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Original Article DOI: 10.1111/ddg.12520 Accepted: 4.9.2014 Conflict of interest None. Early treatment with rutoside and ascorbic
 

Original Article

Submitted: 29.8.2014

DOI: 10.1111/ddg.12520

DOI: 10.1111/ddg.12520

Accepted: 4.9.2014

Conflict of interest None.

Early treatment with rutoside and ascorbic acid is highly effective for progressive pigmented purpuric dermatosis

Sarah M. Schober 1 , Wiebke K. Peitsch 1 , Gisela Bonsmann 2 , Dieter Metze 2 , Kai Thomas 2 , Tobias Goerge 2 , Thomas A. Luger 2 , Stefan W. Schneider 1

(1) Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany (2) Department of Dermatology, University of Münster, Münster, Germany

Summary

Background and Objectives: Progressive pigmented purpuric dermatosis (PPPD, Schamberg disease) is a rare benign, but chronic dermatosis frequently misdiagnosed as vasculitis or bleeding disorder. Although affected patients experience significant impairment in quality of life no effective treatment has been established. The aim of

our two center case series was to evaluate efficacy and tolerability of the antioxidants rutoside and ascorbic acid as combination treatment for PPPD. Patients and Methods: A retrospective review was performed on 35 patients with PPPD treated with 2 × 50 mg rutoside and 1 000 mg ascorbic acid daily between 2004 until 2011. The mean treatment duration was 8.2 months. Results: 71.4 % of the participants experienced complete clearance and 20.0 % an im - provement of more than 50 %, accompanied by increased quality of life. Nine partici - pants (25.1 %) relapsed after discontinuation. In seven, rutoside and ascorbic acid was re-initiated, and all responded again. Only three participants reported mild adverse effects. Participants with shorter disease duration showed better therapeutic success, shorter time to response and lower risk of recurrence. Conclusion: Oral rutoside and ascorbic acid may be an efficient and well tolerated treatment for PPPD. Early treatment is recommended to achieve best clinical outcome.

Introduction

Pigmented purpuric eruptions are chronic and relapsing der- matoses characterized by petechiae, pigmentary macules and red-brown pigmentation typically distributed symmetrically on the lower limbs [1–3]. The most common type is progres- sive pigmented purpuric dermatosis (PPPD), first described in 1901 by Jay Frank Schamberg [3]. PPPD is mostly asym- ptomatic except for mild pruritus [1], but patients are often disturbed by its appearance. Physicians who are unaware of the diagnosis worry about an underlying disease and initiate extensive diagnostics to exclude vasculitis, coagulopathy or

associated hematologic malignancy. A simple clinical test, the Rumpel-Leede test (RLT) demonstrating capillary fragi- lity which is usually positive in patients with PPPD, may be helpful for differential diagnosis [4]. The pathogenesis of PPPD has not yet been fully clari- fied, but according to three different hypotheses, capillary fragility, humoral immunity and cellular immunity may play an essential role [5]. Many potential triggers and amplifica- tion factors have been suggested, including venous hyperten- sion, exercise, focal infections, drugs, contact allergy to clo - thing dyes, and chemicals [1, 6]. Nevertheless, in most cases the etiology is unknown.

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Original Article

Rutoside and ascorbic acid for PPPD

Although many different attempts have been made to treat PPPD, no established treatment exists that has been proven effective in the majority of patients. Since the disease is thought to be due to or aggravated by increased capillary fragility, treatment has been attempted with antioxidants, including the combination of rutoside and ascorbic acid, and there are anecdotic case reports about their efficiency in PPPD [7, 8]. However, there is no formal proof of these findings so far. Therefore, we conducted a retrospective two center study evaluating the efficiency and tolerability of ruto - side and ascorbic acid in 35 patients with PPPD treated with this combination between 2004 and 2011.

