RIME

Reactive infectious mucocutaneous eruption (RIME) is a rare, parainfectious (often recurrent - different intervals) inflammatory syndrome that primarily affects the mucous membranes (mucositis) and to a lesser extent (<10%) also the skin (Mc Dermid A et al. 2024). In 2015, a clinical picture called MIRM (Mycoplasma-induced rash and mucositis) was described, a reactive, inflammatory syndrome of the mucous membranes (and skin) caused by Mycoplasma pneumoniae, which is very close to (if not identical to) the RIME described later in terms of its clinical appearance and course. In the meantime, RIME has also been associated with other pathogens. There is a broad clinical and etiological association with "pluriorificial ectodermosis", which has been known since the 1930s.

The clinical picture is understood as an "infectious-allergic" inflammatory syndrome. The pathogens involved include Mycoplasma pneumoniae, Chlamydophila pneumoniae, influenza A and B, parainfluenza viruses, enteroviruses, metapneumoviruses and SARS-CoV-2 (Ortiz EG et al. 2022).

The criteria for the diagnosis of RIME include an infectious trigger, erosive mucositis affecting two or more sites, vesiculobullous lesions or atypical multiforme lesions affecting less than 10% of the body surface area, a clear absence of medication history.

RIME can be a diagnostic challenge in patients with COVID-19 due to a variety of dermatologic and mucocutaneous findings that can occur in association with COVID-19 infection. In addition, erythema multiforme major (EMM) and EM-like lesions have also been detected in COVID-19, which are difficult to distinguish from RIME.

Common differential diagnoses in RIME include diseases that can cause similar skin findings and/or mucosal manifestations:

MIRM (Mycoplasma-induced rash and mucositis): analogous (possibly identical clinical picture caused by Mycoplasmae pneumoniae by definition).

Pluriorificial ectodermosis (mucosal variant of erythema multiforme)

Erythema multiforme major

SJS/TEN

DRESS

Staphylococcal scalded skin syndrome

Hand-foot-and-mouth disease

Kawasaki syndrome

Gingivostomatitis herpetica (initial manifestation of a herpes simplex infection)

Bullous systemic lupus erythematosus

Stomatitis plasmacellularis

SARS-CoV-2 infection

Behçet's disease

RIME differs from drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis and herpes-related erythema multiforme in its clinically dominant mucosal involvement with relatively sparse skin findings, especially in its prevalence in younger patients and its good prognosis.

As RIME is considered a self-limiting diagnosis and the prognosis is favorable, treatment is generally supportive - with mucosal care, pain management and hydration. Some patients require hospitalization.

The role of immunomodulators, including steroids, is decided on a case-by-case basis.

In most reported cases of RIME as a result of COVID-19 infection, systemic steroids (oral or intravenous) have been administered at different doses and for different durations. In some published cases, systemic steroids were used in combination with intravenous immunoglobulin (IVIG) or systemic steroids followed by cyclosporine (Mc Dermid et al. 2024) Antibiotics and antiviral drugs have also been used sparingly.

RIME has a good prognosis. RIME can cause significant morbidity and recurs in 8% to 38% of patients.

1st case report

A 13-year-old boy was evaluated by an outside physician for cold sores preceded by 3 days of dry cough and runny nose. Limited physical examination and laboratory data were found regarding this episode. The patient was treated with amoxicillin, after which the oral mucositis resolved after 9 days. Due to the elevated MP-IgG levels of 0.35 U/l found 9 months later, this first RIME episode was retrospectively attributed to MP.

Nine months later, the patient presented with painful bleeding lips, fever, sore throat and a burning sensation on urination lasting 2 days. Physical examination revealed dried vesicles on the lips. The urethral orifice was clear. A <1 cm circular, hyperpigmented, targetoid papule was found on the right arm. Biopsy of a lip lesion showed epidermal necrosis. Laboratory results included a positive PCR test for group A streptococcus from the pharynx, elevated MP-IgG levels, negative MP-IgM levels, negative HSV type 1 and 2 PCR from the lip, negative antibodies to desmoglein-1 and -3. Chest radiograph was negative. The suspected diagnosis was recurrent RIME due to group A streptococcus. He was treated with oral amoxicillin 500 mg and clobetasol propionate 0.05% ointment. The lip lesions resolved 12 days later.

