Pityriasis rosea: a distinct entity or viral exanthem?

Introduction

Pityriasis rosea (PR) also known as pityriasis rosea Gibert is a common self-limiting skin disease. It usually occurs in children and young adults and usually begins with a large erythematous scaly plaque followed by eruption of smaller plaques located mainly on the thorax and proximal parts of extremities [1, 2] Although the disease is not rare, there are some difficulties with its cause and management. In this review we would like to take a closer look at them.

Epidemiology

Pityriasis rosea affects approximately 0.5–6% of the population, mostly people between 10 to 35 years old, but it can occur in younger and older patients as well [3–5]. Mondal et al. showed that from 50 pediatric patients between 2 to 18 years old, 31 were above 10 years old, 17 patients were from 5 to 10 years old, and 2 patients were below 5 years of age [6]. The female : male ratio varies from no significant difference between sexes to 1.5 : 1 female : male ratio [6–8]. PR occurs mainly during cold seasons, however, there are studies which showed that PR occurs uniformly during the year [1, 8–10]. PR may recur in around 3% of the patients. In majority of relapsing cases, it reoccurs only once, although there are reported cases with a multiple recurrence rate [11, 12].

Etiology

HHV-6 and HHV-7

It seems that PR might be caused by human herpes virus 6 (HHV-6) and human herpes virus 7 (HHV-7). This hypothesis was first suggested by Drago et al. in 1997, who isolated HHV-7 from peripheral blood mononuclear cells (PBMC), skin and plasma of patients during their acute disease. Whereas in the control group, HHV-7 was only detected in peripheral blood mononuclear cells and there was no HHV-7 in the plasma and the skin. Since then, different groups of researchers have been looking for the evidence of HHV-6 and HHV-7 etiology of PR. Drago et al., Watanabe et al., Vág et al., Broccolo et al., Canpolat Kirac et al. and Kurc et al. agree that the cause of PR is HHV-6 and -7 [13–22]. However, Kempf et al., Yasukawa et al., Yoshida, Kosuge et al., Offidani et al., Chuh et al., Wong et al., Karabulut et al. and Yildirim et al. are against this etiology [23–31]. HHV-6 and HHV-7 are widely distributed in the human population. The seroprevalence of HHV-6 and HHV-7 in the general population is about 80–90%. Primary infections occur mostly during childhood and are usually asymptomatic or may cause roseola, which is an exanthematous disease affecting children before the age of 3 [14, 32]. The reactivation of HHV-6 and HHV-7 may occur in immunosuppressed patients e.g. transplant recipients, during other viral infection and in pregnant women. Based on research there is no evidence that cytomegalovirus, Epstein-Barr virus, parvovirus B19, picornavirus, influenza and parainfluenza virus, Legionella spp., Mycoplasma spp. or Chlamydia spp. infections are associated with PR [33].
In addition to studies on the viral etiopathogenesis and genetic material of viruses in PBMC, plasma or other human specimens, there are also studies on the immunological mechanisms that accompany pityriasis rosea.

Fractalkine

Gangemi et al. studied the role of fractalkine (CX3CL1) in PR. In 14 from 20 patients, the serum level of fractalkine was elevated which is a proof of induction of inflammatory response and activation of cellular immunity [34].

IL-22

Indirectly, the viral etiology of the disease is supported by the cytokines and chemokines increased during PR. In the studies of Al Mokadem et al., the serum levels of IL-22 were elevated, and Drago et al. revealed that also IL-17, IFN-g, VEGF, and CXCL10 were increased [35, 36].

HLA-DQB1

Fu et al. in the study conducted on the Chinese population have found that the frequency of HLA-DQB1*03:03 was significantly higher in patients with pityriasis rosea compared to the control group (p = 0.001; relative risk (RR) = 2.24; 95% CI: 1.38–3.6), and additionally, people with HLA-DQB1*06:06 were less likely to suffer from PR, which may indicate its protective effect (10.90% vs. 27.78%, p < 0.02; RR = 0.39; 95% CI: 0.17–0.90). These results suggest that the immune system is involved in the pityriasis rosea pathogenesis [37].

