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LETTER TO THE EDITOR
Year : 2021  |  Volume : 53  |  Issue : 5  |  Page : 412-414
 

Oxcarbazepine-induced systemic lupus erythematosus: A rare and serious adverse drug reaction to a common anticonvulsant


1 Department of Dermatology, Military Hospital Kirkee, Pune, Maharashtra, India
2 Department of Rheumatology, Command Hospital Pune, Pune, Maharashtra, India
3 Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
4 Department of Dermatology, Armed Forces Medical College, Pune, Maharashtra, India
5 Department of Medicine, Armed Forces Medical College, Pune, Maharashtra, India

Date of Submission23-Jul-2020
Date of Decision06-May-2021
Date of Acceptance09-Sep-2021
Date of Web Publication24-Nov-2021

Correspondence Address:
Dr. Anwita Sinha
22 Delmar Tower, Clover Village, Wanowrie, Pune - 411 040, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_445_20

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How to cite this article:
Sinha A, Hegde A, Kinra P, Neema S, Singh AR. Oxcarbazepine-induced systemic lupus erythematosus: A rare and serious adverse drug reaction to a common anticonvulsant. Indian J Pharmacol 2021;53:412-4

How to cite this URL:
Sinha A, Hegde A, Kinra P, Neema S, Singh AR. Oxcarbazepine-induced systemic lupus erythematosus: A rare and serious adverse drug reaction to a common anticonvulsant. Indian J Pharmacol [serial online] 2021 [cited 2021 Dec 8];53:412-4. Available from: https://www.ijp-online.com/text.asp?2021/53/5/413/331080






Sir,

Drug-induced lupus erythematosus (DILE) constitutes 10% of all systemic lupus erythematosus (SLE) cases. DILE manifests with typical cutaneous manifestations of lupus, with relatively mild systemic involvement and characterized by antinuclear antibody (ANA) and antihistone antibodies positivity, with rare findings of anti-double stranded DNA (anti-dsDNA) and anti-extractable nuclear antigens (ENA) positivity.[1] Commonly implicated anticonvulsants causing DILE include carbamazepine (CBZ), phenytoin, valproic acid, primidone, and ethosuximide. Oxcarbazepine (OXC) is a congener of CBZ with lesser side effects and drug interactions while maintaining equal efficacy. Although 28 cases of SLE have been reported for CBZ,[2] reports of OXC causing SLE are rare with only a few cases described before this report. We herein report an elderly male being treated for seizures developing SLE-induced by OXC.

A 69-year-old male, a case of complex partial seizure disorder on the medication's OXC and levetiracetam, presented with intermittent asymptomatic red raised scaly rash over the body of 6-month duration partially resolving with oral and topical steroids. Patient presented to our center with aggravation of rash, associated with joint pains in the bilateral knee and ankle joints on abruptly stopping oral steroids. General examination revealed pallor, whereas systemic examination was unremarkable. Dermatological examination revealed multiple erythematous scaly plaques over back, chest, and dorsum of hands accentuated over photo exposed areas [Figure 1] along with petechial lesions over both legs. On examination, clinical differentials of subacute cutaneous lupus erythematosus and phototoxic drug reaction were considered. Skin biopsy revealed apoptotic keratinocytes, follicular plugging, and basal layer vacuolation on histopathology and a positive lupus band test on direct immunofluorescence, suggesting a diagnosis of cutaneous lupus erythematosus [Figure 2]. Further investigation revealed strongly positive ANA (160.59 units) on enzyme-linked immunosorbent assay. ENA profile revealed strongly positive antinucleosome, antihistone, and AMA-M2 antibodies, whereas other antibodies were negative. Complement levels were low. Further investigations revealed low hemoglobin of 10.2 g%, platelets of 135,000/cubic mm (cumm), total leukocyte count of 2200/cumm with neutrophils of 70%, and lymphocytes of 15%. Direct Coomb's test was negative. Liver and renal function tests were within normal limits. Further tests for renal involvement revealed urine protein/creatinine of 739 mg/g and 24-h urine protein value of 1125 mg/24 h. The patient was offered kidney biopsy but declined consent. In view of the clinical findings of photoaggravated psoriasiform rash, positive ANA, leukopenia, and renal involvement, SLE was diagnosed based on systemic lupus international collaborating clinics criteria, likely drug induced due to OXC, in view of antihistone antibody positivity.
Figure 1: Erythematous scaly plaque over back

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Figure 2: Skin biopsy, H and E, ×40: Basal cell vacuolation (yellow arrow) with dermal melanophages (red arrow)

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The patient was treated with methylprednisolone pulse therapy 750 mg for 3 days followed by oral prednisolone in tapering doses. Neurology consult was obtained for change of anticonvulsant, and OXC was gradually tapered and stopped with increase in the dose of levetiracetam to 1.5 g BD. Following the withdrawal of OXC, the patient had three episodes of breakthrough seizures. Magnetic resonance imaging of brain was normal. Antiepileptic lacosamide was added with good control of seizures. The patient was also started on tablet hydroxychloroquine for SLE along with mycophenolate mofetil (MMF) for lupus nephritis. On follow-up at 6 months, the patient was continuing tablet MMF and hydroxychloroquine with good resolution of cutaneous symptoms and arthralgia along with decline in ANA titers.

