CASE REPORT

A 34-year-old woman with systemic lupus erythematosus(SLE) presented with a 2-day history of fever, headache, pho-tophobia and vomiting. Systemic lupus erythematosus hadbeen diagnosed previously on the basis of an anti-double-stranded DNA antibody titre of 161 (normal range (NR) < 75),antinuclear antibody titre of 1/320, renal biopsy findings oflupus nephritis, and high titres of the two major antiphos-

phololipid antibodies, anticardiolipin antibody (ACA)(immunoglobulin (Ig)G > 100 G phospholipid (PL) U/mL (NR 1.0–13.3), IgM 22 MPL U/mL (NR 0.0–9.8)) and lupusanticoagulant (LA) (test/normal ratio 2.8 (NR 0.9–1.1)). Shehad been anticoagulated with warfarin since suffering abranch retinal vein thrombosis 2 years earlier, and was alsobeing treated with azathioprine 75 mg daily for the lupusnephritis. She had continued to take her azathioprine, despiteher intercurrent illness.

On the day of admission she was treated with 2 g of ceftri-axone intravenously for suspected meningitis, but a lumbarpuncture and blood cultures were negative. A viral aetiologyfor her symptoms was considered most likely, although specific viral serology was negative. The fever, headache andphotophobia slowly improved over the following 7 days.

The patient’s international normalized ratio (INR) whentested on day 4 was found to be greater than 10, despite norecent change in the warfarin dose. The INR had not beendetermined on admission, but had previously been main-tained within the therapeutic range for patients with antiphos-pholipid syndrome (APS) (between 3 and 4). The high INRwas felt to be the result of either the viral illness itself or theantibiotic therapy given. Warfarin was ceased and, as a resultof menorrhagia, the patient was treated with 4 units of freshfrozen plasma which reduced the INR to 4.5 by day 5. By day 8the INR was still elevated at 4.4.

On day 11 she developed mildly pruritic but non-tender erythematous lesions on the neck and anterior chest, whichby day 14 had evolved into localized haemorrhagic andnecrotic lesions (Fig. 1). The differential diagnoses of antiphos-pholipid antibody (APA)-related skin necrosis, warfarin-induced skin necrosis (WISN) and vasculitis were considered.Laboratory studies revealed that the patient was no longeradequately anticoagulated, with an INR of 1.3. Protein S andprotein C levels were not determined. A skin biopsy takenfrom one of the neck lesions revealed a haemorrhagic dermiswith thrombosis of capillaries in the papillary dermis. Thedeeper dermal vessels and subcutaneous fat were not affected.There was some mild perivascular inflammatory cell infiltratepresent but no evidence of vasculitis (Fig. 2). These findingswere considered to be most consistent with a diagnosis of APA-related skin necrosis. Anticoagulation was reinstituted onday 14, with 20 mg subcutaneous low molecular weightheparin daily to prevent further thrombosis, and warfarin wasrecommenced on day 15 without a loading dose. The heparin

Australasian Journal of Dermatology (2002) 43, 218–220

SIGNS, SYNDROMES AND DIAGNOSES

Localized cutaneous necrosis associated with theantiphospholipid syndrome

Michael P Sharkey,1 Indiver I Daryanani,2 Martin B Gillett3 and Stephen K Jones1

Departments of 1Dermatology, 2Medicine and 3Histopathology, ClatterbridgeHospital, Bebington, Wirral, United Kingdom

SUMMARY

A 34-year-old woman with systemic lupus erythema-tosus and high titres of antiphospholipid antibodies wasadmitted to hospital suffering a viral illness but devel-oped haemorrhagic and necrotic areas on the neck andanterior chest 7 days following cessation of warfarin.Anticoagulation had been initiated following a retinalvein thrombosis, but was ceased on day 4 of admissionwhen she was found to be excessively anticoagulated(international normalized ratio (INR) > 10). However,at the time of developing the cutaneous lesions, the INR was sub-therapeutic. Histology of a skin biopsyfrom the neck revealed thrombosis of upper dermalblood vessels without vasculitis, consistent withantiphospholipid antibody-related skin necrosis. Thiscase illustrates one of the cutaneous features that canoccur in patients with elevated titres of antiphospho-lipid antibodies and the importance of closely monitor-ing anticoagulation in such patients.

Key words: anticardiolipin antibody, Hughes’ syndrome, lupus anticoagulant, systemic lupuserythematosus, warfarin.

Correspondence: Dr Michael Sharkey, Dermatology Department,Princess Alexandra Hospital, Woolloongabba, QLD 4102, Australia.

