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Pityriasis rosea-like adverse reaction: Review of the literature and experience of an Italian drug-surveillance center

  • Author(s): Atzori, Laura
  • Pinna, Anna Luisa
  • Ferreli, Caterina
  • Aste, Nicola
  • et al.
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Pityriasis rosea-like adverse reaction: Review of the literature and experience of an Italian drug-surveillance center
Laura Atzori MD, Anna Luisa Pinna MD, Caterina Ferreli MD, Nicola Aste MD
Dermatology Online Journal 12 (1): 1

Dermatology Department, Cagliari University, Cagliari Italy. ATZORI09@lauraatzori.191.it

Abstract

Pityriasis rosea is a common, acute eruption of uncertain etiology. A rash very similar to this idiopathic disease is also attributed to several drugs, and recovery, which depends on withdrawal of the responsible drug, can be delayed by its late identification. A prospective study to record all cases of adverse cutaneous reactions presenting with pityriasis rosea like manifestations was conducted at the center for drug-surveillance of the dermatology department of Cagliari University. We developed an intensive surveillance program from June 2002 to May 2005, adopting the WHO Collaborating center for Drug Monitoring causality assessment criteria and algorithm. Eight cases, six male and two female, were studied in a 3-year period. None had previously suffered from drug intolerance or allergy. Clinical manifestations were very similar to pityriasis rosea. Responsible drugs were mainly angiotensin-converting enzyme inhibitors, alone or in combination with hydrochlorothiazide, followed by one case each for hydrochlorothiazide plus sartan, allopurinol, nimesulide, acetyl salicylic acid. Recovery was obtained in all cases with drug withdrawal. Final causality assessment was probable for all eruptions. Frequency of drug pityriasis rosea-like eruptions is probably underreported. The mildness of the eruption, mimicking a very common and self-limiting disease does not prompt physicians to verify the use of medications until persistence, severity of lesions and itching require re-evaluation of the original diagnosis.



Introduction

Skin involvement in adverse drug reactions is frequent and diagnosis is often intuitive, but uncommon presentations may mimic and be misdiagnosed for other more frequent skin conditions, such as Gibert's Pityriasis rosea [1]. Several drugs have been reported as being responsible for a rash similar to the idiopathic disease [2-20], but there are no estimations regarding the frequency of such events. Recognition of the iatrogenic origin of the eruption is crucial to avoid an extremely chronic course and also to experiment a rapid recovery with the simple withdrawal of the responsible drug.

As part of an intensive drug-surveillance program, a prospective study was conducted at the dermatology department of Cagliari University to record and analyze all cases of adverse cutaneous reactions presenting pityriasis rosea-like features. Several distinctive criteria were depicted, which can help in the differentiation from the idiopathic disease.


Materials and methods

From June 2002 to May 2005 all cutaneous adverse reactions to drugs were recorded on magnetic support, including outpatients, patients admitted to the dermatology department, and patients hospitalized in other departments of the city (Cagliari, Italy). Diagnosis was based on clinical features, circumstantial evidence, time relationships between taking the drug and onset of the rash, and exclusion of alternative diagnoses. Accurate allergic and pharmacologic anamnesis, as well as history of previous reactions to drugs were obtained from the patients and general practitioners. Histology was performed in all cases. Final causality assessment followed the WHO Collaborating Center for Drug Monitoring international criteria and algorithm [21].


Results


Figure 1
Figure 1. Enalapril eruption: numerous scattered bright red-violet scaling macules and papules confined to the upper part of the trunk, abdomen and proximal aspects of the limbs after starting this drug.

In a 3-year period, as part of the activities of a dermatologic center of drug surveillance eight cases out of 380 (2 %) adverse cutaneous reactions presented an erythematous-squamous eruption mimicking Gibert's pityriasis rosea. Mean age was over the 6th decade (68.6 years) with a clear male prevalence (6M : 2F) (Table 1). None of the patients reported a previous history of drug intolerance. Clinical manifestations were similar in all patients, a blossoming of flat, round or oval scaly patches, bright red to violet in color, and involving the trunk, abdomen, and proximal aspects of the limbs (Figs. 1, 2). The lesions evolve in successive crops and there is no tendency of spontaneous remission. The scaly surface of some lesions showed a typical marginal collarette (Fig. 3). Patients reported severe itching, and this was unresponsive to antihistamine treatment. No prodromic symptoms were reported.

