Are You Confident of the Diagnosis?
What you should be alert for in the history
Pityriasis lichenoides et varioliformis acuta (PLEVA) is characterized by acute outbreaks that progress through a phase of healing to spontaneous resolution. Not only should prior outbreaks be the focus of the history but there should also be a search for any coincident dermatoses. PLEVA was initially categorized vaguely in the group of “rhythmic eruptions”. The history should try to determine the rhythm of a patient’s outbreaks as that will be a key parameter of therapy.
Characteristic findings on physical examination
Lesions typically appear in groups (Figure 1), but solitary 4-20 mm papulovesicles tend to predominate the primary lesion morphology. As lesions age, there may be crusting before resolving, with hyper- or hypopigmentation and scarring. Any patient with active disease should exhibit lesions at all phases of development (truly more varicelliform than varioliform). The lymph node examination is important and usually normal.
Expected results of diagnostic studies
The primary diagnostic test is the punch biopsy. Routine staining of PLEVA typically reveals a wedge-shaped perivascular lymphohistiocytic infiltrate with varying degrees of edema and hemorrhage in the dermis. There may be vacuolization along the basal layer and scattered necrotic keratinocytes. The epidermis often shows spongiosis, parakeratosis, and polymorphonuclear leukocytes in the stratum corneum (“neuts in the horn”). T-cell clonality may be detectable but no atypical lymphocytes are noted and CD30 staining is negative.
The primary lesion of papulovesicular lesions that crust and scar on any part of the body are what bestowed the name “varioliform” on PLEVA. However, variola would only be suspected in the patient with the acute febrile ulceronecrotic variant. But even then, variola is only going to occur in those exposed by way of its role as a biologic weapon. Varicella, however, is a genuine mimicker with lesions at varying stages of development and pox-like scarring; multinucleate giant cells and positive culture distinguish varicella zoster eruptions from PLEVA.
Another mimicker of PLEVA is a postviral eruption that can often persist with papulovesicular lesions over a course of 2 months, known as Gianotti-Crosti syndrome. The latter tends not to scar, is often markedly more pruritic, and has a distribution that also is a bit more organized than PLEVA, with involvement of extensor surfaces, the buttocks and the cheeks.
Both arthropod bites and erythema multiforme may mimic the initial appearance of PLEVA. Histology helps distinguish these and mucous membrane lesions of erythema multiforme making that entity recognizable at presentation. Necrotic lesions that scar are characteristic of leukocytoclastic vasculitis but again the histology showing neutrophilic disease in the latter typically aids in discriminating this from PLEVA. Characteristic secondary lesions of PLEVA are post-inflammatory hyper or hypopigmentation and scarring. The grouplike collections of secondary lesions mimic the secondary lesions of lymphomatoid papulosis.
Who is at Risk for Developing this Disease?
All ages are at risk, including all skin types and both sexes, with a slight male predominance.
What is the Cause of the Disease?
There is no known cause. There have been reports of viral serologies suggesting re-activation or co-infection but none of these are convincing enough to warrant viral serologies in the evaluation of a patient. As discussed below, there may be some insights into etiology and pathophysiology from the therapeutic interventions utilized.
With no identifiable trigger, patients and physicians often discuss the lessons learned from the various components of the therapeutic trials they embark on. Antibiotic therapy, which is the first-line treatment, generally involves antibiotics that also have antiinflammatory properties, so the notions of the disease as a “bacter-id” or spontaneous inflammatory eruption are reinforced. Often there can be T-cell clonality, and along with the clinical mimicry of lymphomatoid papulosis, this eruption could be a clonal eruption without atypia that stimulates an inflammatory anticlonal response that leads to its resolution. The most recent reports of responses to intravenous immunoglobulin would suggest that donor provided antibodies either help control a microbial trigger or they hasten the catabolism of a pathogenic autoantibody.
Systemic Implications and Complications
The major complication of this disease is that it also has potential for a variety of systemic involvement. The acute febrile variant of PLEVA has been associated with inflammation of the central nervous system, joints, lungs, liver, spleen, and thus just about every aspect of the systems review must be conducted on admission to inpatient observation.
Outside of this variant, there is only one implication that should always be monitored for by the dermatologists’ eye: mycosis fungoides. PLEVA is not considered to be a precursor to mycosis fungoides but there have been reports, particularly in children, of mycosis fungoides developing after a diagnosis of PLEVA. In at least one of these reports the location of the mycosis fungoides was similar to that of the PLEVA, suggesting at least a topographic association. PLEVA-like eruptions also occur in patients with established mycosis fungoides, much like the PLEVA mimicker lymphomatoid papulosis. The take-home lesson is that all PLEVA patients should be routinely examined for signs of mycosis fungoides.
Erythromycin 250mg-1000mg per day
Azithromycin 250mg per day
Clarithromycin 500mg per day
Tetracycline 250mg-1000mg per day
Doxycycline 100mg-200mg per day
Minocycline 100mg-200mg per day
Narrowband ultraviolet B phototherapy 2-3 sessions per week
Photochemotherapy with 8-methoxypsoralen and ultraviolet A light 2-3 sessions per week
Methotrexate 5-20mg per week
Dapsone 50-150mg per day
Optimal Therapeutic Approach for this Disease
The first consideration of therapy is to recognize and hospitalize patients presenting with the acute febrile variant. Management of this is discussed in another upcoming section.
Wait and watch
In many patients the lesions are covered by clothing and are infrequent, so that the disease is a minor annoyance. Also, some patients prefer to avoid therapy and the course of wait and watch is followed. Periodic exams are a must even if there is no therapeutic intervention.