Michael P Sharkey, MB BS. Indiver I Daryanani, MRCP. Martin BGillett, FRCPath. Stephen K Jones, FRCP.

Manuscripts for this section should be submitted to Dr L Spelman.

Submitted 31 August 2001; accepted 22 January 2002.

was continued for a total of 7 days until the INR reached atherapeutic level of 3.0. The necrotic areas of skin remainedsuperficial, and were treated with silver sulfadiazine creamand gauze impregnated with petroleum jelly. They healedgradually over the next 2 weeks.

DISCUSSION

Antiphospholipid antibodies are a heterogeneous group ofantibodies directed against negatively charged phospholipids.Two major APA have been identified, namely LA and ACA. TheAPS, also known as Hughes’ syndrome, is a hypercoagulationsyndrome occurring in patients with detectable antiphos-pholipid antibodies who suffer recurrent thrombotic events(either venous or arterial), recurrent fetal loss, thrombo-cytopenia and a sustained elevated titre of IgG ACA or LA.1,2

Patients without an associated disease are said to have primary APS, whereas secondary APS occurs in patients with underlying disorders such as SLE, malignancy, haemato-logic diseases, neurological conditions, infections and drugs.3,4

Our patient fulfils the criteria of secondary APS, with hightitres of both LA and ACA and a history of thrombosis occurring in the setting of SLE. The reported incidence of APA in patients with SLE varies from 2% to 94% for LA, andfrom 21% to 62% for ACA.3 Up to 2% of the normal populationhave detectable APA.5

There have been a number of cutaneous manifestationsdescribed in patients with APA (Table 1). In a retrospectivestudy at the Mayo Clinic, 41% of patients with LA had skinlesions as the first sign of the disease.6

Skin necrosis associated with APA is usually localized, andaffected sites include the face, ears and lower extremities.7

Cases with extensive cutaneous necrosis have also been doc-umented.8,9 The characteristic histopathological feature ofAPA-related skin necrosis is thrombosis of dermal capillarieswithout evidence of vasculitis, as seen in the biopsy taken fromour patient.7 Although a provisional diagnosis of APA-relatedskin necrosis was made, we also considered the differentialdiagnoses of vasculitis and, as the patient was anticoagulatedwith warfarin, WISN. Although vasculitis could be readilyexcluded on the basis of the histological findings, differentia-tion from WISN is more complex, as both APA-related skinnecrosis and WISN feature non-inflammatory thrombosis ofthe cutaneous vasculature.

Warfarin-induced skin necrosis results from the transientand paradoxical hypercoagulable state that is induced whenprotein C levels fall ahead of coagulation factors following theinitiation of warfarin treatment, usually in the setting of

Antiphospholipid syndrome 219

Figure 1 Clinical appearance of necrotic plaques over the lateralneck and anterior chest.

Figure 2 Skin biopsy from lateral neck plaque. Haemorrhagic dermis with thrombus-filled superficial vessels, but no evidence ofvasculitis (H&E).

pre-existing protein C deficiency.10,11 Although protein C levels were not evaluated in our case, there are a number ofother features that can be examined when comparing APA-related skin necrosis and WISN. Skin lesions in WISNusually appear 3–6 days after commencing warfarin, but ourpatient had commenced warfarin 2 years previously.11 Therehave been a small number of reports of skin necrosis occur-ring in patients who have been taking warfarin for up to15 years, which has been referred to as ‘late-onset WISN’.12–15

However the mechanism of necrosis in these patients has notbeen determined, and the possibility of non-warfarin-relatedcauses in such cases needs to be considered.12 The skin necro-sis in our case occurred on the neck, and developed withouta prodrome. While APA-related skin necrosis typically affectsareas with relatively little subcutaneous fat such as the faceand ears, WISN characteristically affects areas with substan-tial subcutaneous fat, such as the breasts, thighs and buttocks,with prodromal pain at the site of the developing lesions.3,11,12

Warfarin-induced skin necrosis usually produces a deep defectthat extends into the subcutaneous fat and often requires sur-gical debridement,11 while APA-related skin necrosis typicallyremains superficial.5 The lesions in our case remained super-ficial and healed readily with simple dressings. Histology inearly WISN reveals thrombi primarily in the venules and arte-rioles of the deeper dermis and subcutis, and later lesionsshow diffuse necrosis of the dermis and subcutaneous fat .12,16

Histology in our case did not show the deeper involvement typ-ical of WISN.7 Therefore, in light of the above features, we feelthat the diagnosis in this case was most consistent with APA-related skin necrosis. We propose that this occurred as a resultof sub-therapeutic anticoagulation.

