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Figurate Erythemas (Chapter 19)
Terms in this set (18)
Erythema Annulare Centrificum
- Peak incidence, gender difference
- Familial form and inheritance
Unfortunately, this has led to some confusion, but until a specific "trigger" can be identified for each individual patient, this situation will persist. As a consequence, some authors have come to the conclusion that EAC, especially the deeper form, represents a clinical reaction pattern rather than a specific clinicopathologic entity.
Although EAC can appear in any age group, its peak incidence is in the fifth decade of life. There is no known gender difference. A rare autosomal dominantly inherited form of EAC, referred to as "familial annular erythema", has also been described
Pathology of EAC
- EAC is hypothesized to be what type of reaction
It has been suggested that EAC, especially the superficial form with epidermal spongiosis histologically, represents a reaction pattern or "hypersensitivity" to one of many antigens.
EAC has been associated with infectious agents, particularly dermatophytes, but also with other fungi (e.g. Candida, Penicillium in blue cheese), viruses (e.g. poxvirus, EBV, varicella-zoster virus, HIV), bacteria (e.g. Pseudomonas), parasites, and ectoparasites (e.g. Phthirus pubis).
Less commonly, EAC has been linked to drugs (e.g. diuretics, nonsteroidal anti-inflammatory drugs, antimalarials, finasteride, amitriptyline, rituximab, pegylated interferon-α-2a plus ribavirin, ustekinumab
Crohn disease, pregnancy, autoimmune endocrinopathies, hypereosinophilic syndrome and, occasionally, neoplasms (e.g. lymphomas, leukemias). The latter has been referred to as paraneoplastic EAC eruption (PEACE). However, most of these associations are anecdotal, and, in the last group, Curth's postulates have not been consistently fulfilled (see Ch. 53). There are patients with EAC who noted resolution of their lesions after the diseases that presumably triggered the EAC were successfully treated. In one series, an associated disease was identified in only one-third of patients
EAC Clinical Presentation
The initial lesions of EAC begin as firm pink papules that expand centrifugally and then develop central clearing. An individual lesion can enlarge to greater than 6 cm in diameter over a period of 1 to 2 weeks.
If expansion of the annular plaque is not uniform, incomplete arcs appear, as do polycyclic lesions, or simply festooned bands. In the superficial form, the lesions are minimally elevated, and there is desquamation at the inner margin, i.e. trailing scale (Fig. 19.1A,B). The scale may not be present in all the lesions in a particular patient (Fig. 19.2A). There may be associated pruritus, especially in lesions that histologically show spongiosis. Occasionally, vesicles develop within the peripheral margin. In deep gyrate erythema, the advancing edge sare obviously elevated (Fig. 19.1C) and there is usually no associated
scale or pruritus.
As lesions resolve, there is no residual scarring, but postinflammatory hyperpigmentation can be seen and, on occasion, purpura. Although the lesions of EAC may be localized or generalized, they rarely, if ever, involve the palms, soles, scalp or mucous membranes. Individual lesions can persist for weeks to months, but associated systemic manifestations are uncommon. While new lesions can appear just as older ones resolve, there may be prolonged intervals of time between flares. The total duration of the disorder ranges from days to decades2, and
an unusual form of EAC has been described that recurs annually.
When EAC is due to an underlying disorder, flares of the former may correlate with recurrences of the latter. However, most patients with EAC do not have an identifiable underlying disorder, nor can the onset, fluctuations, or duration be related to a specific antigen.
In superficial lesions of EAC, the findings are nonspecific, with mild spongiosis and microvesiculation with associated focal parakeratosis, as well as a mild superficial perivascular lymphohistiocytic infiltrate. These histologic features correspond to the scale on the inner margin of the advancing erythematous arc. Characteristically, the inflammatory cells form a fairly tight aggregate around vessels, the so-called "coat sleeve" appearance (Fig. 19.1D). Rarely, eosinophils are found in the perivascular infiltrate. The advancing edge, which is slightly raised, may also show edema in the papillary dermis. The central area of clearing may contain dermal melanophages.