The chronic relapsing behavior of the disease is the primary target of treatment. Arresting outbreaks of new lesions is more measurable than speeding up the spontaneous resolution. Initial therapy is typically with a macrolide antibiotic such as azithromycin, erythromycin, or clarithromycin. Courses of 1-2 months are often needed to see if new outbreaks can be suppressed. For teenagers and adults, tetracycline and its derivatives are often used.
All phototherapies have been utilized: heliotherapy, tanning parlors, broadband ultraviolet B, narrowband ultraviolet B, and photochemotherapy with 8-methoxypsoralen and ultraviolet A light. Typically patients are treated 2-3 sessions per week; after 20-30 sessions, there should be a noticeable decrease in the frequency of eruptions. If so, many patients seek the least numbers of treatments per month to suppress new outbreaks starting with once a week and stretching out to once a month. For those not seeking maintenance therapy, there may be a sustained remission after completing a course of phototherapy.
Weekly doses of methotrexate from 5-20mg are often successful within 8 weeks of initiating therapy but a typical therapeutic trial would go for at least three months. At the time a response is achieved (fewer outbreaks) the challenge is to find the lowest weekly dose needed to suppress lesions. If the patient has had no lesions for 12 weeks it would be prudent to taper methotrexate off and watch for any return.
Once the disease is suspected, a punch biopsy is required for diagnosis. Once the diagnosis is made, the management plan reflects the degree of severity and the degree of scarring that the PLEVA patient is incurring. This is where both history and exam are useful for management. Visible evidence of numerous past eruptions shows that the patient is well aware of the rhythmic nature of the disease and the prevention of future scars becomes the goal of therapy. For the new onset patient, education about the unpredictable rhythmic nature and spontaneous resolution is the first goal of management.
While it is attractive to think that the healing of erupted crusted papules can be hastened by therapy, no study can clearly confirm this. As a result, the goal of treatment becomes the prevention of future outbreaks and disfigurements. Frequent outbreaks require the systemic therapies listed above. For those intolerant of the safe systemic treatments (antibiotics) then phototherapy would be considered. Should phototherapy fail or not be available, methotrexate would be the most reliable agent to arrest the appearance of new lesions.
Antibiotics typically are used for a 2-month trial to see if they can suppress outbreaks. Should the 2- month trial be successful, long-term therapy of 6-12 months is implemented. Once the patient has been lesion-free for 2 months, antibiotics can be stopped and then restarted at the first sign of a relapse.
For those patients with severe disease, a maintenance regimen of once-weekly phototherapy or low-dose methotrexate could provide suppression until the disease is suspected to have remitted.
Unusual Clinical Scenarios to Consider in Patient Management
The most unusual clinical scenario with PLEVA is to be confronted with the acutely ill hospitalized patient suffering from the acute febrile variant. The dramatic illness has been reported to involve up to 90% of the body surface area. Management involves supportive care much like that provided for a burn patient, with petroleum jelly and anti-shear layer dressings. Pain control is essential with patient-controlled analgesics provided intravenously. The therapy typically includes systemic steroids with methylprednisolone at doses from 1mg/kg up to 1gm per day.
Immediate consideration should also be given to the use of intravenous immunoglobulin. However, given the expense and toxicity of this agent, it is probably best reserved for those patients not responding to pulse dose steroids within 24 hours. Methotrexate at doses of 15-25mg per week is typically initiated early in the course of management and continued well after the corticosteroids have been tapered away.
What is the Evidence?
Bowers, S, Warshaw, EM. “Pityriasis lichenoides and its subtypes”. J Am Acad Dermatol. vol. 55. 2006. pp. 557-72. (This comprehensive review summarizes the experiences in treating PLEVA with systemic therapies. In addition the pathology findings are reviewed.)
Sotirou, E, Patsatsi, A, Tsorova, C, Lazaridou, E, Sotiriadis, D. “Febrile ulceronecrotic Mucha-Haberman disease: a case report and review of the literature”. Acta Dermato-Venereol. vol. 88. 2008. pp. 350-5. (The disabling nature of the acute febrile variant of PLEVA is presented here. While there are not enough cases of this rare variant to support a trial, their observations and review support the approach of using high-dose steroids and weekly methotrexate followed by a taper of the steroids to control this disfiguring disease.)
Marenco, F, Fava, P, Fierro, MT, Quaglino, P, Bernengo, MG. “High-dose immunoglobulin and extracorporeal photochemotherapy in the treatment of febrile ulceronecrotic Mucha-Habermann disease”. Dermatol Ther. vol. 23. 2010. pp. 419-22. (The desperate management of the acute febrile variant is described along with the use of intravenous immunoglobulin.)
Lynch, PJ, Saied, NK. “Methotrexate treatment of pityriasis lichenoides and lymphomatoid papulosis”. Cutis. vol. 23. 1979. pp. 634-6. (Little has changed since this paper demonstrated the utility of weekly methotrexate therapy.)
Kempf, W, Kutzner, H, Kettelhack, N, Palmedo, G, Burg, G. “Paraneoplastic pityriasis lichenoides in cutaneus lymphoma: case report and review of the literature on paraneoplastic reactions of the skin in lymphoma and leukaemia”. Br J Dermatol. vol. 152. 2005. pp. 1327-31. (The infrequent association of PLEVA with mycosis fungoides is reviewed here. The association, albeit rare, still impacts patient management.)
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