Material and methods

Participants

All patients with PPPD who were treated with rutoside and ascorbic acid at the Departments of Dermatology of the University Medical Center Mannheim, Heidelberg Universi- ty, and of the University of Münster, Germany, between 01 August 2004 and 27 February 2011 were included in this retrospective analysis (n = 35, 30 from Münster and 5 from Mannheim). Inclusion criteria were diagnosis of PPPD, either based on clinical findings together with positive RLT on unaffected skin, or based on clinical findings and confirmed by histo - pathology. When the diagnosis of PPPD was unambiguously established by two independent, experienced dermatologists (SWS, WL, GB, TG) based on typical clinical findings and lack of abnormal laboratory parameters, we occasionally ab - stained from histological proof. Other inclusion criteria were treatment with rutoside and ascorbic acid for at least four weeks, and a minimum follow-up of three months. Exclusion criteria were liver, kidney or myeloproliferative disease, vas- culitis, active malignancy (except basal cell carcinoma), he - mophilia, coagulopathies, drug-induced thrombocytopenia, disorders of platelet function or severe infections as possible causes for purpura. At the Department of Dermatology of the University of Münster, patients with PPPD had been screened systematically since August 2004. Out of 59 patients treated with rutoside and ascorbic acid, 30 fulfilled all study criteria and were included in our analysis. In Mannheim, patients with PPPD had been systematically recorded since January 2008. Out of 17 patients treated with rutoside and ascor- bic acid, 5 fulfilled all study criteria and were included. So the total number of 76 patients had to be reduced to 35 due to refusal to participate, insufficient compliance and invalid diagnosis. This study was conducted as an initial study to evalua- te parameters for a planned prospective study. In view of a

new potential treatment of PPPD all patients were evalua- ted by two dermatologists and extensive hematologic testing was performed to exclude other purpura-associated diseases, most importantly platelet function disorders. To identify congenital or acquired bleeding disorders patients were asked about mucocutaneous bleeding, recurrent nosebleeds, me - norrhagia or metrorrhagia (women), postsurgical bleeding and easy bruising and bleeding. In addition an initial labora- tory screening test was performed, including quantification of platelets, prothrombin time, activated partial thrombo - plastin time, and a complete blood count.

Study design

All patients were examined at least two times by one of the authors upon treatment with rutoside and ascorbic acid. Data was collected by retrospective review of patient records, microfilms and photographs and by interviews with the par- ticipants. The following Information was extracted from medical records: sex, age, possible triggers and amplificati- on factors of the PPPD, duration and efficiency of previous treatments, comorbidities, comedication, results of RLT and histological examination, laboratory findings, localization, duration and course of the PPPD, dosage of rutoside and as- corbic acid (standard dose: 50 mg rutoside BID and 1 000 mg ascorbic acid QD), duration, time to response, efficiency and adverse events, concomitant treatments and relapses after discontinuation. Interviews were conducted between March and July 2011 with 33 participants by one of the investigators (SMS). The standardized questionnaire used for the inter- views included 33 questions focusing on disease burden befo - re and after treatment with rutoside and ascorbic acid, course after discontinuation, and satisfaction with treatment. Treat- ment satisfaction was assessed on a five-point scale, compri- sing the categories “very satisfied”, “rather satisfied”, “unde - cided”, “rather dissatisfied” and “very dissatisfied”. Standard treatment consisted of 2 × 50 mg rutoside and 1 000 mg ascorbic acid per day. Four patients (including 3 children) received only 50 mg rutoside per day, two parti- cipants only 500 mg ascorbic acid daily. In six participants (17.1 %) the dosage of rutoside was increased to 150 mg daily, in one participant to a mean dosage of 163 mg rutoside per day. Treatment outcome was classified into four levels. Level 1 was defined as complete clearance of the skin lesions, indicating restitutio ad integrum. Level 2 reflected impro - vement of more than 50 %, i.e., clearance of more than 50 % of the lesions documented before initiation of treatment. Level 3 corresponded to improvement of less than 50 % (defined as clearance of less than 50 % of the initial lesions) and level 4 indicated lack of response. In addition professio - nal skin images of affected skin areas were analyzed by two

© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1212

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independent dermatologists (pre- and post-treatment). To avoid overestimation of the therapeutic efficacy, only level 1 and level 2 responses were used to calculate the response rate. Reduction of itch, improvement of cosmetic appearance, adverse effects and treatment costs were assumed to be the main determinants of the reported patient satisfaction. Study procedures were approved by the Ethic Committee of the Medical Faculty Mannheim, University of Heidelberg and performed in accordance with the Declaration of Helsin- ki. Written informed consent was obtained from each adult patient and from both parents (and legal guardians) of child- ren < 18 years of age before study enrolment. This study can be considered a pilot study with retros- pective design to identify important parameters for the inten- ded prospective study. Therefore it does not include a control group.

Statistical analysis

Statistical analysis was performed in cooperation with the Department of Medical Statistics, Biomathematics and In- formation Processing of the Medical Faculty Mannheim, Heidelberg University, using SAS ® software version 9.2. Mann-Whitney U tests or Kruskal-Wallis tests were used to compare continuous variables. The Fisher exact test was applied for comparison of categorical variables. Correlation between disease duration and time to response was assessed with the Pearson product-moment correlation coefficient. Psychological strain of the participants before and after treat- ment was compared based on the Cohen’s kappa coefficient.