PR and PR-like eruption

There are also cases of pityriasis rosea and PR-like eruption (PR-LE) induced by different drugs and vaccinations. Those substances are listed in table 1 [5, 12, 38, 39]. Since the diagnosis of PR is often based on the clinical picture, there is a problem with some of the previous studies in which PR and PR-like eruption might not have been differentiated. However, PR and PR-LE are not the same diseases and clinical features to distinguish them were eventually proposed by Drago et al. (table 2) [40]. In PR-LE there is no evidence of HHV-6 or HHV-7 reactivation and PR-LE is probably a hypersensitivity reaction caused by molecular mimicry of viral epitope or host proteins [41, 42].
Taking everything into consideration, more research is required to fully understand the etiopathogenesis of pityriasis rosea.

Clinical appearance

Pityriasis rosea usually begins with a lesion called a “herald patch” (HP) or “mother spot” [43]. It is a single erythematous scaly plaque with the borders slightly elevated and the center is pale and slightly depressed. It reaches about 3 cm or more in diameter and is typically located on the trunk; however, it may occur on the limbs as well. After approximately 1 to 2 weeks the herald patch is followed by diffuse eruption composed of smaller lesions (5–10 mm) which are similar to the HP and occur symmetrically along the Langer’s lines (skin tension lines, the location of which corresponds to the course of collagen fibers in the dermis) on the trunk (fig. 1) and proximate parts of the limbs which is called “Christmas tree” distribution [11, 44–46]. The duration of PR is typically around 45 days, but may vary from 2 weeks to 5 months [9, 47]. Prodromal symptoms are present in up to 69% of the patients. These include general malaise, loss of appetite, fatigue, nausea, headache, joint pain, enlarged lymph nodes, difficulty in concentration, irritability, gastrointestinal and upper respiratory symptoms, fever or sore throat. They may appear before or simultaneously with the skin lesions [9, 48].
PR can be morphologically atypical and manifest as small vesicles, macular purpura, lesions similar to urticarial wheals, generalized papules, lichenoid lesions, erythema multiforme-like lesions, follicular papules, Darier PR – consisting of 5 cm or larger plaques, exfoliative dermatitis or form of PR without any herald patch or with HP located on the face, scalp, genitalia or other unusual locations [12]. There are cases of PR where the lesions were distributed on acral surface of the limbs, groins, axillae and face [49]. Fetoui et al. describe the case of a 27-year-old patient who had unilateral PR [50]. Oral lesions may also be present, more frequently in the dark-skinned people, but have been found in the Caucasian population as well [9]. There are following types of oral lesions in PR: erosions or ulcerations, punctuate hemorrhages, erythematous macules, erythematous annular lesions and erythematous plaques [51].
Some of patients may complain of itching. Among the pediatric population, 70-90% have experienced pruritus [52, 53]. Mondal et al. showed that in group of 50 pediatric patients, 31 suffered from pruritus [6]. Among adults, pruritus is present in approximately 75% of the patients [44, 54]. However, Drago et al. suggested that severe pruritus is caused by inappropriate treatment by the pharmacist or within the family of the patient rather than by the disease itself and the pruritus in PR is always mild and tolerable and more common in PR-like eruption than in PR [9, 40].

