SYSTEMATIC REVIEW - Philippine Dermatological …plaque psoriasis ranged from 39 to 100% compared to...

SYSTEMATIC REVIEW

Combination therapy versus monotherapy for moderate to severe chronic plaque psoriasis in adults

Maria Elinor Grace Q. Sison, MDa; Francesca Mari P. Sumilang, MDa; Ma. Lorna F. Frez, MD, FPDSb

Background: Combination therapy for moderate to severe chronic plaque psoriasis may be indicated for patients resistant to monotherapy with first line agents such as topical therapy.

Objectives: This review was conducted to assess the efficacy and safety of combination therapies versus monotherapy as treatment for moderate to severe psoriasis.

Methods: Electronic search of of MEDLINE, Cochrane Skin Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, and HERDIN, from 1991 to 2015 was conducted. Search terms used were: “combination treatment” OR “combination therapy” AND “moderate to severe psoriasis”. We also searched trials databases, hand searched journals, cross-references, scanned reference lists and contacted authors.

Randomized controlled studies with head-to-head comparisons of combination therapy with monotherapy for moderate to severe chronic plaque psoriasis were included. Primary outcomes were improvement or clearance of psoriasis as measured by Psoriasis Activity and Severity Index (PASI) scores, PASI 75, PASI 90, achievement of Physician Global Assessment of clear or almost clear, and change in Dermatology Life Quality Index scores. Secondary outcomes were reported adverse events. Treatment effect measured was mean difference between scores of combination therapy and monotherapy?

Results: Six randomized controlled trials which compared etanercept + methotrexate, PUVA + isotretinoin, acitretin + etanercept, clobetasol propionate + etanercept, NBUVB + alefacept, and cyclosporine A + calcipotriol/betamethasone dipropionate ointment favored combination therapy over monotherapy for mean change in PASI with I2 of 75% for a total of 1,308 participants in 6 studies. The combination of narrowband UVB to other therapies comprised majority of the studies (8 out of 17). Etanercept combined with other therapies (3 studies) also showed significant results in achieving PASI 75. These studies are the following: Gottlieb 2012 (ETN + methotrexate, PASI 75 77.3% at week 24 (No mean, SD and CI mentioned), p value <0.001), Lebwohl 2013 (ETN + clobetasol propionate, PASI 75 65.2% at week 12 (No mean, SD and CI mentioned), p value <0.001), Gisondi 2008 (ETN + acitretin, PASI 75 45% (no CI mentioned) at week 24, p value 0.001). The adverse events were mild to moderate, and the incidence of serious adverse events was low and comparable in the treatment groups.

Conclusion: Combination therapy using etanercept + methotrexate, PUVA + isotretinoin, acitretin + etanercept, clobetasol propionate + etanercept, NBUVB + alefacept, and cyclosporine A + calcipotriol/betamethasone dipropionate ointment can be explored in treating patients with moderate to severe psoriasis who are frustrated with their current therapies because they were found to be more effective than monotherapy. Treatment should still be individualized for each patient.

Keywords: combination treatment, combination therapy, moderate to severe psoriasis

INTRODUCTION

Psoriasis is a chronic, immune-mediated disorder resulting from genetic predisposition combined with environmental triggers such as trauma, infections or

medications. The most common form is characterized by multiple, sharply demarcated, erythematous plaques with micaceous scales, which may be localized or widespread in distribution. This is due to abnormal keratinocyte proliferation

and infiltration of inflammatory cells in the dermis and epidermis.1 Psoriasis continues to burden about 0.1-11.8% of the worldwide population. In the Section of Dermatology at the Philippine General Hospital, psoriasis constituted about 4.3% of total consults last 2013 and 5.4% in 2014. It is consistently at the top ten dermatoses in the Philippine General Hospital Outpatient Department for the last three years.2 Psoriasis is also an economic burden, costing as much as 135 billion dollars per year in the United States alone.3 In the Philippines, however, there is still no data on the health care expenditures of psoriasis patients. Psoriasis can also lead to stigmatization, social isolation, and can adversely affect the quality of life.

First line treatment modalities for chronic plaque psoriasis include topical treatments such as topical corticosteroids, vitamin D analogues, tar-based preparations, salicylic acid, and topical retinoids. Systemic treatments such as methotrexate, acitretin, cyclosporine, and phototherapy are used when

Section of Dermatology, Department of Medicine, University of the Philippines - Philippine General Hospitala Resident b Consultant

Source of funding: noneConflict of interest: none Corresponding author: Maria Elinor Grace Q. Sison, MDEmail: [email protected]

36 J Phil Dermatol Soc • May 2017 • ISSN: 2094-201X

patients do not respond to topical treatments anymore.1 Psoriasis patients remain frustrated with their therapy

despite the number of treatment options available. Control of the disease can be difficult to achieve, and therapy must always be tailored for each patient. Treatment must be efficacious as well as safe because therapy for psoriasis is lifelong. Effective systemic regimens often have the most adverse events.4

Rationale for the use of combination therapyThe use of combination therapy in psoriasis can be

explored in patients who are nonresponsive to monotherapies. Combination therapy is helpful when the treatment regimens have different mechanisms of action leading to either additive or synergistic effects. Other factors to consider in switching to combination therapy include “fewer projected side effects, improved therapeutic outcome, improved patient adherence, and increased possibility of tailoring therapy to individual needs”.4

Clearance rates of combination therapies for chronic plaque psoriasis ranged from 39 to 100% compared to 2% to 86% in monotherapies in a systematic review done by Al-Suwadan et al in 2000. Thus there is evidence that combination therapies are more efficacious than monotherapies for psoriasis.4 However, one limitation of this systematic review on combination therapy for chronic plaque psoriasis only reported percentage of patients who are cleared and did not specify if the results were statistically significant or not.

Significance of the systematic reviewNumerous systematic reviews and meta-analyses

have been done using head-to-head comparisons of topical therapies but studies comparing combination therapies versus monotherapy for moderate to severe chronic plaque psoriasis are only very few. The previous systematic reviews on the combination therapy for chronic plaque psoriasis only reported percentage of patients who are cleared and did not specify if the results were statistically significant or not. Hence, there is a need for a systematic review to compare the efficacy as well as safety of combination therapies for psoriasis as more health care professionals utilize this strategy in order to achieve better remission.

OBJECTIVES OF THE SYSTEMATIC REVIEW

General objective:To assess the efficacy and safety of combination therapies

compared with monotherapy as treatment for adults with chronic plaque psoriasis.

Specific objectives:To compare the change in Psoriasis Activity and Severity

Index (PASI) scores from baseline between combination therapy versus monotherapy.

To compare the change in the quality of life scores of patients on combination therapy versus monotherapy.

To determine serious adverse effects reported by patients using combination therapy versus monotherapy.

Research questionIn adult patients with moderate to severe chronic plaque

psoriasis, which combination therapy/therapies can lead to better improvement of psoriasis as compared to monotherapy?

METHODOLOGY

Inclusion Criteria

Types of studiesRandomized controlled trials published from January

1991 until October 2015 that are head-to-head comparisons of combination therapy with monotherapy were included in the systematic review. Studies must have included monotherapy or a combination of placebo plus another therapy as control. Only published studies were included.

Types of participantsOnly studies with adults diagnosed with moderate to

severe chronic plaque psoriasis were included. Studies with elderly, pediatric, or pregnant patients were not included. Study participants should have at least a PASI score of 10 and involvement of the body surface area of at least 10%. We excluded studies if the participants had other types of psoriasis (such as scalp psoriasis, inverse psoriasis, erythrodermic psoriasis, pustular psoriasis, guttate psoriasis, and nail psoriasis).

Types of interventionsRandomized controlled trials using combination therapy

versus monotherapy (systemic monotherapy or topical monotherapy) for treatment of chronic plaque psoriasis among adult patients were included in the systematic review. We excluded if combination therapy is composed of both topical agents, or if they used sequential or rotational therapies.

Types of outcome measuresPrimary outcomes were improvement or clearance of

psoriasis as measured by changes in PASI scores from baseline, reduction in PASI score of 75% or higher from the baseline (PASI 75), reduction in PASI score of 90% or higher from the baseline (PASI 90), achievement of Physician Global Assessment (PGA) of clear or almost clear, and change in Dermatology Life Quality Index (DLQI) scores from the baseline. Secondary outcomes were reported adverse events during the study. We excluded studies if withdrawal or adverse events data could not be obtained from the authors or from the sponsors

SearchesThe following electronic databases were searched:

MEDLINE, Cochrane Skin Group Specialized Register, CENTRAL, EMBASE, and HERDIN. Search terms used were: “combination treatment” OR “combination therapy” AND “moderate to severe psoriasis”. Trials databases such as MetaRegister of Controlled Trials, US NIH Ongoing Trials Register, Australian New Zealand Clinical Trials Registry, WHO International Clinical Trials Registry Platform, EU Clinical Trials Register,

J Phil Dermatol Soc • May 2017 • ISSN: 2094-201X 37

and Philippine Health Research Registry were also searched. We also hand searched the Journal of American Academy of Dermatology, Journal of Drugs in Dermatology, and British Journal of Dermatology from January 1991 to October 2015. Reference list of included studies in the systematic review were scanned to identify additional reports.

Selection of studies

Data extraction The primary author extracted the study data and assessed

the risk of bias for randomization, allocation concealment, blinding of participants, blinding of outcome personnel, incomplete outcome data, and selective reporting using the Cochrane Collaboration risk of bias tool. Biases that were assessed were the following: selection bias, performance bias, detection bias, attrition bias, and reporting bias. High risk studies are defined as studies with at least 3 domains that were high risk from the Cochrane Collaboration risk of bias tool. Intermediate risk studies are studies with at least 3 domains that are unclear while low risk studies are those with at least 3 domains that were assessed as low risk using the Cochrane Collaboration risk of bias tool. The second co-author checked the extracted data and risk of bias judgments. Any disagreement was resolved by consensus or by consulting a third co-author.

Data were organized using Review Manager (RevMan) version 5.3. Meta analysis was planned but could not be done due to heterogeneity of intervention, outcome measures, and treatment duration among included studies.

RESULTS AND DISCUSSION

Results of searchThe initial search identified 50 references that investigated

combination therapy for moderate to severe psoriasis and upon reading the full reports and applying the eligibility criteria, 17 studies were included. (Figure 1). Titles and abstracts were scanned to get a shorter list of potentially relevant studies, after which the full reports were retrieved for potentially relevant studies.

Figure 2. Risk of bias summary of all included studies.

50 records identified through database searching↓

25 full-text articles excluded, after duplicates were removed

↓8 articles excluded with reasons (2 studies were not RCTs, 1

study compared topical combination therapy with another topical therapy, 1 study compared topical combination therapy with either agent alone, and 1 study compared topical combination therapy with another topical therapy, 2 studies used combination therapy

as control, and 1 study is a single arm study)↓

17 studies included in qualitative synthesis

Figure 1. Search and selection process for randomized clinical trials on combination therapy for psoriasis

Risk of bias of the Included StudiesAssessment of the risk of bias of the individual studies

resulted in low risk for 4 trials, intermediate risk for 9 trials, and high risk for 4 trials (Figure 2). The following studies were assessed to have low risk since at least 3 domains have low risk (Calzavara-Pinton 2013, Gisondi 2008, Gottlieb 2012, Lynde 2012). Four studies were assessed to be of high risk since they had at least 3 domains to have high risk (Bagel 2011, Behrens 2000, Giannetti 2009 and Legat 2007). The rest of studies were assessed to be of intermediate risk since at least 3 domains have intermediate risk. The most common reasons for high risk of bias were unclear allocation concealment, inadequate or non-blinding of outcome assessment, and selective reporting.


Characteristics of included studiesThe characteristics of included studies are shown in

Tables 1, 2 and 3.

Study designThe setting was mainly dermatology outpatient clinics,

in 10 countries. Only three studies were multicenter (Gottlieb 2012; Lebwohl 2013; Papp 2015). The rest were single center trials with sample size ranging from 10 to 322 patients (median 38 participants). Length of follow-up ranged from 4 to 24 weeks (median 12 weeks).

ParticipantsA total of 2,399 participants with moderate to severe

chronic plaque psoriasis, ages 18 and above comprised the study population of all included studies with a male to female ratio of 1.7:1 and age range of 18 to 84 years.

InterventionsThe included studies were grouped into four categories:

1) combination of Narrowband UVB with other treatments (8 studies), 2) combination of etanercept with traditional systemic agents (5 studies), 3) combination therapy with retinoids (5 studies) and 4) combination therapy with cyclosporine (2 studies).

OutcomesNine studies assessed the mean change in PASI score from

the baseline (5, 6, 7, 8, 9, 10, 11, 12, 13). Eleven trials assessed the proportion of patients who attained PASI 75 (5, 6, 10, 11, 14, 15, 16, 17, 18, 19, 20). Three trials assessed the proportion of patients who attained PASI 90 or higher (15, 16, 21). Five studies assessed the proportion of patients who attained a PGA of clear or almost clear (13, 14, 16, 19, 20). Two studies assessed the mean change in DLQI (6, 19) .

Effects of Interventions

Combination therapy with Narrowband UVB phototherapy versus monotherapy

The study of Calzavara-Pinton (5) had a lower PASI score in favor of the treatment group NBUVB + etanercept (2.4 + 2.8 mean, SD?) (-13.80 [-20.46, -7.14]. mean difference and CI?) (p value < 0.05, Student’s t-test) compared with NBUVB alone. In the study of Behrens (7), the authors found out that after 4 weeks, the median PASI reduction was 64% (no interquartile range mentioned) with the NBUVB + topical tazarotene while narrow-band UVB alone was 48% (no IQR mentioned). Median (IQR?) PASI score after 4 weeks had decreased to 6.5 (95% CI, 5.29-7.91) for the body half assigned to UVB (311 nm) plus tazarotene compared to 9.5 (95% CI, 7.70-11.70) for the body half assigned to UVB monotherapy (p value <0.05; stat test not mentioned). In another trial by Grundmann-Kollmann (9) combining NBUVB and cream PUVA versus NBUVB alone or cream PUVA alone, authors found out that all 10 patients cleared completely after 3 to 4 weeks (no mean and SD

mentioned for PASI score, p value <0.001, t test). In the trial conducted by Zane et al (11), the combination of NBUVB and efaluzimab during the After 12 weeks, the PASI score was 5.64 + 2.52, and after 24 weeks it was 3.36 + 3.49 and the differences were both statistically significant (p value < 0.05) compared with efalizumab alone. For the combination of NBUVB and alefacept by Legat 2007 (17), PASI 75 after week 12 had been achieved significantly more on the combination of NBUVB + alefacept compared with alefacept alone (mean and SD not mentioned, p value 0.03, McNemar test). Results were not statistically significant (all p values > 0.05) for the combinations of etanercept + NBUVB (5, 19, 20), and NBUVB + efalizumab (10). The combinations of NBUVB + etanercept versus NBUVB alone (5, 19, 20) showed that there was also no significant difference (p values > 0.05) in the proportion of patients who reached PASI 90. No statistically significant differences in PGA of ‘clear or almost clear’ were found in the combination of NBUVB + etanercept (19, 20) (p values > 0.05). The trial by Lynde et al (19) on the combination of NBUVB + etanercept versus etanercept alone also did not find statistically significant differences between treatment groups from weeks 12 to 24 for mean change in DLQI.

No serious adverse events were noted in the combination of efalizumab + NBUVB (11). All studies on the combination of NBUVB and etanercept (5, 19, 20) reported injection site reaction, erythema, burning, and withdrawal due to worsening of psoriatic arthritis (one participant). These were not considered as adverse events by the authors. Studies on the combination of NBUVB with other treatments had adverse events that were few and well-tolerated by study participants.