One and a half years later, he presented with a 5-day history of headache and malaise without fever or cough and one day of oral mucositis with an erythematous rash on the neck and face. Physical examination revealed erosions on the lips, erythematous papules on the lateral tongue, and ulcers on the upper and lower gums. Laboratory results showed elevated MP-IgG and negative MP-IgM titers. The suspected diagnosis for this episode was recurrent RIME, presumably due to influenza A infection. The patient received topical 0.05% clobetasol propionate ointment, azithromycin (500 mg × 2 days, 250 mg × 4 days), oseltamivir 75 mg and a decreasing dose of oral prednisolone (50 mg × 3 days, 40 mg × 2 days, 30 mg × 2 days and 20 mg × 2 days). The lip lesions were almost completely healed after 10 days.

Eleven months later, the patient presented again with oral mucositis. He reported cough, fever and aching limbs in the three days before the onset. Physical examination revealed oral mucositis with mild desquamation on the lower lip. Hypopigmentation was noted on the upper lip. The patient had a positive SARS-CoV-2 PCR test from the nasopharynx the week before the outbreak. Due to the suspicion of recurrent RIME, no additional laboratory tests were performed. The most likely diagnosis was recurrent RIME, most likely due to SARS-CoV-2. He was treated with a decreasing dose of oral prednisolone (30 mg × 3 days, 20 mg × 3 days, 10 mg × 5 days), topical 0.05% clobetasol propionate ointment and petrolatum ointment.

2nd case report

An 18-year-old girl presented with persistent cough and fever for a week, followed by eye, mouth and genital ulcers with rash. Physical examination revealed bilateral conjunctival injection, bleeding and drainage. The lips showed diffuse ulceration. Her face had multiple vesicular lesions. Pink papules, spots and multiple intact vesicles 3-5 mm in size were noted on her back, chest and right upper arm. Her labia minora showed ulceration. Biopsy of her right posterior shoulder showed interface dermatitis with subbasilar microvesicle formation. Chest x-ray showed patchy opacities in the left lung. Laboratory results showed negative MP-IgG and IgM levels, but a positive MP-PCR from sputum. Other test results included a negative EBV PCR from EDTA plasma and HSV-1 and -2 PCR from the left labia and mouth. The presumptive diagnosis was RIME due to MP. The patient was treated with 4 doses of 0.5 g/kg IVIG for 5 days, a decreasing dose of prednisone (90 mg at the beginning, then reduced by 10 mg every 3 days), 100 mg doxycycline twice daily, 0.1% triamcinolone ointment and Vaseline ointment. The clinical course was complicated as the patient developed bilateral complete conjunctival epithelial defects requiring urgent amniotic membrane transplantation. The patient's ocular and oral lesions regressed after 3 months.

5 years later, she presented with oral and genital ulcers that had been preceded by cold symptoms for three weeks. She reported that she had tested positive for influenza A one week earlier. Physical examination revealed ulcerative lesions in the buccal mucosa and lips and on the clitoris with erythematous, eroded papules. Laboratory: elevated MP IgG (1.08 U/L) and IgM (1.0 U/L), negative MP PCR, negative HSV 1 and 2 PCR. The presumed diagnosis was recurrent RIME due to influenza A. The patient was treated with 0.5 g/kg IVIG daily for 4 days, intravenous methylprednisolone 500 mg twice daily for 3 days, tapering prednisone therapy (60 mg × 2 days, 40 mg × 2 days and 20 mg × 2 days), doxycycline 100 mg (2x/day) and locally with a Vaseline-containing ointment. One week later, her lesions healed.

Eight months later, she complained of cough and cold symptoms for more than three weeks, followed by mouth ulcers on the lips two weeks after the onset of symptoms. Physical examination revealed erosions of the lips and buccal mucosa. Laboratory results showed a negative SARS-CoV-2 PCR test, elevated MP-IgG and negative IgM levels, negative MP-PCR, negative PCR for HSV1 and 2, adenovirus, coronavirus, rhinovirus, influenza A and B, parainfluenza, RSV and Chlamydia pneumoniae. The chest X-ray showed opaque shadowing of the left basilar airspace. The presumed diagnosis was recurrent RIME. Infection unknown. The patient was treated with 0.5 g/kg IVIG for 4 days, 500 mg intravenous methylprednisolone twice daily for 3 days and 250 mg azithromycin daily. The mucosal lesions healed 2 weeks later.

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