Central nervous system demyelination associated with tofacitinib use in alopecia areata: A case report and literature review

INTRODUCTION

Alopecia areata (AA) is a common autoimmune disease characterized by patchy hair loss. Standard therapies include corticosteroids, immunosuppressants (e.g., methotrexate, cyclosporine), and topical agents, but many cases are refractory. The oral Janus kinase (JAK) inhibitor tofacitinib (a JAK1/3 inhibitor) has shown promise in severe AA, with significant hair regrowth observed in the majority of treated patients.^[1] In a retrospective series of 65 AA patients, 58% achieved >50% improvement in scalp hair (severity of alopecia tool [SALT]) score on tofacitinib, and the drug was generally well tolerated.^[2] Although not Food and Drug Administration (FDA) approved for AA (tofacitinib’s approved indications are rheumatoid arthritis (RA), psoriatic arthritis, ulcerative colitis, etc.), its use in dermatology is growing.

JAK inhibitors modulate immune signaling by blocking phosphorylation of signal transduction and activation of transcription (STAT) transcription factors downstream of multiple cytokine receptors. While effective, serious adverse events have emerged. In 2021, the FDA mandated black-box warnings for tofacitinib and related JAK inhibitors due to increased risks of serious infections, malignancy, thromboembolism, cardiovascular events, and mortality observed in large post-market trials.^[3] Neurological complications have also been reported. There is growing recognition that targeted immunotherapies can trigger central nervous system (CNS) demyelination (an “iatrogenic MS-like” syndrome).^[4] Case reports have now described new-onset CNS demyelination temporally related to tofacitinib use.^[5] We present the first detailed account of tofacitinib-associated CNS demyelination in an AA patient and review the literature on reported cases, possible pathophysiology, risk factors, diagnostic workup, and outcomes after discontinuation of the drug.

CASE REPORT

A 23-year-old woman with a 6-month history of patchy AA and madarosis presented with new neurological symptoms [Figures 1 and 2]. Her AA had been severe and treatment-refractory, with little response to prior courses of systemic steroids, intralesional steroids, cyclosporine, and phototherapy. She was started on tofacitinib 5 mg (Tab. Betrecep, Pfizer Inc.,) twice daily and topical tofacitinib ointment (2% Jakauto Ointment, Eris Oaknet Health Care) for local application. After 3 months of therapy, the patient experienced significant hair regrowth (her SALT score improved from severe alopecia to near-complete scalp coverage).

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Figure 1:

Patchy alopecia areata.

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Figure 2:

Madarosis of the right eye with adduction restriction in the right eye. Madarosis of the right eye is shown in red arrow.

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During the 4^th month of tofacitinib therapy, the patient developed double vision, gait difficulty, and loss of taste sensation. She also reported numbness in the left upper and lower limbs. Owing to these neurological symptoms, her activities of daily living were significantly restricted, resulting in a poor quality of life. Concerned about these developments, the patient discontinued tofacitinib and underwent neurological evaluation. Neurological examination revealed bilateral (B/L) upbeat nystagmus and adduction restriction in the right eye with abduction nystagmus in the left eye, suggestive of right-side internuclear ophthalmoplegia. Magnetic resonance imaging (MRI) of the brain showed T2-hyperintense lesions in the right pontine tegmentum, showing mild diffusion restriction and subtle contrast enhancement and patchy non-enhancing T2/fluid attenuated inversion recovery sequence (FLAIR) hyperintensities in the juxtacortical region of the right parietal lobe, deep white matter region of the right occipital and left frontoparietal lobes, and in the callosal septal interface [Figure 3]. These features were suggestive of demyelination. Spinal cord imaging and visually evoked potentials (VEP) were normal. Cerebrospinal fluid (CSF) analysis revealed acellular, normal glucose (83 mg/dL), with very high protein (164 mg/dL). CSF gene Xpert tuberculosis was negative, CSF myelin oligodendrocyte glycoprotein/neuromyelitis optica antibodies were negative, and there were no oligoclonal bands; CSF immunoglobulin G index was negative (0.08).

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Figure 3:

Magnetic resonance imaging of the brain - Sagittal T2 FLAIR image (1 mm) section showing a linear hyperintense signal in the dorsal pons close to the midline. Red arrow indicate demyelination changes.

