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DERMATOLOGICA SINICA 30 (2012) 51e56

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Dermatologica Sinica

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CASE REPORT

Concomitant occurrence of acneiform eruption, alopecia areata, and urticariaduring adalimumab treatment in a patient with pustulosis palmoplantaris:Case report and literature review

Guan-Yi He, Tsen-Fang Tsai*

Department of Dermatology, National Taiwan University Hospital, Taipei, Taiwan

a r t i c l e i n f o

Article history:Received: Sep 24, 2010Revised: Nov 9, 2010Accepted: Apr 11, 2011

Keywords:acneadalimumabalopecia areataurticariaustekinumab

* Corresponding author. Tsen-Fang Tsai, DepartmeTaiwan University Hospital, No. 7 Chung-Shan SoutTel.: þ886 2 23562141; fax: þ886 2 23934177.

E-mail address: tftsai@yahoo.com (T.-F. Tsai).

1027-8117/$ e see front matter Copyright � 2012, Tadoi:10.1016/j.dsi.2011.09.010

a b s t r a c t

Adalimumab is a fully human immunoglobulin G1 monoclonal antibody against tumor necrosis factor(TNF)-a that is increasingly used for the treatment of many autoimmune diseases. However, it has alsobeen reported that adalimumab can induce many adverse cutaneous reactions, including paradoxicalpsoriasiform eruptions. We describe a patient with pustulosis palmoplantaris who developed fourcutaneous adverse reactions, including eczematous lesions, acneiform eruption, alopecia areata, andurticaria during adalimumab treatment. A common histopathological finding in these acneiform andurticarial lesions was the presence of eosinophilic infiltrates. Some authors assume that cross-regulationbetween TNF-a and interferon-a may contribute to development of a clinical spectrum of cutaneousreactions in predisposed individuals undergoing anti-TNF therapy. The use of different biologics,including adalimumab, etanercept, and ustekinumab, did not seem to improve pustulosis palmoplantarisdisease activity in our patient.

Copyright � 2012, Taiwanese Dermatological Association.Published by Elsevier Taiwan LLC. All rights reserved.

Introduction

Adalimumab is a fully human monoclonal antibody against tumornecrosis factor (TNF)-a that is increasingly used for the treatment ofmany autoimmune diseases, including psoriasis and pustulosispalmoplantaris (PPP), owing to its efficacy and safety. However, ithas also been reported that adalimumab induces various adversecutaneous reactions. We describe a patient with PPP who devel-oped four unusual adverse cutaneous reactions during adalimumabtreatment.

Case report

A 50-year-old Taiwanese male who was a smoker presented withrecurrent painful pustules with hyperkeratosis and desquamationover his palms and soles since 2008 (Figure 1A,B). PPP was diag-nosed. He had been treated with different conventional therapeuticagents, including methotrexate, acitretin, cyclosporine, and topical

nt of Dermatology, Nationalh Road, Taipei 100, Taiwan.

iwanese Dermatological Associatio

corticosteroids, with limited effects. He had also experienced mildelevation of liver enzymes due to methotrexate and complained ofheadaches and hypertension due to high-dose cyclosporine. Hewasunable to undergo regular phototherapy because he lived in a ruralarea. He was referred to our hospital in 2009. After screening fortuberculosis and hepatitis B, he received subcutaneous injections ofadalimumab (Humira�, Abbott Laboratories, Abbott Park, IL, USA)at a dose of 40 mg every other week in combination with metho-trexate (15 mg/week).

However, within 1week after the third injection of adalimumab,many mildly tender follicular erythematous papulonodules withpustules developed over his face and trunk, especially over theaxillae, groin, and buttocks (Figure 2B). Histopathological exami-nation of a skin biopsy from the left cheek revealed a follicularpustule containing keratins with dense neutrophilic and eosino-philic infiltrates. The eosinophils were located mainly in the peri-follicular dermis, whereas the neutrophils and a few eosinophilswere located at the orifice of the follicle. No bacterial clumps werefound (Figure 2C,D). A pus culture yielded small amounts ofcoagulase-negative staphylococci and Propionibacterium acnes, andinflamed acne was diagnosed. The peripheral eosinophil count waswithin normal limits.

One week after the development of acneiform eruptions,a generalized eczematous rash and itchy wheal-like papules and

n. Published by Elsevier Taiwan LLC. All rights reserved.

