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Abstract
Importance:
Pityriasis Rubra Pilaris (PRP) is a rare papulosquamous disorder with limited epidemiologic and clinicopathologic data. Little information is available on long-term outcomes, comorbidities and treatment efficacy.
Objective:
To evaluate objective and subjective disease experience metrics from patient and provider perspective, this study surveyed 100 patients with the putative diagnosis of PRP.
Design:
Following informed consent, the patients who elected to participate filled in a comprehensive survey, followed by acquisition of their medical records, including histopathology slides and reports. The data were analyzed separately from the healthcare provider and the patient perspective.
Setting:
Two academic dermatologists examined clinical notes, pathology reports and photographs, confirming diagnoses via predetermined criteria. Patients were categorized into four Levels of Diagnostic Certainty to allow stratification of the findings for subgroup analysis.
Participants:
Patients with the diagnosis of PRP were solicited through patient support organization websites. Data on patients were carefully evaluated through available clinical information, histopathology, and treatment history.
Main Outcomes:
The results revealed precise data regarding the clinical outcomes, unexpected association of comorbidities, and efficacy (or lack of it) of various treatment modalities.
Results (among the 100 participants)
Among the 100 patients,
50 were diagnosed with classic, unquestionable PRP. Of these Level 1 patients, only 26% were correctly diagnosed at initial presentation; diagnosis was delayed, on average, by 29 months (range, 0.25 to 288; median, 2), with most (54%) having undergone ≥2 biopsies. At enrollment, PRP symptoms had persisted in 36 (72%) patients for an average of 58 months (range, 1 to 300; median 30). Thirty-one patients (62%) had comorbidities, including hypothyroidism (20%). Nearly all (98%) patients received some form of therapy. Patients cited topical emollients, corticosteroids and salicylic acid along with oral retinoids, methotrexate and TNF-α inhibitors as most helpful.
Conclusions and Relevance:
PRP remains a challenging diagnosis without established and specific treatment. Our data highlight new potential avenues for research with therapeutic perspective.
Introduction
Pityriasis Rubra Pilaris (PRP) is an inflammatory papulosquamous skin disorder first reported by Tarral in 18351 and later fully characterized by Devergie in 1856.2 The clinical features of classic PRP affecting the skin and nails are detailed elsewhere.3–5 Histopathology reveals psoriasiform dermatitis with irregular hyperkeratosis and alternating vertical and horizontal ortho- and parakeratosis, referred to as the “checkerboard pattern”.6 Acantholysis and focal acantholytic dyskeratosis within the epidermis have been described, features which have been suggested to be helpful in distinguishing PRP from psoriasis. 7
Based on the age of onset, the disease course, and associated underlying conditions, Griffiths8 categorized PRP into five types: Type I: Classic adult type; Type II: Atypical adult type; Type III: Classic juvenile type; Type IV: Circumscribed juvenile type; and Type V: Atypical juvenile type. More recently, HIV-associated PRP was categorized as a separate type (Type VI).9
PRP is considered a rare disease, with an estimated incidence of 1 in 400,000, yet the precise prevalence is unknown.8 Because of its low prevalence, relatively little has been reported about epidemiologic trends, clinicopathologic features, and disease course. This multinational study of 100 patients seeks to describe epidemiologic, clinicopathologic, diagnostic, and therapeutic features, as well as patient impressions, of adult and pediatric PRP.
Methods
Study Design and Patient Recruitment
Prospective patients were recruited through two PRP support group websites (www.prp-support.org/wp/and www.prpalliance.com). Patients requesting enrollment received a Thomas Jefferson University Institutional Review Board-approved informed consent, together with a release of medical records forms, and the survey tool.
Study Procedures
The patient survey consisted of seven sections: (1) diagnosing/identifying information on treating physician(s), (2) demographic data, (3) description of symptoms and signs, (4) diagnostic procedures, (5) treatments, (6) medical history, and (7) disease course. Regarding treatments, patients were queried about the utility and perceived helpfulness of each modality. Using the informed consent and authorization to release medical records, study personnel obtained original clinical notes, pathology reports, and photographs.
