key: cord-1042315-k05dfxgm authors: Chahed, Ferdaous; Ben Fadhel, Najah; Ben Romdhane, Haifa; Youssef, Monia; Ben Hammouda, Seifeddine; Chaabane, Amel; Aouam, Karim; Ben Fredj, Nadia title: Erythema nodosum induced by Covid‐19 Pfizer‐BioNTech mRNA vaccine: A case report and brief literature review date: 2022-04-27 journal: Br J Clin Pharmacol DOI: 10.1111/bcp.15351 sha: e209657f18ddecf33006eddc9d22bf607da8ca1c doc_id: 1042315 cord_uid: k05dfxgm Erythema nodosum (EN), the most common form of panniculitis, is a reactive inflammation of the subcutaneous fat clinically presented with a sudden onset of painful, erythematous, nodular, subcutaneous lesions, typically localized to the pretibial area. EN is commonly caused by numerous infections (especially beta‐haemolytic streptococcal infections), autoimmune diseases (sarcoidosis), inflammatory bowel conditions and drugs. EN induced by Covid‐19 vaccines is rarely reported. We describe an original clinical observation of a 75‐year‐old woman who presented with EN after receiving the second dose of BNT162b2, an mRNA vaccine. Erythema nodosum (EN) is a reactive inflammation of the subcutaneous fat clinically characterized by painful, tender, nodular and erythematous lesions located symmetrically on pretibial surfaces. EN subsides classically in 3-6 weeks with mild hyperpigmentation. 1 The pathogenesis is thought to be related to deposition of immune complexes in venules of the deep dermis and adipose tissue. 2 EN is commonly caused by numerous infections (especially betahaemolytic streptococcal infections), autoimmune diseases (sarcoidosis), inflammatory bowel conditions and drugs. 3 Up to 10% of EN cases are attributed to medicines, particularly antibiotics and oral contraceptives. 4 However, EN associated with vaccines has been rarely reported. 5 Since March 2020, the Coronavirus disease 2019 (Covid- 19) pandemic has affected and caused the death of millions of people all over the world and vaccines are considered the most effective strategy to end it. 6 A wide variety of skin reactions occurring after Covid-19 vaccination has been described in the literature mainly urticaria, angioedema and maculo-papular eruption. 7 Nevertheless, there is currently a paucity of literature on EN associated with Covid-19 vaccines. [8] [9] [10] [11] We describe here a clinical observation of EN induced by BNT162b2, an mRNA vaccine. A 75-year-old woman presented with diffuse erythematous painful and nodular lesions, located symmetrically over her legs. Six days before, she had received the second dose of Covid-19 vaccine (BNT162b2 [Pfizer-BioNTech]), which was followed by a sudden asthenia, polyarthralgia, throbbing and oedema over her lower limbs. She had a medical history including type-2 diabetes, hypertension and psoriasis. She had no known drug allergy. She had been given the first dose of the same Covid-19 vaccine 29 days prior to the second without incident. General physical examination was normal. Skin examination showed multiple, tender, erythematous and nonulcerative nodules, which ranged from 10 to 30 mm in diameter symmetrically located over the tibial area ( Figure 1 ). Laboratory tests including a complete blood count, renal and hepatic tests, antistreptolysin O titer, and antinuclear antibody and thyroid tests were carried out and were negative. Chest radiograph and PCR were performed with normal results. Histopathology showed a slight perivascular and periadnexal We describe the clinical observation of a patient who developed EN thought to be related to the Covid-19 vaccine. In view of the close temporal relationship between administration of the Pfizer vaccine and symptom onset, which was compatible, the spontaneous remission of symptoms and the absence of other attributable aetiologies of the eruption, the diagnosis of EN was retained. Based on the Naranjo scale, our case was assigned a score of 8, qualifying the diagnosis of EN to be probable. Consequently, the systemic reaction was probably related to the Covid-19 vaccine. 12 EN is regarded as an immune-complex deposition disease affecting venules of the deep dermis and adipose tissue. In contrast to our patient, EN is most commonly observed in young women (between 20 and 50 years). 13 The localization of the EN in the current case was typical since the extensor leg below the knee is the most frequent The differential diagnosis of EN encompasses principally EN leprosum, which is a severe multisystem immune-mediated complication of leprosy, 14 battered child syndrome, Henoch-Schönlein purpura, urticaria, erythema induratum and nodular fat necrosis. 4 The majority of EN cases are believed be idiopathic, but some cases are associated with conditions such as tuberculosis, sarcoidosis and inflammatory bowel disease. 2 Drugs are also involved in inducing EN, especially sulphonamides, analgesics, oral contraceptives and proton pump inhibitors. 3 23 and severe cutaneous adverse reactions. 24 Moreover, the exacerbation of chronic immuno-mediated dermatoses (mainly psoriasis and atopic dermatitis) and reactivations of herpes infection have been reported. 25, 26 However, EN has been rarely described as a drug side effect to Covid-19 vaccines and to our knowledge it has been previously reported in four isolated cases. [8] [9] [10] [11] Mehta et al 8 Generally, cutaneous reactions to Covid-19 vaccines are slightly more common after the first dose compared to the booster (53% vs 46%, respectively), 19 but in these reported cases of EN, the offending dose of Covid-19 vaccine was the first one in three of five patients and the median time to symptom resolution was 2 weeks. However, in the present case, the EN onset was after the second booster shot of mRNA Covid-19 vaccine and a complete resolution of symptoms was observed 3 months after the initial presentation. The pathogenesis of EN secondary to vaccinations remains unclear, but it is thought to be related to a reaction to antigens of the infectious agent or a hypersensitivity reaction to components of the vaccine. 5 Episodes of autoimmune disease flares following Covid-19 vaccination have been reported usually within a maximum of 1 week following vaccination. 30 In the previous reported cases of EN associated with Covid-19 vaccines, an underlying autoimmune disease was noted in one patient, 10 who had Hashimoto thyroiditis. Our patient had a past history of psoriasis and type 2 diabetes. These underlying autoimmune conditions suggest an interaction between the immune system and the messenger RNA molecules and their lipid carrier particles. We also suspect a genetic predisposition to EN, which may induce the EN's onset. Indeed, a possible genetic susceptibility may be a risk factor to developing EN. Up to 70% of patients with GATA2 mutations have dermatological features, mainly panniculitis or EN and lymphoedema. 31 In conclusion, the current observation is the third case of EN particularly induced by the second dose of BNT162b2 (Pfizer-BioNTech) Covid-19 vaccine occurring in a 75-year-old patient. It is important for clinicians to be aware of this rare, yet potential, adverse effect to this vaccine. The literature is likely to reveal more cutaneous reactions induced by Covid-19 vaccination in the future. Erythema nodosum Erythema nodosum: A sign of systemic disease Erythema nodosum: an experience of 10 years Combined reduced-antigen content tetanus, diphtheria, and acellular pertussis (tdap) vaccine-related erythema nodosum: case report and review of vaccine-associated erythema nodosum The need of health policy perspective to protect healthcare workers during COVID-19 pandemic. 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