Laboratory investigations were within normal range, except for a slight leukocytosis and eosinophilia (9-17 %) in six cases. Hepatic and renal functionality were normal, as well as the electrocardiogram and chest X-ray. All blood tests were negative for prior or concomitant infections. Histological examination on cutaneous biopsy demonstrated similar features in all cases, a superficial perivascular dermatitis, with parakeratosis, spongiosis and marked edema of the papillary dermis. The inflammatory infiltrate was mainly composed of lympho-monocytes, but with frequent eosinophils.


Figure 2AFigure 2B
Figures 2. Acetylsalicylic acid pityriasis rosea-like eruption in a 43-year-old man: A)anterior aspects of the trunk B) lateral surface of the trunk.

Figure 3Figure 4
Figure 3. Lisinopril eruption: surface pattern of the lesions on the back, with a marginal collarette of scales.
Figure 4. Complete resolution of the case presented in figure 2, after simple discontinuation of the drug.

Pharmacological anamnesis was simple because no patient was taking any other drugs. Responsible drugs were mainly angiotensin-converting enzyme (ACE) inhibitors, alone or in combination with hydrochlorothiazide, followed by one case each for hydrochlorothiazide plus sartan, allopurinol, nimesulide, acetylsalicylic acid. Time from first dose intake to onset of the eruption varied from 5 to 20 days; the time for a specialist diagnosis of the iatrogenic origin ranged from 13 to 50 days. Suspected drugs were discontinued and the clinical manifestations improved soon after, with complete resolution within 5-10 days. No relapses were observed in a 6-month followup.

Final causality assessment following the WHO program algorithm [21] defined as probably related to the drug all cases, in absence of rechallenge information.


Discussion

The dermatologist's commitment in adverse drug reactions is crucial because the skin is a very common target and any skin disorder can be imitated, induced or aggravated by drugs. Constant, detailed attentions has been given to uncommon presentations and pityriasis rose-like eruptions since a specialized center devoted to drug-surveillance was created in our dermatology department. Isolated case reports for different medication have been reported in current literature [2-20] (Table 2). The frequency of pityriasis rosea-like eruptions in our case reports, compared to the overall number of adverse cutaneous reactions (2 %) is remarkable and suggests underreporting. Clinical manifestations are very similar to the pityriasis rosea of Gibert. In addition, the following distinctive characteristics from the idiopathic disease were noted:

  • The absence of an evocative, single "herald" patch.
  • The marked inflammatory color of the lesions, tending to bright violet-red.
  • The severity of itching, and lack of response to antihistamine treatment.
  • The presence of increased eosinophils in the blood and in the skin infiltrate.

The clinical suspicion of an iatrogenic etiology was confirmed by the sudden recovery after withdrawal of the drug (dechallenge). Extent of eruption and patients' advanced age required hospitalization in the vast majority of cases (94 %). Responsibility of ACE inhibitors seems to be more frequent than that of other drugs [3, 4, 5, 6, 7], but extensive marketing of these antihypertensive drugs in recent years may have played a role, especially considering the quite obsolete prescription of certain medication reported in the past: gold salts, metronidazole, meprobamate, bismuth [1, 2, 15, 16]. The mechanisms of skin involvement are unknown and vary according to the molecules. Following Wilkin's hypothesis [3, 4, 5], ACE inhibitors might induce increased plasma and tissue levels of kinins, whose generic pro-inflammatory effects are implicated in different cutaneous adverse reactions, including pityriasis rosea-like eruptions. NSAIDs are also able to evoke cutaneous inflammation [8, 9, 10]; the inhibition of cyclo-oxygenases may cause a collateral availability of the prostaglandin precursor, arachidonic acid, which activates lypoxygenase pathway and final leukotriene release. No previous reports were found regarding administration of allopurinol or hydrochlorthiazide (whose responsibility in combination with ACE inhibitors or sartan cannot be fully excluded ).

After our first case description [7] we hypothesized that the frequency of drug-related pityriasis rosea-like eruptions is underreported, and we conducted a prospective study collecting all new cases observed in our department. In a 3-year period, 2 percent of all cutaneous adverse drug reactions presented this peculiar manifestation, confirming our impression. The mildness of the eruption, mimicking a very common and self-limited disease, probably does not prompt physicians to check for drug association until persistence, severity of lesions, and itching require reconsideration of the original diagnosis. Responsibility of ACE inhibitors, as well as NSAIDs merits further investigations and suggest analogies among pro-inflammatory pathways affecting the skin. Prevalence among old patients on long-term treatment is an interesting finding and may represent a distinguishing feature from the idiopathic disease, which is characteristic of young adults [2]. Misdiagnosis and consequent waiting for pityriasis rosea self-healing should have further prolonged illness and caused a notable delay in adopting the more important measure, which is discontinuation of the drug.

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