Are You Confident of the Diagnosis?
What you should be alert for in the history
First described in 1831 by Bright, this disease was named “erythema marginatum rheumaticum” by Cheadle in 1889. This name already pointed to the link between this dermatosis and rheumatic fever (RF). In fact the diagnosis of erythema marginatum (EM) can be considered only in patients with associated active RF and/or carditis. EM usually, precedes the joint manifestations and represents one of the major criteria of Duckett Jones for RF. An antecedent ß-hemolytic streptoccoccal infection of the pharynx is frequently associated with RF, so this bacterium has been implicated in the pathogenesis of EM.
Characteristic findings on physical examination
Patients present an evanescent annular dermatosis. EM begins as a macular eruption, consisting in rings or segments of rings, pink or bright red in color, whith flat or raised borders (Figure 1). The lesions can remain stable or extend peripherally in a centrifugal way, migrating 2-12 mm over a period of 12 hours. They may become patches or plaques, or merge to produce a polycyclic or reticular pattern.
The most frequently involved sites are the trunk, especially abdomen, the axillae and, occasionally, the limbs. EM is usually asymptomatic and the lesions, more evident in the afternoon, fade in a few hours or at most in 2-3 days leaving pale or lightly pigmented macules. Recurrent crops can occur over some weeks, often in different sites. Subcutaneous nodules (SN), another cutaneous criterium of RF, can be present in a minority of patients with EM. SN are painless and can be found on the extensor surfaces of wrists, elbows, knees and ankles.
Expected results of diagnostic studies
Laboratory tests are not necessary for the diagnosis of EM, but are essential to confirm the presence of RF. In fact, some laboratory tests are part of the diagnostic criteria of RF. Major criteria of Duckett Jones include carditis, migratory polyarthritis, Sydenham’s chorea, erythema marginatum and subcutaneous nodules. Minor criteria are fever, arthralgias, elevation of erytrocyte sedimentation rate (ESR) or C-reactive protein (CRP) and a prolonged P-R interval on electrocardiography (ECG). The presence of two major criteria or one major and two minor criteria allows the diagnosis of RF.
American Heart Association guidelines recommend determination of the likelihood of a preceding ß-hemolytic streptoccoccal infection of the pharynx. Positive throat cultures and high or rising anti-streptolysin titers, used in combination with the presence of other streptococcal antibodies, including anti-DNase B and antihyaluronidase, increase the sensitivity in detecting a true streptoccoccal infection. Moreover other objective findings, such as elevation of erytrocyte sedimentation rate or C-reactive protein and a prolonged P-R interval on ECG can be detected. ECG and echocardiography can be useful to detect carditis.
Biopsy specimens obtained from skin lesions usually show a perivascular infiltration of lymphocytes and neutrophils in the papillary dermis and upper portion of the reticular dermis; sometimes leukocytoclasia may be associated, but without true vasculitis. Extravasation of erythrocytes can be seen in the later stages. Direct immunofluorescence is negative for immunoglobulins and complement .
An unusual histopathologic finding is the presence of a sparse superficial perivascular mononuclear infiltrate composed entirely by lymphocytes and histiocytes, apparently without neutrophils.
The differential diagnoses includes:
Annular urticaria (pruriginous and not associated with systemic symptoms of RF)
Still’s disease (skin rash is different: it is maculo-papular, salmon pink in colour and usually occurs at the same time as high fever)
Hereditary periodic fever syndromes (recurrent febrile episodes associated to erisipela-like erythemas, positive familial anamnesis for periodic fever)
Erythema annulare centrifugum (It is characterized by a small pink, infiltrated papule which slowly enlarges and forms a ring as the central area flattens and fades. The disease may be self limiting or chronic with periodic fluctuations or persistent over many years. It represents an isolated condition)
Kawasaki syndrome (The diagnosis requires fever (>39°C) ofat least 5 days’ duration and the presence of four of the following: changes in extremities including erythema, edema, and desquamation, bulbar conjunctivitis, polymorphous rash, Cervical lymphadenopathy, changes in the lips and oral cavity such as pharyngeal erythema, fissured lips, and strawberry tongue).
Hereditary angioedema (an appearance similar to EM can precede this condition).
Psittacosis (EM has been reported in association with this pneumologic infection).
Who is at Risk for Developing this Disease?
Now rare, the prevalence of EM appears to be much higher in less developed countries, particularly in indigenous and less affluent areas, and varies significantly from one region to the next. Approximately 3% of patients with untreated ß-hemolytic streptoccoccal infections can develop acute RF. EM is present in less than 10% of patients with acute RF, mainly in childhood reflecting the predominance of RF in children.
What is the Cause of the Disease?