Combination therapy with Etanercept with traditional systemic agents

The study of Gottlieb et al (14) found statistically significant difference (p value <0.0001, van Elteren stratified rank test) favoring the combination of etanercept and methotrexate versus etanercept plus placebo and that 77.4% of patients in the combination group attained a PASI 75 compared with 60.3% in the etanercept plus placebo group. The combination of acitretin and etanercept in the trial of Gisondi et al (15) showed that PASI 75 was achieved by 45% of participants in the etanercept group, 30% in the acitretin group and 44% of patients treated with etanercept plus acitretin at the end of 24 weeks (p value 0.001, one way ANOVA). On the other hand, results were not statistically significant (all results with p value >0.05) for the combination of etanercept + topical steroid by Papp 2015 (13).

The study of Lebwohl et al (16) using the combination of clobetasol proprionate and etanercept showed that 65.2% of patients were able to achieve PASI 75 as compared to 48.3% in etanercept monotherapy at the end of 12 weeks (p value <0.001, stratified Cochran-Mantel-Haenszel test). However, results between treatment arms were not significant at the end of 24 weeks.

For PASI 90 the study conducted by Gottlieb et al (14)


found a statistically significant difference, with 53.8% of patients in the etanercept plus methotrexate group attaining a PASI 90 compared with 34.2% of patients in the etanercept plus placebo group at the end of 12 weeks (p value 0.001, Cochran-Mantel-Haenszel test). In the trial conducted by Lebwohl et al (16) using the combination of clobetasol proprionate and etanercept, results showed that 29.7% of patients were able to achieve PASI 90 as compared to 19.4% in etanercept monotherapy at the end of 12 weeks (p value <0.009 stratified Cochran-Mantel-Haenszel test).

For PGA of clear or almost clear, Gottlieb et al (14) found that 72.0% in the etanercept plus methotrexate group attained a PGA of clear or almost clear compared with 54.4% ( p value = 0.01, Cochran-Mantel-Haenszel test) in the etanercept plus

placebo group at week 24. The trial by Lebwohl and colleagues (16) also reported a statistically significant result wherein 63% of patients in the clobetasol + etanercept group attained a PGA of clear/almost clear compared with 47% in the etanercept monotherapy (p value <0.001 stratified Cochran-Mantel-Haenszel test) at the end of 12 weeks, but these were not significant at week 24 (p value >0.05). No statistically significant differences were found in the combination of etanercept + topical steroid (p value > 0.05) (13).

For the combination of etanercept with NBUVB, acitretin, methotrexate, and clobetasol proprionate, there were no significant alterations in the mean value of AST, ALT, cholesterol and triglycerides in any of the treatment arms (in these 4 studies p value > 0.05 )(15). Four patients of the acitretin group

Table 1. Characteristics of included studies (combination of NBUVB with other treatments).

Behrens et al, 2000

Calzavara-Pinton et al, 2013

Grundmann-Kollmann et al, 2004

Legat et al, 2007

Lynde et al, 2012

Park et al, 2013

Zane et al, 2009

AUTHOR INTERVENTIONSTUDY DESIGN

Open-label

Open-label

RCT, open-label

Randomized

half-body comparisonstudy

RCT, investigator-masked

RCT, open-label, study

Randomizedintrapatient comparison study

NUMBER OF

PATIENTS

10

322

30

14

75

30

10

DURATION OF TRIAL

4 weeks

20 weeks

10 weeks

12 weeks

12 weeks

12

24 weeks

NBUVB once a day 5 times a week with an intensity of 15.3mW/cm2 +Topical tazarotene 0.05% once daily for 4 weeks

NBUVB 0.1 to 0.4 J/cm2 three times a week + etanercept (ETN) 50mg SC twice weekly for 20 weeks

NBUVB 0.1 to 0.3 J/cm2 four times per week+ cream PUVA 0.001% applied 4 times a week for 10 weeks NBUVB 3 times per week at 50% of the patient’s individual minimal erythema dose +

Alefacept 7.5mg IV bolus for 12 weeks

NBUVB 3 times a week (no dose specified) +Etanercept 50mg twice a week for the first 12 weeks

NBUVB 3 times a week (130-400mJ/cm2 depending on Fitzpatrick skin phototype) +Etanercept 50mg twice a week until week 12 then 50mg once a week NBUVB 0.1 to 0.4 J/cm2 3 times a week for 4 weeks +Efalizumab 0.7mg/kg body weight SC, followed by once weekly injections of 1mg/kg for 24 weeks

CONTROL GROUP

NBUVB alone

NBUVB alone

NBUVB alone

cream PUVA alone

Alefacept alone

Etanercept alone

Etanercept alone

Efalizumab alone

OUTCOMES

reduction in PASI score from the baseline

Psoriasis Severity Index (PSI); side effects

PASI score, number of treat ments, mean cumulativeUVA and UVB doses

reduction in PASI score from the baseline

adverse events

PASI 75, PASI 90, PGA of clear or almost clear,Withdrawal due to lack of efficacy,mean change in DLQI, serious adverse events

PASI 75, PASI 90, PGA of clear or almost clear,mean change in PASI

reduction in PASI score from the baseline, PASI 75adverse events

RISK OF BIAS

High

Low

Unclear

High

Low

Unclear

Unclear

REASONS

Open-label

Open-label

Open-label

Participants not blinded; unclear if investigators were blinded or not

Open label

Open-label

No mention of blinding of participants or investigators


in the study of Gisondi et al (15) withdrew due to inefficacy of the treatment, whereas no patients withdrew in the two other groups (acitretin + etanercept and etanercept alone). The most commonly reported adverse event in the etanercept + topical steroid combination were nasopharyngitis (n = 44; 14.2%), injection site reaction (n = 33; 10.6%) and headache (n = 28; 9.0%) (15). These were not considered as serious adverse events by the authors.

Combination of traditional systemic agents with retinoids

The combination of PUVA and isotretinoin in the study of Gahalaut et al (6) also had statistically significant results in terms of PASI score at the end of 12 weeks favoring the treatment group (6.6 (mean) + 6.5 (SD) with p value of 0.03 compared with PUVA alone (12.02 (mean) + 4.46 (SD). For PASI 75, 63.15% of patients achieved PASI 75 as compared to 12.5% of patients in PUVA alone (p value 0.002, t test). They also reported a statistically significant change in DLQI in the domains of leisure (p value= 0.001, t test) and personal relationships (p value= 0.04, t test). In the study done by Giannetti (8) using

the combination of oral etretinate and calcipotriol versus oral etretinate alone, they found out that after 9 weeks, reductions were 81.4% and 70.3% (3.8 (mean) +0.6 (SD) [CI -3.19, -2.61], p value < 0.001, ANOVA), which was statistically significant. The study of Tanew et al (12) on actitretin + PUVA showed that 96% of patients were able to achieve PASI 90 at 11 weeks but results were not statistically significant (p value > 0.05). Results were not statistically significant (all results with p value > 0.05) for the combination of acitretin + pioglitazone (11) and acitretin + PUVA (12). Results were also not statistically significant (all p values > 0.05) for the combination of acitretin + pioglitazone (11) for PASI 75.

Combination of traditional systemic agents with cyclosporine

In the study of Vena et al, (18) they found that a significantly greater proportion of patients treated with cyclosporine A + calcipotriol/betamethasone dipropionate ointment combination achieved the PASI 75 as early as week 8 (87% vs 37% in the cyclosporine A and emollient group; p value 0.0001, Mann-Whitney test). Using the combination

Table 2. Characteristics of included studies (Etanercept with traditional systemic agents).

Gottlieb et al, 2012

Lebwohl et al, 2013

Papp et al, 2015

Gisondi et al, 2008


RCT, double-blind

Phase 3b RCT, multi-center

RCT, assessor-blinded

RCT, investigator-masked

NUMBER OF

PATIENTS

478

592

287

60

DURATION OF TRIAL

12 weeks

24 weeks

24 weeks

24 weeks

Etanercept 50mg SC twice weekly for 12 weeks followed by 50mg once weekly for additional 12 weeks +Methotrexate titrated from 7.5mg to 10mg to a maximum of 15mg from week 5 to 12 Etanercept 50mg twice weekly for 12 weeks followed by 50mg once weekly for 12 weeks +clobetasol proprionate applied twice daily only where lesions were present for 2 weeks Etanercept 50mg twice a week for the first 12 weeks then 50mg twice a week for another 12 weeks +topical steroid (hydrocortisone 2.5%, betamethasone valerate 0.1%, betamethasone dipropionate 0.05%, clobetasol 0.05%, calcitriol or calcitriol plus betamethasone dipriopionate 0.05%) Etanercept 25mg once weekly +

Acitretin 0.4mg/kg daily single oral dose for 24 weeks

CONTROL GROUP

Etanercept +

Placebo

Etanercept alone

Etanercept alone

Acitretin alone

Etanercept alone

OUTCOMES

PASI 75, PASI 90, PGA of clear or almost clear,

Withdrawal because of lack of efficacy

adverse events

PASI 75, PASI 90, PGA of clear or almost clear,patient satisfactionadverse events

change in PASI score, PASI 50, PASI 75, PASI 90,

PGA of clear or almost clear,adverse events

PASI 75, withdrawal due to lack of efficacy, adverse events

RISK OF BIAS

Low

Unclear

Unclear

Low

REASONS

No mention who were blinded in the study (participants, investigators or outcome assessors)

No mention how blinding was done

No mention if participants are blinded

No mention of blinding of participants or investigators


of calcipotriol ointment and very low dose cyclosporine, Grossman et al (21) found that PASI 90 was achieved in 50.0% of patients in the calcipotriol/cyclosporine group compared with 11.8% of patients treated with placebo/cyclosporine (p value = 0.0019, t test).

No serious adverse events were noted in the combination of low-dose cyclosporine and calcipotriol/betamethasone dipropionate ointment18.

In summary, 6 out of 20 studies evaluated in this systematic review showed superior efficacy of combination therapy compared with monotherapy with statistically significant results in terms of achieving PASI 75. These

combinations include the combination of etanercept + methotrexate (16), PUVA + isotretinoin (6), acitretin + etanercept (15), clobetasol propionate + etanercept (16), NBUVB + alefacept (17), and cyclosporine A + calcipotriol/betamethasone dipropionate ointment (18). The adverse events were mild to moderate, and the differences between treatment groups did not reach statistical significance. Baseline characteristics of patients in the studies likewise showed similarities in disease severity, disease duration, or prior therapies between treatment groups.

Significant heterogeneity in interventions, clinical outcome measures and treatment duration among trials

Table 3. Characteristics of included studies (Combination of traditional systemic agents with retinoids).

Mittal et al, 2009

Tanew et al, 1991Gahalaut et al, 2014 Giannetti et al, 1999


RCT, double-blind

RCT, double-blind

RCT, open-label

Randomizedhalf-body comparison study

NUMBER OF

PATIENTS

41

60

35

86

DURATION OF TRIAL

12 weeks

not mentioned

12 weeks

9 weeks

Acitretin 25mg per day+ Pioglitazone 15mg/day for 12 weeks

Acitretin 1mg/kg/day + PUVA 4 times a week for 11 weeks

Isotretinoin 0.5mg/kg/day+ PUVA (no duration or frequency mentioned)

Oral etretinate 50mg/day +Calcipotriol creamapplied twice daily to one hemipart for 9 weeks

CONTROL GROUP

Acitretin 25mg per day +Placebo for 12 weeks

PUVA 4 times a week+ placebo for 11 weeks

PUVA alone

Oral etretinate alone

OUTCOMES

change in PASI score,

PASI 75, PGA of clear

or almost clear, adverse eventswithdrawal because of adverse events or

lack of efficacy

adverse events

PASI 90, adverse events

PASI 75, reduction in PASI score,mean duration to achieve PASI75, adverse events, DLQI

reduction in PASI score fromthe baselineadverse events

RISK OF BIAS

Unclear

Unclear

High risk

High

REASONS

No mention of allocation concealment

No mention who was blinded in the study

Open-label

No blinding

Table 4. Characteristics of included studies (Combination of traditional systemic agents with retinoids).

Vena et al, 2012

Grossmann et al, 1994


Randomized, open-label

RCT, double-blind

NUMBER OF

PATIENTS

60

69

DURATION OF TRIAL

8 weeks

6 weeks

Cyclosporine A 2mg/kg/day in 2 divided daily dosages for 8 weeks +calcipotriol/betametha-sone dipriopionate

Ointment for 4 weeks

Cyclosporine A 2mg/kg/day in 2 doses at 12 hour intervals +Calcipotriol applied in the morning and evening at 12 hour intervals for 6 weeks

CONTROL GROUP

Cyclosporine A +

emollient

Cyclosporine A +

Placebo

OUTCOMES

PASI 75, PASI 50, PASI 90

adverse events

PASI 90, adverse events

RISK OF BIAS

Unclear

Unclear

REASONS

Open-label

No mention how randomization, blinding and allocation concealment was done


included in this study are some sources of biases and limitations in this systematic review. Some studies also have no raw data available, thus the results cannot be pooled into a meta-analysis. Most of the studies also had small sample sizes which can affect the quality of evidence for the outcomes in this review. Another limitation was that only published studies were included in this review.

CONCLUSION

Implications for PracticeThe available results on the efficacy and safety of

combination therapies show that most evidence exists for the superior efficacy of NBUVB, etanercept, and acitretin combined with other treatment modalities. These combinations may be utilized in the treatment of monotherapy-resistant patients with moderate to severe psoriasis. Treatment monitoring and dose reductions are a must to minimize adverse events.

Such combinations can be explored in treating patients who are unsatisfied or frustrated with their current therapies. Cost effectiveness must be taken into consideration when utilizing combination therapy, and treatment should still be individualized for every patient.

Implications for Research

There is still a need for high quality studies for combination therapies (NBUVB + efalizumab, NBUVB + topical tazarotene, and NBUVB + alefacept) with small sample sizes. Outcome measures should be the same among trials in order to determine the combined effects of various studies on combination therapy for moderate to severe psoriasis. Moreover, follow-up period must be long enough (24 weeks or longer since the longest duration is 24 weeks) to be able to identify adverse events and relapse rates even after stopping treatment.