Diagnosis

The diagnosis is based on clinical features and medical interview with the patient. The patient should be asked about the presence of the herald patch, medications including vaccines, prodromal symptoms or upper respiratory tract infection. In the physical examination, the papulosquamous skin eruption is expected to be found [1]. Chuh suggested diagnostic criteria for establishing the diagnosis of pityriasis rosea [55]. According to them, it is required for the patient to have:
1) lesions which are circular or oval,
2) majority of the lesions with a scale,
3) at least two of the lesions with central clearance and borders with a scale.
Optional features mentioned by Chuh, from which at least one must be present, are:
1) distribution of the lesions on the trunk and limbs with less than 10% of lesions distal to mid-upper-arm and mid-thigh,
2) distribution of the lesions mostly along the ribs,
3) presence of a HP at least 2 days before the generalized eruption.
Chuh established also clinical features excluding diagnosis of pityriasis rosea. These include:
1) lesions mostly on the palms and soles,
2) clinical or serological evidence of syphilis,
3) many small vesicles at the center of at least two lesions [55].
To summarize, the diagnosis of pityriasis rosea can be made if a patient has all the essential clinical features, at least one of the optional clinical features and none of the exclusion clinical features [55]. Dermoscopy Dermoscopy examination may be useful, especially for the differential diagnosis. Jindal et al. showed PR lesions in dermoscopy which have usually yellow or yellow-orange background, dotted vessels in a patchy distribution in about 63% of cases, and the most prominent scale color is yellow-white [56]. Histopathological examination The histological features are nonspecific for pityriasis rosea, however, in cases difficult to differentiate on a clinical background, a skin biopsy may help to establish the correct diagnosis – rather by excluding other skin diseases than confirming pityriasis rosea. The histopathology shows superficial perivascular lymphohistiocytic dermatitis with acanthotic epidermis with spongiosis and lymphocyte exocytosis, focal parakeratosis in the shape of a lens or teapot cap on the top, and diminished granular layer underneath (fig. 2). In the dermis of the “herald patch”, edema and red blood cells extravasation with perivascular infiltration can be observed [1, 9, 12, 57, 58].

LC-OCT

Line-field confocal optical coherence tomography (LC-OCT) may also be used to differentiate pityriasis rosea from other skin conditions. In LC-OCT there may be seen hyperkeratosis as thickened bright structure, parakeratosis as dark polygonal structures, acanthosis and islands of keratinocytes with spongiosis manifested as broadened outlines and dark rounded areas. There can be observed focal areas of dark globular structures at the tips of the dermal papillae which may correspond to dilated capillaries with infiltrate or extravasated erythrocytes [59].

Differential diagnosis

Pityriasis rosea may mimic different skin diseases. The most common are drug eruptions, secondary syphilis, guttate psoriasis, pityriasis lichenoides chronica, tinea corporis, pityriasis versicolor, erythema dyschromicum perstans, erythema annulare centrifugum, nummular eczema and lichen planus. Table 3 contains a brief description of those diseases to facilitate the differential diagnosis [56, 60–72]. From mentioned diseases, secondary syphilis is the most important to exclude, especially in pregnant women [12]. Table 2 presents selected criteria for differentiation of pityriasis rosea and similarly to PR-looking eruption [40].