Figure 1 (A,B) Many pustules with hyperkeratosis and desquamation on the patient’s palms and soles.

G.-Y. He, T.-F. Tsai / Dermatologica Sinica 30 (2012) 51e5652

plaques developed over the patient’s trunk and extremities. Indi-vidual urticarial lesions subsided within 24 hours, whereas theeczematous lesions persisted beyond 24 hours (Figure 3). More-over, several well-defined hairless patches of up to coin sizeappeared over his parietal scalp at the same time. No overlyingscalp skin changes were found and a hair pull test was positivewithexclamation mark hairs (Figure 4). Alopecia areata (AA) was diag-nosed clinically. The patient reported that he had not had previousepisodes of acne vulgaris, urticaria or AA. A skin biopsy from one ofthe urticarial plaques over his shoulder showed perivascular andinterstitial infiltrates composed of eosinophils, lymphocytes, and

Figure 2 (A,B) Many follicular-corresponding erythematous papules, pustules, and nodulesa follicular pustule containing keratins, and neutrophilic and eosinophilic infiltrates. Many n(D) Most eosinophils were located in the perifollicular dermis (H&E, 200�).

neutrophils without vasculitis. Interstitial dermal edema was alsonoted. The histopathological findings favored a hypersensitivityreaction. When the fourth and fifth doses of adalimumab weregiven, all of the skin lesions became more severe. Therefore, wediscontinued adalimumab and prescribed doxycycline 100 mgtwice daily for the acneiform eruptions. Intra-lesional triamcino-lone acetonide was also given for the larger inflamed nodules, withgood efficacy. However, the urticarial eruptions responded poorlyto different oral antihistamines, including levocetirizine, fex-ofenadine, and desloratadine. He was thus treated with metho-trexate (15 mg/week) and cyclosporine (75 mg/day) because both

were noted over the patient’s face, axillae, groin, and buttocks. (C) Pathology revealedeutrophils and a few eosinophils were located at the orifice of the follicle (H&E, 40�).

Figure 3 (A,B) Generalized wheal-like papules and plaques with many eczematous patches over the patient’s trunk and extremities. (C,D) Close-up images of the urticarial andeczematous lesions.

Figure 4 Several well-defined hairless patches of up to coin size were noted over thepatient’s frontal and parietal scalp. No overlying scalp skin changes were found.

G.-Y. He, T.-F. Tsai / Dermatologica Sinica 30 (2012) 51e56 53

drugs have been used for the treatment of PPP and refractoryurticaria.

The treatment was then changed to etanercept, a dimericTNF-a receptor fusion protein, and acitretin (20 mg/day). All of thefour cutaneous adverse reactions, including the eczematouslesions, acneiform eruptions, AA, and urticaria, improved gradu-ally, with clinical remission 1, 3, 4, and 7 months after their onset,respectively (Figure 5). However, PPP disease activity persisteddespite a 5-month course of etanercept. He was then treated withustekinumab, a human anti-interleukin-12 and anti-interleukin-23 monoclonal antibody, at a dose of 45 mg by subcutaneousinjection (in weeks 0 and 4) in combination with methotrexate(15 mg/week), acitretin (20 mg/day), and low-dose cyclosporine(75 mg/day). Unfortunately, he still experienced frequent recur-rence of pustular eruptions on his palms and soles during the2 months after the second injection of ustekinumab. He was thuskept on cyclosporine and acitretin. The PPP skin lesions improvedgradually, with only occasional minor recurrence of pustules onthe soles 2 months after he started taking acitretin alone. He alsoquit smoking during this period. We assume that he is currently inremission from PPP.

Figure 5 Clinical course of adverse cutaneous reactions in the patient.

G.-Y. He, T.-F. Tsai / Dermatologica Sinica 30 (2012) 51e5654

Discussion

Adalimumab is a fully human immunoglobulin G1 monoclonalanti-TNF-a antibody that has shown efficacy for the treatment ofmany autoimmune diseases, including plaque-type psoriasis,psoriatic arthritis, and PPP.1,2 A variety of cutaneous adverse reac-tions have been reported during anti-TNF-a therapy, includinginfusion reactions, injection site reactions, cutaneous infection,eczema, atopic dermatitis, pruritus, drug-induced lupus eryth-ematosus, new onset or exacerbation of psoriasiform lesions, andhypersensitivity reactions.3e5 The prevalence of each skin lesionvaries among different studies.4,5 A prospective study of 150patients with rheumatic diseases who were using TNF-a antago-nists found that 35 (23%) of the 150 patients developed some sort ofadverse cutaneous reaction.6 However, most cutaneous reactionsoccur during treatment for rheumatoid arthritis, Crohn’s disease,and ankylosing spondylitis. Only isolated case reports and a fewcase series have described adverse skin effects in patient withpsoriasis.