Table 5. Characteristics of excluded studies


CONTROL GROUP REASON FOR EXCLUSION

Takeshita 2014

Lowenthal 2008

Siadat 2013

Levine 2010

Emer 2011

Ozdemir 2008

Bagel 2011

Zachariae 2008

Cross sectional

Case series

RCT

Randomized, double-blinded, multicenter, bilateral, comparison controlled trial

RCT

RCT

Single arm

RCT

Adalimumab + MTX, ETN + MTX, Infliximab + MTX

MTX + acitretin

Nicotinamide + calcipotriol

Nicotinamide + calcipotriene

Ammonium lactate + halobetasol ointment

Acitretin + NBUVB

NBUVB + Adalimumab

ETN + MTX

Monotherapy tx using MTX, cyclosporine, infliximab, and acitretin

none

Calcipotriol monotherapy

Nicotinamide alone or calcipotriene alone

Ammonium lactate + placebo

Acitretin + PUVA

None

ETN + MTX taper

Not an RCT

Not an RCT

Study compared topical combination therapy with another topical therapy

Study compared topical combination therapy with either agent alone

Study compared topical combination therapy with another topical therapy

Control is also a combination therapy

Study is only single arm

Control is also a combination therapy but with tapered dose of MTX


STUDY P VALUEINTERVENTION AND COMPARATORMEAN PASI + SD AND 95%

CONFIDENCE INTERVAL OF TREATMENT

MEAN PASI + SD AND 95% CONFIDENCE INTERVAL OF

CONTROL

Behrens 2000

Calzavara-Pnton 2013

Grundmann-Kollmann 2004

Legat 2007

Lynde 2012

Park 2013

Zane 2009

Gottlieb 2012

Lebwohl 2013

Papp 2015

Gisondi 2008

Mittal 2009

Tanew 1991

Gahalaut 2014

Giannetti 1999

Vena 2012

Grossman 1994

NBUVB + topical tazarotene VERSUS NBUVB alone

NBUVB + Etanercept (ETN) Versus NBUVB alone

NBUVB + cream PUVA Versus NBUVB alone Versus cream PUVA alone

NBUVB + Alefacept Versus Alefacept alone

NBUVB + ETN Versus ETN alone

NBUVB + ETN Versus ETN alone

NBUVB + Efalizumab Versus Efalizumab alone

ETN + Methotrexate Versus ETN + placebo

ETN + clobetasol propionate Versus ETN alone

ETN + topical steroid Versus ETN alone

ETN + acitretin Versus ETN alone Versus Actitretin alone

Acitretin + pioglitazone Versus Acitretin + Placebo

Acitretin + PUVA Versus PUVA + Placebo

Isotretinoin + PUVA Versus PUVA alone

Oral etretinate + calcipotriol cream Versus Oral etretinate alone

Cyclospoine A + calcipotriol/ betamethasone dipropionate ointment Versus Cyclosporin A + emollient

Cyclosporine A + calcipotriol Versus Cyclosporine A + placebo

<0.05

<0.05

<0.001

0.03

0.647

>0.05

<0.05

<0.0001

<0.001

>0.05

0.001

>0.05

>0.05

0.03

<0.001

0.0001

0.0019

No mean and SD mentioned (median PASI score 6.5, no IQR)

Mean PASI 2.4 + 2.8 [-20.46, -7.14] at week 24

No mean PASI, SD and CI mentioned. Mean number of treatment was 14 + 2 (p vaue <0.001, ANOVA), mean cumulative dose was 18.7 + 4.7 J/cm2 (p value <0.001, t test), and mean cumulative UVB dose was 8.2 + 3,3 J/cm2 (p value <0.001, t test).

PASI 75 86% at week 12 (No mean, SD and CI mentioned)

PASI 75 51.4%No mean, SD and CI mentioned. No significant difference in the proportion of patients who reached PASI 75 between the two treatment arms at week 24

Mean PASI 3.21 + 3 [-2.07, 2.23]

Mean PASI 4.5 + 1.65 [-4.32, -0.08]

PASI 75 77.3% at week 24 (No mean, SD and CI mentioned)


Percentage change in PASI score 0.9% CI (-13%, 14.8%) at week 24

Mean difference in change in PASI score 16.2%, CI -3.5%, 35.8%) between the treatment and control groups at week 24

PASI 75 45% (no CI mentioned) at week 24

Mean PASI 6 + 5.6 [9.35, -0.65]

PASI 90 96% (no CI mentioned) at 11 weeks

Mean PASI 6.5 + 6.5 [-10.20, -0.84] at 12 weeks

Mean PASI 3.8 +0.6 [-3.19, -2.61]

PASI 75 87% at week 8 (no CI mentioned)

PASI 90 50% (CI 17.8% to 58.7%) at 6 weeks

No mean and SD mentioned (median PASI 14, no IQR)

Mean PASI 16.2 + 9.2 [-20.46, -7.14] at week 24

No mean PASI, SD and CI mentioned.Mean number of treatments for cream PUVA alone was 24 + 5, mean cumulative UVA dose was 45 + 16.3 J/cm2. Mean number of treatments for NBUVB 21 + 3 and the mean cumulative UVBdose was 17.1 + 4.1 J/cm2. The number of treatments, UVA dose, and UVB dose were significantly reduced in the combination therapy compared with both monotherapies (p value < 0.001)

PASI 75 43% at week 12 (No mean, SD and CI mentioned)

PASI 75 44.7%No mean, SD and CI mentioned. No significant difference in the proportion of patients who reached PASI 75 between the two treatment arms at week 24

Mean PASI 3.13 + 3 [-2.07, 2.23]

Mean PASI 6.7 + 1.77 [-4.32, -0.08]



Percentage change in PASI score 17.0% CI (3.1%, 30.9%) at week 24

PASI 75 30% in acitretin alone and PASI 75 45% at week 24(no CI mentioned)

Mean PASI 10 + 8.5 [9.35, -0.65]

PASI 90 80% at 11 weeks (no CI mentioned)

Mean PASI 12.02 + 7.46 [-10.20, -0.84] at 12 weeks

Mean PASI 6.7 +1 [-3.19, -2.61]

PASI 75 37% at week 8 (no CI mentioned)

PASI 90 11.8% (CI 17.8% to 58.7%) at 6 weeks

Table 5. Summary of treatment effects of included studies


REFERENCES

1. van de Kerkhof PCM and Nestle FO. Psoriasis. In: Bolognia JL et al, eds. Dermatology. 3rd Edition. Elsevier Limited; 2012. pp. 135-157.

2. Philippine General Hospital Section of Dermatology Annual Reports 2012, 2013, and 2014.

3. Leavitt M. Psoriasis costs U.S. up to $135 billion a year. [document on the Internet]. National Psoriasis Foundation; 2015 [cited 2015 January 12]. Available from:http://www.psoriasis.org/advance/psoriasis-costs-us-up-to-135-billion-a-year.

4. Lebwohl M, Menter A, Koo J and Feldman SR. Combination therapy to treat moderate to severe psoriasis. J Am Acad Dermatol. 2004; 50:417-430.

5. Calzavara-Pinton PG, Sala R, Arisi M, Rossi MT, Venturini M, and Ortel B. Synergism between narrowband ultraviolet B therapy and etanercept for the treatment of plaque-type psoriasis. Br J Dermatol. 2013; 169:130-136.

6. Gahalaut, P, Soodan PS, Mishra N, Rastogi MK, Soodan HS, and Chauhan S. Clinical efficacy of psoralen + sunlight vs. combination of isotretinoin and psoralen + sunlight for the treatment of chronic plaque-type psoriasis vulgaris: a randomized hospital-based study. Photodermaol Photoimmunol Photomed. 2014; 30:294-301.

7. Behrens S, Grundmann-Kollmann M, Schiener R, Peter R, Kerscher M. Combination phototherapy of psoriasis with narrow-band UVB irradiation and topical tazarotene gel. J Am Acad Dermatol. 2000; 42:493-495.

8. Giannetti A, Coppini M, Bertazzoni MG, Califano A, Altieri E, Pazzaglia A, Lega M, Lombardo M, Pelfini C, Fornasa CV, Rabbiosi G, Cespa M. Clinical trial of the efficacy and safety of oral etretinate with calcipotriol cream compared with etretinate alone in moderate-severe psoriasis. J Euro Acad Dermatol Venerol. 1999; 13:91-95.

9. Grundmann-Kollmann M, Ludwig R, Zollner TM, Ochsendorf F, Thaci D, Boehncke W, Krutmann J, Kaufmann R, and Podda M. Narrowband UVB and cream psoralen-UVA combination therapy for plaque-type psoriasis. J Am Acad Dermatol. 2004; 50:734-739.

10. Zane C, Capezzera R, Venturini M, Sala R, Facchineti E, Pedretti A, and Calzavara-Pinton P. Dermatology. 2009; 218:321-326.

11. Mittal R, Malhotra S, Pandhi P, Kaur I, and Dogra S. Efficacy and safety of combination acitretin and pioglitazone therapy in patients with moderate to severe chronic plaque-type psoriasis. Arch Dermatol. 2009; 145(4):387-393.

12. Tanew A, Guggenbichler A, Honigsmann H, Geiger JM, and Fritsch P. Photochemotherapy for severe psoriasis without or in combination with acitretin: A randomized, double- blind comparison study. J Am Acad Dermatol. 1991; 25:682-684.

13. Papp KA, Barber K, Bissonnette R, Bourcier M, Lynde CW, Poulin Y, Shelton J, Toole J, Vieira A, and Poulin-Costello, M. A randomized, blinded assessor study to evaluate the efficacy and safety of etanercept 50 mg once weekly plus as needed topical agent vs etanercept 50 mg twice weekly in patients with moderate to severe plaque psoriasis. J Euro Acad Dermatol Venerol. 2015; 29:361-366.

14. Gottlieb AB, Langley RG, Strober BE, Papp KA, Klekotka P, Creamer K, Thompson EHZ, Hooper M, and Kricorian G. A randomized, double-blind placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2012; 167:649-657.

15. Gisondi P, Del Giglio M, Cotena C and Girolomoni G. Combining etanercept and acitretin in the therapy of chronic plaque psoriasis: a 24- week, randomized, controlled, investigator blinded pilot trial. Br J Dermatol. 2008; 158:1345-1349.

16. Lebwohl M, Kircik L, Duffin KC, Pariser D, Hooper M, Wenkert D, Thompson EHZ, Yang J, Kricorian G and Koo J. A randomized study to evaluate the efficacy and safety of adding topical therapy to etanercept in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol. 2013; 69:385-392.

17. Legat FJ, Hofer A, Wackernagel A, Salmhofer W, Quehenberger F, Kurl H, and Wolf P. Narrowband UV-B phototherapy, alefacept, and clearance of psoriasis. Arch Dermatol. 2007; 143(8):1016-1022.

18. Vena GA, Galluccio A, Pezza M, Vestita M, and Cassano N. Combined treatment with low-dose cyclosporine and calcipotriol/betamethasone dipropionate ointment for moderate-to-severe plaque psoriasis: a randomized controlled open-label study. J Dermatolog Treat. 2012; 23:255-260.

19. Lynde CW, Gupta AK, Guenther L, Poulin Y, Levesque A, and Bissonnette R. A randomized study comparing combination of nbUVB and etanercept monotherapy in patients with psoriasis who do not exhibit an excellent response after 12 weeks of etanercept. J Dermatol Treat. 2012; 23:261-267.

20. Park KK, Wu JJ and Koo J. A randomized, ‘head-to-head’ pilot study comparing the effects of etanercept monotherapy vs. etanercept and narrowband ultraviolet B (NB-UVB) phototherapy in obese psoriasis patients. J Euro Acad Dermatol Venerol. 2012.

21. Grossman RM, Thivolet J, Claudy A, Souteyrand P, Guilhou JJ, Thomas P, Amblard P, Belaich S, de Belilovsky C, de la Brassinne M, Martinet C, Bazex JA, Beylot C, Combemale P, Lambert D, Ostojic A, Denoeux JP, Lauret P, Vaillant L, Weber M, Pamphile R, and Dubertret L. A novel therapeutic approach to psoriasis with combination calcipotriol ointment and very low-dose cyclosporine: results of a multicenter placebo-controlled study. J Am Acad Dermatol. 1994; 31:68-74.


CASE REPORTS

A novel mutation in the EDA gene in a Filipino family with X-linked hypohidrotic ectodermal dysplasia

INTRODUCTION

X-linked Hypohidrotic ectodermal dysplasia (XLHED; MIM 305100) is a rare genetic disorder that affects the development and function of several structures

of ectodermal origin, such as hair, teeth and sweat glands.1

Hypohidrotic ectodermal dysplasia is associated with mutations in genes that encode ectodysplasin-A (EDA), EDA receptor (EDAR), EDA receptor-associated death domain (EDARADD), and WNT10A. Mutations in any of these genes affects the NF-κB signal transduction pathway necessary for initiation, formation, and differentiation of skin appendages.2

HED is a rare X-linked recessive genodermatosis with a low prevalence worldwide, with an incidence rate of 0.001% in the Philippines according to the Philippine Dermatological Society (PDS) central registry.3,4

The characteristic findings of X-linked HED are hypotrichosis, hypodontia and reduced sweating.1 Lack of sweating leads to an increased body temperature, presenting as recurrent fever or collapse. Hence, we were able to determine the cause of the ‘fever of unknown origin’ of a young boy with a history of multiple admissions and consults due to recurrent febrile episodes through the dermatologic findings and genetic testing.

Several mutations in the EDA gene have been reported in XLHED, although none has been reported from the Philippines.5 Here we report the clinical, histopathological and molecular findings of a Filipino family with HED. Furthermore, we found

in this family a novel mutation in exon 8 leading to a frameshift and a delayed downstream termination codon, an unusual consequence even in the global database of all pathogenic mutations.

CASE REPORT

A 3-year-old boy was referred to our clinic in May 2016 suffering from recurrent fever and rash. He was born to non-consanguineous parents, with an uneventful perinatal history. His younger brother (6-month old) had similar dermatologic findings and thermoregulation disturbances (Figure 1) but no other family members, including both parents, had any other relevant history.

a Department of Dermatology, Southern Philippines Medical Center, Davao, Philippinesb St. John’s Institute of Dermatology, King’s College London, London, UKc Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

d Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan

e Viapath, St. Thomas’ Hospital, London, UK

Source of funding: noneConflict of interest: none Corresponding author: Email:

Bryan Edgar K. Guevara, MDa; Maria Vinna N. Crisostomo, MDa; Chao-Kai Hsu, MDb-d, Lu Liu, MDe;Maria Mercedes S. Cauilan, MD, FPDSa; John A. McGrath, MD, FRCP, FMedScib

X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder that affects the development and function of several structures of ectodermal origin, such as hair, teeth and sweat glands. It is associated with ectodysplasin-A (EDA) gene mutation, necessary for ectodermal development.

We present a case of two brothers who were referred to our clinic due to recurrent fever and rash. Prior to referral, patients had multiple admissions due to fever and underwent a series of tests to determine the cause of fever but to no avail. Upon examination, erythematous scaly papules and plaques on the extremities, alopecia, absence of dermatoglyphic patterns, and atypical facial features were noted. Skin biopsy revealed absence of eccrine glands. Genetic analysis revealed EDA mutation in exon 8 that resulted in a delayed termination codon rather than a premature termination codon, causing XLHED. This novel mutation has never been reported in the literature.

Figure 1. Family pedigree. The proband is a 3-year old boy (1) who has a similarly affected 6-month old younger brother (2).

The two brothers had several consults and admissions due to fever, although their guardian could not recall the diagnoses made on these occasions. In all these visits, the patients were given medications for fever, including antibiotics. Their latest visit to their pediatrician was for a 2-week fever accompanied with a rash. Multiple diagnostic tests, including hematologic, biochemical, radiologic and bacterial cultures were done by their attending doctor but no cause for the fever


was identified. He was subsequently referred to our clinic for review of some skin lesions.

Upon examination, his face revealed prominent features comprising frontal bossing, large nostrils, wide cheek bones, scanty eyebrows & eyelashes, low-lying and anteriorly placed ears, thick everted lips with delayed dentition and conical incisors (Figure 2). Dermatologic examination revealed erythematous scaly papules and plaques on the extremities (Figure 3). The scalp showed patchy alopecia, and dermoscopy revealed sparse, lightly pigmented short hairs (Figure 4). Nail findings were normal, but there was an absence of whorls and ridges in the patient’s fingerprints (Figure 5). The patient’s younger brother also had a similar facial appearance and dermatologic findings (Figure 6). There were no developmental and motor delays observed in the brothers. We were not able to examine the parents, since both of them work abroad.

Figure 2. Facial and dental features. Prominent frontal bossing, wide cheek bones, low-lying, scanty eyebrows & eyelashes, and anteriorly placed ears as well as thick everted lips (A). The 3-year old boy had only two conical lower incisors (B).

Following informed consent, a skin biopsy of the patient’s palms revealed a normal epidermis but an absence of eccrine structures (Figure 7). Genetic and molecular analyses on the two brothers’ blood specimen were done following consent

Figure 3. Erythematous scaly papules and plaques on the left (A) and right (B) upper extremities.

Figure 4. Hair examination. Presence of alopecia (A), with sparse, lightly pigmented short hairs on dermoscopy (B).