The first 100 patients requesting enrollment, who self-identified with a diagnosis of PRP, were included in the study. Two study dermatologists (HJC and MSK) systematically reviewed each patient record, independently, using predetermined criteria to assess the Level of Diagnostic Certainty.
| Level of Diagnostic Certainty | Definitiona | Nb |
|---|---|---|
| 1 | Patients with unquestionable clinical, histopathologic or photographic evidence, or combination thereof, “consistent with,” “in keeping with,” or “confirmatory of,” PRP. Typical clinical presentations included follicular hyperkeratosis, salmon-colored to orange-red plaques with distinctive “islands of sparing”, prominent erythema on the extensor surfaces of the elbows and knees, palmar-plantar hyperkeratosis, erythrodermic appearance with varying degrees of exfoliation and erythema with a fine diffuse scale on the scalp. Histopathology revealed psoriasiform hyperplasia with irregular hyperkeratosis and alternating vertical and horizontal ortho- and parakeratosis. Presence of spongiosis, acantholysis and/or focal acantholytic dyskeratosis were helpful in distinguishing PRP from psoriasis, but were not sine qua non. | 50 |
| 2 | Patients with clinical, histopathologic or photographic evidence suggestive of PRP, but having neither all the classic features of PRP nor findings that were more suggestive of another disease as a more likely diagnosis. | 15 |
| 3 | A mixed group of patients with findings that may, in fact, be those of PRP, although there were insufficient data to confirm the diagnosis of PRP or rule it out. A mixture of histopathologic features, including specific (checkerboard alternating ortho- and para-keratosis) and non-specific (hyperkeratosis, parakeratosis, psoriasiform hyperplasia) provided evidence for the diagnosis of PRP, but the histopathologic differential remained suggestive of alternative diagnoses. | 30 |
| 4 | Patients enrolled with a self-reported diagnosis of PRP but having clinical, histopathologic or photographic evidence favoring an alternative diagnosis. These patients lacked the classic clinical features of PRP and histopathologic features seen on biopsies that were non-specific with a constellation of findings more consistent with an alternative diagnosis. | 5 |
Results
Epidemiologic Characteristics of the Cohort
Of the 100 enrolled patients with the putative diagnosis of PRP, 50 were categorized as Level 1; 15 as Level 2; 30 as Level 3; and five as Level 4, respectively.
At the time of enrollment, patients of this cohort of 100 were an average of 57 years of age (range, 5 to 87 years; median, 61 years). Forty-six (46%) patients were female. The self-identified ethnic distribution was 93% White, 4% Black, 1% Arabic, and 1% Hebrew. Twelve countries (United States of America, Canada, The Netherlands, Germany, France, Sweden, Denmark, Switzerland, United Kingdom, Dubai, Australia, and New Zealand) were represented in the cohort. The demographics are summarized in Table S1.
Level 1 patients were an average of 59 years of age (range, 5 to 84 years; median, 65 years) at enrollment. This subgroup was 56% female. The average age at symptom onset in Level 1 adult cases (>19 years of age) was 57 years (range, 25 to 80 years; median, 60 years). In pediatric cases (≤19 years of age) the onset was at 7 years of age (range, 2 to 13 years; median, 4 years). Bimodal peaks in the age at the onset of symptoms were noted in the entire study cohort during the first and second (12% of cases) and again in the sixth and seventh decades (60%) of life (Fig. 1). Similar distribution was also observed in the Level 1 patients (6% and 52%, respectively).
Diagnostic Features
Strikingly, only 13 (26%) Level 1 patients reported being correctly diagnosed with PRP upon initial presentation. The next most common initial diagnoses reported were psoriasis, contact dermatitis and eczema/spongiotic dermatitis, which accounted for 42% of Level 1 initial diagnoses (Table 2). The average time to obtain the correct diagnosis was 29 months from the initial presentation (range, 0.25 to 288 months; median, 2 months). Twenty-seven (54%) patients reported undergoing two or more biopsies (average 2, range 0–7 biopsies) to establish the diagnosis of PRP. The average age at the time of diagnosis in Level 1 adult cases was 58 years (range, 29 to 80 years; median, 60 years). In pediatric cases it was 16 years (range, 2 to 37 years; median, 4 years).