Long-term anticoagulation with warfarin is the treatmentof choice when thrombosis occurs in APS, and the INR shouldbe maintained between 3 and 4.17 However, if the only clini-cal manifestation is superficial venous thrombosis, low-doseaspirin may be sufficient.1 In patients without a history ofthrombosis, prophylactic low-dose subcutaneous heparin isrecommended for at-risk periods such as surgical procedures

or prolonged immobility.1,4 Although immunosuppressiveagents have been shown to reduce elevated APA levels, thereis usually a rebound to pretreatment levels rapidly after ces-sation of treatment, and their use for the purpose of loweringAPA titres is not recommended.4

This case demonstrates one of the cutaneous features of theAPS and stresses the importance of maintaining therapeuticanticoagulation in patients with symptomatic APS. It also high-lights the need to consider WISN when cutaneous necrosisoccurs in those patients anticoagulated with warfarin. As cuta-neous features can occur as the first sign of APS, their recog-nition by dermatologists familiar with the disorder will allowfor the early diagnosis and treatment of the condition.

REFERENCES

1. Gibson G, Su W, Pittelkow M. Antiphospholipid syndrome and theskin. J. Am. Acad. Dermatol. 1997; 36: 970–82.

2. Hughes G. Thrombosis, cerebral disease and lupus anticoagulant.BMJ. 1983; 287: 1088–9.

3. Nahass G. Antiphospholipid antibodies and the antiphospholipidantibody syndrome. J. Am. Acad. Dermatol. 1997; 36: 149–68.

4. Asherson R, Cervera R. Antiphospholipid syndrome. J. Invest.Dermatol. 1993; 100: 21s–7s.

5. Fleck R, Rapaport S, Rao L. Anti-prothrombin antibodies and thelupus anticoagulant. Blood 1988; 72: 512–19.

6. Algere V, Gastineau D, Winkleman R. Skin necrosis associatedwith circulating lupus anticoagulant. Br. J. Dermatol. 1989; 120:419–29.

7. Hill V, Whittaker S, Hunt B, Liddell K, Spittle M, Smith N.Cutaneous necrosis associated with the antiphospholipid syn-drome and mycosis fungoides. Br. J. Dermatol. 1994; 130: 92–6.

8. Roubey R. Autoantibodies to phospholipid-binding plasma proteins: A new view of lupus anticoagulants and other ‘antiphos-pholipid’ autoantibodies. Blood 1994; 84: 2854–67.

9. Alegre V, Gastineau D, Winkelmann R. Skin lesions in patientswith circulating lupus anticoagulant. Br. J. Dermatol. 1989; 120:419–29.

10. Cole M, Minifee P, Wolma F. Coumarin necrosis: A review of theliterature. Surgery 1988; 103: 271–7.

11. Eby C. Warfarin-induced skin necrosis. Hematol. Oncol. Clin.North Am. 1993; 7: 1291–300.

12. Weedon D. The vasculopathic pattern. In: Skin Pathology.Edinburgh: Churchill Livingstone, 1997; 185–231 (187).

13. Chan Y, Valenti D, Mansfield A, Stansby G. Warfarin induced skinnecrosis. Br. J. Surg. 2000; 87: 266–72.

14. Franson T, Rose H, Spivey M, Maroney J, Libnoch J. Late-onset,warfarin-caused skin necrosis in a patient with infectiousmononucleosis. Arch. Dermatol. 1984; 120: 927–31.

15. Scarff C, Baker C, Hill P, Foley P. Late-onset warfarin necrosis.Australas. J. Dermatol. 2002; 43: 202–6.

16. Sternberg M, Pettyjohn F. Warfarin sodium-induced skin necrosis. Ann. Emerg. Med. 1995; 26: 94–7.

17. Khamashta M, Cuadrado M, Mujic F, Taub N, Hunt B, Hughes G.The management of thrombosis in the antiphospholipid-antibodysyndrome. N. Engl. J. Med. 1995; 332: 993–7.

220 MP Sharkey et al.

Table 1 Cutaneous signs reported in association with antiphos-pholipid antibodies2,4,5

Livedo reticularisSuperficial cutaneous necrosisNecrotizing vasculitisLivedoid vasculitisLeg ulcerationThrombophlebitisEcchymoses, purpuraDigital ischaemiaGangrene

