Summary

• Two cases of posterior reversible encephalopathy syndrome (PRES), also known as reversible posterior leukoencephalopathy syndrome (RPLS), were reported in clinical trials. Cases have also been reported in post-marketing experience in patients with psoriasis, psoriatic arthritis, and Crohn's disease (CD). Clinical presentation included headaches, seizures, confusion, visual disturbances, and imaging changes consistent with PRES a few days to several months after ustekinumab initiation. A few cases reported latency of a year or longer. Patients recovered with supportive care following withdrawal of ustekinumab.¹
• Monitor all patients treated with STELARA for signs and symptoms of PRES. If PRES is suspected, promptly administer appropriate treatment and discontinue STELARA.¹
• Additionally, pooled safety data through 5 years in CD and 4 years in UC and published case reports of PRES in patients receiving STELARA treatment are summarized below.^2-6

Pooled Safety data From Phase 2/3 CD and UC Studies

Ghosh et al (2024)² evaluated the cumulative safety of STELARA from 6 phase 2/3 CD and UC studies (5 CD studies and 1 UC study) through 5 and 4 years of treatment, respectively.

• All patients receiving ≥1 dose of STELARA were included in the analysis.
• Concomitant immunomodulators and corticosteroids were permitted.
• The pooled analysis included 2575 and 1389 patients who received STELARA and placebo, respectively. The patient-years (PY) of follow-up was 4826 for STELARA and 943 for placebo.
• No cases of PRES were reported.

PUBLISHED CLINICAL DATA

Available published cases are presented below.

STELARA Psoriasis Clinical Trials

Gratton et al (2011)³ reported 1 case of RPLS in the STELARA psoriasis clinical trial program (1 out of 3758 STELARA-treated patients).

• This was a 65-year-old female patient enrolled in a phase 3 psoriasis study.
• She was diagnosed with psoriasis at 36 years of age, was previously treated with topical steroids and acitretin only, and had not received any other systemic immunomodulatory agents before STELARA.
• Her past medical history was also notable for smoking, heavy alcohol use with alcoholic hepatitis, and hypercholesteremia.
• She had been on STELARA 45 mg therapy for over 2 years.
• Six weeks after her twelfth dose of STELARA, she developed headache, nausea, and vomiting over a period of a few hours, followed by a probable seizure. She was found unconscious with upward deviation of her eyes. By the time medical help arrived, she was conscious but confused.
• While she did not have a history of hypertension, her blood pressure at the time was 152/92 mmHg.
• In the emergency department (ED), she had 2 additional witnessed generalized seizures with focal features; the patient was treated with lorazepam, phenytoin, and propofol, and she was intubated for airway protection.
• Laboratory and cerebrospinal fluid (CSF) evaluation did not reveal any evidence of infection. Specifically, her CSF was negative for white blood cells, herpes simplex virus, John Cunningham (JC) virus, and West Nile virus.
• Brain imaging by both computed tomography (CT) and magnetic resonance imaging (MRI) showed no evidence of ischemia, infarction, or thrombosis, but did show abnormalities in the cerebral hemispheres, hypothalamus/thalamus, and in the periventricular white matter of the parietal lobes.
• The patient’s condition improved rapidly, and she was extubated within 24 hours, although she remained confused for a few days. She was discharged from the hospital 6 days after admission, and she continued taking phenytoin for 1 month.
• The patient has made a full neurologic recovery.
• Steady state trough ustekinumab serum concentrations (1.06 μg/mL) were detected approximately 6 weeks before the onset of signs and symptoms of RPLS and approximately 6 weeks after they resolved (0.80 μg/mL). The ustekinumab serum levels were within the therapeutic range throughout the patient's treatment and within the therapeutic range reported in all patients treated with STELARA 45 mg in this phase 3 study.
• STELARA therapy was permanently discontinued.

Case Reports

Jordan et al (2022)⁴ reported a case of PRES in a 64-year-old female with a history of ileocolonic (Montreal class B3), vulvar, and perianal CD who received STELARA maintenance treatment (90 mg every 8 weeks) for 2.5 years.