The spectrum of signs and symptoms in Level 1 patients was broad. Forty-five (90%) patients reported widespread erythematous plaques, ten (20%) reported prominent erythema on the extensor surfaces of the elbows and knees, and 14 (28%) reported associated hyperkeratosis, skin thickening or tightening. Thirty-nine (78%) noted palmar-plantar hyperkeratosis, thickening, or tightening. Skin flaking or ichthyosis was reported by 45 (90%) patients. The presence of perifollicular erythema and scales was reported by 38 (76%) individuals. Alopecia was noted in 35 (70%) patients. Twelve (24%) indicated associated eczematous changes. Nail involvement, ranging from thickening and discoloration to complete sloughing of the nails, was described by 36 (72%) patients. Pruritus was noted by 40 (80%) patients, yet a burning sensation of the skin was noted only by 25 (50%) patients.In Level 1 adult and pediatric patients, 32 (64%) and 4 (8%) indicated persistent, ongoing symptoms of PRP, at the time of the study, respectively. Thirteen (26%) of Level 1 adults and 1 (2%) of pediatric patients reported remission at the time of study enrollment (Table S1). The former patients (adult plus pediatric) noted that their symptoms had been present for an average of 58 months (range, 1 to 300; median, 30). Twenty-four (48%) of these individuals indicated that they were diagnosed with PRP Type I, two (4%) indicated Type II, four (8%) Type III, and none as Types IV to VI. The remaining 20 (40%) patients did not indicate their type of PRP. Of the 14 patients in remission, the average length of their disease course had been 84 months (range, 4 to 516 months; median, 44 months). Only one of these was a pediatric case, with a five year disease course (diagnosed at 7 years of age). In the remaining four Level 1 pediatric cases, symptoms had persisted, on average, 124 months (range, 12 to 348 months; median, 96 months). The symptoms in Level 2 pediatric cases had persisted, on average, 81 months (range, 15 to 156; median, 72), in Level 3 pediatric cases, on average, 68 months (range, 36 to 120; median, 48), and in the Level 4 pediatric case, 40 years.
Histopathologic Findings
Representative biopsies of 69 (69%) patients were obtained. Most Level 1 patients (54%) reported having had 2 or more biopsies (average 2; range 0–7 biopsies). Characteristic epidermal features noted were acanthosis, hyperkeratosis, as well as orthokeratosis and parakeratosis in a “checkerboard pattern” (Table S2).The dermis most commonly showed alterations (e.g., dilation) in vasculature with primarily perivascular, lymphohistiocytic infiltrates. In the study cohort of 100 patients, PRP was the most common clinical differential diagnosis on the histopathology referral forms available for review (n=31); the next most common were psoriasis (n=16), cutaneous T-cell lymphoma (n=9), eczema (n=6), and drug reaction (n=4) (Table S3).
Comorbidities
The available medical history revealed that 31 (62%) patients of Level 1 of Diagnostic Certainty had one or more significant comorbidity; these are detailed in Table 3. The three most common disorders were hypothyroidism (20%), dyslipidemias (18%) and other cutaneous comorbidities (14%).
Treatment History
Ninety-six patients (96%) of the total cohort of 100 indicated that they received either a topical or oral therapy during the course of their disease; 49 (98%) Level 1 patients used some form of therapy (Table 4). The three most commonly reported topical therapies were emollients (90%), corticosteroids (76%) and urea (68%). Among these, emollients (76%), corticosteroids (50%) and salicylic acid (45%) were perceived most helpful by the patients.
Discussion
This study presents epidemiologic, clinicopathologic as well as diagnostic and management challenges in 100 patients with a self-reported diagnosis of PRP. As such, this is the largest reported cohort of patients with PRP. In addition, this is also the first study to provide patient perspectives regarding the diagnostic and treatment course of PRP. The evidence supporting the putative diagnosis of PRP was subsequently reviewed in order to subcategorize the patients to four Levels of Diagnostic Certainty. As such, cases belonging to Levels 1 to 3 represent a spectrum of phenotypes that dermatologists around the world, to the best of their knowledge, are diagnosing and treating as PRP. Interestingly, although Level 4 patients were deemed to have a diagnosis other than PRP, each one of these patients were, at one point, suspected of having PRP. This further demonstrates the diversity and variation in presentations over time and the diagnostic challenge that this entity poses.