CASE HISTORY

A 27-year-old woman had a 6-year history of a recurrentphotosensitive eruption that occurred in the summer monthsand was concentrated on the central face and upper trunk.The episodes settled with sun protection and sun avoidance.In 1998, the patient experienced a marked flare associatedwith two patches of alopecia. A skin biopsy from her shoulder

showed changes of lupus erythematosus. The skin lesions and alopecia settled with topical corticosteroids and sun pro-tection. The patient was seen initially in consultation 2 yearslater when there was a fresh episode of hair loss that had commenced in summer. Over the ensuing 3 months, twopatches of alopecia appeared over the scalp, as well as isolated erythematous plaques on the face. There was no history of Raynaud’s phenomenon, arthritis or fever. Thepatient had experienced recent increased fatigue and malaise.Clinical examination revealed erythematous non-scarringtumid papules on both cheeks and glabella. On the scalp therewas a 1-cm diameter area of non-scarring circumscribedalopecia in the hair part (Fig. 1) and a 2-cm diameter patchover the vertex. These patches were associated with faint erythema but there was no evidence of scarring and the follicular orifices appeared intact. The area of alopecia overthe vertex was associated with tenderness on palpation. Fullblood count, liver function tests, electrolytes, renal functiontests and thyroid function were all normal. Antinuclear antibody was detected at a titre of 1:160 speckled pattern.Protein immunoelectrophoresis showed elevated gamma and beta globulins but no monoclonal band. The patient wascommenced on hydroxychloroquine 200 mg daily and this wasassociated with subsequent resolution of the erythematouspatches and alopecia.

HISTOPATHOLOGICAL FINDINGS

A scalp biopsy from the area of alopecia showed within thedeep dermis and subcutis prominent lymphocytic inflam-mation that surrounded the deep segments of the follicles andhair bulbs, as well as the eccrine glands (Fig. 2). The subcutisshowed hyalinization of the fat and mucinosis (Fig. 3), as wellas increased numbers of interstitial lymphocytes with focalgerminal centre formation. The upper dermis showed focalperivascular inflammation as well as exocytosis of isolatedlymphocytes into the infundibular isthmus segments of thefollicles, but no evidence of follicular necrosis or lichenoidreaction as seen in discoid lupus erythematosus. The inter-follicular epidermis was of normal thickness and had no evident lymphocytic inflammation or liquefaction of degener-ation of the basal compartment (Fig. 4). The transverse sections of the scalp biopsy contained 25 follicles with 10 follicles that were in telogen or catagen phase, while the restwere in anagen. These findings were consistent with lupus

Australasian Journal of Dermatology (2002) 43, 221–223

DERMATOPATHOLOGY PRESENTATION

Lupus panniculitis clinically simulating alopecia areata

Steven Kossard

Skin and Cancer Foundation Australia, Sydney, New South Wales, Australia

SUMMARY

A 27-year-old woman with a known history of lupuserythematosus presented with two circumscribedpatches of non-scarring alopecia closely resemblingalopecia areata. Scalp biopsy showed a predominantlysubcutaneous and deep dermal lymphocytic infiltratethat surrounded the deep follicular segments and hair bulbs, as well as the eccrine glands. There wasassociated hyaline fat sclerosis. The epidermis,infundibular and isthmus segments of follicles wererelatively spared and lacked the lichenoid inflam-mation and fibrosis seen with lupus erythematosus.

The biopsy findings illustrate that the deep variantof lupus panniculitis may be concentrated around the hair bulbs and deep temporary segments of hair follicles and spare the permanent stem cell-rich follic-ular segments. This pattern is capable of producing atemporary hair-loss, clinically simulating alopeciaareata. The clinical history, presence of subtle eryth-ema and scalp tenderness on physical examination, as well as the biopsy findings, were important clues indistinguishing our case from a true combination ofalopecia areata and lupus erythematosus.

Key words: lupus profundus, subcutaneous lupuserythematosus.

Correspondence: Assoc. Prof. S Kossard, Skin and CancerFoundation Australia, 277 Bourke Street, Darlinghurst, NSW 2010,Australia. Email: skossard@scfa.edu.au

Steven Kossard, FACD.Manuscripts for this section should be submitted to Assoc. Prof.

S Kossard.Submitted 21 January 2002; accepted 14 March 2002.

panniculitis producing alopecia as a consequence of deep follicular and peribulbar inflammation.

DISCUSSION

Lupus erythematosus may be complicated by the developmentof localized or diffuse forms of alopecia.1 Localized scarring

222 S Kossard

Figure 2 Transverse scalp section through the deep reticular der-mis demonstrating prominent lymphoid infiltrate targeting the deepfollicular segments and hair bulbs, as well as the eccrine glands(H&E).

Figure 3 Transverse scalp section at level of subcutis demonstrat-ing hyaline sclerosis of fat with interstitial infiltrate of lymphocytesand mucinosis (H&E).

Figure 1 Focal area of non-scarring alopecia adjacent to hair part.