Treatment

Pityriasis rosea is a self-limiting disorder thus in most of the cases there is no need to put the patients on any treatment, unless pruritus is intense and relieving treatment helpful.
Additionally, there are a few problems associated with PR treatment:
• The diseases can disappear itself after 2 to 12 weeks, thus it is hard to indicate whether the treatment was effective,
• The etiopathogenesis is not fully understood, we cannot prescribe treatment targeting the cause,
• The conducted studies had small research groups and the results were not always consistent,
• While using macrolide antibiotics and antiviral agents, the risk of bacterial and viral drug resistance to those drugs is increasing,
• Since the disease is self-limiting, the risk of any treatment can be higher than its potential benefits [12].
According to Cochrane review which included 14 trials with 761 patients, among macrolide antibiotics, antiviral agents, phototherapy, steroids and antihistamine drugs, there is no strong evidence to recommend any of the listed method of treatment. The researchers in this meta-analysis took into consideration rash and itch improvement as well as adverse drugs reaction. The quality of evidence of included studies was measured as moderate to very low [73].
The moderate evidence was obtained for 3 antibiotics: clarithromycin, azithromycin and erythromycin. Both oral clarithromycin and oral azithromycin did not result in itch resolution or rash improvement. Erythromycin may lead to increased rash improvement, rated by a medical practitioner, but the result may also be compatible with a benefit of placebo. The itch score was measured in one of the studies comparing antibiotics, and for erythromycin there was probably better reduction of itch compared to placebo [74–78].
From a group of antiviral agents, acyclovir was the investigated drug. However, the validity of using acyclovir in PR is questionable, because PR’s etiopathogenesis is unclear and acyclovir has weak activity against HHV-6 and no activity against HHV-7 in laboratory conditions [79]. In one trial, compared to placebo, itch resolution was probably higher with placebo than with acyclovir. Nevertheless, in rash improvement, acyclovir was better than placebo or vitamins with a significant difference [80–82]. In one study, acyclovir was added to calamine lotion and oral cetirizine and compared with the treatment without acyclovir [83]. The result showed that the addition of acyclovir may lead to itch resolution and reduction in itch score [73]. There is also a study comparing acyclovir to erythromycin. Acyclovir was found to be more effective in full recovery rated at week 8 and in pruritus resolution, but the results were not statistically significant [84]. Thus, acyclovir may be a promising drug in the treatment of pityriasis rosea, but more research is needed.
Another group of medicaments used in PR is topical or systemic corticosteroids. The advantage of using glucocorticosteroids is reduction of inflammation, pruritus and visibility of the lesions by reduction of erythema and scaling. In a study comparing steroids to placebo, the itch resolution and rash improvement was higher in the prednisolone group [85]. High doses of systemic corticosteroids should not be used as they can trigger exacerbation of the disease [86]. The skin lesions may then be larger, raised and eczematous as in figure 3. Phototherapy can be used for treatment of pityriasis rosea as well. UV-B can reduce the severity of PR. As far as the itching is concerned, Valkova et al. did not observe decrease in pruritus [87]. However, Jairath et al. noticed improvement in itching, but the limitation of this study was the assessment time, which was after 4 weeks, thus, it is hard to determine whether it was the effect of phototherapy or spontaneous remission of PR itself [88]. Another study compared using three combinations, such as NB-UVB phototherapy with indigo naturalis, vs indigo naturalis alone or NB-UVB in monotherapy. These results of Wang et al. demonstrated that a combination of NB-UVB and indigo naturalis provided better therapeutic effects than NB-UVB and indigo naturalis used alone, but the researchers indicate that further clinical studies are required due to study limitations (e.g. a small sample size and small number of studies) [89].
To summarize, there is a need to conduct more research regarding therapeutic results. The assessment of the treatment should be done within 2 weeks since the disease may spontaneously disappear after 2 to 12 weeks. The control groups are needed as well to compare whether the disease has limited itself or the treatment does work. It should be also remembered that some patients will not need any treatment and will achieve complete remission of the disease.

