First case of mirtazepine-induced Stevens-Johnson syndrome from India.

A 28-year-old woman, a known case of systemic lupus erythematosus (SLE), was admitted with mucocutaneous ulceroerosive lesions with blisters and thrombocytopenia after taking antidepressant mirtazepine. Exacerbation of SLE and drug-induced eruption was diagnosed. Clinical and laboratory markers were suggestive of Stevens-Johnson syndrome. This is a rare adverse effect of the newer generation antidepressant mirtazepine.

Introduction

Mirtazepine, an antidepressant, increases noradrenergic and serotonergic neurotransmission in the central nervous system.[1] Increased appetite, vivid dreams, weight gain, drowsiness, dizziness, and headache are known adverse drug reactions due to mirtazepine. However, cutaneous drug reactions induced by mirtazepine are extremely rare and not reported from India.[2]

The present case was a known patient of systemic lupus erythematosus (SLE); mirtazepine was prescribed for depressive illness. However, 15 days following intake of the drug, she developed exacerbation of mucocutaneous lesions.

Case Report

A 28-year-old woman, a diagnosed case of SLE, presented with complaints of fever with chills followed by swelling and confluent erythema and edema involving lips and oral mucosa progressing to blistering and ulceration [Figure 1]. The lesions were extremely painful and accompanied with dysphagia. Diffuse erythema of the skin progressed over days into purpuric vesicles, target lesions, individual lesions less than 3 cm in diameter with a regular round shape and well-defined border over the whole body. The lesions started over the face and thorax before spreading to other areas. Multiple petechial lesions were noted over bilateral upper limb, lower limb, and trunk, along with facial erythema and oral crusting ulcers. No significant history of exposure of sunlight could be elicited. Intermittent high-grade temperature was recorded, and the urine output was 500 ml/day. Tachycardia was present, though blood pressure and other vitals were maintained. The patient had thrombocytopenia, with high ESR (74 mm in the first hour) and hypoproteinemia. Mild anemia and elevation of blood urea nitrogen and transaminases were noted. Urine examination showed leukocyte esterase negative, RBCs 40-60/ HPF, casts nil, no active urinary sediments, and 24 h urine protein of 274 mg/dL. CRP was positive. ANA was 2+ speckled, negative dsDNA, nRNP/Sm (4+), Sm (4+), anti-SSA (Ro52 4+). C3 was negative. Blood, wound, and mucosal cultures were negative for pathogens. No history of recent febrile illness could be elicited.

Figure 1

Swelling and confl uent erythema and edema involving lips and oral mucosa progressing to blistering and ulceration

The patient had been started on mirtazepine, 15 mg once a day a fortnight back for depressive symptoms. Since investigations ruled out active lupus and the positive drug history of mirtazepine administration, the diagnosis of SJS secondary to mirtazepine was made in consultation with the dermatology department. Adequate supportive care including wound care, fluid and electrolyte management, nutritional support, ocular care, temperature management, pain control, and monitoring for superinfections was provided to the patient. After 48 h of stopping the drug, the patient started showing signs of improvement and was subsequently discharged after 2 weeks of supportive inpatient care.

Discussion

Stevens-Johnson syndrome (SJS) is a rare mucocutaneous blistering disorder of considerable severity. Its more severe form is called toxic epidermal necrolysis (TEN).[3]

Mirtazepine is an antidepressant which increases noradrenergic and serotoninergic neurotransmission in the central nervous system. The intrinsic score of imputability of mirtazapine, according to the French pharmacovigilance criteria was _C2S2_ with a suggestive causal link. Mirtazapine is derived from mianserin and shows chemical structural similarities with other psychotropic drugs, such as clozapine, and certain tricyclic antidepressants. Thus, the patient should avoid using the causal agent, i.e., mirtazepine as well as its structural congeners such as mianserin, clozapine, and tricyclic antidepressants.[1]

SJS has a polyetiologic pattern, drugs being the most frequently implicated [Table 1].[4] Other risk factors for SJS include HIV, viral infections, genetic factors, vaccination, graft versus host disease, malignancy, and idiopathy.[4] Patients are at a greater risk of this type of drug reaction during the first 4 weeks of therapy, particularly between 1 and 3 weeks. When SJS develops within a few days or after months of starting a drug, a causal link is less convincing.[3]

Table 1

Drugs causing Stevens-Johnson syndrome and toxic epidermal necrolysis

There is no standardized laboratory test to confirm drug etiology. Identification of the causative agent relies primarily on history, as skin testing and in vitro tests are usually not useful, and exposure tests are deemed ethically unacceptable. Occasional reports describe positive lymphocyte transformation tests; however, lack of infrastructure and the cost and poor predictive value outweighing the clinical advantage have rendered these tests to be virtually useless. Hence, identification of the initiating event is based on the evaluation of probability, considering both the nature of the pharmacological agent and the temporal association with the clinical onset of the disease process.[3]

Majority cases begin with a week or two long prodrome of fever, malaise, and nonspecific symptoms. This is followed by burning sensation, edema, and erythema of the lips and buccal mucosa and widespread skin lesions. Initially erythematous macules are seen, which rapidly develop central necrosis with vesicles, bullae, and denudation on the face, trunk, and extremities. Mucosal erosions typically occur in at least two sites including bulbar, oral, nasal, anorectal junction, vulvovaginal region, and the urethra. Involvement of the respiratory and gastrointestinal tract may follow in complicated cases.[5]

The clinical differential diagnosis of SJS includes erythema multiforme, viral exanthems, ampicillin-induced rash, morbilliform drug eruptions, fixed drug eruptions, staphylococcal scalded skin syndrome, Kawasaki disease, acute graft-versus-host disease, and SLE.[36]

SJS has been known to be more common in patients with multisystem disorders, particularly those of autoimmune etiology.[3] Numerous case reports have surfaced highlighting occurrence of SJS in patients with SLE.[78] This could probably be attributed to underlying immune mechanisms which remain unexplored yet. In our case, coexistence of both the possibilities led to diagnostic dilemma. However, the complete clinical and laboratory picture, temporal association, as well as the final response to drug withdrawal favoured the diagnosis of SJS. In most cases, active SJS as well as SLE presents as leucocytoclastic vasculitis on biopsy specimens. Lack of consent rendered biopsy impossible; however, since biopsy is not mandatory for clinical diagnosis, SJS was considered to be the primary pathology and mirtazepine was deduced to be the etiologic factor due to its temporal association with the onset of the symptoms and improvement of symptoms following drug withdrawal. Mirtazepine intake was the only significant preceding event that could be elicited.[3]

Hence, this case study brings to light SJS as one of the side effects of mirtazepine which till now has been infrequently reported worldwide with no published report from the Indian subcontinent.