Figure 4 Transverse scalp sections through the upper dermisdemonstrating a normal epidermis lacking lichenoid reaction and anormal number of follicles with focal perivascular lymphocyticinflammation (H&E).

patches of alopecia are usually caused by discoid lupus erythematosus.2 These present as multifocal areas of alopeciathat clinically are grossly scarred with scaling, telangiectasiaand variegated pigmentation. Patulous follicles plugged by keratin and lipoatrophy may be seen. Scalp biopsy in discoidlupus erythematosus usually reveals panfollicular lympho-cytic inflammation targeting whole follicles including theinfundibular, isthmus and bulb regions, resulting in perman-ent follicular destruction.3 Rare cases of alopecia in lupus mayhave a prominent papular element, reflecting the presence of gross mucinosis4 or conversion of follicles into basaloid follicular hamartomas.5

Diffuse non-scarring alopecia may complicate systemiclupus erythematosus as a result of diffuse telogen effluviumcaused by severe systemic disease, anaemia or treatmentssuch as immunosuppressives, retinoids or anticoagulants.6

Localized non-scarring alopecia is rarely seen in lupus erythematosus, and the possibility of fungal infection mayneed to be considered in the presence of broken hairs, pustules or scaling, particularly in those receiving immuno-suppressive treatment. There is an increased frequency ofalopecia areata in patients with lupus erythematosus7 and thischaracteristically presents as localized or extensive hair-lossthat is non-scarring and clinically is non-inflamed and is not tender. Exclamation mark hairs or black dots within follicular orifices due to dystrophic hair production may beseen in the areas of alopecia areata. Our patient illustrates the potential of lupus profundus when it is confined to the panniculus and deep dermis to produce a non-scarring alopecia that may clinically resemble alopecia areata. In most examples of lupus panniculitis affecting the scalp, theprocess extends into the dermis and often involves the epidermis, producing ulceration or scarring that leads to late lipoatrophy and permanent alopecia.8

The histopathology of alopecia areata is characterized by the presence of peribulbar inflammation, and the upper perm-anent follicular segments comprising the infundibular andisthmus portions of the follicles are spared. In our patient, the lupus panniculitis was confined to the subcutis and deepdermis and shared the histopathological features of alopecia

areata in targeting the temporary deep segments of the follicles and hair bulbs, inducing localized patches of non-scarring hair-loss seen clinically. These areas of non-scarringalopecia may clinically closely resemble alopecia areata, asthe patches may be circumscribed and may contain dystrophicor exclamation mark hairs. The presence of scalp tenderness,subtle erythema and the biopsy findings of lupus panniculitiswere the key features in arriving at a correct diagnosis in ourpatient. The presentation in our case needs to be distinguishedfrom the true combination of alopecia areata and lupus erythematosus that may occur but can be distinguished bycareful clinical and histological correlation.

ACKNOWLEDGEMENT

Colour printing of this presentation has been made possibleby a grant from the Australasian Dermatopathology Society.

REFERENCES

1. Yell JA, Mbuagbaw J, Burge SM. Cutaneous manifestation of systemic lupus erythematosus. Br. J. Dermatol. 1996; 135:355–62.

2. Wilson CL, Burge SM, Dean D, Dawber RP. Scarring alopecia in discoid lupus erythematosus. Br. J. Dermatol. 1992; 126: 307–14.

3. Kossard S. Lymphocytic mediated alopecia: Histological classifi-cation by pattern analysis. Clin. Dermatol. 2001; 19: 201–10.

4. Lee WS, Chung J, Ahn SK. Mucinous lupus alopecia with papu-lonodular mucinosis as a manifestation of lupus erythematosus.Int. J. Dermatol. 1996; 32: 72–3.

5. Akasaka T, Kon S, Mihm MC. Multiple basaloid cell hamartomawith alopecia and autoimmune disease (systemic lupus erythe-matosus). J. Dermatol. 1996; 23: 821–4.

6. Wysenbeck AJ, Leibovici L, Amit M, Weinberger A. Alopecia insystemic lupus erythematosus: Relation to disease manifestations.J. Rheumatol. 1991; 18: 185–6.

7. Werth VP, White WL, Sanchez MR, Franks AG. Incidence of alopecia areata in lupus erythematosus. Arch. Dermatol. 1992; 128: 368–71.

8. Grossberg E, Scherchun L, Fivenson DP. Lupus profundus: Not abenign disease. Lupus 2001; 10: 514–16.

Lupus panniculitis and alopecia 223

INTRODUCTION

Occupational dermatitis in timber workers is well recognized.While the suspect allergen is often sawdust, alternatives needto be considered.