Pityriasis rosea during pregnancy

The course of pityriasis rosea in pregnant women and its impact on the fetus is under investigation. The incidence of PR in pregnant women is 18% versus 6% in the general population [3]. Although the abortion rate in pregnant women with PR is not different from the general population (around 13%), the abortion rate when PR develops within 15 weeks of gestation is much higher and reaches around 57–62% [90, 91]. Drago et al. conducted studies on a group of 38 pregnant women. Other risk factors for miscarriage have been ruled out in this group including drugs taken. IgG antibodies titers for HHV-6 were from 1 : 40 to 1 : 160 and for HHV-7 from 1 : 40 to 1 : 320, whereas IgM antibodies were absent. In the study group, out of 38 women, 14 developed PR before 20 weeks of gestation. 5 out of 14 women miscarried and 6 bore children with problems (weak motion, hypotonia, patent foramen ovale, hyporeactive or with need of the incubator). From 1 out of 5 women who had the miscarriage, plasma, PBMC, skin samples, placenta and embryonic tissues were collected for further testing and HHV-6 DNA was detected in that material, whereas no evidence of HHV-7 DNA was found. Moreover, HHV-6 viremia and HHV-6 p41 antigen expression were detected immunohistochemically in the skin lesions of the mother, in the placenta and fetal tissues, what is the confirmation of active HHV-6 infection. All the women who miscarried, had an atypical course of PR with additional symptoms (fatigue, insomnia, concentration problems, headaches, loss of appetite) and unusual widespread lesions [90].
In 2014, Drago et al. extended the previous research to a group of 61 pregnant women with PR. As in the previous study, other risk factors for miscarriage were excluded. 22 of 61 women had unfavorable pregnancy outcomes – 8 women miscarried and 14 women had neonates with perinatal complications (hypotonia, weak motion, patent foramen ovale, hydramnios or low birth weight). In women who miscarried, the course of PR was atypical – skin lesions were widespread, the duration longer and PR was associated with constitutional clinical manifestations as in the previous study. All 61 women had IgG and IgM antibodies titers for HHV-6 and HHV-7 measured and 14 women had the HHV-6/7 DNA assessed in skin lesions, plasma, and placenta and in the fetal tissues as well. Specific HHV-6 and HHV-7 IgG antibodies were detected in all 61 patients and none of them had IgM antibodies. From the further studied group of 14 women, 4 women miscarried, 5 had babies with perinatal problems and 5 had normal pregnancy. 3 out of 4 women who miscarried, had HHV-6 DNA found in plasma, in the placenta and in the fetal tissues and all 4 women had HHV-6 DNA in skin lesions. HHV-6 DNA found in plasma, PR skin lesions, and placenta in only 1 of 5 women with perinatal problems and among PR patients with normal pregnancies – in plasma of 2 patients and in the skin lesions in 1 of them. There was no HHV-6 DNA in the placenta of the PR patients with normal pregnancies. HHV-7 DNA was never detected in fetal tissues, but it was found in the plasma and PR lesions in 3 out of 4 miscarrying women. Among patients with perinatal problems, HHV-7 DNA was wound in 1 patient’s plasma, 2 patients’ placenta and 3 patients’ skin lesions. Among patients with normal pregnancy, HHV-7 DNA was found in 3 patients’ plasma, 2 patients’ skin lesions and there was no HHV-7 DNA found in the placenta same as HHV-6 DNA [91]. Both of these studies suggest a distinct impact of PR and its viral cause on the course of pregnancy.
Moreover, Rebora et al. analyzed 76 women with PR during pregnancy and tried to establish which risk factors such as the week of the pregnancy with PR onset, the presence of an exanthem and additional clinical symptoms, the PR body surface area involvement, the age at conception and the viral load of HHV-6 and HHV-7 in plasma, could threaten the outcome of the pregnancy the most. The study revealed that the high viral load of HHV-6 in plasma is the most important risk factor for perinatal complications, whereas there is no evidence of HHV-7 viral load impact on pregnancy complication in patients with PR [92, 93]. The early onset of PR and the presence of the rash are also proved to be significantly associated with complications during pregnancy (p-value of 0.0017 and 0.0392, respectively) [92].
In a case series and literature review conducted by Wenger-Oehn et al., the results did not differ much. In most of the cases, PR did not influence the course of pregnancy, but when the onset of PR occurred in the early gestation, the risk of unfavorable pregnancy outcomes was higher and PR was widely spread, lasted longer and was associated with extracutaneous features [94].
In all pregnant women with a suspicion of PR attending the dermatologist, PR-like eruption should be excluded, thus the proper history taking is very important with special attention paid to the medications the patient is taking, presence of HP, lesion distribution, prodromal symptoms, sparing of the face, and oropharynx involvement [95]. The next step is to determine the risk of pregnancy complication, which includes: the onset before 15 weeks of gestation, the presence of extensive lesions and additional clinical manifestations. This should be followed by the assessment of the HHV-6 and HHV-7 viral DNA loads in the plasma (> 200 copies/ml represents a potential risk) [92, 93]. All pregnant patients with PR are recommended to be closely observed by the gynecologist [94].
Nevertheless, there is a need for further prospective controlled studies with larger sample sizes to further validate the association of PR with unfavorable pregnancy outcomes in pregnant patients with PR [96].

Conclusions

Although pityriasis rosea seems to be a well-known and common skin disease with the clinical symptoms easy to manage, there are some controversial points which need more attention. Taking into consideration the circumstances of the disease onset mentioned in our manuscript, we would like to point out that PR may be considered as a reactive disease associated with decreased immunity caused by infections or pregnancy rather than sui generis disease. Certainly, further research is needed to confirm this thesis, nevertheless PR should not be underestimated by the physicians, especially in pregnant women, in whom it may be responsible for miscarriages and fetal complications.

Funding

No external funding.

Ethical approval

Not applicable.

Conflict of interest

The authors declare no conflict of interest.

References