Figure 5. Dermatoglyphics. Absence of whorling and ridging pattern in patient’s fingerprints (A), in contrast to normal dermatoglyphic pattern (B).

Figure 6. Facial and dermatologic features of the patient’s brother.

from the patients’ guardian. DNA was isolated from peripheral blood leukocytes of the patients. We noted a hemizygous single nucleotide deletion, c. 1131delC, in exon 8 of EDA. This mutation led to a frameshift and a delayed downstream termination codon, designated p.Thr377Thrfs*37 (Figure 8). These molecular data support a diagnosis of X-linked hypohidrotic ectodermal dysplasia (XLHED).

The pat ient and fami ly were managed with multidisciplinary care. Dermatologic management involved


Figure 7. Histopathology of the skin. Patient’s skin noted absence of sweat glands (eccrine structures) (A). Normal histology of the skin, with eccrine structures in the papillary dermis (B).

Figure 8. Genetic and molecular analysis of X-linked hyophidrotic ectodermal dysplasia affected patients that revealed a single nucleotide deletion, c. 1131del C, in exon 8 of EDA located on X-chromosome (a), and normal control (b).

Table 1. Risk of transmission among family members

FAMILY MEMBER RISK OF TRANSMISSION TO OFFSPRING/S

GENE MUTATION

Father

Mother (Obligate carrier)

Two brothers (patient 1 & 2)

Two elder brothers, with no manifestations

-

+

+

-

0%

50%, regardless of sex- 50% (affected males)- 50% (female carriers)

100% to all daughters, obligate carriers(show minimal manifestations)

0% to sons

0%

use of emollients and mild corticosteroids (hydrocortisone 1% cream) twice a day for one week with complete resolution of lesions. Future plans for the hair and dental defects will focus on wigs and orthodontic prosthesis.

The patient was referred back to pediatrics, informed them of the diagnosis, and was made aware of the cause of the “fever of unknown origin”. This important information will now hopefully lead to measures to prevent episodes of hyperpyrexia, consults/admissions, unnecessary antipyretic medication use, and administration of antibiotics that could lead to resistance of infection and economic burden. The family was advised about proper thermoregulation of the affected individuals with frequent cooling and hydration, especially during the summer months time. Early guidance about temperature regulation and its risks were given. Proper skin care and monitoring was also instructed to the caregivers.

Furthermore, patient/family education and genetic counseling were also provided to the family. This important process of providing the patients and family with information

on the nature, inheritance and implications of their genetic condition can help make informed medical and personal decisions. Risk and prognostication to family members were provided, as summarized in Table 1.

DISCUSSION

HED or Christ-Siemens-Touraine syndrome is a rare X-linked recessive genetic condition characterized by the triad of reduced sweating, hypotrichosis, and defective dentition.1 To date, several different mutations in the EDA gene have been described in the literature.6-8 The EDA gene is located on chromosome X (Xq12.2-q13.1), and encodes ectodyplasins A1 and A2 (EDA-A1 and EDA-A2) involved in the differentiation of skin appendages and other ectodermal structures.9,10 ED genes provide signals for producing proteins (ectodysplasin A) that forms a signaling pathway for the interaction between the ectoderm and mesoderm cell layers (Figure 9).11 These interactions are essential for the formation of several structures

Figure 9. Genetic pathogenesis. EDA, as a signaling pathway for the embryonic placode that is critical for the formation of ectodermal structures, such as the sweat glands, hair and teeth. EDA, ectodysplasin A; EDAR, ectodysplasin A receptor; BMP-4, Bone morphogenetic protein type-4; CTGF. Connective tissue growth factor.


that arise from the ectoderm, including the sweat glands, hair and teeth.11 Mutations in EDA will lead to improper signaling leading to the characteristic features of HED.

In our case, the mutation does not appear to have been reported in the literature.6-8 This novel mutation appears to be the most 3’ of all reported mutations in EDA this far, and furthermore, it results in a delayed termination codon rather than a premature termination codon. Potentially, this scenario could lead to a slightly less disruptive change to the protein with perhaps a milder phenotype. However, the C-terminus of the protein is a functionally important domain and so even this mutation could result in almost identical changes to the majority of other mutations reported, with similar phenotypic consequences. Identification of this mutation confirms the diagnosis of X-linked HED. Furthermore, the diagnosis could translate to a better genetic counseling to the family. Being transmitted as X-linked recessive and although we were unable to test the parents, it is highly likely that the mother is an obligate carrier of the disease-causing EDA mutation. The genetic counseling for future pregnancies indicates 4 possible outcomes: 25% will be clinically and genetically normal females; 25% will be heterozygous carrier females (clinically mostly normal but perhaps with subtle, focal dental or sweating defects); 25% will be clinically and genetically normal males; and, 25% will be males with XLHED.

The most remarkable phenotypic manifestation of HED is hypohidrosis, which can be apparent in the second year of life due to repeated episodes of unexplained fever.12 The inability to sweat results in intolerance to heat, leading to hyperpyrexia, precisely what our HED patients experienced. The unexplained fever may be more severe especially during the summer months.

Dermatologic findings include dry and thin skin with hyperpigmentation and appears prematurely aged, due to the partial absence of sweat and sebaceous glands.12,13

Furthermore, there is an increased susceptibility to atopic or allergic disorders.14 Other phenotypic findings include hypotrichosis, due to reduced hair follicles, hypodontia with conical-shaped teeth, facial abnormalities and dermatoglyphic anomalies that were all present in our case.1,3

Significant morbidity and mortality is due to hyperthermia and risk of respiratory tract infections due to the lack of nasal, tracheal and bronchial glands,15 although the clinical emphasis is always on prevention of hyperpyrexia through hydration and thermoregulation.

With regards to more specific treatments, studies in mouse and dog models of XLHED using recombinant ectodysplasin A (Fc:EDA1) protein have shown partial reversal of disease, and improvement of airway infections,16 although a human clinical trial using recombinant protein in affected male infants failed to demonstrate clinical benefits. Nevertheless, future trials to test recombinant ectodysplasin A in human fetuses (i.e. during pregnancy) have been approved, the rationale being that even earlier treatment might lead to better ectodermal recovery.

Patients afflicted with this hereditary deformity suffer

from poor psychological and physiologic development as a result of aesthetic and abnormal features.17 Early intervention with multidisciplinary collaborative efforts from dermatologists, pediatricians, geneticists, psychologists, dentists and other specialists can help rehabilitate and improve the appearance and function among these patients.

Genetic testing on the proband’s mother should be endeavored in the future to substantiate genetic counselling for this family. An ongoing surveillance of the children’s growth and development is important as this novel mutation may involve other problems such as developmental delay and/or immune deficiency in the future.

CONCLUSION

Dermatologists play a role in early recognition of this rare hereditary condition that present mainly with fever of unknown origin. The dermatologic manifestations can prompt further investigation of HED through molecular analysis. This approach confirmed our diagnosis by disclosing a novel mutation in EDA.


REFERENCES

1. Visinoni AF, Lisboa-Costa T, Pagnan NA, Chautardo Freire-Maia EA. Ectodermal dysplasias: Clinical and molecular review. Am J Med Genet A. 2009; 149A:1980-2002.

2. Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, et al. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat. 2011; 32:70-72.

3. Mortier K, Wackens G. Ectodermal dysplasia syndrome. Orphanet encyclopedia. 2004.

4. Philippine Dermatological Society Health Information System. Philippine Dermatological Society. c2011. 2011-2014; cited July 18, 2016. Available by request from: [email protected].

5. Mikkola ML. Molecular aspects of hypohidrotic ectodermal dysplasia. Am J Med Genet A. 2009; 149A:2031-2036.

6. Monreal AW, Zonana J, Ferguson B. Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations. Am J Hum Genet. 1998; 63:380-389.

7. Swee LK, Ingold-Salamin K, Tardivel A, Willen L, Gailde O, Favre M et al. Biological activity of ectodysplasin A is conditioned by its collagen and heparan sulfate proteoglycan-binding domains. J Biol Chem. 2009; 284:27567-27576.

8. Hashiguchi T, Yotsumoto S, Kanzaki T. Mutations in the ED1 gene in Japanese families with X-linked hypohidrotic ectodermal dysplasia. Exp Dermatol. 2003; 12: 518-522.

9. Zonana J, Clarke A, Sarfarazi M, Thomas NS, Roberts K, Marymee K. X-linked hypohidrotic ectodermal dysplasia: localization within the region Xq11-21.1 by linkage analysis and implications for carrier detection and prenatal diagnosis. Am J Hum Genet. 1988; 43:75-85.

10. Mues G, Griggs R, Hartung AJ, Whelan G, Best LG, Srivastava AK et al. From ectodermal dysplasia to selective tooth agenesis. Am J Med Genet A. 2009; 149A(9): 2037-2041.

11. Wright JT., Grange DK., Ritcher MK. Hypohidrotic ectodermal dysplasia. Gene Reviews. NCBI BookShelf. Updated. 2009

12. Wiśniewski SA, Kobielak A, Trzeciak WH, Kobielak K. Recent advances in understanding of the molecular basis of anhidrotic ectodermal dysplasia: discovery of a ligand, ectodysplasin A and its two receptors. J Appl Genet. 2002; 43(1):97-107.

13. Nieminen P. Genetic basis of tooth agenesis. J Exp Zool B Mol Dev Evol. 2009; 312B: 320-334.

14. Itthagarun A, King NM. Ectodermal dysplasia: a review and case report. Quintessence Int. 1997; 28(9):595-602.

15. Clarke A, Phillips DI, Brown R, Harper PS. Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Arch Dis Child. 1987; 62(10):989-96.

16. Favre M, Paradies F, Demotz S, Gaide O, Schneider P. Significant correction of disease after postnatal administration of recombinant ectodysplasin A in canine X-linked ectodermal dysplasia. Am J Hum Genet. 2007 Nov; 81(5):1050-6.

17. Bonilla ED, Guerra L, Luna O. Overdenture prosthesis for oral rehabilitation of hypohidrotic ectodermal dysplasia: a case report. Quintessence Int. 1997; 28(10):657-65.


Juvenile hyaline fibromatosis and infantile systemic hyalinosis: The first two reported cases in the Philippines

INTRODUCTION

Juvenile Hyaline Fibromatosis (JHF) and Infantile Systemic Hyalinosis (ISH) are previously two distinct entities that are now considered to be part of the spectrum of Hyaline

Fibromatosis Syndrome (HFS) characterized by hyaline deposition in the skin and other organs.

HFS is an autosomal recessive disorder triggered by mutations of gene ANTXR2 (anthrax toxin receptor-2), also known as gene CMG2 (capillary morphogenesis gene-2), located in chromosome 4q21. After Rahman et al. (2002) mapped JHF gene locus on chromosome 4q211, Hanks et al. (2003)2 and Dowling et al. (2003)3 identified mutations in the CMG2 gene as the cause of both ISH and JHF, indicating that these disorders are allelic and part of the same phenotypic spectrum. CMG-2 is a transmembrane protein that binds extracellular matrix proteins laminin and collagen IV. Abnormal CMG2-laminin contact has been demonstrated in HFS derived fibroblasts, this probably underlies their pathogenesis. The gene is expressed in all tissues with exception of the brain, a finding consistent with normal cognitive development of the affected individuals.4

Multiple skin lesions, joint contractures, gingival hypertrophy, osteolysis and osteoporosis characterizes both syndromes. JHF occurs much later in infancy with a milder course and survival into adulthood. JHF typically presents with larger nodules. ISH is more severe with multiple visceral involvement, persistent diarrhea, frequent severe infections, failure to thrive,

and death before the age of two. Overlaps have been reported.5,6

HFS remains a stigmatizing and incapacitating disorder. Risks of potentially life-threatening complications in people with HFS, particularly of the ISH form may be due to persistent diarrhea, infections, and malnutrition. There is currently no cure for HFS, and treatment is supportive and generally aims to alleviate the signs and symptoms. Early recognition is invaluable in providing improved outcome of treatment and a better quality of life.

CASE REPORT 1

We describe a 9 month-old Filipino male born to non-consanguineous parents after a normal pregnancy and delivery. He presented at birth with stiffness of both knees and hyperpigmentation of skin overlying the malleoli and metacarpophalangeal joints and an erythematous soft nodule on the left gluteal area. He was also noted to be irritable on joint manipulation; despite this, he had good feeding and activity. At 2 months of age, the patient developed stiffening of both upper extremities, and the knees (were) already in permanent flexion. He also developed multiple erythematous papules on the neck and the back. During this time, the nodule on the left gluteal area started to ulcerate; he was admitted at the Philippine General Hospital Pediatric ward for 5 days with the diagnosis of a sacral decubitus ulcer and was given IV antibiotics. He was on constant follow up on out patient basis for recurrent upper respiratory tract infections. At 8 months-old, the patient started to have constipation with alternating diarrhea. He also developed rectal prolapse due to straining on defecation and there was increase in number of the erythematous papules on the neck and back. There are no similar conditions in the family but the patient’s older sibling has congenital cataracts.

Hyaline Fibromatosis Syndrome (HFS) is a rare, autosomal recessive condition characterized by abnormal deposition of amorphous hyaline material in the skin, joints and visceral organs. It represents a disease spectrum with infantile systemic hyalinosis (ISH) being the severe form with deaths in the first 2 years of life and juvenile hyaline fibromatosis (JHF) being the mild form with survival to adulthood. In both disorders, mental development is normal.

The first case is a 1-year-old male with a coarse facial appearance and gingival hypertrophy, multiple painful joint contractures, frog leg deformity, and characteristic cutaneous findings of multiple erythematous plaques with cobblestone appearance on the neck, back, perianal area and hyperpigmented patches overlying malleoli and metacarpophalangeal joints. He also had recurrent upper respiratory tract infections and intractable diarrhea. The second case is a 4-year-old girl who had a coarse facial appearance, wide-based gait and multiple joint contractures. She had multiple papules and plaques on the head and neck, multiple hard masses of the scalp and digits, gingival hyperplasia and sessile perianal masses. Diagnosis of ISH and JHF, respectively were confirmed by histopathology and skeletal survey.

HFS is a rare genetic disorder and only a few are reported in literature. Our paper highlights the importance of early recognition by presenting the characteristic clinical manifestations and diagnostic work-ups; genetic counselling of both the patients and their families; and the long-term, multidisciplinary approach in the management of such conditions. To the best of our knowledge, these are the first reported cases in the Philippines.

Keywords: Hyaline fibromatosis syndrome, juvenile hyaline fibromatosis, infantile systemic hyalinosis

Section of Dermatology, University of the Philippines-Philippine General Hospital

Source of funding: noneConflict of interest: none Corresponding author: Mariecon O. Escuadro-Chin, MD, DPDSEmail: [email protected]

Mariecon O. Escuadro-Chin, MD, DPDS; Patricia Anne Z. Pontejos, MD, DPDS and Marie Eleanore O. Nicolas, MD, FPDS


At the time of consultation, the patient was 9 months old; he was malnourished and weighed only 6.3kg (<5 percentile) and 70cm (<5 percentile). Vital signs were normal. There was note of a coarse facial appearance, low set ears, depressed nasal bridge, gingival hypertrophy and clear nasal discharge. Multiple erythematous papules and plaques with cobblestone appearance were present in the neck, back and perianal area (Figure 1). There were hyperpigmented patches overlying the lateral and medial malleoli and metacarpophalangeal joints (Figure 2). All hand joints were in permanent flexion. Shoulder, elbow, hip and ankle joints all had limited range of motion. The knees were in permanent flexion causing a frog leg deformity. Tenderness on joint manipulation was also elicited for all joints. There was also note of rectal prolapse and a hypertrophic scar on the left gluteal area (Figure 3). Systemic physical examination was unremarkable as well as the neurologic and ophthalmologic examination.