Acneiform eruption, urticaria, and AA following TNF-a antago-nists are quite rare (Table 1).11,13e16,18,19e21,24 Eleven patients whodeveloped AA after anti-TNF-a agents have been reported in theEnglish literature, of whom five received adalimumab therapy.7e17

Table 1 Literature review of clinical characteristics and outcomes for patients who deve

Skin reaction CaseNo

Sex Age Diagnosis Onset afteradalimumab

Clinical featu

Alopeciaareata (AA)

1 F 23 Rheumatoid arthritis 2 months Patchy-type2 M 43 Psoriatic arthritis 6 months Patchy-type

3 F 38 Rheumatoid arthritis 24 months AA totalis4 F 30 Rheumatoid arthritis 9 months Patchy-type

5 F 52 Psoriatic arthritis 15 days Patchy-typeUrticaria 1 F 60 Rheumatoid arthritis 3 months Urticaria, an

and hypoten2 F 41 Psoriasis 1 weeks Urticaria

3 F 31 Behcet’s disease 1 month Urticaria andangioedema

4 M 32 Ankylosing spondylitis 1 month Urticaria

Acneiformeruption

1 M 55 Pustular psoriasis 2 months Acneiform e

2 M 62 Rheumatoid arthritis 3 months Acneiform e

F ¼ female; M ¼ male; AA ¼ Alopecia areata; NA ¼ not available; IV ¼ intravenous.

Although the exact mechanism for AA development during anti-TNF-a therapy is unknown, it has been suggested that TNF-ablockage could contribute to dysregulation of immune responsesleading to the development of AA.13 According to published reports,only four patients have developed urticarial lesions after adali-mumab therapy.18e21 In two cases, the urticaria was accompaniedby angioedema.18,20 However, no pathology was available for thesepatients.

In addition to AA and urticaria, acneiform eruptions followinganti-TNF-a therapy are also rare. To the best of our knowledge, onlyseven cases (five treated with infliximab and two with adalimu-mab) have been described in the English literature.22e25 Sun et alreported on three patients with acneiform eruptions followinganti-TNF-a treatment, two of whom were receiving adalimumabtherapy.24 Most patients developed asymptomatic erythematousfollicular papules, pustules or nodules over the face and trunk 1e2months after therapy initiation. Of the seven documented cases,only two patients had underlying psoriasis. One case with plaque-type psoriasis received infliximab and another case with pustularpsoriasis received adalimumab. The severity of acneiform eruptionsvaried. Some patients improved with doxycycline monotherapy,whereas others needed isotretinoin to control the skin lesions. Nodetailed histopathological descriptions of acneiform eruptions havebeen documented previously. In our case, pathology revealeda follicular pustule containing keratins with dense neutrophilic andeosinophilic infiltrates.

The follicular eruptions in our patient showed eosinophilicinfiltration and thus drug-induced eosinophilic pustular folliculitiswas a possible differential diagnosis.26

However, eosinophils in eosinophilic pustular folliculitis arepredominantly within hair follicles, whereas the eosinophils in ourcase were located mainly interstitially, with only a few eosinophilsat the orifice of the follicle. We did not observe any eosinophilicinfiltration into the follicular epithelium or sebaceous glands.Moreover, the clinical morphology was papulonodular lesions, andnot papular lesions alone.We added indomethacin to the treatmentfor 2 months without efficacy. Thus, acneiform eruption seems tobe a better diagnosis to cover the possibility of eosinophilicpustular folliculitis. The significance of the Propionibacterium acnesin the acneiform eruptions in our patient is unclear, and mightrepresent an infection, colonization, or only contamination.We alsoassumed that the acneiform eruption was an unusual hypersensi-tivity reaction, and not true acne vulgaris.

loped alopecia areata, urticaria, and acneiform eruptions after adalimumab therapy.

