Continuing Education Activity

Erythema marginatum is reactive inflammatory erythema seen most commonly in association with acute rheumatic fever. Although a rare cutaneous manifestation, it is of utmost diagnostic value for acute rheumatic fever as well as other rare disorders. Erythema marginatum, an evanescent nonpruritic macular rash, is one of the major diagnostic criteria of acute rheumatic fever seen generally on the trunk and extremities. This activity outlines, reviews, and describes the evaluation and management of erythema marginatum and reviews the role of the interprofessional team in managing and improving care for patients with this condition.

Objectives:

• Identify the etiology and epidemiology of erythema marginatum medical conditions and emergencies.
• Review the appropriate history, physical, and evaluation of erythema marginatum.
• Outline the treatment and management options available for erythema marginatum.
• Summarize interprofessional team strategies for improving care coordination and communication to advance the management of erythema marginatum and improve outcomes.

Introduction

Erythema marginatum is reactive inflammatory erythema seen most commonly in association with acute rheumatic fever. Although a rare cutaneous manifestation, it is of utmost diagnostic value for acute rheumatic fever as well as other rare disorders. It can be described as an evanescent, blanchable, nonpruritic macular rash seen generally on the trunk and extremities. It can also be seen in hereditary angioedema and psittacosis.[1][2][3][4]

Etiology

The most common diseases associated with erythema marginatum include acute or chronic rheumatic fever, psittacosis, and C1esterase inhibitor deficiency (hereditary angioedema). Acute rheumatic fever is predominantly associated with beta-hemolytic streptococcal infection but has also been reported with group C streptococcus. Serotypes M3 and M18 of group A beta-hemolytic streptococcus associated with acute rheumatic fever have been linked with the formation of anti-collagen IV antibodies, which are responsible for post-streptococcal rheumatic disease.[2][5] The mechanism of formation is unclear, but molecular mimicry has been suggested, especially in acute rheumatic fever.

Epidemiology

There is no sex predilection. It occurs more commonly in childhood (5 to 15 years) than in adults. Erythema marginatum has been reported in only 6% of patients with acute rheumatic fever.[1]

Pathophysiology

The underlying mechanism of cutaneous lesions in erythema marginatum is by and large unknown. However, it is presumed that molecular mimicry between the reacting streptococcal epitopes and laminin, tropomyosin, vimentin, keratin, and N-acetyl glucosamine may play a role.[3] The pathogenesis for the occurrence of these lesions in cases of hereditary angioedema is proposed to be bradykinin mediated.[6] This was evidenced by the presence of dense stromal and endothelial deposits of bradykinin in skin biopsy specimens taken from lesions of erythema marginatum in patients with hereditary angioedema. The pathogenesis of these lesions in psittacosis remains unknown.

History and Physical

Generally, patients with acute rheumatic fever present in the age group of 5 to 15 years. Following an episode of acute streptococcal pharyngitis, there occurs a latent period of nearly 2 to 5 weeks before the onset of acute carditis. Erythema marginatum may either precede, coincide, or follow the development of episodes of carditis. These lesions have also been reported in patients with chronic carditis.

The classical clinical lesion begins as an asymptomatic erythematous macule that spreads peripherally and coalesces to form polycyclic or serpentine patches or plaques. Lesions occur in crops over days to weeks and are evanescent. The rate of migration is 2 to 12 mm over a period of a few hours.

Lesions are accentuated on exposure to heat and resolve with mild hypopigmentation without any atrophy or scaling. The commonest sites are the trunk, axillae, and proximal extremities, usually with the sparing of the face. Lesions tend to last from a few hours to a few weeks and are often more perceptible during the afternoon.

Evaluation

Erythema marginatum is a clinical diagnosis. The presence of this lesion can aid in the diagnosis. In fact, it is one of the major criteria in the diagnosis of acute rheumatic fever.

Jones criteria, used in the diagnosis of acute rheumatic fever include major and minor criteria.

Major Criteria

• Polyarthritis
• Sydenham's chorea
• Clinical and subclinical carditis
• Erythema marginatum
• Subcutaneous nodules

Minor Criteria

• Fever higher than 38 C 
• Polyarthralgia
• Increased ESR >=60mm in 1 hour and CRP greater than or equal to 3 mg/dl
• Prolonged PR interval

For diagnosis of acute rheumatic fever: 2 major or 1 major+2 minor criteria along with raised anti-Streptolysin O titer or throat swab culture positive for group A streptococcus.

Laboratory investigations such as complete blood count, erythrocyte sedimentation rate, C-reactive protein, anti-streptolysin o titer, throat swab, blood culture, EKG and echocardiography, and skin biopsy have a corroborative value in the diagnosis.

For erythema marginatum associated with hereditary angioedema serum levels of complement C4, C1 esterase inhibitor, and C1q are performed.

For the diagnosis of psittacosis a history of avian contact in presence of clinical suspicion, isolation of chlamydia psittaci from respiratory secretions or detection by a polymerase chain reaction, four-fold or more increase of antibody titer between paired sera, and detection of IgM antibodies against C. psittaci by microimmunofluorescence may be performed.[7]

The skin biopsy findings of erythema marginatum are nonspecific and comprise of a dermal and perivascular mixed inflammatory infiltrate with neutrophilic predominance. Later stages are characterized by erythrocyte extravasation. There is an absence of vasculitis. There is a clinical and histological overlap observed with neutrophilic figurate erythema of infancy.