Pathogenesis of EM is still unclear, but some mechanisms leading to the appearance of cutaneous lesions have been emphasized; an abnormal humoral and cellular immune response to antigens of ß-hemolytic streptoccoccus may be present. The targets of cross-reaction in this antigenic mimicry are: myosin, actin, tropomyosin, keratin, laminin, N-acetylglucosamine and vimentin.
Systemic Implications and Complications
EM is a self-healing condition, never complicated by other symptoms. The presence of one or more associated major criteria of RF condition the prognosis of the disease.
The dermatosis has no specific therapy. Its clinical course is unaltered by the treatment of the underlying RF. Lesions are asymptomatic, with at least mild pruritus. In this case, oral antihistamines could be used: Cetrizine (2-6 years: 5mg/day; >6 years: 10mg/day); Oxatomide (<15 kg: 0.5 mg/kg twice/day; 15-35 kg: 15mg twice/day; adults: 30 mgtwice/day.
Optimal Therapeutic Approach for this Disease
It is most important to first rule out any of the associated conditions that can mimic EM. Once the diagnosis is established, and RF is treated appropriately, from a dermatologic perspective, only symptomatic treatment is necessary.
What is the Evidence?
Espana, A, Bolognia, JL, Jorizzo, JL, Rapini, RP. “Figurate Erythemas”. Dermatology. 2008. pp. 281-2. (Erythema marginatumbegins as a macular eruption, consisting in red-colored rings whith flat or raised borders. Itis usually asymptomatic and the lesions, more evident in theafternoon, fade in a few hours or at most in 2-3 days leaving pale orlightly pigmented macules. It represent a major criterion for the diagnosis of rheumatic fever. Other annular dermatoses could be considered in differential diagnosis with erythema marginatum.)
Troyer, C, Grossman, ME, Silvers, DN. “Erythema marginatum in rheumatic fever: early diagnosis by skin biopsy”. J Am Acad Dermatol. vol. 8. 1983 May. pp. 724-8. (Skin biopsy of a 10-year-old boy with a 3-week history of recurrent rashand fever demonstrated histologic changes suggesting a diagnosis oferythema marginatum associated with rheumatic fever. Subsequently, thepatient developed classic cardiac and arthritic manifestations.Skin biopsyis recommended for the early diagnosis of rheumatic fever).
Sahn, EE, Maize, JC, Silver, RM. “Erythema marginatum: an unusual histopathologic manifestation”. J Am Acad Dermatol. vol. 21. 1989. pp. 145-7. (The histopathologic findings in erythema marginatum originally described by Carol and van Krieben in 1935 include a perivascular neutrophilic and mononuclear cell infiltrate in the papillary and upper half of reticular dermis. This report shows a different histopathology with superficial perivascular infiltrate composed entirely of lymphocytes and histiocytes without neutrophils).
Tani, LY, Veasy, LG, Minich, LL, Shaddy, RE. “Rheumatic fever in children younger than 5 years: is the presentation different”. Pediatrics. vol. 112. 2003. pp. 1065-8. (Of 541 cases of RF seen from January 1985 through March 2000, 27(5%) were in children who were younger than 5 years (median: 4.0 years;range: 1.9-4.9 years). Major Jones criteria at presentation were arthritis in 17, carditis in 14, chorea in 3, and erythema marginatum in 3. The carditis was mild in 4 and moderate to severe in 10 patients.Compared with older children, younger children were more likely to present with moderate to severe carditis, arthritis without carditis orchorea, or the rash of erythema marginatum and were less likely to have chorea.The incidence of carditis was similar in the twogroups as was the ratio of boys to girls. At follow-up (9.6 +/- 5.6 years), 69% of younger children who presented with carditis have clinical rheumatic heart disease. Subclinical, echocardiographically detected valvular abnormalities were detected both at presentation (33% of all childrenwith RF before 5 years of age) and at follow-up [55% of those who initially had carditis]).
Rullan, E, Sigal, LH. “Rheumatic fever”. Curr Rheumatol Rep. vol. 3. 2001. pp. 445-52. (Rheumatic fever is a multisystem inflammatory disease that occurs as a delayed sequel to group A streptococcal pharyngitis. It is less common than it was 50 years ago but is still a major cause of heart disease in developing areas of the world. The relationship between the site of infection, the type of causative organism, and susceptibility of the host is essential in the development of the disease.Its major clinical manifestations include carditis, migratory polyarthritis, chorea, erythema marginatum, and subcutaneous nodules. It can manifest as anacute febrile illness consisting of migratory polyarthritis involving the large joints, as carditis and valvulitis, or as Sydenham's chorea with involvement of the central nervous system. The disorder in its milder form resolves itself without sequelae.Carditis is the condition most associated with increased mortality and morbidity and may be fatal in its severe forms. Penicillin is the most appropriate primary andsecondary prophylaxis. Antiinflammatory agents provide symptomatic relief but do not prevent rheumatic heart disease.)
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