Drug-Induced Lupus Erythematosus After 14 Years of Carbamazepine Use in a Patient With Neuromyelitis Optica Spectrum Disorder: A Case Report

Abstract

Patient: Female, 61-year-old

Final Diagnosis: Drug induced lupus erythematosus

Symptoms: General fatigue • intermittent fever • night sweats • weight loss

Clinical Procedure: —

Specialty: Rheumatology

Objective: Challenging differential diagnosis

Background

Carbamazepine (CBZ) is a common therapy for seizures, neuropathic pain, and painful tonic spasms following spinal cord disease; however, it is associated with rare autoimmune complications, including drug-induced lupus erythematosus (DILE). Diagnosis of DILE can be challenging, especially when onset occurs after a prolonged latency period. Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune disease characterized by recurrent inflammation of the central nervous system, frequently coexists with other autoimmune disorders. This report describes a case of DILE in a 61-year-old woman with NMOSD involving the cervical and thoracic spinal cord after 14 years of CBZ therapy.

Case Report

A 61-year-old woman with aquaporin-4-IgG-positive NMOSD involving the cervical and thoracic spinal cords had received CBZ for 14 years to control painful tonic spasms. She presented with fatigue, weight loss, intermittent fever, and pleural effusion. Laboratory testing showed a high antinuclear antibody titer (1: 640) and elevated anti–single-stranded DNA, anti-DNA, and anti-histone antibodies. Chest imaging demonstrated pleural effusion and pleural thickening; malignancy and infection were excluded. Discontinuation of CBZ led to resolution of symptoms, normalization of inflammatory markers, and a decline in lupus-related autoantibodies, confirming the diagnosis of DILE. No recurrence was observed during a 30-month follow-up period.

Conclusions

This report describes a rare delayed-onset autoimmune adverse effect of CBZ that developed 14 years after treatment initiation. It highlights the importance of clinical awareness of potential autoimmune associations, particularly when CBZ is used in patients with preexisting autoimmune disorders such as NMOSD.

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is a recurrent inflammatory disease of the central nervous system that primarily affects the optic nerves, brainstem, and spinal cord. This disorder is closely associated with aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) and requires long-term immunosuppressive therapy [1]. Multiple studies have demonstrated a strong association between NMOSD and systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SjS), as well as with conditions involving non-organ-specific autoantibodies, including antinuclear antibodies (ANA) and extractable nuclear antigens [2–6]. These observations suggest that, in some individuals, NMOSD represents a manifestation of a heightened predisposition to humoral autoimmunity and multiple autoimmune disorders [5].

Several medications can cause symptoms and laboratory findings that resemble those of SLE, a condition referred to as drug-induced lupus erythematosus (DILE). The frequency of DILE may be underestimated because it often presents mildly and is frequently underdiagnosed, constituting an estimated 10% of all SLE cases [7,8].

Various antiepileptic drugs, including phenytoin, trimethadione, primidone, ethosuximide, clobazam, valproic acid, and carbamazepine (CBZ), have been associated with DILE [7]. CBZ is commonly prescribed for seizures, chronic neuropathic pain, trigeminal neuralgia, and psychiatric disorders. In patients with NMOSD, it is used to manage painful tonic spasms after transverse myelitis [9]. Although most individuals tolerate CBZ well, its adverse effects range from mild to severe systemic reactions. Common side effects include drowsiness, ataxia, diplopia, nausea, and vomiting; more serious complications include DILE, pseudolymphoma syndrome, aplastic anemia, agranulocytosis, and hypersensitivity reactions [10]. Since Simpson’s first report in 1966 describing CBZ-induced lupus erythematosus [11], several DILE cases have been documented, most frequently in patients with epilepsy. However, its occurrence in patients with autoimmune diseases has not been reported.

Diagnosing DILE in patients with autoimmune diseases such as NMOSD is challenging due to overlapping clinical manifestations. Differentiation from disease flares, opportunistic infections secondary to immunosuppressive therapy, or malignancies such as lymphoma can be particularly difficult, especially when DILE develops after prolonged immunosuppressive treatment.

This report describes a case of DILE in a 61-year-old woman with NMOSD, which developed after 14 years of CBZ therapy for painful tonic spasms.