Figure 4. Histopathology H&E stain shows homogenous collagen in the papillary dermis with chondroid appearance

Figure 3. Rectal prolapse and a hypertrophic scar on the left gluteal areaFigure 5. Vimentin immunostain was positive confirming the presence of multiple fibroblasts in the area of homogenous collagen

Figure 2. Hyperpigmented patches overlying the lateral and medial malleoli and metacarpophalangeal joints

Histopathology of an erythematous plaque over the nape revealed homogenous collagen in the papillary dermis with chondroid appearance (Figure 4). Vimentin immunostain was positive (Figure 5). Complete blood count and serum electrolytes were normal. Rheumatoid factor, erythrocyte sedimentation rate, C3, serum VDRL and routine urinalysis and fecalysis were unremarkable. The patient had low albumin probably secondary to a protein losing enteropathy. AST and ALT were 2x and 1.5x elevated raising the suspicion of hyaline deposition in the liver, however, Holoabdominal ultrasound was normal. Intestinal biopsy and upper GI series were however not done to confirm malabsorption. Electromyography and nerve conduction studies showed decreased compound muscle action potential for all extremities but no nerve conduction defects were found. On skeletal survey, there was generalized osteopenia signifying delayed bone growth again consistent with ISH. 12-L ECG and Chest X-rays were normal. Patient is co-managed with Pediatrics. Patient was given oral Paracetamol for pain He was referred to Rehabilitation Medicine for physiotherapy and dietician for nutritional build-up.

Figure 1. Multiple erythematous papules and plaques with cobblestone appearance were present in the neck, back and perianal area


Figure 6. Marked gingival hypertrophy with malpositioned carious teeth

Figure 7. Multiple confluent, pearly papules on the forehead, around the alae nasi, cheeks, chin, earlobes, and neck

Figure 8. Many sharply demarcated transluscent and doughy nodules were present on the proximal and distal interphalangeal joints of both fingers (A,B) and toes (C).

CASE REPORT 2

We describe a 4-year-old Filipino girl who was born to non-consanguineous parents after a normal pregnancy and delivery. Her birthweight was 2800 grams and her length was 37 cm. She was normal at birth. At one month of age, there was note of multiple skin-colored, sessile perianal masses. She also had constipation with abdominal pain and distention. At 3 months of age, she developed multiple pearly-pink, pruritic papules and confluent plaques on the head and neck. These progressively increased with age. At nine months of age, patient developed multiple hard non-painful nodules over the scalp, digits and toes. She was also noted to have coarse fascies, low-based ears and broad, infiltrated nose with a depressed bridge. At 1-year of age, there was noted pain upon passive and active movements of the shoulders and elbows. She became irritable when lifted by the arms or dressed. At 2 years of age, there was note of gingival hypertrophy and malpositioned teeth. She had difficulty in reaching objects and combing her hair. She was described to have a characteristic wide-based gait and was unable to catch up with playmates when running. She easily loses balance and falls. Intellect and fine motor skills were at par with age. There are no similar conditions in the family.

At the time of consultation, the patient was 4-years-old. She was malnourished with short stature. She weighed 13.6 kg (<5 percentile) and was 99cm (<5 percentile) in height. Vital signs were normal. Patient has coarse fascies characterized as large, infiltrated, low set ears and a broad infiltrated nose with a depressed nasal bridge. There was marked gingival hypertrophy with malpositioned carious teeth (Figure 6). She had characteristic skin lesions as manifested by multiple confluent, pearly papules with excoriations on the forehead, around the alae nasi, cheeks, chin, earlobes, and neck (Figure 7). There were multiple hard, non-movable, non-tender nodules on the scalp. Many sharply demarcated transluscent and doughy nodules with erosions and excoriations were present on the proximal and distal interphalangeal joints of both fingers and toes (Figure 8). Multiple flesh-colored sessile nodules were on the perianal area (Figure 9). She had a limited range of motion over both shoulders and elbows associated with pain on movement. Her gait was wide-based. Her feet showed pes planus. Systemic physical examination was unremarkable as well as the neurologic and ophthalmologic examination.

Histopathology of lesional biopsy specimens from the nape and gingiva revealed a flattened epidermis with an abundance of homogeneous, amorphous, eosinophilic extracellular matrix that contained spindle shaped cells in the dermis (Figure 10). The amorphous material was Periodic acid-Schiff positive and Diastase resistant but did not stain with Alcian blue (Figure 11A). The spindle-shaped cells stained with Vimentin (Figure 11B).

Hematologic and biochemical investigations were normal including complete blood count, electrolytes, renal and liver function tests, rheumatoid factor, erythrocyte sedimentation

Figure 9. Multiple flesh-colored sessile nodules on the perianal area


rate, C3, serum VDRL and routine urinalysis and fecalysis. Skeletal radiography showed well-defined osseous lucencies in both parietooccipital and distal metaphyseal region of the left humerus (Figure 12). Chest X-ray, Holoabdominal ultrasonography and 12-L ECG were all normal.

Figure 10. Histopathalogy. H&E shows flattened epidermis with an abundance of homogenous, amorphous, eosinophilic extracellular matrix that contained spindle shaped cells in the dermis of the skin (A, B) and the gingiva (C, D)

Figure 11. The amorphous material was Periodic acid-Schiff positive and Diastase resistant (A). The spindle-shaped cells stained with Vimentin indicating they are fibrolasts (B).

Figure 12. Skeletal radiography showed well-defined osseous lucencies in both parietooccipital and distal metaphyseal region of the left humerus

Patient was given oral Paracetamol for pain relief and topical antibiotics for secondarily infected lesions. Patient underwent serial excision of perianal masses. She was referred to Pediatrics for co-management, Rehabilitation Medicine for physiotherapy, dietician for nutritional build-up and Dental Services for gingivectomy and oral care.

DISCUSSION

HFS is a rare genetic disorder. ISH and JHF represent both ends of the spectrum.5 ISH and JHF has a prevalence of <1/1000000 cases.7,8 Less than 20 cases of ISH9 have been reported in literature and only about 70 cases of JHF10 have been reported. There is no apparent ethnic or gender predilection.

Originally, ISH and JHF were considered as two distinct entities on the basis of onset, with ISH manifesting in the first few weeks of life and JHF at a later onset. However, subsequent work demonstrated that both forms of hyalinosis were caused by mutations in the CMG2 gene (also known as ANTXR2)2,3, indicating that these disorders are allelic and part of the same phenotypic spectrum, now known as HFS11. While the precise physiologic function of this protein is currently unknown, it was demonstrated to encode a transmembrane protein that links itself to laminin and collagen IV, which suggests alteration in adhesion of the basement membrane to the extracellular matrix and in endothelial cell morphogenesis.12-14 This alteration causes extravasation of hyaline material through the basement membrane to the perivascular space, which would explain histological findings observed in both diseases. The gene is expressed in all tissues with exception of the brain, a finding consistent with normal cognitive development of the affected individuals.15

The more severe form ISH manifests in the first weeks of life by painful swelling of the skin and the large joints as well as edema of the skin. Overtime, affected individuals develop cutaneous tumors over regions of chronic mechanical stimulation, such as the gingiva, the perianal region, the alae nasi, the external ears and the nuchal region of the skull. In addition, patients suffer from flexion contractures of the joints and osteolytic lesions of the long bones and distal phalanges. ISH may lead to death in the first 2 years of life because of chronic malabsorption and diarrhea or pulmonary infection.16,17 Patients suffering from the milder form, JHF, usually do not present with these complications and do not have the infantile painful phase, but do present with cutaneous tumors and debilitating loss of joint mobility. The onset of JHF is later in infancy, usually with severe pain on movement, progressive joint contractures, and pearly papules of the face and neck. These papules eventually coalesce and most often occur on the alae nasi, around the mouth, behind the ears, and the nape.6 The first sign of joint involvement may be difficulty in leg extension. Complete immobility occurs much later at the age of 4 usually with flexion contractures. In contrast to ISH, larger nodules characterize JHF. These large cutaneous tumors occur on the scalp, trunk, and extremities. They may be soft or

A

B

C

D

A B


hard and calcified and may eventually ulcerate. Perianal masses develop and grow slowly. Doughy nodules occur on the hands. The skin may be thickened and hyperpigmented over joints.12 Gingival hypertrophy is prominent leading to irregular teeth growth. Problems with hygiene lead to tooth decay.18 Difficulty in mastication may contribute to malnutrition. Punched out osteolysis usually occurs, especially in the terminal phalanges. Osteopenia, osteoporosis, and short stature have been described. Cognitive development is normal and patients survive into adulthood.

Other disorders that may share similar features with JHF and ISH include Lipoid Proteinosis of Urbach and Wiethe, Winchester Syndrome, and Multicentric Infantile Myofibromatosis. Lipoid Proteinosis is a rare autosomal recessive genodermatosis also characterized by deposition of hyaline material in the skin, mucosa and viscera.19 Patients of this case initially present with inflammatory, vesicular and crusted eruptions and later become diffuse, thickened and waxy in appearance. Patients, however, present with hoarseness, temporal lobe calcification, seizures, learning disabilities and rage attacks. Winchester Syndrome, an extremely rare connective tissue disease is characterized by patches of thickened, hyperpigmented skin with hypertrichosis; gingival hypertrophy, severe joint contractures, generalized osteoporosis, and corneal opacities. In Multicentric Infantile Myofibromatosis, patients present with multiple nodules in the skin, subcutis, muscle, bone and internal organs brought about by hyperproliferation of myofibroblasts. The gums and joints are spared.20-22

Other deposition disorders that may share similar symptoms include Farber Disease, Mucolipidosis and Stiff skin syndrome. Farber Disease is characterized by accumulation of ceramide with progressive tissue destruction particularly of the joints, liver, lungs and nervous system. Patient presents with painful joint contractures, progressive hoarseness and skin nodules over bony prominences. However, patients usually have neurologic involvement and do not present with hyperpigmented patches compared to HFS. Patients die by the age of 2, usually from lung disease.23 Mucolipidosis are a group of autosomal recessive disorders characterized by accumulation of mucolipids and mucopolysaccharides.24

One subtype is I-cell disease characterized with coarse facial features, gingival thickening, joint contractures, dysostosis, organomegaly and recurrent respiratory tract infections. Patients usually die before 7 years old due to congestive heart failure or respiratory tract infections. Another subtype is Pseudohurler polydystrophy, a less severe form of I-cell disease characterized with coarse facial features, joint stiffness, scoliosis, deformities of the hand, corneal clouding, mental retardation and heart disease. Skin findings in HFS usually distinguish from these two. Stiff skin syndrome is characterized by mucopolysaccharide deposition with thickened skin, flexion contractures, recurrent episodes of stiffness and spasms, stiff gait and early deaths.25

The diagnosis of JHF and ISH is based on clinical findings, histopathologic demonstration of hyaline deposition and

molecular genetic testing. The discovery that CMG2 mutations result in the allelic disorders JHF and ISH, provides a noninvasive molecular diagnostic tool, defines these two diseases as being on either end of the same disease spectrum, and highlights novel information on the in vivo function of this integrin-like cell surface molecule and its role in key developmental and physiological processes. Histopathological demonstration of hyaline material in the dermis confirms the clinical diagnosis. The hyaline material appears as an amorphous eosinophilic substance that is Periodic acid Schiff (PAS) positive and Diastase resistant. The spindle-shaped fibroblasts dispersed in abundant amounts of hyaline material are Vimentin positive.5,16,

26 Electron microscopy demonstrates cells filled with fine, fibrillary material with an enlarged endoplasmic reticulum and Golgi apparatus. Internal organ involvement (gastrointestinal tract, lymph nodes, spleen, cardiac muscle, skeletal muscle, thyroid gland, adrenal gland, lungs) with hyaline deposition has been reported with HFS. Intestinal biopsy and imaging may show villous atrophy, edema, lymphangiectasia and hyalinosis. Imaging shows rapid transit time in real-time upper GI imaging studies. Abdominal distention, intractable diarrhea, and elevated fecal alpha-1 antitrypsin levels characterize a protein losing enteropathy in ISH patients. Skeletal survey shows osteopenia, periosteal reactions and luscent lesions.27,28 These skeletal changes usually affect the long bones and axial skeleton. Myopathic changes on muscle biopsy may be evident.6 Appropriate evaluations may be necessary when internal organ involvement is suspected. Risk of cardiomyopathy prompts a cardiovascular evaluation. Hearing, eyesight and mental development are almost always normal.20 MRI of the brain is unremarkable. Serologic studies may demonstrate a normal or slightly elevated ESR, anemia and/or thrombocytosis, immunoglobulin levels may be low and cellular immune responses depressed and biochemical examinations are usually unremarkable.29 CD3 and CD4 lymphocyte subsets and ANA are unremarkable.

There is no specific treatment for HFS. The severity of HFS can vary broadly. The long-term prognosis depends on how severely the patient is affected. Overall, the prognosis is poor, especially for those with systemic involvement. In all patients, it is important to establish the extent through complete nutritional evaluation, evaluation for immune deficiency, evaluations for internal organ involvement and genetic counselling.5,30,31

Pain management is the mainstay treatment in patients with ISH and JHF. Non-steroidal anti-inflammatory drugs (NSAIDs), opiates and possibly gabapentin may be used for pain control.32 Gentle handling is a necessity and splinting of affected joints may provide comfort. Referral to a pain management specialist may be helpful and palliative care may be an option for severe cases. Skin lesions involving the intertriginous areas are prone to dermatitis and secondary skin infections and should be addressed promptly. Lesions that obstruct the airway or interfere with oral intake are particularly problematic. Partial gingivectomy for gingival overgrowth offer short term improvement and may be repeated as necessary.5,6,33 Uslu et.al


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12. Glover MT, Lake BD, Atherton DJ. Infantile systemic hyalinosis: newly recognized disorder of collagen? Pediatrics. 1991; 87:228-234.

13. Katagiri K, Takasaki S, Fujiwara S, Kayashima K, Ono T, Shinkai H. Purification and structural analysis of extracellular matrix of a skin tumor from a patient with juvenile hyaline fibromatosis. J Dermatol Sci. 1996; 13:37-48.

14. Tanaka K, Ebihara T, Kusubata M, Adachi E, Arai M, Kawaguchi N, Utsunomiya J, Miki Y, Hiramoto M, Hattori S, et al. Abnormal collagen deposition in fibromas from patient with juvenile hyaline fibromatosis. J Dermatol Sci. 2009; 55:197-200.

15. Jaouad I, Guaoua S, Haijioui A, et.al. Hyaline fibromatosis syndrome with mutation c.1074delT of the CMG2 gene: a case report. Journal of Medical Case Reports. 2014; 8:291, Sept, 2013.

16. Arbour L, Reilly C, McGillivray B, Prendiville J, Dimmick J. Infantile systemic hyalinosis: A rare syndrome of progressive, painful contractures with peculiar hyperpigmentation and death in infancy. Greenwood, SC: Proceedings of the Greenwood Genetic Center; 2001.