In deep lesions of EAC, the epidermis is usually unremarkable, and a mononuclear cell infiltrate with a sharply demarcated perivascular arrangement is present primarily within the mid and lower dermis. For this reason, the lesions are generally elevated and are more indurated than in the superficial form of EAC, and they do not have trailing scale.
EAC ddx and Treatment
EAC must be differentiated from other annular erythematous lesions, particularly tinea corporis and annular psoriasis, when there is associated scale. Additional entities to consider include annular urticaria, allergic urticarial eruption, cutaneous lymphoid hyperplasia (pseudolymphoma), and lymphoma cutis. Patients with autoimmune disorders, including linear IgA bullous dermatosis, Sjögren syndrome, and lupus erythematosus (LE tumidus, subacute cutaneous LE, neonatal LE), can also have erythematous annular, arciform and polycyclic lesions.
If EAC is due to an underlying disorder, the skin lesions will usually resolve once the latter has been successfully treated. Topical corticosteroids applied to the advancing border of the lesions may be of benefit. Topical antipruritics and sedating antihistamines can be prescribed if there is associated pruritus. Even in the absence of an identifiable cause, some authors have advocated the empiric use of antibiotics or antifungal agents. Although systemic corticosteroids can induce a clinical remission, recurrences are common when the medication is discontinued. Based solely on case reports, the following have been reported
as beneficial: topical tacrolimus, topical calcipotriene (calcipotriol), NB-UVB, oral metronidazole, subcutaneous etanercept, and subcutaneous interferon-α (2 × 106 IU three times per week). However, systemic therapies are seldom necessary.
- What is rheumatic fever, organism involved, triad of disease
- Cutaneous Manifestations
- What % of untreated strep pharyngitis leads to RF
- How common is erythema marginatum in patients with RF
- Peak age of incidence
■ Migratory, annular and polycyclic, erythematous eruption
■ Cutaneous manifestation of acute rheumatic fever
■ Associated findings include carditis, migratory polyarthritis, Sydenham chorea, and subcutaneous nodules
■ Seen more commonly in children than in adults
Rheumatic fever (RF) is characterized by an abnormal immunologic response to a preceding infection with group A β-hemolytic streptococci and by the triad of fever, arthritis, and carditis. Cutaneous manifestations
include erythema marginatum and subcutaneous nodules, but they are seen in a minority of patients.
Epidemiology: Attacks of acute RF are associated with antecedent group A β-hemolytic streptococcal infections of the pharynx. Approximately 3% of patients with untreated infections can develop acute RF. It is estimated that in high-income countries, the incidence is 5 per 100 000, whereas in lowincome
countries, it ranges from 100 to 1000 per 100 000. Erythema marginatum is seen in less than 10% of patients with acute RF. The higher incidence of erythema marginatum in children (as compared to
adults) reflects the predominance of RF during childhood; the peak age-related incidence is between 5 and 15 years.
Pathogenesis of RF
- How soon after strep infection does RF Occur
- Describe the lesions of erythema marginatum
- When erythema marginatum is seen it commonly occurs in conjunction with what?