Case Report

A 46-year-old previously healthy woman presented with subacute walking difficulties, lower-body dysesthesia, and urinary incontinence. Neurological examination revealed paraplegia, pyramidal signs, sensory disturbance below the Th4 spinal cord level, and loss of urinary and bowel sensation. Blood test results were unremarkable; among the various autoantibodies tested, only SS-A positivity was detected. Sicca symptoms were absent, and the Schirmer test result was negative. Cerebrospinal fluid analysis showed an elevated cell count of 163/mm³ (reference: ≤5/mm³) with 100% lymphocytes, increased protein at 106 mg/dL (reference: 10–40 mg/dL), and substantially elevated myelin basic protein at 1385 pg/mL (reference: ≤102.0 pg/mL). Oligoclonal bands were absent, the IgG index was within the normal range (0.61), and microbiological analysis results were negative. Evoked potential testing demonstrated a normal N20 response bilaterally, whereas the P40 response was considerably reduced on both sides. Thoracic spinal magnetic resonance imaging revealed a longitudinal lesion extending from Th1 to Th5 with partial gadolinium enhancement (Figure 1A(A1, A2)). These findings were consistent with transverse myelitis of the thoracic spinal cord. Early differential diagnoses included an initial attack of NMOSD or multiple sclerosis. Treatment was initiated, but there were no signs of optic neuritis, and the result of serological testing for AQP4-IgG was negative. Two cycles of 5-day infusions of 1 g methylprednisolone followed by oral prednisolone (40 mg/day) were administered; however, recovery was limited. Consequently, 7 days of immunoadsorption therapy using tryptophan columns were performed. The patient’s condition gradually improved, and she regained independent ambulation within 7 months after onset. Residual painful tonic spasms persisted, for which CBZ was started at 200 mg/day and gradually increased to 900 mg/day because of ongoing pain. She tolerated the medication well, experiencing only mild sleepiness.

Figure 1.

Magnetic resonance imaging of the spinal cord at onset and relapse. (A) T2-weighted sagittal image of the spinal cord showing a high-intensity lesion extending from Th1 to Th5 (A1); T2-weighted axial view at the Th2/3 level, demonstrating a prominent high-intensity lesion in the ventral cord (A2). (B) T2-weighted sagittal image of the thoracic cord showing lesions at the Th3–4 and Th10 levels (B1), with gadolinium enhancement (B2). Arrowheads indicate the lesions.

After 2 years, she was urgently hospitalized with stiffness in her right arm, numbness in both legs, gait disturbance, and urinary incontinence. Magnetic resonance imaging revealed a second attack of multifocal myelitis involving the C2–3, Th3–4, and Th10 levels (Figure 1B(B1, B2). Two cycles of intravenous methylprednisolone were administered, followed by oral prednisolone (40 mg/day), in combination with a 3-day course of plasma exchange. Her condition improved, and she regained the ability to walk with a walker after 6 months. To prevent further relapse, azathioprine (100 mg/day) was initiated, followed by tacrolimus (3 mg/day). She remained clinically stable; prednisolone was gradually discontinued at age 52. CBZ therapy was continued to control painful tonic spasms in both legs.

At age 61, she developed generalized fatigue, weight loss of 8.8 kg, intermittent fever, and night sweats. No new focal neurological signs were detected; brain and spinal magnetic resonance imaging findings showed no evidence of NMOSD relapse. Laboratory tests revealed elevated inflammatory markers, with a peak C-reactive protein (CRP) level of 24.71 mg/dL (reference: ≤0.14 mg/dL) and a white blood cell count of 10,100/μL (reference: 3,300–8,600/μL). Serum AQP4-IgG positivity was detected (9.2 U/mL, reference: <3.0 U/mL) for the first time, confirming AQP4-positive NMOSD. Residual urine volume consistent with sequelae of prior myelitis was present, and a urinary tract infection caused by Escherichia coli was diagnosed. Despite multiple antibiotic courses targeting complicated cystitis, only partial improvement was achieved. Persistent low-grade fever and fatigue with chronic inflammation prompted a referral to rheumatology after 6 months.