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A broad serum workup [complete blood count (CBC), metabolic panel, thyroid function, antinuclear antibody (ANA), rheumatoid factor, anti-cyclic citrullinated peptide (CCP), vitamin B12 and vitamin D levels, and extractable nuclear antigen (ENA) profile] was unremarkable except for mild vitamin D deficiency, which was treated. The neurology team concluded the presentation met McDonald’s criteria for multiple sclerosis [new CNS lesions with clinical symptoms, even in the absence of CSF oligoclonal bands (OCB)]. The sudden onset after the 4^th month of tofacitinib suggested a drug-related effect.

DISCUSSION

Our case adds to the sparse but concerning reports linking tofacitinib to CNS demyelination. The strong temporal association – new CNS lesions emerging after several months of therapy – and reproducible outcomes, namely symptom resolution following drug discontinuation and corticosteroid treatment,^[4,5] support a drug-related effect rather than coincidental multiple sclerosis onset. The rapidity of neurological improvement and lesion stabilization contrasts with the typical course of untreated MS, suggesting an iatrogenic phenomenon. However, definitive causality cannot be established; it remains possible that tofacitinib unmasked a pre-existing MS. The patient’s negative CSF oligoclonal bands argue against longstanding MS. Furthermore, both reported cases occurred in individuals with other autoimmune diseases, raising the possibility of shared immunogenetic susceptibility.

The immunologic basis of JAK inhibitor-associated demyelination remains hypothetical. Experimental studies by Yoshida and hypotheses by Massoud implicate Th17/IL-17 pathway skewing.^[4,7] IL-17 has a well-established role in MS pathogenesis,^[7] and if tofacitinib shifts the cytokine milieu toward IL-17, it could precipitate or exacerbate autoimmunity. Alternatively, off-target effects on the JAK pathway – such as altered microglial activation or disruption of blood–brain barrier integrity – may contribute. The absence of progressive multifocal leukoencephalopathy (PML) in these cases suggests that JC virus reactivation is not the mechanism, although a single PML case has been reported with ruxolitinib.^[6]

Clinically, these reports underscore the need for vigilance. Tofacitinib and other JAK inhibitors have transformed the management of autoimmune diseases, but clinicians should be alert to rare yet serious neurotoxic effects. Dermatologists and neurologists should be aware of this potential complication in patients with AA receiving tofacitinib or related agents. Baseline neurological assessment may be prudent, particularly in patients reporting subtle symptoms. At the first sign of CNS involvement – such as numbness or visual changes – prompt MRI evaluation is recommended, and corticosteroid therapy should be initiated if demyelination is confirmed, along with immediate discontinuation of the JAK inhibitor.

Regarding risk–benefit considerations, tofacitinib remains an effective treatment for refractory AA.^[1,2] The incidence of CNS demyelination is extremely low, with only two published cases among thousands of users. Nevertheless, given the potential for severe disability, even rare events warrant attention. At present, there is insufficient evidence to alter general prescribing practices – no formal guidelines or label changes address demyelination specifically – but informed consent should include discussion of this emerging risk. Future pharmacovigilance studies, such as analyses of FAERS or other registries, may help quantify the risk more accurately. A recent pharmacovigilance review of 105,000 tofacitinib reports identified numerous neurological adverse events, although demyelination was not singled out.^[6]

CONCLUSION

Tofacitinib-induced CNS demyelination is an emerging but potentially serious adverse effect. We report a case of multifocal demyelinating lesions in a patient with AA following 4 months of tofacitinib therapy, with clinical and radiological improvement after drug discontinuation and corticosteroid treatment. This observation adds to a previously reported case in a patient with rheumatoid arthritis and suggests a consistent pattern characterized by a temporal association between drug exposure and the onset of multiple sclerosis– like lesions, followed by stabilization after withdrawal of the offending agent. The proposed pathophysiological mechanism involves cytokine imbalance under Janus kinase inhibition, particularly enhanced IL-17/Th17-mediated immune activity. Clinicians should consider this diagnosis in patients receiving tofacitinib who develop new neurological symptoms. Further studies are warranted to identify predisposing risk factors, establish optimal monitoring strategies, and determine whether certain patient populations should avoid JAK inhibitors. Until such data are available, heightened clinical vigilance and a low threshold for neurological evaluation are recommended. Continued reporting of similar cases will be essential to better define the scope and clinical implications of this adverse effect.