re Treatment Prognosis Reference

AA Topical dexamethasome Evolution to AA universalis 11

AA Potent topicalcorticosteroids

Evolution to AA universalis 13

NA Evolution to AA universalis 14

AA Topical & systemiccorticosteroids

Minimal hair regrowth 15

AA NA NA 16

gioedemasion

IV hydrocortisonic &antihistamines

Disappeared 2 hours later 18

No treatment Less severe with eachinjection

19

IV corticosteroids &antihistamines

Disappeared within24 hours and 36 hours,respectively

20

Oral antihistamines &corticosteroids

Disappeared within afew days

21

ruption Acitretin 25 mg daily Minimal improvement1 month later

24

ruption No treatment NA 24

G.-Y. He, T.-F. Tsai / Dermatologica Sinica 30 (2012) 51e56 55

Interestingly, a common denominator in the histopathologicalfindings for our patient is the presence of eosinophilic infiltrates inthe acneiform and urticarial lesions. Although we did not performa biopsy of the AA lesions, eosinophilic infiltration is a commonpathologic feature of AA.27 Although the combination of adversecutaneous reactions observed here has not been previously repor-ted, a common mechanism may be involved in the cause of all theadverse reactions to adalimumab in our case.

Laga et al evaluated the histopathologic spectrum of psoriasi-form skin eruptions associated with TNF-a inhibitor therapy, andfound that scattered to numerous eosinophils were observed inmost cases (14 out of 16 specimens).28 However, anti-TNF-a drugsseem to elicit a spectrum of cutaneous reactions that go beyond theclassical eosinophilic-rich hypersensitivity reaction. The truemechanism between eosinophilic infiltration and TNF-a blockingremains to be fully determined. De Gannes and colleaguesproposed that there is cross-regulation between TNF-a and inter-feron (IFN)-a, which may lead to an increase in IFN-a.29 They alsosuggested that aberrant IFN-a expression in predisposed individ-uals during anti-TNF-a therapy may contribute to psoriasiform skineruptions and lupus-like syndrome. Similarly, acne, AA, and urti-caria have been observed in patients receiving IFN therapy.30e32Wepropose that overexpression of IFN during anti-TNF-a therapy playsa role in the pathogenesis of the diverse clinical spectrum ofcutaneous reactions in predisposed individuals and may partlyaccount for eosinophilic infiltration.

Some authors consider these adverse reactions a class effect ofanti-TNF-a agents.33 However, in our patient, the skin lesionsimproved after changing to etanercept therapy. The differentimmunosuppressive strength of these two biologics may accountfor the difference. Moreover, differences in the mechanism ofreaction at injection sites have been reported for adalimumaband etanercept.34 We suggest that some adverse cutaneousreactions, such as psoriasiform eruptions, are a class effect,whereas others, such as injection-site reactions, may be drug-specific.

PPP is a challenging disease for which no therapeutic stan-dard has yet been defined; acitretin is the drug of choiceaccording to most recommendations. The difference betweenPPP and psoriasis has long been debated, and some currenttherapeutic guidelines do not recommend the use of biologics inPPP because of inconsistent therapeutic responses and a possiblyhigher risks of adverse cutaneous reactions.35e38 However, mostof the drugs used for psoriasis have been used for PPP. Someauthors have also suggested that concomitant use of biologicagents and methotrexate has a synergic effect on psoriasis. Wethus used acitretin, ustekinumab, methotrexate, and low-dosecyclosporine concomitantly for the patient because of the poorresponse to previous biologics and the refractory nature of hisurticaria and PPP.

Ustekinumab is a new biologic that has been approved for thetreatment of moderate to severe plaque psoriasis in many coun-tries. It is a fully human immunoglobulin G kappa monoclonalantibody that binds to interleukin-12 and interleukin-23 andsubsequently reduces the activity of T-helper 17 cells. In a recentcase series available online, only one out of four patients with PPPexperienced good but slow efficacy for ustekinumab, unlike the fastonset of treatment response observed in plaque psoriasis.39 Thisresult is consistent with our experience.

In conclusion, this is a rare case of a patient who showed fouradverse cutaneous reactions concurrently following adalimumabtreatment for PPP. The pathological findings in our case suggesta shared pathogenic mechanism, but further studies are necessaryto clarify the exact causes of adalimumab-related cutaneous sideeffects. As the use of TNF-a antagonists continues to increase,

recognition and management of such side effects will becomeincreasingly important.

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