Rheumatologic evaluation revealed no skin rash, arthritis, or lymphadenopathy. Laboratory studies showed an elevated CRP level of 15.2 mg/dL (reference: ≤0.14 mg/dL) and a soluble interleukin-2 receptor level of 1053 U/mL (reference: ≤496 U/mL). Complete blood count results indicated anemia with hemoglobin at 9.6 g/dL (reference: 11.6–14.8 g/dL) and thrombocytosis with a platelet count of 543×10³/μL (reference: 158–348×10³/μL). The white blood cell count and differential were within normal limits. Urinalysis findings were unremarkable. Liver and kidney function tests, thyroid hormone levels, and hepatitis B and C serologies were normal. The rheumatoid factor test result was negative, whereas the ANA test result was positive at a titer of 1: 640, showing a homogeneous nuclear and cytoplasmic staining pattern (reference: <1: 40). Autoantibody testing revealed positivity for anti-DNA antibody by radioimmunoassay (RIA) (11.8 IU/mL; reference: ≤6.0 IU/mL), anti-single-stranded DNA (ssDNA) antibody by fluorescence enzyme immunoassay (FEIA) (58 U/mL; reference: <7.0 U/mL), anti-histone antibody (5.6 U; reference: <1.0 U), and anti-SS-A antibody (250 U/mL; reference: <7.0 U/mL). Other antibodies – including anti-double-stranded DNA (dsDNA) detected by FEIA, anti-Sm, anti-SS-B, and anticardiolipin IgM/IgG – showed negative findings. Complement C3 was within the normal range (129 mg/dL; reference: 73–138 mg/dL), whereas C4 was mildly elevated (35 mg/dL; reference: 11–31 mg/dL). Computed tomography (CT) demonstrated bilateral pleural effusions and pleural thickening (Figure 2); echocardiography revealed a small pericardial effusion.

Figure 2.

Chest computed tomography showing bilateral pleural effusions and pleural thickening. Axial chest computed tomography demonstrates bilateral pleural effusions and pleural thickening. Arrowheads indicate pleural abnormalities.

The differential diagnoses included malignancy, tuberculosis, SjS, SLE, and DILE. Thoracentesis was initially considered to evaluate malignancy and tuberculosis; however, fluid collection was not feasible due to the minimal pleural effusion volume. A biopsy of the thickened pleura was recommended but declined by the patient because of its invasive nature. Imaging studies – including chest and abdominal CT, gallium scintigraphy, and upper gastrointestinal endoscopy – revealed no evidence of malignancy. Fecal occult blood test results were negative. Although tuberculous pleurisy could not be entirely excluded, the T-SPOT^®.TB test result was negative. The patient exhibited elevated anti-SS-A antibody titers and positive results on both the gum and Schirmer tests but did not report dryness symptoms. Given the rarity of pleuritis in SjS cases [12], a diagnosis of SjS was considered unlikely. According to the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria [13], the patient met the ANA entry criterion (1: 640) and accrued 2 points for fever, 5 points for serositis, and 6 points for anti-dsDNA antibodies detected by a high-specificity immunoassay (Farr RIA), totaling 13 points and meeting the classification threshold. Notably, anti-dsDNA antibody testing by FEIA showed negative findings, which were interpreted as methodological discordance between the 2 assays. Although the patient met the classification criteria for SLE, she lacked characteristic manifestations of idiopathic SLE, such as nephritis, cutaneous lesions, or inflammatory arthritis. Complement levels were not decreased, and anti-Sm antibody negativity was noted. These findings argued against idiopathic SLE. The patient had taken CBZ at a dosage of 900 mg/day for 14 years without prior adverse effects; serum concentrations had ranged from 5.1 to 10.8 μg/mL, all within the therapeutic range. Nonetheless, CBZ-induced DILE was considered based on the presence of elevated ANA, anti-ssDNA, and anti-histone antibodies – findings frequently observed in DILE. The clinical presentation was also consistent with the typical subacute, systemic, serosal-predominant pattern of DILE. CBZ was discontinued because the painful tonic spasms remained stable. After discontinuation, the spasms did not worsen, and systemic symptoms – including fatigue, fever, and night sweats – completely resolved. Pleural effusions and pleural thickening improved, and the CRP level decreased to 0.15 mg/dL (Figure 3). The patient was diagnosed with CBZ-induced lupus erythematosus. Over the subsequent 30 months, she attended 11 follow-up visits, with the most recent in January 2025. Lupus-related symptoms did not recur, her weight increased, anti-DNA antibody detection by RIA became negative, and the ANA titer decreased from 1: 640 to 1: 160.

Figure 3.

Clinical course of the patient. Timeline depicting the patient’s clinical course, including onset and progression of systemic symptoms, CRP levels, and anti-DNA antibody titers before and after discontinuation of carbamazepine. After carbamazepine withdrawal, systemic symptoms resolved; CRP levels and anti-DNA antibody titers both decreased. CRP – C-reactive protein; NMOSD – neuromyelitis optica spectrum disorder.