CASE REPORTS

A 26-year-old Maori woman had been working in the pro-cessing section of a plywood factory for 18 months. She initially worked as a reliever, but after 10 months hadbecome a spreader. The spreader places the sheets of plywood,coated with a fine glue film, together. These are then passedthrough rollers and heated (i.e. cured). Within a few weeksof starting as a spreader, she developed an acute dermatitison the sides of her neck and face. She wore gloves, but wasin the habit of rubbing her neck and face during work. Shehad no personal or family history of atopic disorders.

She had had no prolonged breaks from work but did notethat her dermatitis was improving after 3 days off (she worked4 days on, 3 days off). When placed back onto relieving duties,where she did not do any spreading, her dermatitis clearedwithin 10 days. She thought she was allergic to sawdust (Pinusradiata).

All workers were supplied with safety clothing includinggloves, overalls, masks, hair nets, safety helmets, ear and eyeprotectors.

Standard patch testing was performed with readings at 48 and 96 hours. She was tested to the extended standardseries (Chemotechnique, Malmo, Sweden) using IQ chambers(Chemotechnique). In addition, specific series of antimicro-bials, perfumes and flavourings, woods, sawdust (Pinus radi-ata), plastics and glues were applied (see Table 1). She hadtwo positive reactions, a 1+ reaction to nickel sulfate (48 and96 hours) and a 1+ reaction to phenol-formaldehyde resin (96 hours only). She did not react to the sawdust or formalde-hyde. She was not tested to the glue used in the factory, but itdid contain phenol-formaldehyde resin.

A second 28-year-old female employee from the same ply-wood mill complained of repeated dermatitis on the backs ofboth hands and forearms over the preceding 12 months. Sheblamed sawdust (Pinus radiata). The dermatitis had worsened6 months earlier. She gained some temporary relief from theuse of clobetasol-17 propionate cream. She had worked in theplywood factory for 2 years, but she developed the hand der-matitis within 2 months of becoming a spreader. The der-matitis cleared on holiday and when placed on relieving dutywhere she was not spreading. The dermatitis flared withinseveral days of returning to spreading. She had a personal andfamily history of atopic eczema.

On examination, she had post-inflammatory pigmentationwith lichen simplex on forearms, wrists, and back of hands.She had also developed hypertrichosis from the use of super-potent topical corticosteroid creams.

Patch tests were performed as above. Her only positive reac-tion was a 2+ reaction to phenol-formaldehyde resin, whichonly appeared at 96 hours. She did not react to the sawdustor formaldehyde. She has continued to work as a reliever,avoiding spreading, and has not had further problems.

DISCUSSION

Both cases are very similar. During the manufacturingprocess, the highest contact with uncured resin is during thespreading stage. This was when both patients developed theirdermatitis. Interestingly, even though both were sensitized tophenol-formaldehyde resin, they could still work with thecured boards.

Allergy to wood products is well recognized.1,2 It is there-fore not surprising that sawdust allergy is the initial suspect

Australasian Journal of Dermatology (2002) 43, 224–225

VIGNETTE IN CONTACT DERMATOLOGY

Contact dermatitis to phenol-formaldehyde resinin two plywood factory workers

Marius Rademaker

Department of Dermatology, Honorary Associate Professor, Waikato Hospital,Hamilton, New Zealand

SUMMARY

Two cases of occupational allergic contact dermatitisin plywood mill workers are presented. Although bothpatients thought they were allergic to sawdust, theywere in fact allergic to a phenol-formaldehyde resinused to bond the plywood sheets together. Both patientsonly developed their dermatitis when they came intocontact with uncured glue.

Key words: glue, occupational dermatitis, wood.

Correspondence: Assoc. Prof. Marius Rademaker, DermatologyDepartment, Waikato Hospital, Private Bag, Hamilton, New Zealand.Email: rademaker@xtra.co.nz

Marius Rademaker, FRACP.Manuscripts for this section should be submitted to Dr M

Rademaker.Submitted 29 August 2001; accepted 23 October 2001.

allergen in timber workers who present with a clear historyof occupational dermatitis. However, in an occupational survey in a particle-board manufacturing facility, cutaneousexamination identified a heterogeneity of skin problems, withdermatitis being most frequently irritant rather than allergic.3

Quaternium-15 (Dowicil 200) was the only allergen to which more than one individual reacted. Aside from theodours, exposure to wood dust accounted for the other repor-ted symptoms.

