over the next few months, although the patient only improved to roughly 50% of her prior neurocognitive baseline.

The patient began an off-label tofacitinib prescription due to the patient’s serum biomarker abnormalities and partial improvement on IVIG monotherapy. Within six weeks of starting this intervention, the patient was able to speak in 1–2-word phrases, toilet independently, and was showing emotion towards family members. By ten weeks, the patient was nearly independent with all activities of daily living (continued to need prompting) and was speaking in full sentences. The patient continued to have mild slowed processing speed and bradykinesia although was subjectively 90% back to her baseline. Further, she showed a marked improvement in ability to understand and complete the cognitive assessment tasks, including the NEPSY-II Visuomotor, KBIT-2, and PPVT-5 tests (Table 2).

4. DISCUSSION

Over the past decade, DSRD, a subacute, significant decline in behavioral, cognitive, and adaptive function, has drawn increased attention and need for exploration given the devastating effects of this diagnosis on the individual with DS and their caregivers. A number of etiologic hypotheses have been proposed for DSRD, including hormonal changes, psychosocial stressors, anesthesia, and neuroimmunologic and neuroinflammatory etiologies (Devenny and Mathews, 2011, Handen et al., 2021). Historically, treatment interventions have ranged from psychotherapy and behavioral activation to IVIG and ECT. Treatment outcomes of each intervention have been variable (Stein et al., 2013, Ghaziuddin et al., 2015, Walpert et al., 2021, Cardinale et al., 2019, Hart et al., 2021, Santoro et al., 2022a, Patel and Sannar, 2017, Tamasaki et al., 2016).

Within the general DS population, hyperactivation of the IFN pathway and downstream JAK/STAT signaling has been involved as a driver of many of the clinical, developmental, and cognitive impacts of DS (Sullivan et al., 2016, Sullivan et al., 2017, Galbraith, 2023, Waugh et al., 2023). Therefore, it is conceivable that this pathway may also have further impact for those with DSRD. In fact, a recent study comparing individuals with DSRD to a cohort with only DS found neurodiagnostic abnormalities in the cohort with DSRD, suggesting possible neuroimmunologic etiology, further supporting this hypothesis (Santoro et al., 2022a). Our findings within this series of cases also suggests a neuroimmunologic pathogenesis. In all three cases, tofacitinib demonstrated observable changes in day to day functioning as noted by caregivers, as well as improvement in performance on objective cognitive measures. In addition, one individual (Case 1) demonstrated improvement of features of encephalopathy on EEG background with the use of tofacitinib, although concurrent use of lamotrigine makes attribution difficult. It is notable that prior EEG were normal in midst of regression, making it unlikely that 7 years of only subclinical seizures were a cause of her episodes of regression, providing a potential biomarker of clinical response.

Serious consideration should be given to further evaluating a neuroimmunologic etiology for DSRD, as this may result in an accessible, effective, life-changing treatment intervention for those suffering from DSRD.