• The patient presented to the ED with complaints of headache, upper back pain, weakness, and numbness of bilateral hands for 4 days.
• New-onset hypertension with a blood pressure of 175/89 mmHg was reported in the ED. After the blood pressure improved spontaneously, the patient was discharged; however, the same evening, the patient presented again to the ED after developing new-onset urinary incontinence and difficulty in walking.
• The patient’s systolic blood pressure was approximately 200 mmHg. Laboratory tests revealed mild leukocytosis (10.3 K/µL) and an erythrocyte sedimentation rate of 54 mm. Blood and urine cultures were negative and the patient’s hemoglobin, creatinine, and creatine kinase levels were within normal range.
• For the treatment of CD, the patient had been receiving a maintenance dose of STELARA (90 mg every 8 weeks) for 2.5 years and did not experience any adverse events. She had been in clinical and endoscopic remission (based on the colonoscopy done 1 year ago) and had received her last STELARA dose approximately 2 months ago.
• Due to her neurologic symptoms, MRI of the brain was performed which revealed multifocal T2/fluid-attenuated inversion recovery hyperintensities in bilateral cerebellar hemispheres (left>right), particularly in the supratentorial area and posterior fossa. MRI of the spine was negative for epidural abscess or demyelinating process. Vitamin B12 and copper levels were within normal range, which ruled out any vitamin deficiencies due to a long-standing history of CD with small bowel involvement.
• The imaging findings along with clinical history were felt to be most consistent with PRES, likely associated with STELARA treatment. STELARA was discontinued and intravenous (IV) labetalol followed by oral antihypertensives was administered due to her hypertension.
• Around day 2 of admission, the patient also developed hyponatremia, believed to be a sequela of PRES, with sodium levels reaching 129 on day 3. The patient responded to fluids and sodium chloride (NaCl) tablets.
• After 10 days, the patient was discharged on amlodipine due to persistent hypertension.
• At the follow-up visit 1 month later, hypertension and difficulty in ambulation were persistent; however, urinary incontinence had resolved. A repeat MRI of the brain did not show any changes. For CD, vedolizumab was initiated. The patient required over a month of care in a skilled nursing facility for rehabilitation services and continues to require home assistance.

Mishra et al (2017)⁵ reported a case of PRES in a 18-year old female with a history of CD with ileocolonic involvement and stricturing and fistulizing phenotype who received STELARA induction treatment.

• Since diagnosis, the patient was managed with oral mesalamine, 6-mercaptopurine, methotrexate (MTX), and infliximab in a step-up fashion with periods of reported nonadherence.
• The patient had multiple complicated hospitalizations due to active CD, and during this time infliximab was increased to 10 mg/kg every 4 weeks and MTX was continued weekly.
• The patient presented with abdominal pain after receiving an infliximab infusion and a CT scan also showed worsening of small bowel disease with new enterocolic and enteroenteric fistulas.
• Detectable infliximab trough level and low titer anti-drug antibodies were reported and with the lack of response, infliximab was discontinued and induction treatment with STELARA 390 mg IV was administered 1 week after the last MTX dose.
• Twelve days after STELARA was administered, the patient presented with tonic-clonic seizures. The patient was also reported to have hyponatremia, and an MRI of the brain showed bilateral foci of high signal intensity on T2/FLAIR imaging within the frontal, parietal, and occipital lobes consistent with PRES.
• Anti-epileptic medications were started and the patient had no further seizures or neurologic deficits. STELARA was also discontinued.

Dickson et al (2017)⁶ reported a case of RPLS in a 58-year-old man with a history of psoriasis and psoriatic arthritis who received STELARA 90 mg every 8 weeks for over 6 years.

• The patient presented to the ED with confusion and memory difficulties after being found shaking in his vehicle.
• The patient had a blood pressure of 177/83, with normal heart and respiratory rates.
• Electrocardiogram, chest x-ray, lumbar puncture, and neurological exam were normal.
• The patient had a National Institutes of Health stroke score of 0.
• A urine drug screen was positive for 3,4-Methylenedioxymethamphetamine (MDMA), benzodiazepines, barbiturates, and marijuana.
• Other current medications included valsartan, zolpidem, alprazolam, and trazodone.
• Prior to initiating treatment with STELARA, the patient received infliximab, etanercept, MTX, and phototherapy for treatment of psoriasis.
• Imaging with CT and MRI revealed bilateral occipital parenchymal edema with an appearance and distribution suggestive of RPLS.
• The patient was diagnosed with RPLS and STELARA was withheld.
• Symptoms completely resolved once blood pressure was sufficiently controlled, with no residual sequelae.
• A neurologist who evaluated the patient felt that STELARA was the most likely cause of his RPLS, though he could not rule out substance abuse as the cause.
• There was no evidence of RPLS on repeat imaging. The patient’s blood pressure was within normal limits during a follow-up examination.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 19 March 2024.