However, in a Swedish plant that produced fibre-resin com-posite by impregnation of cellulose fibre with phenol-formaldehyde and melamine-formaldehyde resins, a newmanufacturing technique was introduced that resulted inproblems in the handling of uncured products.4 Subsequently,six out of 88 workers developed contact allergy to phenol-formaldehyde, and five to melamine-formaldehyde resin.Other glues used in particle-board manufacturing which havebeen reported to cause allergy include epoxy resin.5

Phenol-formaldehyde resins (phenolic resins) are polycon-densation products of phenols and aldehydes. They can beclassified as resols or novolaks, depending on whether thereaction is under alkaline or acidic conditions and whetherthe phenol or the formaldehyde is in excess.6 When phenolreacts with an excess of formaldehyde under alkaline condi-tions, a resol resin is produced. As formaldehyde is in excess

in the process, various low-molecular weight methylol phenol compounds are formed. The polycondensation processis deliberately stopped before completion; this can later berestarted by heating, which means resols are self-cross-linking and can be considered prepolymers.

Phenol-formaldehyde resins are used as adhesives, gluesand glue films in plywood factories. Because of their moistureresistance, the glues and laminates are used in boat and air-craft construction. The resins are also good insulators againstelectricity so are often used in electronics. In addition, phenol-formaldehyde resins are used as decorative laminates, bindersfor glass and mineral fibres for the production of noise- andfire-insulation, and in abrasives such as sandpaper, abrasivecloth and flexible sanding discs.

Allergy to phenol-formaldehyde resin is not uncommon.7 Ina large series of occupational contact dermatitis to plastics andglues from Finland, 3.1% of 360 patients patch tested wereallergic to phenol-formaldehyde resin. This was the secondhighest reaction rate, others being epoxy (5.1%), 4-tert-butylcatechol (2.6%), phenyl glycidyl ether (2.6%), diamino-diphenyl methane (2.2%), benzoyl peroxide (2.2%), hexam-ethylene tetramine (2.0%) and o-cresyl glycidyl ether (1.6%). Formaldehyde is not the major sensitizer in phenol-formaldehyde resins. At least 14 contact sensitizers have beenidentified, with the most potent being 4,4�-dihydroxy(hyd-roxymethyl)-diphenyl methanes. Simultaneous reactions tophenol-formaldehyde resins, colophony and balsam of Perucan occur, although the significance of this is unclear.6

REFERENCES

1. Cook DK, Freeman S. Allergic contact dermatitis to multiple sawdust allergens. Australas. J. Dermatol. 1997; 38: 77–9.

2. Siregar RS. Occupational dermatoses among foresters. ContactDermatitis 1975; 1: 33–7.

3. Saary MJ, House RA, Holness DL. Dermatitis in a particle-boardmanufacturing facility. Contact Dermatitis 2001; 44: 325–30.

4. Isaksson M, Zimerson E, Bruze M. Occupational dermatoses in composite production. J. Occup. Environ. Med. 1999; 41: 261–6.

5. Goulden V, Wilkinson SM. Occupational allergic contact dermatitisfrom epoxy resin on chipboard. Contact Dermatitis 1996; 35:262–3.

6. Bjorkner B. Plastic materials. In: Adams RM (ed.). OccupationalSkin Disease, 3rd edn. Philadelphia: WB Saunders Co., 1999;434–62.

7. Kanerva L, Jolanki R, Alanko K, Estlander T. Patch-test reactionsto plastic and glue allergens. Acta Derm. Venereol. 1999; 79:296–300.

Contact dermatitis to plywood glues 225

Table 1 Plastic and glues series

Tricresyl phosphate 5.0%Triethylenetetramine (TETA) 0.5%Turpentine peroxide 0.3%Dibutylphthalate 5.0%Phenol-formaldehyde resin 5.0%Isophorone diamine (IPD) 0.1%Toluene sulfonamide formaldehyde resin 10.0%Diaminodiphenyl methane 0.5%Hexamethylenetetramine 2.0%Phenylglycidylether 0.25%Diethylenetriamine 1.0%Epoxy resin, cycloaliphatic 0.5%Diphenylmethane-4,4-diisocyanate (MDI) 2.0%Toluene-2,4-diisocyanate (TDI) 2.0%Hexamethylene diisocyanate (HDI) 0.1%Abitol 10.0%Bisphenol A 1.0%Triphenyl phosphate 5.0%Diethylhexylphthalate 2.0%4 tert Butylcatechol 0.5%Azodiisobutylrodinitrile 1.0%