Results

Patient characteristics

Among the 35 participants included in this study 45.7 % were male (Table 1). The median age was 43.2 years, the mean di- sease duration 23.9 months. In 22 participants (62.9 %) diag - nosis of PPPD was confirmed by histology. In five children we did not take a biopsy but the diagnosis was confirmed by two independent dermatologists as it was in eight adult patients. Conducting a subanalysis only with those patients having a histological proven PPPD (n = 22) we showed that the study outcome and the benefits of rutoside and ascorbic acid were almost equally high (86 % of patients experienced complete clearance or improvement of more than 50 %). In the majo - rity (61.8 %) the etiology of the PPPD was unknown. The course was most frequently progressive (56.3 %), followed by relapsing-remitting (28.1 %). 31.3 % of the participants had previously been treated with topical and 9.4 % with systemic steroids (Table 1). However, in two-thirds (65.0 %) of the

Table 1 Socio-demographic and clinical characteristics of the study cohort (n = 35)

Characteristics

n (%)

 

Sex

Male

16 (45.7)

Female

19 (54.3)

 

Age, y

Mean (range)

43.2 (8–85)

Disease duration, mo

 

Mean (range)

23.9 (2–103)

Amplification factors

 

Heat

12 (38.7)

Long standing

3 (9.7)

Alcohol

1 (3.2)

None

20 (64.5)

No. missing

4

Localization

 

Lower legs

32 (91.4)

Thighs

22 (62.9)

Feet

17 (48.6)

Arms

15 (42.9)

Generalized

11 (31.4)

Other location*

5 (14.3)

 

Course

Progressive

18 (56.3)

Relapsing-remitting

9 (28.1)

Chronic persistent

5 (15.6)

No. missing

3

Previous treatments

 

Topical corticosteroids

10 (31.3)

Systemic corticosteroids

3 (9.4)

Compression therapy

2 (6.3)

Hirudin

1 (3.1)

Dimethindene

1 (3.1)

Basic skin care

6 (18.8)

None

26 (71.9)

No. missing

3

Effect of previous treatments

 

Improvement

7 (35.0)

Ineffective

13 (65.0)

No. missing

15

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Rutoside and ascorbic acid for PPPD

 

Table 1

Continued.

Characteristics

n (%)

Duration of previous treatment, wk

 

Mean (range)

13.3 (1–156)

No. missing

19

Comorbidities

 

Chronic venous insufficiency

6 (14.3)

Deep vein thrombosis

3 (8.6)

*Other locations included gluteal, inguinal, genital or axillary petechiae. Abbr.: No, number; mo, months; wk, weeks; y, years

 

patients these treatments had been ineffective. None had been treated with ascorbic acid and rutoside (flavonoids) before. In 34.3 % rutoside and ascorbic acid were prescribed in combination with other treatments, most frequently, in com- bination with topical steroids (14.7 %) or with compression therapy (17.7 %). Participants without concomitant treatment experienced significantly shorter disease duration than parti- cipants with concomitant treatment (17.6 vs. 40.2 months).

High efficiency and good tolerability of rutoside and ascorbic acid for treatment of PPPD

71.4 % of the participants treated with rutoside and ascorbic acid experienced complete resolution of all lesions and 20 % achieved improvement of more than 50 % (Figure 1a). One participant (2.9 %) had an improvement of less than 50 % and only two participants (5.7 %) did not respond to the treatment (Figure 1a). Worsening of purpura was not observed in any participant. When participants receiving the standardized do - sage of 2 × 50 mg rutoside and 1 000 mg ascorbic acid without any concomitant therapy were analyzed separately (n = 14), treatment efficiency was equally high. 71.4 % (n = 10) of this subpopulation experienced complete clearance and 21.4 % (n = 3) improvement of more than 50 % (Figure 1b, 2). A different subanalysis only among patients with histo - logically proven PPPD (n = 22) showed similar results. 15 pa- tients (68.1 %) experienced complete clearance, four (18.1 %) improvement of more than 50 %, one (4–5 %) improvement of less than 50 % and two (9 %) showed no response at all to rutoside and ascorbic acid. Analysis of a dose-response relationship showed no sta- tistically significant associations between the dosage of either rutoside or ascorbic acid and the therapeutic outcome (p = 0.798 or p = 1.0). Among the participants in whom RLT was performed (n = 23), the vast majority (95.7 %) had a positive test re -

Original Article Rutoside and ascorbic acid for PPPD Table 1 Continued. Characteristics n (%) Duration of