17. Criado GR, González-Meneses A, Cañadas M, Rafel E, Yanes F, De Terreros IG. Infantile systemic hyalinosis: a clinicopathological study. Am J Med Genet A. 2004; 129A:282-5.

in 2007 combined full mouth gingivectomy with consistent oral hygiene and concluded aesthetic and functional success in a two year follow-up.34 Proteolytic enzymes has also been tried for gingival hypertrophy but no significant regression was noted.35 Recurrent excision of cutaneous tumors may be done for cosmesis and improved function.5,27,36,37 Bedford et.al. attempted intralesional steroid injections for dermal lesions with very limited response.35 Raney et.al used chemotherapy, radiotherapy and endocrine-based therapy (antiestrogens and progestational agents) for recurrent or unresectable fibromatosis in children and showed regression of tumors in some of the patients.38 Perianal masses can be resected but with a high recurrence rate. Nakipoglu et.al, in his report of the rehabilitation of 3 siblings with JHF, demonstrated the great value of rehabilitation in preventing contractures and their progression, and in stopping functional loss.39 Gentle physiotherapy of painful contractures can be carried out.33,36 The contractures can also be diminished by capsulotomy, but improvement is transient.5,31 Although the prognosis is good with capsulotomy, the final outcome is that patients are left with deformities.40 Orthopedic Surgery followed by local radiotherapy and physiotherapy may be tried for intraosseous lesions, however, functional prognosis is poor 41. O’ Neill and Kasser stated that operative release is contraindicated, as it can result in activation of hyaline fibromatosis.42 In contrast, Suzuki et.al believe that when gentle physical therapy fails to improve range of motion, surgery is indicated.43 Oral Penicillamine has been used in some cases

and improved joint mobility and flexibility with variable success.30,37 Therapeutic trials with dimethyl sulfoxide, ketotifen and calcitriol have been attempted to decrease contractures, however, improvements were transient.44

Routine nutritional assessment is appropriate. Periodic assessment for gastrointestinal malabsorption may aid in optimizing nutritional status. Nasogastric tube or gastrostomy tube feeding may be considered. Co-management with a nutritionist is recommended. Chronic diarrhea and protein-losing enteropathy with subsequent edema are treated with hydration and albumin infusions; an effective long-term treatment is lacking. The effectiveness of dietary therapies with intestinal lymphangiectasia is not known.45,46

Because of the rarity of JHF and ISH, there is no sufficient experience concerning the effectiveness and long-term results of these treatments. Given the chronic nature of this disorder and the patients having normal intelligence, family counseling should be considered in order to develop coping strategies for both the patient and the immediate family. The Inherited Systemic Hyalinoses remain a stigmatizing, incapacitating and sometimes fatal disorder with no satisfactory treatment.47

The discovery of the responsible mutations provide the basis for diagnostic testing, genetic counseling for families and a potential target for gene therapy in the future. Early recognition is invaluable in providing improved outcome of treatment. We highlight the value of early recognition and diagnosis, genetic counselling and multi disciplinary approach in the management of HFS.


18. Gupta LK, Singhi MK, Bansas M et.al, Juvenile Hyaline Fibromatosis in siblings, Indian J Dermatol Venereo Leprol, 2005.

19. Hamada T. Lipoid proteinosis. Clin Exp Dermatol. 2002; 27:624-9.

20. Zankl A, Bonafé L, Calcaterra V, Di Rocco M, Superti-Furga A. Winchester syndrome caused by a homozygous mutation affecting the active site of matrix metalloproteinase 2. Clin Genet. 2005; 67:261-6.

21. Azzollini J, Rovina D, Gervasini C, Parenti I, Fratoni A, Cubellis MV, Cerri A, Pietrogrande L, Larizza L. Functional characterisation of a novel mutation affecting the catalytic domain of MMP2 in siblings with multicentric osteolysis, nodulosis and arthropathy. J Hum Genet. 2014; 59:631-7.

22. Bhavani GS, Shah H, Shukla A, Gupta N, Gowrishankar K, Rao AP, Kabra M, Agarwal M, Ranganath P, Ekbote AV, Phadke SR, Kamath A, Dalal A, Girisha KM. Clinical and mutation profile of multicentric osteolysis nodulosis and arthropathy. Am J Med Genet A. 2016; 170A:410-7.

23. Alves MQ, Le Trionnaire E, Ribeiro I, Carpentier S, Harzer K, Levade T, Ribeiro MG. Molecular basis of acid ceramidase deficiency in a neonatal form of Farber disease: identification of the first large deletion in ASAH1 gene. Molec. Genet. Metab. 2013; 109:276-281.

24. Cathey SS, Leroy JG, Wood T, Eaves K, Simensen RJ, Kudo M, Stevenson RE, Friez MJ. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands. J Med Genet. 2010; 47:38-48.

25. Loeys BL, Gerber EE, Riegert-Johnson D, Iqbal S, Whiteman P, McConnell V, Chillakuri CR, Macaya D, Coucke PJ, De Paepe A, Judge DP, Wigley F, Davis EC, Mardon HJ, Handford P, Keene DR, Sakai LY, Dietz HC. Mutations in fibrillin-1 cause congenital scleroderma: stiff skin syndrome. Sci. Transl. Med. 2010; 2:23ra20.

26. Al Thani G, Selim ED, An overlap of ISH and JHF: a report of 2 sisters, Gulf J Dermatology Venereol, 1999.

27. Antaya RJ, Cajaiba MM, Madri J, Lopez MA, Ramirez MC, Martignetti JA, Reyes-Múgica M. Juvenile hyaline fibromatosis and infantile systemic hyalinosis overlap associated with a novel mutation in capillary morphogenesis protein-2 gene. Am J Dermatopathol. 2007; 29:99-103.

28. Slimani S, Haddouche A, Haid S, Ladjouze-Rezig A. Juvenile hyaline fibromatosis: Focus on radiographic features in adulthood. Rheumatol Int. 2011; 31:273-276.

29. Nofal A, Sanad M, Assaf M, Nofal E, Nassar A, Almokadem S, Attwa E, Elmosalamy K. Juvenile hyaline fibromatosis and infantile systemic hyalinosis: A unifying term and a proposed grading system. J Am Acad Dermatol. 2009; 61:695-700.

30. Dhingra M, Amladi S, Savant S, Nayak C. Juvenile hyaline fibromatosis and infantile systemic hyalinosis: Divergent expressions of the same genetic defect? Indian J Dermatol Venereol Leprol. 2008; 74:371-374.

31. Ribeiro SL, Guedes EL, Botan V, Barbosa A, Freitas EJ. Juvenile hyaline fibromatosis: A case report and review of literature. Acta Reumatol Port. 2009; 34:128-133.

32. Shieh J, Hoyme E, Arbour L. Hyalinosis, Inherited Systemic, Gene Reviews, 2008.

33. El-Maaytah M, Jerjes W, Shah P, Upile T, Murphy C, Ayliffe P. Gingival hyperplasia associated with juvenile hyaline fibromatosis: A case report and review of the literature. J Oral Maxillofac Surg. 2010; 68:2604-2608.

34. Uslu H, Bal N, Guzeldemir, Pektal et.al., Three siblings with JHF. J Oral Patho Med, 2007.

35. Bedford CD, Sills JA et.al., JHF: a report of two severe cases. J Ped, 1991.

36. Mallet S, Boye T, Hesse S, Fournier B, Guennoc B, Carsuzaa F. Juvenile hyaline fibromatosis. Ann Dermatol Venereol. 2010; 137:364-368.

37. Park KT, Chang DY, Sung MW. Juvenile hyaline fibromatosis. Clin Exp Otorhinolaryngol. 2010; 3:102-106.

38. Rancy B, Evans A, Granowetter L, et.al. Non surgical management of children with recurrent or unresectable fibromatosis.

39. Nakipoglu GF, Dogan A, et.al, JHF: Case presentation (The rehabilitation of 3 siblings). Turk J Med Sci, 2004.

40. Llarade M, Santos-Munoz et.al, JHF, Ped Derm, 2001.

41. Keser G, Karabulut B et.al, Two sibling with JHF: Case reports and review of literature. Clinical Rheuma, 1999.

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43. Suzuki S, Kasahara Y, Seto Y et al, JHF, J Bone Joint Surg, 1992.

44. Mancini GMS, Stojanov L, Willemsen R et.al., JHF: clinical heterogeneity in three patiets, Dermatology, 1999.

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47. Muniz M, Lobo A et.al, Exuberant JHF in two patients, Ped Der, 2006.


Pachydermoperiostosis mimicking acromegalyin an adult Filipino male: Case report

INTRODUCTION

Pachydermoperiostosis is a rare genetic disorder that presents with pachydermia (thickening of the skin), periostosis (formation of new bone), and clubbing.1

Some cases also present with periorbital edema, as well as cutis verticis gyrata, or irregular thickenings on the scalp so named for their resemblance to cerebriform folds.2 Worldwide, the incidence of pachydermoperiostosis is unknown. In the authors’ dermatology clinic at the Outpatient Department of a tertiary government hospital, only three such cases were reported from 2011 to 2015.

Certain endocrinologic disorders may present similarly. When excessive production of growth hormones occurs in childhood while epiphyseal plates are open, the result is gigantism. In adulthood, when epiphyseal plates have fused, this same disorder is referred to as acromegaly.1 Acromegaly is an endocrinologic disorder characterized by excess growth hormones in adults, most often due to a pituitary adenoma. Clinically, pachydermoperiostosis may resemble acromegaly, particularly when the skin of the face and extremities are involved.

Here the authors present the case of a patient with pachydermoperiostosis who was initially misdiagnosed as acromegaly.

CASE REPORT

A 19-year-old Filipino male without any co-morbidities consulted at the Outpatient Department of a tertiary government hospital for thickened skin folds on the scalp and face. In 2009, six years prior to consult, he first noticed gradual enlargement of both feet, manifesting as an increase in shoe size from a size 9 to a size 10 within one year. The patient was 13 years old at this time. He denied any trauma or associated pain, arthralgia, numbness or weakness. No medical attention was sought, and no medications were applied or ingested.

In 2013, he noted gradual enlargement of both hands, manifesting as the inability to fully close his hand and grasp objects properly. No other symptoms were noted, hence no consult or treatment was done.

In 2014, one year prior to consult, the patient then noticed coarsening of facial features, described as “worsening of eyebags.” While getting a haircut, he also noticed irregular, thickened folds on his scalp.

These symptoms led him to consult a private physician, who diagnosed and managed him as a case of elephantiasis. Over time, however, symptoms did not improve to the prescribed antibiotics, and the patient was lost to follow up.

In April 2015, he consulted at tertiary government hospital where he was eventually seen by Endorcinology and Dermatology for further evaluation and co-management. At this time, the patient also complained of blurring of vision, described as difficulty reading. However, he did not report any headache, vomiting, or any other symptoms.

Upon consulting at Dermatology, he was awake, ambulatory and coherent. He weighed 59 kg and stood 1.59 m tall, giving him a BMI of 24.5 kg/m2 and categorizing

Pachydermoperiostosis is a rare genetic disorder. The pathophysiology remains incompletely understood, and various patterns of inheritance have been proposed: autosomal dominant, autosomal recessive and x-linked. Variable penetrance has also been observed. Frequently manifesting with pachydermia, cutis verticis gyrata and enlarged limbs, pachydermoperiostosis may clinically resemble acromegaly. Features more frequently seen in pachydermoperiostosis rather than acromegaly include seborrhea, periorbital edema and clubbing. A 19-year-old Filipino male was referred to our clinic for further evaluation of coarsened skin on the scalp and face. Symptoms started at the age of 13 as insidious, progressive enlargement of bilateral lower extremities and hands, followed by thickening facial features and skin folds on the scalp. On work up, serum cortisol, FSH, LH, growth hormone levels and 75 gram oral glucose growth hormone suppression test were all normal. This led endocrinologists to consider this as a case of “burned out acromegaly,” a condition characterized by spontaneous involution of a pituitary adenoma. However, normal predicted height measurements and histopathologic findings did not support an endocrinologic disorder. Furthermore, cranial imaging and ophthalmologic findings were not consistent with pituitary apoplexy. Periorbital edema, clubbing, and radiographic evidence of periosteal thickening pointed to pachydermoperiostosis. Similar physical findings in the patient’s siblings have prompted further investigation. This case highlights the importance of an exhaustive history and physical exam in any diagnostic dilemma, emphasizing that seemingly simple cases may not always be as straightforward. This report further underscores the importance of a multi-disciplinary approach to patient care, highlighting the role of dermatologists in systemic diseases.

Keywords: pachydermoperiostosis, cutis verticis gyrata, acromegaly

Section of Dermatology, University of the Philippines-Philippine General Hospitala Resident Graduate b Consultant

Source of funding: noneConflict of interest: none Corresponding author: Jessica Nohealani Marie J. Brillantes-QuiazonEmail: [email protected]

Jessica Nohealani Marie J. Brillants-Quiazon, MDa; Claudine B. Yap-Silva, MD, FPDSb


him as overweight. Blood pressure and other vital signs were all normal. There was marked bilateral, periorbital edema. He also presented with bilateral, symmetric enlargement of the hands, and prominent clubbing (Figures 1-3). There was likewise bilateral, symmetric enlargement of the feet, accompanied by Grade II, non-pitting edema. The rest of the systemic physical examamination was normal. Neurologic examination was also normal.

Dermatologic examination revealed irregularly shaped, soft, non-tender folds on the right temporal area of the scalp, as well as multiple erythematous papules and pustules on the forehead, both cheeks and upper third of the back. There were some visible open comedones on the nose. (Figures 4-5)

Work-up for this patient included measurement of follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone and insulin like growth factor-1 (IGF-1) levels. A skeletal survey and cranial MRI were also ordered, and a 4 mm punch biopsy of the indurated skin on the right leg was done. The patient was also referred to ophthalmology for evaluation.

Contrary to expected results, FSH, LH, testosterone and IGF-1 levels were all normal. Following this, a 75 gram oral

Figure 1. Whole body image of the patient showed bilateral, symmetric enlargement of upper and lower extremities.

glucose growth hormone suppression test was ordered.Cranial MRI results were normal. The pituitary and the

sella appeared normal in size and homogenous, without any filling defects or intracranial masses. Skeletal survey showed a mesocephalic skull, and an intact sella and clinoids. There was no prognathism. Chest x-ray was normal. However, symmetric, periosteal thickening was seen in the shafts of both radii, ulnae, and tibae. The cortices of the metatarsal shafts of both big toes were also thickened. These radiographic findings were compatible with mild, hypertrophic pachydermoperiostosis.

Histologic findings of the skin segment obtained from the right leg showed a mild, superficial, perivascular lymphocytic infiltrate and slight widening of the collagen bundles in the dermis, consistent with papillomatous epidermal hyperplasia. Sebaceous glands were not noted to be prominent, nor were the collagen bundles or fibroblasts increased.

Formal evaluation by an ophthalmologist confirmed the presence of bilateral periorbital edema. He was diagnosed with bilateral error of refraction, but all other findings were normal.

At this time, endocrinologists proposed that the patient might be in a state of burned out acromegaly, a condition


Figure 2. Close up view of the hands showed enlarged, “sausage-like” digits in the absence of any nail changes.

Figure 3. Close up view of the thumbs showed prominent clubbing.Figure 6. Gingival hyperplasia, macroglossia and prognathism, typical findings in acromegaly, were absent in this patient.

Figure 5. View of the right temporal area of the scalp showed regular, cerebriform folds or cutis verticis gyrata. The folds were soft, non-tender, and the overlying hair appeared normal in color, texture and distribution.

Figure 4. The face showed deepening of the forehead, glabellar, infraorbital, nasolabial, and labiomental grooves. Very notable was the presence of bilateral palpebral edema. There were also multiple erythematous papules and atrophic scars on the forehead cheeks and neck indicative of acne vulgaris.

characterized by spontaneous apoplexy of the pituitary gland.

DISCUSSION

Coarsened facial features, cutis verticis gyrata and enlarged hands and feet may present in both pachydermoperiostosis and acromegaly. For this reason, an exhaustive and analytic review of the history, physical exam and laboratory findings are necessary to differentiate the two.

The consistently normal hormone levels in this patient was very remarkable. In acromegaly patients, growth hormone measurement may prove challenging because of its pulsatile

nature and short half-life. However, insulin-like growth factor-1 has excellent correlation with growth hormone, and is the most reliable biochemial indicator of acromegaly. Therefore, the normal IGF-1 level found in this patient was a reliable indicator of normal growth hormone levels.