- What age patients are more prone to skin findings
The mechanisms that underlie the appearance of cutaneous lesions of erythema marginatum are unknown. Presumably, there is an abnormal humoral and cellular immune response to one or more antigens associated with group A β-hemolytic streptococci (e.g. M protein). Antigenic mimicry may play a role in that epitopes that cross-react with group A streptococcal antigens have been identified in human myosin, actin, tropomyosin, keratin, laminin, N-acetylglucosamine, and vimentin. Specific characteristics of certain strains of group A β-hemolytic streptococci, such as higher M protein content and mucoid colony formation, may facilitate the development of acute RF. Enhanced expression of genes that encode cysteine proteases (e.g. Streptococcus pyogenes exotoxin B [SpeB], immunoglobulin G degrading enzyme of Str. pyogenes [IdeS]) is also thought to be related to cardiotoxicity and virulence
- Following the initial streptococcal pharyngitis, there is usually a latency period of 2-5 weeks before the development of the acute attack of RF. The lesions of erythema marginatum begin as erythematous macules that spread peripherally and become patches or plaques with no scale. Erythema marginatum can also have a polycyclic arrangement. The lesions are usually asymptomatic, and, over a period of 12 hours, they can migrate from 2-12 mm; in areas of previous involvement,
the skin may appear pale or lightly pigmented15. As with other erythemas, exposure to heat can accentuate lesions. The most common locations for erythema marginatum are the trunk, axillae and proximal extremities, with sparing of the face. New
lesions usually last from a few hours to a few days and are often most noticeable during the afternoon. Recurrent crops can occur over a number of weeks. Erythema marginatum is associated primarily with the active phase of RF, and, in general, it is seen in conjunction with the carditis. Of note, children less than 5 years of age appear to have a higher incidence of erythema marginatum as well as carditis and arthritis
- Describe Histology, can cross over with what disease
- An interstitial and perivascular infiltrate composed predominantly of neutrophils without vasculitis is observed. Occasionally, eosinophils are seen and in later stages, there can be extravasation of erythrocytes. Direct immunofluorescence microscopy for immunoglobulin and complement deposits is negative. These histologic findings are not unique to erythema marginatum, and overlapping features with the neutrophilic variant of annular erythema of infancy (neutrophilic figurate erythema of infancy) may be observed
- The differential diagnosis includes primarily annular urticaria (e.g. urticaria multiforme) and annular erythema of infancy (Fig. 19.4) as well as its variant neutrophilic figurate erythema of infancy21. Less often, Still disease, hereditary periodic fever syndromes (particularly TNF receptor-associated periodic syndrome [TRAPS]; see Table 45.2), EAC, Kawasaki disease, and other entities listed in Table 19.1 need to be considered. There is also an annular erythema with an appearance similar to erythema marginatum that precedes or accompanies episodes of hereditary angioedema22 and is seen only occasionally in patients with cat scratch disease or psittacosis23,24. The angioedema-associated figurate erythema may be related to deposits of bradykinin within the dermis while the latter may reflect an overlap between erythema marginatum and EAC.
In a patient receiving sorafenib, figurate lesions with associated scale-crust and hemorrhage developed and the name "erythema marginatum hemorrhagicum" was proposed, but clinically these lesions can easily be distinguished from erythema marginatum
- What is the cause of lyme disease, how is it transmitted
- Where is lyme disease most prevelant
- What animals serve as hosts
Lyme disease (LD) is an infection due to Borrelia burgdorferi spirochetes that are transmitted by bites from several species of Ixodes ticks (e.g. I. scapularis, I. pacificus, I. ricinus). Erythema migrans represents the initial cutaneous manifestation.
Although LD has a worldwide distribution, it is seen most commonly in the US (Northeast, mid-Atlantic, and Great Lakes regions) and in northern and eastern Europe. The competent hosts that serve as a reservoir for Borrelia include mice, chipmunks and birds, with deer playing a role in sustaining the life cycle27. In temperate regions, the peak incidence for LD is during the spring and the summer, and it occurs more commonly in those who spend time outdoors in or near fields and woods. Over 27 000 cases of confirmed LD were reported in the US during 2015, with 95% of confirmed cases coming from 14 states (www.cdc.gov/lyme/). In Europe, approximately 85.000 cases of LD have been diagnosed each year, but the number may reflect significant over-diagnosis27a,28. Not all patients who have positive serologic tests for B. burgdorferi develop LD.
Pathogenesis of Erythema Migrans
- what mouse protein helps to protect BB
- What happens when borrelia is in the body
In mice, B. burgdorferi has been shown to usurp a tick salivary protein, Salp15, as a means of enhancing transmission29. By binding to the outer surface protein C (OspC) of B. burgdorferi, Salp15 provides protection against antibody-mediated killing. In addition, Salp15 inhibits adaptive immune responses against both Borrelia and tick antigens30. Of note, one of the strategies for preventing LD in the future is the development of anti-tick vaccines that utilize tick salivary proteins.