Figure 1 Efficiency of rutoside and ascorbic acid. Among all study participants 71.4 % experienced complete clearance of all skin lesions, 20 % an improvement of more than 50 % and 2.9 % an improvement of less than 50 %. Only 5.7 % did not benefit at all (a). If only participants receiving the standardized daily dosage of 2 × 50 mg rutoside and 1 000 mg ascorbic acid without any concomitant therapy were considered (n = 14), treatment outcome was equally successful: 71.4 % achieved complete cure and 21.4 % improvement of more than 50 % (b). Results of Rumpel-Leede tests before and after treatment (c).

sult before starting the treatment (Figure 1c). After treatment the test was positive in less than half (43.8 %) (Figure 1c). However, these differences were not statistically significant, possibly due to the small sample size (p = 0.2171).

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Original Article Rutoside and ascorbic acid for PPPD Figure 2 Example of a patient successfully treated

Figure 2 Example of a patient successfully treated with rutoside 50 mg twice daily and ascorbic acid 1 000 mg/day. Before initiating therapy the patient had suffered from PPPD on both thighs, lower legs and feet for four months, pictures taken on 31 st of August 2004 (a–b). After four weeks of treatment with rutoside and ascorbic acid the lesions had completely resolved; only mild post-inflammatory hyperpigmentation can be spotted, pictures from 4 th of October 2004 (c–d).

The mean time to response to rutoside and ascorbic acid was 7.9 weeks, the mean treatment duration 8.2 months. Af- ter discontinuation of the therapy, nine participants (25.1 %) had a relapse. Out of this group six relapsed within two months. The maximum disease free interval of the other three participants was six months. Seven were restarted on rutoside and ascorbic acid and all responded again. In eleven participants (31.4 %) the treatment is still being continued. Generally treatment with rutoside and ascorbic acid was well tolerated. Only three participants (8.6 %) experienced mild to moderate adverse effects presenting as palpitations, dizziness and abdominal pain. No severe adverse events were recorded. High efficiency and good tolerability of rutoside and as- corbic acid were mirrored by high rates of patient-reported treatment satisfaction: 59.4 % of the participants identified themselves as very satisfied and 9.4 % as rather satisfied, whereas only 15.6 % were undecided, 9.4 % “rather dissatis- fied” and 6.3 % “very dissatisfied”.

Shorter disease duration is associated with better treatment outcome

Shorter duration of PPPD was significantly associated with better therapeutic success (p = 0.0025) (Figure 3a). Mean disease duration (first appearance of PPPD until clearan - ce) of participants who were completely cured was 12.6 months, whereas the three participants with improvement of less than 50 % or no response had a mean disease dura - tion of 74.7 months. Furthermore there was a linear cor - relation between duration of PPPD and time to respon - se to rutoside and ascorbic acid, with faster response in participants with shorter disease duration (r = 0.59955) (Figure 3b). Patients with longer disease duration were si - gnificantly more likely to suffer a relapse after discontinua- tion of rutoside and ascorbic acid (p = 0.0069) (Figure 3c). Mean disease duration of participants with recurrence was 35.4 months, that of participants without recurrence 14.2 months.

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Rutoside and ascorbic acid for PPPD

Original Article Rutoside and ascorbic acid for PPPD Figure 3 Impact of disease duration on treatment

Figure 3 Impact of disease duration on treatment outcome. Shorter disease duration was associated with more favorable outcome. Patients with shorter disease duration experienced a higher probability of cure (71.4 %) or of improvement of more than 50 % (20.0 %, p = 0.0025) (a). Time until onset of a therapeutic effect was shorter in patients with shorter disease duration (r = 0.59955) (b). Moreover, patients with shorter disease duration had a lower risk of recurrence (p = 0.0069) (c). Abbr.: Q1, lower quartile; Q3, upper quartile; Imp., impro - vement.

Discussion

In this retrospective two center case series we show that the combination of rutoside and ascorbic acid is an efficient