As a confirmatory test, the 75 or 100 gram oral glucose tolerance test can be done. This entails measuring growth hormone levels 1-2 hours after administering oral glucose. Normally, growth hormones are suppressed, and failure to do so is diagnostic of acromegaly. Two hours after glucose ingestion, the patient’s growth hormone levels were markedly below normal, ruling out acromegaly.


Nonetheless, because the patient complained of blurring of vision and because most cases of acromegaly are caused by a pituitary adenoma, the authors thought it prudent to evaluate for an intracranial mass. However, neurologic exam was normal, and cranial MRI did not detect any intracranial mass. Furthermore, ophthalmologic examination was normal except for bilateral error of refraction and bilateral periorbital edema. A patient with a pituitary mass would be expected to have visual field cuts, which this patient did not have. Finally, patients with acromegaly present with tortuous retinal vessels3, and these were not seen in the patient.

Gingival hyperplasia, macroglosia and prognathism are also consistent with acromegaly. These findings were not present, and radiographic imaging of the skull confirmed the absence of prognathism. (Figure 6)

Studies have described cases of acromegaly where the pituitary tumor undergoes infarction and necrosis, and resolves spontaneously without intervention.4 This pituitary apoplexy may manifest as a normally appearing sella on imaging. However, following this necrosis, the space previously occupied by the pituitary would persist as a filling defect containing cereborspinal fluid. On sagittal views of cranial MRI images, this was not seen. Furthermore, pituitary apoplexy is rarely associated with complete normalization of growth hormone levels.5

On histopathology, prominent sebaceous glands and increased fibroblasts are expected in patients with acromegaly.6 These characteristics were notably absent in the patient’s skin biopsy.

Pachydermoperiostosis, on the other hand, roughly translates to “thickening of the skin and bones.” It is a rare genetic disorder that may clinically mimic acromegaly.

While the patient’s initial appearance may suggest acromegaly, an analytic review of the history suggests otherwise. The patient’s symptoms began at 13-years-old, when the epiphyseal plates are still expected to be open. If this were truly a condition marked by excess growth hormone, more appropriately called gigantism in a pediatric patient rather than acromegaly, the manifestation would be an increase in height. Unfortunately, the patient’s anthropometric records were neither complete nor available for review. Only his foot size had been reliably documented, however this is not a routinely measured parameter in growing children, and normograms for them are non-existent. In an effort to compensate for this, the authors computed his expected height

based on both his parents’ height. The investigators saw that, at a current height of 158.5 cm, he did not even meet his expected height of 169 cm. This made growth hormone excess unlikely.

Furthermore, studies have described a greater incidence of periorbital edema, clubbing and seborrhea among pachydermoperiostosis patients compared to acromegaly patients.2 All these were present in this patient.

Radiographically, symmetric periosteal thickening was seen in the cortices of both radii, ulnae, tibiae, and metatarsal shafts. This is also consistent with pachydermoperiostosis.

The Borochowitz criteria has been proposed to establish the diagnosis of pachydermoperiostosis.3 This is comprised of family history of the same condition, clubbing, hypertrophic skin changes, and bone pain or radiographic changes. This patient presented with coarsened facial and scalp skin, clubbing, and had radiographic evidence of periostosis, satisfying three out of the four requirements. The absence of any opthalmologic or neurologic symptoms, hormonal level abnormalities, histopathologic changes suggestive of an endocrinopathy, prognathism and intracranial mass further underscores that this is a case of pachydermoperiostosis rather than acromegaly.

CONCLUSION

Pachydermoperiostosis and acromegaly have remarkable clinical overlap. However, clubbing and periostosis without prognathism, an enlarged sella turcica or abnormal levels of growth hormone point more towards pachydermoperiostosis.2

Both primary and secondary forms of pachydermoperisotosis may exist. Currently, the patient is undergoing further tests geared towards identifying a possible malignancy to rule out a cause of secondary pachydermoperiostosis. Appropriate management of acne vulgaris has likewise been started, and the possibility of plastic surgery to correct coarsened facial folds has been discussed with the patient. The patient’s brothers, who present with similar but milder clinical features, have been advised and encouraged to undergo work up.

This case highlights the complex nature of dealing with diseases that span both the pediatric and adult ages. History and examination findings must always be taken with the appropriate context. This case likewise demonstrates how a multi-disciplinary approach is most beneficial for patients, and emphasizes the role dermatologists play in diagnosing and managing systemic diseases.

REFERENCES

1 Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw Hill; 2012. 3076.

2. Sandoval AR, Robles BJ, Llanos JC, Salvador P, Dardon JD, Harrison RM. Cutis verticis gyrata as a clinical manifestation of Touraine-Solente-Gole’ syndrome (pachydermoperiostosis). BMJ Case Rep [Internet]. 2013 Jul [cited 2015 Jul]; undefined. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736327/

3. Supadeeptha C, Shandilya S, Reddy K, Satyprasad J. Pacherdermoperiostosis – a case report of complete form and literature review. JCOT [Internet]. 2014 Mar [cited 2015 Jul]; 5(1): 27-32. Available from: http://www.journal-cot.com/article/S0976-5662(14)00009-5/fulltext

4. Login I, Santen RJ. Empty sella syndrome: sequela of the spontaneous remission of acromegaly. Arch Intern Med [Internet]. 1975 Nov [cited 2015 Jul]; 135(11): 1519-21. Available from: http://jamanetwork.com/journals/jamainternalmedicine/article-abstract/585102

5. Gupta M, Lehl SS, Singh R, Sachdev A. Touraine-Solente-Gole’ syndrome. BMJ Case Rep [Internet]. 2011 Sep [cited 2015 Jul]; undefined. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3185449/

6. Calonje JE, Brenn T, Lazar A, Mckee P. McKee’s Pathology of the Skin. 4th Ed. Philadelphia: Saunders; 2011. 1906.


Mutilating pyoderma gangrenosum in an infant: A case report

INTRODUCTION

Pyoderma gangrenosum (PG) is a rare, inflammatory, ulcerative skin condition of unknown etiology. It has been reported that around 4% of the cases occur in

infants and children.1,2 The diagnosis of PG is established by the clinical presentation and laboratory findings to exclude all alternative diagnoses. In children, the most common sites of involvement are the head, face, buttocks, genital and perianal area. The most common type of infantile PG reported to date is the ulcerative type. Ulcerative PG evolves as an inflammatory pustule that rapidly ulcerates. It can occur at sites of trivial trauma such as needlestick, inoculation site and insect bites (the pathergy phenomenon). The lesions progress rapidly into a marginated and undermined ulcer with distinct borders and violaceous edge. It can also be excruciatingly painful. Typically, a thin atrophic, cribriform scar is left after healing.2 Atypical presentations, such as genital involvement, have been described previously in case reports but to our knowledge, the destruction of cartilage in cases of pyoderma gangrenosum has not yet been reported.

CASE REPORT

A previously well 6-month-old boy developed several erythematous papules on the left ear with no other accompanying symptoms. The lesions rapidly evolved into ulcers, which healed with scars. However, new papules appeared on the right ear, neck and nose despite oral antibiotics. Serum zinc levels were low and he was also given oral zinc. The chest x-ray showed paratracheal densities and patient was started on triple anti-Koch’s.

Four months later, similar papules appeared on the nose and penis. These, later on, became necrotic ulcers and healed with the destruction of the nasal cartilage (Figure 1a) and disappearance of the penile shaft (Figure 1b). CBC showed leukocytosis and thrombocytosis. The culture of the oral mucosa revealed heavy growth of Enterobacter cloacae while the culture of the perianal area revealed heavy growth of Klebsiella oxytoca. Both specimens were negative for fungi or acid-fast bacilli. He was given topical and oral antibiotics. The ulcers improved and resolved with hyperpigmentation and atrophic scarring.

At 1 year of age, he developed fever and cough. There was again the appearance of new lesions despite the continuous treatment of zinc, oral and topical antibiotics and anti-Koch’s regimen. Chest x-ray showed pneumonia so he was given IV antibiotics. Chest CT scan revealed thickened tracheal wall with suspicious bronchial wall thickening and segmental atelectasis of the right lobe. Rapid plasma reagin (RPR) test was non-reactive but treponemal antibody (FTA-ABS) test was positive. He was given Penicillin G (54,000 IU mkd) for 10 days. New lesions were noted to appear on sites where the diaper was tight. A skin biopsy taken from the erythematous border of an ulcer on the sacral area showed focal loss of epidermis and dermal necrosis, moderate superficial to deep dermal perivascular and periadnexal mixed cell infiltrate consisting of lymphocytes, histiocytes, neutrophils, and few eosinophils (Figure 2a-b). Histopathological assessment was “consistent with pyoderma gangrenosum.” Prednisone (0.6 mkd) was started and improvement of the ulcers was noted. Two weeks later, he developed a productive cough with difficulty of breathing and was subsequently admitted. There were new ulcers and erosions noted over the arms, ears and neck. He was intubated and was started on IV antibiotics and hydrocortisone (40 mkd). Chest x-ray revealed pneumonia. The patient had anemia and blood transfusions were done. The previous areas of trauma including the sites of intravenous line on the scalp (Figure 1c), endotracheal tube insertion and the neck, and over areas where adhesives were applied developed lesions. The lesions later on dried up and IV hydrocortisone was shifted to tapering doses of oral prednisone. The lesions completely resolved. The patient was discharged.

Pyoderma gangrenosum (PG) is a rare, inflammatory, ulcerative skin condition characterized by an ulcer with advancing violaceous border, negative cultures, unresponsiveness to antibiotics, the phenomenon of pathergy and histopathology showing neutrophilic infiltration. It usually occurs in all age groups but is rare among infants and very young children. A 6-month-old boy presented with papules which evolved into necrotic ulcers on the ears, perioral area, nose, neck, inguinal, scrotal, intergluteal and genital areas. The destruction of the ear cartilage made the clinical picture unusual and to the best of our knowledge, has rarely been reported as a feature of pyoderma gangrenosum in published case reports. The patient responded well to Hydrocortisone IV and tapering doses of oral prednisone. The long term effects in patients who developed infantile PG are still unknown and further follow-up of these unusual cases is recommended.

Keywords: Pyoderma Gangrenosum, neutrophilic dermatosis, pediatric dermatology

Department of Dermatology, University of Santo Tomas Hospitala Consultant dermatologist, The Medical City b Consultant dermatologist and dermatopathologist

Source of funding: noneConflict of interest: none Corresponding author: Mary Rose Lim-del MindoEmail: [email protected]

Mary Rose Lim-del Mindo MD, DPDSa; Daisy King-Ismael MD, FPDSb


DISCUSSION

Pyoderma gangrenosum is protean in its clinical expression, with variable clinical presentation according to type and stages of the disease.3 The four morphological variants of PG are ulcerative, pustular, bullous, and vegetative. As mentioned earlier, the most common type of infantile PG is ulcerative. The buttocks or perineum are commonly involved.2 Pyoderma gangrenosum in childhood demonstrate certain characteristic features. In children, the ulcers usually begin as pustules.4 In our patient, the lesions started as papules. In children, the lesions are also seen on the head and face, buttocks, perianal and genital regions.4 Infants tend to have perianal or genital involvement.5 In literature, the involvement of cartilage was never reported. In our patient, the major lesions of PG occurred on the ears, nose, mouth, perioral area, neck, inguinal, intergluteal and genital areas. The phenomenon of pathergy (the development of a new inflammatory lesion at the site of trauma) is described in 25% of patients with ulcerative pyoderma gangrenosum.6 In our

patient, new ulcers appeared over sites of the intravenous line, endotracheal tube insertion and over areas where adhesives were applied. The key point in making a diagnosis of PG is the exclusion of other causes of cutaneous ulcers through biopsy, culture, and clinical acumen.7 The lesions in our patient presented with sharply marginated, undermined border.

Initially, our patient had been treated as a case of acrodermatitis enteropathica due to the low zinc levels. However, lesions progressed despite prolonged zinc supplement. In acrodermatitis enteropathica, zinc replacement therapy results in rapid clinical improvement and takes only a few days to a week to detect a significant change in serum zinc levels.8 The patient also completed the standard 6 months regimen of anti-Koch’s and was given several IV and oral antibiotics, however, the patient still had recurrent cough and colds. He had a positive treponemal test and a negative nontreponemal test. However, a single positive treponemal test cannot be solely relied upon as a means of diagnosing syphilis. The characteristic lesions of syphilis should also be

Figure 1. Ulceration and destruction of the nasal cartilage (a). The ulceration in the genital area has a sharply marginated, undermined violaceous border (b). Crusted ulcer on an IV site demonstrating pathergy (c).

Figure 2. Histopathologic findings of ulcerated epidermis with moderately dense superficial to deep dermal perivascular and periadnexal mixed cell infiltrate consisting of lymphocytes, histiocytes, neutrophils, and few eosinophils (a) (H and E, 100x). Higher magnification shows a predominantly neutrophilic infiltrate consistent with pyoderma gangrenosum (b) (H and E, 400x).


present. In a study by Peter and colleagues, their findings illustrated that false-positive or borderline FTA-ABS results can also be associated with a wide variety of viral infections including adenoviruses, coxsackievirus B, cytomegalovirus, herpes simplex virus (genital infection), influenza, mumps, parainfluenza, rubella, and rubeola.9,10 Our patient presented with a persistent cough and colds unresponsive to anti-Koch’s and antibiotics. The positive treponemal test could be a false positive result.

The histopathological findings of pyoderma gangrenosum are non-specific. Biopsies taken from the center of the lesion shows a central necrotizing suppurative inflammation, usually with ulceration and those taken from the peripheral areas show a peripheral lymphocytic vascular reaction comprising perivascular and intramural lymphocytic infiltrates, usually without fibrin deposition or mural necrosis. Tissue neutrophilia with epithelial undermining and ulceration in the absence of leukocytoclastic vasculitis, fungal, bacterial or mycobacterial organisms highly implicates pyoderma gangrenosum.12 Histopathologic findings in our patient from a specimen taken from the erythematous border of an ulcer on

REFERENCES

1. Kechichian E, Haber R, Mourad N. Pediatric pyoderma gangrenosum: a systematic review and update. Int J Dermatol. 2017; 56:486-495.

2. Mc Aleer M, Powell F, Devaney D, O’Donell B. Infantile pyoderma gangrenosum. J Am Acad Dermatol. 2008; 58:S23-8.

3. Powell F, Hackett B. Pyoderma gangrenosum. In: Wolff K, Goldsmith L, Katz S, Gilchrest B, Paller A, Lefell D, eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York: Mc Graw-Hill Co. Inc. 2008; 296-302.

4. Bhat R, Shetty S, Kamath G. Pyoderma gangrenosum in childhood. Int J Dermatol 2004; 43:205-207.

5. Callen J. Seminar: Pyoderma gangrenosum. Lancet. 1998; 351:581-85.

6. Ahmadi S, Powell F. Pyoderma gangrenosum: uncommon presentations. Clin Dermatol. 2005; 23:612-620.

7. Miller J, Yentzer B, Clark A, Jorizzo J, Feldman S. Reviews: Pyoderma gangrenosum: A review and update on new therapies. J Am Acad Dermatol. 2010; 62:646-54.

the sacral area, revealed focal loss of epidermis and dermal necrosis and with higher magnification showed moderate superficial to deep dermal perivascular and periadnexal mixed cell infiltrate consisting of lymphocytes, histiocytes, neutrophils and few eosinophils.

PG is associated with systemic illnesses in about 50% of the adult cases, however, newborns rarely present with systemic diseases. Involvement of the lungs is the most common extracutaneous manifestation of PG. It is characterized by patchy infiltrates or interstitial pneumonitis.12 Our patient had episodes of cough and colds with interstitial infiltrates seen radiographically that was diagnosed to be tuberculosis and pneumonia.