DILE has a temporal relationship with drug exposure of inciting drug for months or years, resolving after discontinuation of the offending drug. In contrast to SLE, there is no female gender or racial predilection for DILE, and also the average age of DILE presentation is older compared to SLE as corroborated by our patient being an elderly male.

The occurrence of CBZ-induced lupus-like symptoms is rare with a reported incidence of <0.001% in treated patients or 2–3 cases per 100,000.[2] The pathogenesis of DILE due to CBZ is unclear; however, metabolism of CBZ to reactive intermediates by activated leukocytes has been widely considered to result in adverse reactions including DILE.[3] The mechanism of the action of OXC is same as CBZ-sodium channel blockage, with similar efficacy, better side effect profile and is used for the same indications such as treatment of seizure disorders, psychiatric diseases, trigeminal neuralgias, and other chronic pain syndromes. The side effects of OXC include headache, somnolence, dizziness, fatigue, and nausea and less commonly vomiting,  Parkinsonism More Details, hyponatremia, and leukopenia. DILE has been rarely reported with OXC.

Finding the culprit drug is always challenging in any suspected case of adverse drug reaction when the patient is on polypharmacy. In our case, the patient was on two antiepileptics, but based on the notoriety of CBZ in causing lupus, with OXC being its close congener, the causality was ascribed to OXC rather than levetiracetam. It is often difficult to differentiate DILE with idiopathic SLE due to similar clinical presentations such as fever, arthritis, and serositis, with ANA positivity seen in both entities. However, DILE generally shows a milder clinical picture than idiopathic SLE. The cutaneous presentation in DILE is also less severe compared to SLE with photosensitivity, erythema nodosum, and purpura more frequently seen in DILE, whereas alopecia, malar butterfly rash, discoid rash, and oral ulcers are rarely seen compared to SLE.[4] Our patient had similar skin findings with a photosensitive rash, petechial lesions, and arthralgia but with no mucosal lesions or alopecia. Unlike SLE, renal disease is uncommon in DILE, with the pathogenesis of renal disease in DILE often ascribed to P-ANCA positivity causing a necrotizing glomerulonephritis, but immune complex-mediated glomerulonephritis can also occur.[5] Complement-fixing ANA is often seen in SLE but rarely seen in DILE. Our patient had significant renal involvement necessitating treatment with MMF. Complement levels were found to be low in our patient, but P-ANCA could not be done.

Various serologic markers differentiate DILE from SLE. ANA is present in 85% of patients with either idiopathic or drug-induced SLE and is nonspecific in differentiation of the two entities. Antihistone antibodies are important in differentiation as they are present in 95% of patients with drug-induced SLE, but only in 50% of patients with idiopathic SLE.[1] Anti-dsDNA antibodies are mostly absent in drug-induced SLE while being present in 85% of patients with idiopathic SLE, thus further contributing to the differentiation between two entities.[2] In fact, the presence of antihistone antibody in the absence of anti-dsDNA antibody suggests a diagnosis of DILE as was seen in our case.

Diagnosing the disease early and withdrawing the triggering medication is of paramount importance in the treatment of DILE. The course of our patient's treatment was complicated with breakthrough seizures on OXC withdrawal, requiring switch to alternate anticonvulsant lacosamide while increasing the dose of levetiracetam. Most of DILE symptoms ameliorate in a few weeks after the withdrawal of the culprit medication, although it may take up to 1 year in some patients for symptoms to recover. It may take further longer time for ANA titers to turn negative, or in approximately 60% of cases on follow-up, it may not return to negative.[2] Our patient showed improvement in DILE symptoms postOXC withdrawal along with decline in ANA titers and is presently on regular follow-up.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Vedove CD, Del Giglio M, Schena D, Girolomoni G. Drug-induced lupus erythematosus. Arch Dermatol Res 2009;301:99-105.  Back to cited text no. 1
    
2.
Álvarez-Lario B, Bártulos-Iglesias M, Colazo-Burlato M, Macarrón-Vicente J. Carbamazepine-induced systemic lupus erythematosus: A case-based review. Eur J Rheumatol 2019;6:48-54.  Back to cited text no. 2
    
3.
Furst SM, Uetrecht JP. Carbamazepine metabolism to a reactive intermediate by the myeloperoxidase system of activated neutrophils. Biochem Pharmacol 1993;45:1267-75.  Back to cited text no. 3
    
4.
Marzano AV, Vezzoli P, Crosti C. Drug-induced lupus: An update on its dermatologic aspects. Lupus 2009;18:935-40.  Back to cited text no. 4
    
5.
Zuckerman R, Patel M, Costanzo EJ, Dounis H, Haj RA, Seyedali S, et al. Hydralazine-associated adverse events: A report of two cases of hydralazine-induced ANCA vasculitis. J Bras Nefrol 2018;40:193-7.  Back to cited text no. 5
    


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