Once the Borrelia organisms have entered the body, spirochetal lipoproteins trigger an innate immune response, with cytokines being produced by macrophages31. In addition, a Th1 response is triggered and B-cell responses facilitate the synthesis of antibodies against different antigens of B. burgdorferi. Spirochetemia is present in approximately 45% of patients at the time of their presentation with erythema migrans32, and these organisms can disseminate widely due to their ability to resist elimination by macrophages, adhere to brain and epithelial cells, penetrate into the cytoplasm via intracellular junctions, and induce TNF-α production33. Even though the lesion expands centrifugally, B. burgdorferi organisms have been found both in the center and at the periphery of lesions of erythema migrans. The persistence of the spirochete in the skin after
the tick bite may be due to an absence of the production of interferon-γ and an ineffective immune response31. Also, different immune responses to the various genospecies of the B. burgdorferi sensu lato complex (B. burgdorferi sensu stricto, B. afzelii, B. garinii) may lead to different clinical presentations34 (e.g. borrelial lymphocytoma in Europe but not the US; see Ch. 74). More recently, an additional genospecies was identified in the upper midwestern US, candidatus B. mayonii, which may lead to a more severe clinical presentation due to an unusually
Clinical Features of Lyme Disease
- What are the three stages of lyme disease
- When is E Migrans seen
- is it possible to have multiple lesions?
- Systemic manifestations
LD is divided into three clinical stages: (1) early localized disease; (2) early disseminated disease; and (3) chronic disease
Erythema migrans is an important clinical feature of early disease. Typically, 7-15 days (range, 3-30 days) after tick detachment, an erythematous, expanding, circular or annular plaque appears that may have a lighter-colored central area or a bull's-eye appearance (Fig. 19.5). The eventual diameter is usually at least 5 cm, and the center may become darker red to violaceous in color, crusted, or even vesicular. Lesions of primary erythema migrans favor the trunk, axilla, groin and popliteal fossa. Untreated, the lesions usually last less than 6 weeks
(median, 4 weeks). In 20-25% of patients, multiple lesions can appear due to multiple tick bites or as a result of disseminated disease secondary to spirochetemia. Disseminated lesions tend to be smaller in size and less pronounced and usually appear days to weeks after the appearance of the primary erythema migrans (Fig. 19.6)35. Erythema migrans is seen in 60-90% of patients diagnosed with LD.
In the US, the systemic manifestations of this initial phase tend to be acute, with influenza-like symptoms, including fatigue, headache, arthralgias, myalgias and fever, as well as lymphadenopathy, conjunctivitis or hepatitis (see Table 19.2)36. In Europe, this initial clinical phase is usually less severe, and the lesions of erythema migrans tend to last longer. If untreated, approximately 60% will go on to have monoarticular
or oligoarticular arthritis (usually the knee) within weeks to months after the initial infection; approximately 10%, a neurologic manifestation (most commonly facial nerve palsy); and approximately 5%, a cardiac complication (usually varying degrees of atrioventricular block)32. For a discussion of borrelial lymphocytoma and acrodermatitis chronica atrophicans.. Depending upon the geographic region, Ixodes ticks can be co-infected with the following microbes (in addition to B. burgdorferi): Babesia microti (babesiosis), Anaplasma phagocytophilum (human [granulocytic] anaplasmosis), Borrelia miyamotoi, or Powassan virus. Co-infections should be considered when patients with LD have prolonged
or severe manifestations of infection, cytopenias, or an unusually high or persistent fever27.
Stages of Lyme Disease
- erythema migrans
- regional lymphadenopathy
- erythema migrans
- meningitis, cranial neuritis, bells palsy
- arthralgias, myalgias
- AV block, pericarditis, pancarditis
- Conjunctivitis, iritis, hepatitis
- chronic arthritis
DDx and Diagnosis
DDx: Erythema migrans must be distinguished from exaggerated local arthropod reactions (including to the tick bite), erysipelas, cellulitis, allergic contact dermatitis and non-pigmented fixed drug eruption, and less often, other entities outlined in Table 19.1. An erythema migrans-like skin lesion can be seen in southern tick-associated rash illness (STARI or Masters disease) which follows the bite of the lone star tick, Amblyomma americanum (see Ch. 85).