Since PG is a rare condition, most treatment recommendations are based on experience. These often include combinations of oral corticosteroids and other medications that can inhibit the immune system.7 Systemic steroid therapy (1-2 mg/kg per day) remains the treatment of choice in most patients.5,12 Corticosteroids remain the cornerstone of management in pediatric PG.1 Our infant’s new lesions responded well to prednisone.

8. Maverakis E, Fung MA, Lynch PJ, Draznin M, Michael DJ, Ruben B, Fazel N. Review: Acrodermatitis enteropathica and an overview of zinc metabolism. J Am Acad Dermatol. 2007; 56:116-24.

9. Zanto SN, Montana H. Changing algorithms in syphilis laboratory diagnosis. Elsevier Clinical Microbiology Newsletter. 2010; 32:8:59-64.

10. Peter C, Thompson M, Wilson D: False-positive reactions in the rapid plasma reagin-card, fluorescent treponemal antibody-absorbed, and hemagglutination treponemal syphilis serology Tests. J Clin Microbiol. 1979; 9(3):369-372.

11. Magro C, Crowson A, Dyrsen M, Mihm Jr, M, Cutaneous manifestations of nutritional deficiency states and gastrointestinal disease. In: Elder D, et al. Lever’s Histopathology of the Skin. 10th ed. Philadelphia: Lippincott Williams & Wilkins. 2009; 411-412.

12. Reichrath J, Bens G, Bonowitz A, Tilgen W. Clinical Review: Treatment recommendations for pyoderma gangrenosum: An evidence-based review of the literature based on more than 350 patients. J Am Acad Dermatol 2005; 53:273-83.


Bubbly lupus: A case of a Filipino woman with bullous systemic lupus erythematosus successfully treated

with prednisone and hydroxychloroquine

INTRODUCTION

Most patients with systemic lupus erythematosus (SLE) develop cutaneous manifestations. However, bullous skin lesions are uncommon and are found in less than

5% of such patients.1,2 Bullous systemic lupus erythematosus (BSLE) is a sub-epidermal blistering disease that occurs in a group of patients with systemic lupus erythematosus (SLE).2-4 It is characterized histologically by subepidermal bullae with the predominance of neutrophilic infiltrates and the deposition of immunoglobulins and C3 on the basement membrane zone including circulating antibodies to Type VII collagen 5.

CASE SUMMARY

The patient is a 21-year-old woman who was diagnosed to have systemic lupus erythematosus since two years prior to consult based on the presence of a malar rash, photosensitivity, oral ulcers, arthritis, telogen effluvium, anemia, presence of anti-nuclear antibodies(ANA), and proteinuria. She

was initially maintained on prednisone 40mg per day and hydroxychloroquine 200mg/tablet once a day that controlled the manifestations of SLE.

Six weeks prior to consult, the patient noted multiple pruritic vesicles on the neck arising from normal skin. The lesions increased in size and number, with bullae appearing on the face, trunk, and hands, upper and lower extremities. The lesions became crusted and eroded. The patient sought consult at a health center and was initially diagnosed with varicella zoster. She was then referred to a different hospital where she was admitted and treated as a case of bullous impetigo. The patient was given oral ofloxacin, oral paracetamol and mupirocin ointment. The prednisone and hydroxychloroquine were discontinued. The lesions eventually dried up leaving multiple hyperpigmented macules and patches without scarring. No new lesions were noted and the patient was discharged after one and a half weeks.

Two weeks prior to consult, there was a recurrence of vesicular lesions on both upper and lower extremities with no associated systemic symptoms. The patient sought consult with her rheumatologist who resumed the patient’s prednisone at 40mg/day and hydroxychloroquine 200mg/tablet once a day. She was referred to our institution for further evaluation.

On physical examination, there were multiple tense vesicles and well – defined irregular erythematous to hypopigmented macules and patches with crusts and erosions on the face, neck, trunk, and bilateral upper and lower

Grace Monica P. Ibaviosa, MDa; Johanna O. Flordelis, MDb; Johannes F. Dayrit, MD, FPDSc

Bullous systemic lupus erythematosus (BSLE) is an autoimmune-mediated, chronic, widespread, non-scarring, sub-epidermal blistering skin disease. It is typically caused by autoantibodies against type VII collagen. BSLE is an uncommon manifestation of SLE and is found in less than 5% of SLE cases.

We report a case of a 21-year-old woman with a two-year history of systemic lupus erythematosus who developed multiple pruritic vesicles on the neck six weeks prior to consultation. The lesions increased in number, size, and distribution, becoming bullae on the face, trunk, upper and lower extremities. Nikolsky and Asboe – Hansen signs were negative. Mucosal involvement and visceral organ impairment were not identified on physical examination. A 4-mm skin punch biopsy of a vesicle showed a subepidermal blister. Direct immunofluorescence of perilesional skin revealed linear deposits of IgG (+1), C3 (+1), IgM (+2) and granular fibrinogen (+2) at the basement membrane zone, consistent with bullous systemic lupus erythematosus. Oral prednisone 40 mg/day and hydroxychloroquine 200mg once a day were prescribed. The lesions became dry and flat after two weeks and no new eruption was noted after three months.

Patients with BSLE manifest with a widespread symmetrical distribution of vesicular skin lesions frequently favoring the upper part of the trunk, flexural and extensor aspects of the upper extremities, neck and face but may occur anywhere on the cutaneous surface. Treatment with corticosteroids and hydroxychloroquine was effective in our case. The prognosis of BSLE is good with variable duration characterized by spontaneous exacerbations and remissions influenced more by the systemic disease rather than by the eruption hence the need to follow closely the systemic disease activity.

Keywords: bullous systemic lupus erythematosus, lupus, prednisone, hydroxychloroquine

Department of Dermatology, Research Institute for Tropical Medicinea,b Resident c Consultant

Source of funding: noneConflict of interest: none Corresponding author: Grace Monica P. Ibaviosa, MDEmail: [email protected]


extremities (Figure 1). There were no mucosal lesions. Nikolsky and Asboe Hansen signs were negative. No extracutaneous manifestations of SLE were noted on physical examination.

Our initial impression was bullous systemic lupus erythematosus. A 4-mm skin punch biopsy of a vesicle was done and revealed focal atrophy of the epidermis with vacuolar alteration of the basal cell layer and a sub-epidermal blister containing fibrin, lymphocytes and many neutrophils. There was thickening of the basement membrane zone and the dermis revealed numerous pigment-laden macrophages and a mild superficial perivascular and periadnexal inflammatory infiltrate consisting of lymphocytes, neutrophils and few eosinophils (Figure 2). These findings were consistent with BSLE.

Figure 1. Few tense vesicles and well-defined, irregular erythematous to hypopigmented macules and patches with crusts and erosions on the neck, trunk, upper and lower extremities. Inset: A close up of the tense vesicle

Figure 2. Histopathology of skin punch biopsy specimen (Hematoxylin & Eosin stain) a:10x closer view of the infiltrates within blister; b:40x magnification reveals fibrin, lymphocytes and many neutrophils within the blister)

Direct immunofluoresence of perilesional skin showed linear deposits of IgG (+1), C3 (+1), IgM (+2) and granular fibrinogen (+2) on the basement membrane zone, also consistent with BSLE (Figure 3).

Prednisone 40 mg/day and hydroxychloroquine 200mg/tablet once a day were continued. There was flattening and drying of the lesions after two weeks. Prednisone was tapered down by her rheumatologist to 5mg/tab once a day and hydroxychloroquine was tapered down to 50mg/day. Follow-up after three months revealed no new eruptions of vesicles and bullae while maintained on the said regimen (Figure 4). No scarring from the previous lesions were noted.

a b


Figure 3. Direct Immunofluouresence showing linear deposits of (a) IgG (+2), (b) C3 (+1), (c) IgM (+2) and (d) fibrinogen (+2).

Figure 4. Flattening and hyperpigmentation of lesions after 3 months of treatment with Prednisone and Hydroxychloroquine.

DISCUSSION

Systemic lupus erythematosus is an autoimmune disease in which organs and cells undergo damage initially mediated by tissue-binding autoantibodies and immune complexes.8 The disease usually affects women in 80-90% of the cases.6 Seventy-six percent of patients develop cutaneous manifestations during the course of SLE.3,5 The occurrence of bullous skin lesions in patients with SLE is a well recognized but rare phenomenon and manifests in the second through third decades of life.7 It occurs in less than 5% of SLE cases.8

In the Philippines, there were 34 cases from 2011-2016. The pathology of bullous SLE (BSLE) is thought to be associated with antibodies against the non-collagenous domain of collagen VII,

as well as other antibodies against different components of the basement membrane.8-12 Camisa and Sharma (1988) have given the following criteria in diagnosing BSLE: a) a diagnosis of SLE based on fulfillment of the American Rheumatism Association (ARA) criteria for SLE, b) acquired, non-scarring bullous eruption arising on, but not limited to, sun-exposed areas, c) histologic evidence of a sub-epidermal blister with neutrophilic infiltrates at the basement membrane zone, d) direct immunofluorescence (DIF) of perilesional skin showing IgG, IgA, IgM, and C3 deposits at the basement membrane zone, and (e) evidence of circulating basement membrane zone autoantibodies to type VII collagen.7,8,13 The diagnosis of bullous systemic lupus erythematosus type 1 requires all of the following. But types 2 and 3 could be diagnosed with the

a b

dc


first four criteria.14 Our patient fulfilled the first four criteria. Investigations for the presence of autoantibodies to type VII collagen was not done.

BSLE is characterized by a widespread, vesiculobullous eruption that is nonscarring.7,15,16 Vesicles and bullae are tense and fluid – filled with an erythematous or urticarial background.17 Clinically, the vesiculobullous lesions are predominantly on the face, neck and upper trunk but may be more widespread, as seen in our patient.13

Dapsone is an effective treatment for BSLE, based on a number of studies, and has been shown to have an efficacious response even if given in low doses.3 It has anti-inflammatory action, mainly by inhibiting the functions of polymorphonuclear leukocytes and of complement activation.3,5,7,8 Our patient was not started on Dapsone because there was a three-fold increase in the creatinine of our patient as well as there was noted improvement with Prednisone and Hydroxychloroquine. As dapsone often causes renal and hepatic toxicity, corticosteroid alone or with low dose dapsone might be the treatment of choice for BSLE.3 Corticosteroids are usually required to improve clinical symptoms and laboratory abnormalities, and are still the mainstay for inducing remission in SLE patients.3 Some studies have shown patients who respond effectively to systemic corticosteroids, although they require relatively high doses. Corticosteroids are used to improve clinical and laboratory abnormalities and a mainstay in inducing remission in patients with SLE. Several studies have shown that a short course of moderate-dose corticosteroids can not only treat active disease but can also help prevent flares in clinically stable but serologically active patients.19 Corticosteroid treatment, however, is not without its complications.18 Patients are at

risk of a myriad of different problems like fluid retention, hypertension, blurred vision, and infection.18 It can contribute to atherosclerosis, through adverse effects on metabolic factors such as body fat distribution, blood pressure and glucose metabolism.18 Other medications that have been studied as treatment options are methotrexate, hydroxychloroquine, cyclophosphamide and mycophenolate mofetil. Azathioprine and biologic agents such as rituximab however, mostly showed that they are useful in controlling the cutaneous lesions and disease activity of SLE.3 Hydroxychloroquine is the most useful antimalarial drug in the treatment of mucocutaneous, musculoskeletal and constitutional symptoms (such as fatigue and fever) in SLE.18 It has a good safety profile and toxicity is infrequent, mild and largely reversible.18

The prognosis of BSLE is good with variable duration and may be characterized by spontaneous exacerbations and remissions.7 The prognosis is influenced more by the systemic disease rather than by the eruption hence there is a need to follow closely the systemic disease activity.7

CONCLUSION

Patients with BSLE manifest with a widespread symmetrical distribution of vesicular skin lesions frequently favoring the upper part of the trunk, flexural and extensor aspects of the upper extremities, neck and face but may occur anywhere on the cutaneous surface. Treatment with the combination of corticosteroids and hydroxychloroquine was effective in controlling the lesions and manifestations of SLE in our case. BSLE has a good prognosis which is influenced more by systemic disease activity and must be followed closely.7

REFERENCES

1. Shirahama S, Yagi H, Furukawa F, Takigawa M. A Case of Bullous Systemic Lupus Erythematosus. Dermatology. 1994; 189(suppl I):95-96.

2. Yung A, Oakley A. Bullous systemic lupus erythematosus. Aust J Dermatol. 2000, vol 41, no 4, pp. 234-237.

3. Duan L, Chen L, Zhong S, Wang Y, Huang Y, He Y, Chen J, et al. Treatment of Bullous Systemic Lupus Erythematosus. Journal of Immunology Research, 2014 Aug. Volume 2015.

4. Rothfield N, Sonthelmer RD. Lupus erythematosus; systemic and cutaneous manifestations. Clinics in Dermatology, 2006, vol 24, no 5, pp 348-362.

5. Grover C, Khurana A, Sharma S, Singal A. Bullous Systemic Lupus Erythematosus. Indian J Dermatol. 2013 Nov-Dec; 58(6):492.

6. Madiyal A, Ajila V, Hegde S, Babu S, Alva P. Bullous Systemic Lupus Erythematosus: Report of a rare case with oral manifestations and literature review. Balkan Military Medical Review 2015; 18(4):134-139.

7. Wojnarowska F, Briggaman RA. Management of Blistering Diseases. Springer Science + Business Media, B.V. 1990; 18:264-275.

8. Dos-Santos CE, Velho PHI, Marques FMM, Werner B, Aragao SC, Filho AR. Bullous systemic lupus erythematosus in a pregnant woman: a case report. Rev Bras Reumatol. 2013; 53(5):438-440.

9. Tincopa M, Puttgen KB, Sule S, et al. Bullous Lupus: An Unusual Initial Presentation of Systemic Lupus Erythematosus in an Adolescent Girl. Pediatric Dermatology. 2010; 4:373-6.

10. Stith RH, Erickson QL, et al. Bullous Eruption: A Manifestation of Lupus Erythematosus. Cutis. 2003; 72:31-7.

11. Fujimoto W, Hamada T, Yamada J, Matsuura H, Iwatsuki K. Bullous Systemic Lupus Erythematosus as an Initial Manifestation of SLE. J Dermatol. 2005; 32:1021-27.

12. Ludgate MW, Greig DE. Bullous systemic lupus erythematosus responding to dapsone. Australas J Dermatol. 2008; 49:91-3.

13. Aswani V., Vaz B., et al. Bullous Systemic Lupus Erythematosus. Indian J Dermatol, Venerol and Leprol. 1993; 59(2):97-100.

14. Yogarajah, M, Sivasambu, B, Jaffe EA. Case reports in Rheumatology Volume 2015. Article ID 930683.

15. Vijayalakshmi AM, Jayavardhana A. Bullous Systemic Lupus Erythematosus and Lupus Nephritis in a 10-year-old Boy. Indian Pediatrics. November 2007. Vol 44; 861-863.

16. Eckman JA, Mutasim DF. Bullous Sustemic Lupus Erythematosus With Milia and Calcinosis. Cutis. July 2002; 70;31-34.

17. Sáez-de-Ocariz M, Espinosa-Rosales F, Lopez-Corella E, de Leon-Bojorge B. Bullous lesions as a manifestation of systemic lupus erythematosus in two Mexican teenagers Pediatric Rheumatology. 2010; 8:19.

18. Amissah-Arthur MB, Gordon C. Contemporary treatment of systemic lupus erythematosus: an update for clinicians. Therapeutic Advancements in Chronic Disease, July 2010; 1(4):163-175.


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