Treatment / Management

There is no specific therapy for this dermatosis as it is self-limited. Treatment of underlying rheumatic fever does not alter the clinical course of the skin lesions.

For patients with hereditary angioedema, conventional therapy consists of fresh frozen plasma infusion during acute attacks as well as for short and long-term prophylaxis. Newer therapies like icatibant and ecallantide have been introduced.[8][9] However, these therapies are effective only during the acute attack. Prophylaxis with plasma-derived or recombinant C1 esterase inhibitor infused at the time of appearance of the heralding erythema marginatum lesions has been found to be effective.[8]

Doxycycline at 100 mg every 12 hourly for 2 weeks has been considered a treatment of choice for psittacosis. For conditions where tetracyclines are contraindicated, macrolides such as azithromycin and fluoroquinolones (third line), may be used.[10]

Differential Diagnosis

All figurate erythemas have a mixed clinical and histopathological diagnostic approach.

The clinical differential diagnosis for erythema marginatum include

1. Annular urticaria
2. Annular erythema of infancy
3. Erythema annulare centrifuged (EAC)
4. Autoinflammatory diseases such as TNF receptor-associated periodic syndrome Still disease.
5. Erythema multiforme
6. Erythema marginatum hemorrhagicum -figurate erythema with hemorrhagic crusting in patients taking sorafenib

Histopathologically the figurate erythemas can be classified based upon the predominant inflammatory infiltrate, which can be lymphocytic, neutrophilic-eosinophilic, granulomatous, and plasma cells. The presence or absence of associated vasculitis with fibrinoid necrosis is also a differentiating feature.

Neutrophilic-eosinophilic infiltrates: this group includes annular psoriasis, annular erythema of infancy, annular leukocytoclastic vasculitis, urticaria multiforme, and eosinophilic dermatitis. The presence of stratum corneum microabscesses as well as spongiform pustules (psoriasis), and extensive capillary dilation with dermal edema (urticaria) are some of the differentiating histopathological features.

Lymphocytic infiltrate: this group includes erythema annulare centrifugum (superficial and deep forms), chronic erythema migrans, erythema gyratum repens, erythema multiforme, and necrolytic erythema.

The presence of a “coat sleeve” pattern of perivascular infiltrates (EAC), hyperkeratosis, and parakeratosis with the clinical appearance of concentric rings (erythema gyratum repens), vacuolar interface dermatitis with epidermal edema, and necrosis (erythema multiforme) are characteristic differentiating features.

Granulomatous diseases: this group includes granuloma annulare, sarcoidosis, borderline tuberculoid leprosy. The presence of classical epithelioid or naked granuloma (sarcoidosis) is a differentiating characteristic.

Secondary syphilis is also known as the “great mimicker,”  has a variable clinical presentation with papulosquamous lesions (commonest), papular, follicular, psoriasiform, and rarely EAC-like annular forms. The presence of mixed lymphocyte plasmacytic infiltrates as well as lichenoid interface dermatitis is a diagnostic feature. 

Apart from plain histopathology use of special stains (examples: silver staining for spirochetes in secondary syphilis and erythema migrans) and immunofluorescence for dermal and perivascular immune deposits are additional diagnostic aids. [11]

In erythema marginatum associated with hereditary angioedema, there is a presence of dermal deposits of bradykinin, while in psittacosis, a histopathological overlap with EAC is observed.

Prognosis

The lesions of erythema marginatum are usually self-limiting and have a tendency to recur intermittently or persist for a few days during or after an episode of acute rheumatic fever.

Complications

The cutaneous lesions of erythema marginatum follow an uncomplicated course. However, they herald the onset of carditis in patients with acute rheumatic fever, in which a small percentage may progress to rheumatic heart disease.

Deterrence and Patient Education

Primary prevention measures should aim at avoiding household overcrowding, which has been identified as the single most important risk factor in acute rheumatic fever. The primary prevention of acute rheumatic fever is not practical, especially in developing countries, as the cost/benefit ratio is not favorable.[1][5] Most of the patients with rheumatic heart disease have an untreated or unnoticed episode of sore throat. Hence in countries with increased prevalence of acute rheumatic fever, patients and caretakers are advised to seek medical opinions for fever, sore throat, skin rash, and joint pain.

Enhancing Healthcare Team Outcomes

There are two main points of focus in planning a strategy for improving health care outcomes. The first being systematic documentation and maintenance of registers of acute rheumatic fever, and the second being the availability of clinical expertise and high-quality therapeutic aids of benzathine penicillin at all levels of the health care system. The primary care physicians should not ignore the skin lesions in patients presenting with a sore throat, fever, and joint pain and should seek the advice of a dermatologist for the same. Although a clinical diagnosis, a skin biopsy may sometimes be required to rule out other differential diagnoses.[1] [Level 5]

In patients with C1 esterase inhibitor deficiency or hereditary angioedema, erythema marginatum is commonly confused with acute urticaria leading to a common misdiagnosis of anaphylaxis. Hence prompt recognition of erythema marginatum can reduce the mortality associated with hereditary angioedema.[12]