and well tolerated treatment for PPPD. So far no treatment has been identified that is effective in the majority of PPPD patients. Topical corticosteroids are used most frequently. While they have vasoconstrictive, permeability-reducing and antipruritic effects [1, 9], reports on their effectiveness are contradictory [1, 6, 10, 11], and their long-term use may even worsen the course of PPPD by evoking skin atrophy and increased vascular fragility [9]. Systemic corticosteroids are associated with considerable systemic side effects and high rates of recurrence after tapering [1, 4, 5]. Another treatment option is pentoxifylline, but observations regarding its effec - tiveness are conflicting [12–14]. Phototherapy with psoralens plus ultraviolet A light (PUVA) or with narrowband UVB are considered as therapeutic alternatives for extensive PPPD [15–18]. Furthermore, there are case reports on treatment of PPPD with topical pimecrolimus [19], calcium dobesila- te [20], aminaphtone [21], griseofulvin [22], colchicine [23], photodynamic therapy [24] and vascular laser [25], as well as with immunosuppressants including cyclosporine [26] and methotrexate [27]. Treatment with oral bioflavonoids (rutoside 50 mg BID and ascorbic acid 500 mg BID) in three females with PPPD was first reported by Reinhold et al [8]. All three patients responded within one week and cleared comple - tely within four weeks of treatment. During a follow-up of three months, no recurrence was noted [8]. Furthermo - re, Laufer described the successful treatment of a 42-year- old male with eczematid-like purpura receiving the same regimen [7]. Bioflavonoids and ascorbic acid are potent antioxidative radical scavengers. They reduce capillary permeability and fragility by decreasing reactive oxygen species, which play a major role in vascular inflammation and edema [8, 28–32]. Moreover, it was recently shown that bioflavonoids control SOCS3 (suppressor of cytokine signalling 3) gene expressi- on and suppress STAT3 (signal transducer and activator of transcription 3) signalling in endothelial cells. Both effects attenuate vascular inflammation and support endothelial cell integrity [33]. Due to these effects, bioflavonoids are successfully used for treatment of venous insufficiency [8, 34]. Ascorbic acid is also essential for collagen synthesis, a substantial element of the basal lamina and the connective tissue of capillaries [35, 36]. Due to the therapeutic efficacy of rutoside and ascorbic acid, and the absence of mucosal bleeding, as well as normal platelet numbers and function, one could speculate that the petechiae in PPPD arise from a disorder of the extracellular matrix or the vessel wall (i.e. the basement membrane of endothelial cells) [37]. However, further studies are needed to understand the pathomecha- nism of PPPD. A limitation of our study is its retrospective nature. In - formation obtained in interviews might have been influenced

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by recall bias. Dosage of rutoside and ascorbic acid was not fully standardized, and some participants obtained additi - onal treatments. However, separate analysis of participants receiving rutoside and ascorbic acid at the standard dosage without concomitant treatment showed equally high res - ponse rates as in the whole sample. Moreover, the durati - on of the treatment was not standardized, and we cannot exclude the possibility that some of the study participants would have experienced spontaneous remission during treatment with rutoside and ascorbic acid. Spontaneous remission has been reported to occur rather frequently in patients with PPPD. In a large study by Ratnam et al. up to 67 % of patients experienced improvement or clearing of their lesions, most of them without any treatment. Howe - ver, spontaneous remission occurred only late in the course of the disease (after a mean disease duration of more than six years) [38]. The mean disease duration of our cohort treated with rutoside and ascorbic acid was substantial - ly shorter (23.9 months). Another limitation of our pilot study is the lack of a control group. Clearly, double-blind, randomized, placebo-controlled trials on larger patient cohorts are required to confirm efficiency of rutoside and ascorbic acid in PPPD. Nevertheless, our study is the first to systematical - ly investigate this promising treatment for PPPD taking into account other bleeding disorders, i. e. platelet dys - function. Our results confirm case reports indicating that the combination of rutoside and ascorbic acid is highly effective in the treatment of PPPD. After experiencing a relapse all seven participants who re-initiated rutoside and ascorbic acid responded again. This observation un - derscores that therapeutic success was indeed attributable to rutoside and ascorbic acid. Our finding that treatment outcome was especially favorable in patients with short disease duration implies that rutoside and ascorbic acid should be administered as early as possible in the course of PPPD. To the best of our knowledge there is no established re - gimen to treat of PPPD. Since rutoside and ascorbic acid are not associated with any potentially severe adverse effects and since response rates to this combination observed here were extraordinary high (> 90 %), our study opens a promising perspective for a novel first-line treatment of a so far extre - mely refractory condition.

Financial support

This work was supported by grants from the Deutsche For- schungsgemeinschaft (SFB/TR23 subprojects A9 to S.W. Schneider) and DFG “SHENC” (SCHN 474/5-1 to S.W. Schneider) and GO 1360/4-1 to Tobias Goerge.

Original Article Rutoside and ascorbic acid for PPPD by recall bias. Dosage of rutoside and ascorbic

Correspondence to

Prof. Dr. med. Stefan W. Schneider Department of Dermatology University Medical Center Mannheim Heidelberg University Theodor-Kutzer-Ufer 1-3 68167 Mannheim, Germany E-mail: stefen.schneider@medma.uni-heidelberg.de

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