Discussion

This case illustrates that DILE can develop even after long-term, well-tolerated use of CBZ, particularly in patients with preexisting autoimmune disorders such as NMOSD. Awareness of this possibility is essential to prevent delayed diagnosis and unnecessary investigations.

DILE is diagnosed based on 3 principal criteria recognized by most experts [14,15]: the absence of lupus manifestations before exposure to the causative drug; the presence of at least 1 clinical manifestation of SLE accompanied by characteristic immunologic abnormalities; and the resolution of clinical and laboratory abnormalities after discontinuation of the offending agent. The clinical presentation of DILE is typically milder than that of idiopathic SLE, and improvement after drug withdrawal is critical for diagnosis [7]. In the present case, no lupus-related symptoms were observed before CBZ initiation. After prolonged CBZ use, the patient developed fever and serositis, with anti-DNA antibody positivity according to RIA, anti-ssDNA, and anti-histone antibodies. Following CBZ discontinuation, the patient’s symptoms resolved, anti-DNA antibody negativity was eventually noted, and the ANA titer progressively decreased. These findings confirmed the diagnosis of DILE. Although the 2019 EULAR/ACR classification criteria for SLE were met (13 points from fever, serositis, and anti-dsDNA positivity) [13], these criteria are designed for research classification and do not supersede clinical judgment. The absence of renal or cutaneous involvement, normal complement levels, negative anti-Sm antibodies, presence of anti-histone and anti-ssDNA antibodies, and resolution of clinical and serologic abnormalities after CBZ withdrawal supported a diagnosis of DILE rather than idiopathic SLE [7]. Notably, anti-DNA antibody results were positive by RIA but negative by FEIA. Such inter-assay discordance is well recognized: RIA preferentially detects high-avidity anti-dsDNA antibodies in solution, whereas FEIA differs in antigen presentation and cutoff parameters. Consequently, the results of these 2 assays are not interchangeable [16].

A review by Alvarez-Lario et al. identified 26 reported cases of CBZ-induced DILE and described several characteristic features, including arthralgia or arthritis, mucocutaneous lesions, constitutional symptoms, and serositis; no renal involvement was noted [7]. The mean interval between CBZ initiation and the onset of DILE symptoms was 36.5±60.2 months (range, 1–240 months). The present case is notable for its exceptionally delayed onset, with symptoms appearing after 14 years (168 months) of CBZ therapy – substantially longer than the average latency reported in previous studies. To our knowledge, this represents the first documented case of CBZ-induced DILE in a patient with NMOSD. Because NMOSD is characterized by humoral autoimmunity and frequent coexisting autoantibodies [2–6], affected patients may be particularly susceptible to drug-induced immune dysregulation from agents such as CBZ.

Identification of the causative agent in DILE is the most critical aspect of management. However, DILE is often underrecognized in clinical practice because of its insidious onset, delayed symptom development after drug exposure, and the incomplete understanding of its pathophysiologic mechanisms. Proposed mechanisms include genetic predisposition, drug biotransformation, and epigenetic dysregulation of immune cells [17].

Among antiepileptic drugs, the risk of DILE associated with CBZ is considered “low” (approximately 0.1% at standard doses), whereas most other agents carry a “very low” risk (<0.1%) [8]. CBZ acts as a histone deacetylase inhibitor [18], and both histone acetyl transferases and histone deacetylases play key roles in gene expression regulation [19]. Through histone acetylation, CBZ may induce broad epigenetic alterations that contribute to immune dysregulation. In genetically or immunologically predisposed individuals, these epigenetic changes may promote autoantibody production and systemic autoimmunity.

DILE usually follows a mild course, such that symptoms resolve after discontinuation of the offending medication. Patients may require short-term symptomatic management after drug withdrawal, most commonly brief courses of corticosteroids or topical therapy. The need for potent immunosuppressive treatment is uncommon, and DILE-associated mortality is exceedingly rare. Notably, autoantibodies may persist long after clinical symptoms resolve [19]. In the present case, lupus-related manifestations resolved rapidly following discontinuation of CBZ alone. Tacrolimus, administered concurrently to prevent NMOSD relapse, may have contributed to the accelerated recovery.

Conclusions

This case underscores that DILE can develop even after prolonged, previously well-tolerated CBZ use, particularly in patients with underlying autoimmune conditions such as NMOSD. Clinicians should consider DILE in patients who present with unexplained systemic symptoms. Prompt recognition and withdrawal of the causative drug are essential for favorable clinical outcomes.