- There are three categories Confirmed, probable, and suspected
1) Confirmed: Requires the presence of erythema Migrans plus known exposure or lab evidence of infection (isolation of Borrelia from tissues or anti-Borrelia antibodies by the two-test approach of a sensitive enzyme immunoassay (e.g. ELISA) followed by a Western
****Of note, the peak specific IgM response occurs 3-6 weeks into the infection33. As a result, serologic testing has a low sensitivity
Treatment of Lyme Disease
- Doxy 100 BID 14 days
- Amoxicillin 14 days
- cefuroxime 14 days
meningitis, cranial nerve palsy, carditis
- 14 days of ceftriaxone or cefotaxime
Erythema Gyratum Repens
■ A figurate erythema that is migratory and composed of concentric
rings with a wood-grain appearance
■ It represents a paraneoplastic phenomenon and the most
common underlying neoplasm is carcinoma of the lung
■ The lesions may have associated pruritus and scale, and they
characteristically exhibit rapid migration (up to 1 cm per day)
■ The cutaneous lesions resolve when the neoplasm is successfully
Erythema Gyratum Repens pathogenesis
A leading hypothesis is that EGR represents an immune reaction in which there is a cross-reaction between tumor and cutaneous antigens44. In a few patients, direct immunofluorescence (DIF) has demonstrated deposits of IgG and C3 in the basement membrane zone (BMZ) of the skin, and, in isolated cases, similar deposits were seen in the associated neoplasm45. However, this could simply represent a nonspecific finding. Caux et al.45 suggested that the tumor produces a modification in its basement membrane and this subsequently induces an immune response. Recognition of similar antigens in the BMZ of the skin then leads to the cutaneous eruption. The responsible antigen(s) is not known, but a curious finding is an accumulation of active Langerhans cells in the upper layers of the epidermis46. Recently, a link between glutamine metabolism within the skin and the distinct pattern of EGR lesions was proposed46a.
EGR clinical features and pathology
- Patients usually have multiple, annular or polycyclic, erythematous lesions that develop scale at their edges and advance at a rapid rate (up to 1 cm per day)47. This rate of peripheral spread is significantly faster than that of EAC. Lesions have a wood-grain or zebra-like pattern, due to the development of "rings within rings" (Fig. 19.8). In some patients, the eruption is also pruritic. Additional findings in patients with EGR include acquired ichthyosis, palmoplantar keratoderma, and hypereosinophilia.
In at least 70% of patients, EGR is associated with an underlying neoplasm, most commonly of the lung then breast, esophagus or stomach48. The cutaneous lesions usually develop from 1 year prior to 1 year after the diagnosis of the neoplasm. EGR may coincide with underlying pulmonary tuberculosis, and patients with other disorders (see below) can also have EGR-like lesions. Occasionally, no underlying disorder or malignancy can be identified.
- The histopathologic findings are nonspecific and include hyperkeratosis, focal parakeratosis, moderate patchy spongiosis and a mild, perivascular lymphohistiocytic infiltrate. In some cases, eosinophils and melanophages are seen in the dermis. By immunoelectron microscopy, DIF-detected immune deposits of IgG at the BMZ (see Pathogenesis) were shown in one patient to be beneath the lamina densa45. In addition, anti-EGF receptor, anti-vimentin and anti-α-actin staining was more intense in lesional skin and tumor tissue than in controls. Nevertheless, the meaning of these findings is unknown, given their anecdotal nature, and DIF is not required for confirmation of the diagnosis.
EGR differential diagnosis
- In addition to excluding the other types of figurate erythema, EGR-like lesions may be seen in patients with erythrokeratodermia variabilis and resolving pityriasis rubra pilaris (Fig. 19.9) as well as autoimmune bullous diseases, in particular bullous pemphigoid (both paraneoplastic and classic) and epidermolysis bullosa acquisita48,49. Similar appearing lesions can occasionally be seen in mycosis fungoides, resolving psoriasis, hypersensitivity reactions to azathioprine, urticarial vasculitis, and autoimmune connective tissue diseases, primarily lupus erythematosus (subacute variant [also referred to as LE gyratus repens] or an associated neutrophilic dermatosis or small vessel vasculitis), and Sjögren syndrome. In certain regions of the world (e.g. maritime and mainland Southeast Asia), tinea imbricata would also be included in the differential diagnosis.
- EGR resolves when the associated neoplasm is successfully treated. There may be a return of cutaneous lesions in association with the development of metastases or local recurrences of the malignancy
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