The clinical features, forming the basis of the diagnosis of PRP, are varied but well described in the literature. 3,5 Its highly variable clinical presentation indeed raises the question whether PRP is a single disorder or numerous disorders with a common final pathway. While the influences are likely varied, it seems that it is a single disorder with a multitude of factors leading to varied presentations that progress to a more uniform, final appearance of exfoliative erythroderma in most cases. We demonstrated two peaks of onset: one during the first decade of life and a second one in the sixth and seventh decade of life. This has similarities with previously reported peaks of onset of the disease.3,8,10 It also appears that the patients progress to “full bloom” (both clinically and histopathologically) at different rates, which results in variable timing required to obtain the correct diagnosis (e.g., with repeat biopsies and clinical examinations). Further studies aimed at defining the exact timing of the disease progression would be useful to dermatologists to determine the return visit timing in cases with an inconclusive initial diagnosis; this may in turn reduce diagnostic delay and costs associated with this difficult diagnosis.
One of the most striking observations in this study was that only 26% of Level 1 patients were correctly diagnosed at initial presentation. Diagnosis was delayed 29 months, on average, with a wide range. This delay may primarily reflect the fact that at early stages presentation of cutaneous findings can be highly variable. Over time, these signs most often evolve into classic features of PRP, facilitating diagnosis. A similar trend was seen in histopathologic diagnosis: the broad array of findings necessitated numerous follow-up biopsies in the majority of patients to enable establishment of the correct diagnosis. Many times, even follow-up biopsies were inconclusive, necessitating clinicopathologic correlation.
Traditionally, PRP has been suggested to be a self-limiting condition, the symptoms subsiding within a 2–3 year timeframe.8 However, at the time of our study 72% of Level 1 patients had persistent clinical findings which had lasted for 58 months on average with a range up to 300 months. Only 28% of adult plus pediatric patients had entered remission before our study was completed; in these cases, the length of skin manifestations was 84 months (range, 4–516 months), on average. These findings clearly suggest that PRP, while in some cases a readily self-limiting condition, can persist well beyond the anticipated 2–3 years course in other cases.11 In fact, the natural history of this seems to be more variable than previously realized. This has obvious implications when counseling newly diagnosed patients.
Survey of the patients with PRP in our study revealed a number of comorbidities, some of which, such as dyslipidemia, may not differ from the frequency in general population. An increased incidence of hypothyroidism was found in Level 1 PRP patients (20%) versus the general US population (4.6%).12 In this context, several case studies have previously reported hypothyroidism in patients with PRP, and some studies have suggested disappearance of PRP upon correction of the hypothyroid state.13,14 While the pathomechanistic link between thyroid function and cutaneous manifestations in PRP remain unclear, further study of this connection may provide potentially new therapeutic avenues.
Essentially all of the entire cohort (96%), and 98% of Level 1 patients, had been placed on some form of oral or systemic therapy. The patients were queried in this study about their impressions of the helpfulness of specific treatment modalities. While most patients found topical treatment with emollients, corticosteroids and urea to be helpful, it is not clear as to what extent they improved the disease signs and symptoms. Among the systemic therapies, Level 1 patients with definitive PRP found systemic retinoids and methotrexate most helpful, and a limited number of patients, 10 (20%) who received treatment with TNF-α inhibitors, found them helpful. Of note, patients were not asked specifically regarding ustekinumab, although it shows promising utility in familial PRP.15–19 Interestingly, among the 15 patients treated with light therapy, only 1 (8%) found it helpful. It should be noted that this study did not examine the length of systemic treatment or the dosages of the drugs used in detail; nevertheless, none of the topical or systemic treatments lead to uniform improvement in all patients with PRP. The difficulty in treating PRP is also reflected by the number of therapies patients had tried, as listed in the footnote to Table 4.
In summary, PRP remains an extremely challenging disease to diagnose and treat. At the same time, search for biomarkers, such as genetic alterations linked to development and progression of PRP, would be helpful for diagnosis and prognostication in these challenging cases.20
References