Dear Editor,

Peptides in the treatment of inflammatory skin disease

T-cells, and more specifically the T-cell antigen receptors(TCR), play a critical role in a variety of skin conditions. Stableinteractions between the protein chains that constitute theTCR are localized to a stretch of eight amino acids within the transmembrane region of the TCR-�. In this region, thecharged amino acids, arginine and lysine, play a critical rolein TCR assembly. Core peptide (CP; Gly-Leu-Arg-Ile-Leu-Leu-Leu-Lys-Val) is the prototype of a number of analogue pep-tides designed from the amino acid sequence in this region,to interfere with the lipid–protein charge interactions. Priorto this development, a number of other therapeutic strategieshad been devised to modulate immune function. Thesefocused on the major histocompatibility complex and theTCR-antigen trimolecular complex to alter the immuneresponse. They included the use of monoclonal antibodies toeither delete T-cells or regulate their function,1–3 T-cell vaccines against pathogenic T-cells and TCR,4,5 the synthesisof analogue peptides to compete with antigenic peptides,6

and the inhibition of cytokine production.7,8

Core peptide is hypothesized to prevent higher order TCRoligomerization complexes in sphingolipid rafts by trans-membrane lipid peptide interactions. Core peptide has pre-viously been shown to inhibit in vitro T-cell activation byinhibiting interleukin (IL)-2 production, and in vivo, in models of experimental allergic encephalitis, adjuvantinduced arthritis and cyclophosphamide-induced diabetes inmice.9 Confocal microscopy studies suggest that CP enterscells and colocalizes with the TCR, but not with other receptors, such as the transferin receptor, IL-2 receptor orCD2 molecules. Core peptide inhibits � phosphorylation following antigen stimulation, and has no downstream TCReffects when cells are stimulated with phorbol ester or CD3cross-linking (X Wang, pers. comm., 2001). Core peptide alsoinhibits natural killer (NK) cytotoxicity using chromiumrelease assays. Experiments under investigation are trying to

determine whether pure NK cells or NK-T subsets areinvolved.

This study involved an open-label animal trial to determinewhether CP could effectively inhibit allergic contact derma-titis, a form of T-cell mediated inflammation. Core peptide wassynthesized commercially by Auspep Australia (Vic.), andpurified by high performance liquid chromatography. The solvents used were 0.1% trifluoroacetic acid (TFA) and 90%acetonitrile/water plus 0.09% TFA. Core peptide had a purityof >90% examined at 218 nm. Twenty-week-old, femaleBALB/c mice (n = 30) were primed with 400 �L of 0.5% fluorescein isothiocyanate (FITC) in acetone/dibutyl pthalte(50:50), applied to the shaved belly. The mice were then challenged with 20 �L applied to the dorsal surface of the left ear on day 6. One group of mice (n = 20) received CP(2 mg/mouse), and a second control group (n = 10) receivedbovine serum albumin (BSA; 2 mg/mouse) intraperitoneallyon day 6, 24 hours before challenge. Considering BSA was asimple agent to obtain, and was used in previous experimentswith diabetic mice,9 we used this product as a control. Baselineear thickness measurements were made prior to the appli-cation of FITC, and ear-swelling responses to FITC were measured at 24 and 48 hours after the chemical was appliedto the ear on days 7 and 8, using a spring-loaded caliper.Changes in the ear thickness were calculated as described,10

namely (thickness of ear at 24 and 48 hours after challengeon ear) minus (baseline ear thickness measured on day 0)divided by (baseline ear thickness measured on day 0) multi-plied by 100. Ear swelling in the CP-treated group was signifi-cantly less than the control peptide group at 24 hours(P = 0.002). This effect is most notable in the first 24 hours.At 48 hours, the CP-treated group exhibited 10% less swellingcompared to the control group (P = 0.5; Fig. 1). This experi-ment was repeated on three separate occasions with similarresults. Statistical differences were calculated using a Student’st-test (Microsoft Excel).

These results suggested that systemic administration of CP was effective in reducing the induction of type IV hyper-sensitivity response by T-cells, and confirmed recent studiesthat CP significantly inhibited human T-cell function in vitroand in vivo.11 The anti-inflammatory response of CP testedusing our model is time-dependent. The therapeutic effect ofCP during the active inflammatory episode was not assessed.However, CP inhibited the active inflammatory phase of adjuvant-induced arthritis by 70–80%, similar to cyclosporinin relieving inflammation (N Kurosaka and N Manolios, pers.comm., 2001). We predict that this effect would be similar in this model. These results suggested that CP had potentialas a steroid-sparing agent in T-cell-mediated inflammatorydisease. Future studies should aim to assess the safety of thispeptide as a novel immunosuppressive agent for use inhumans.

REFERENCES

1. Watts RA, Isaacs JD. Immunotherapy of rheumatoid arthritis. Ann.Rheum. Dis. 1992; 51: 577–9.

Australasian Journal of Dermatology (2002) 43, 226–228

LETTERS TO THE EDITOR

Figure 1 Core peptide-inhibited ear-swelling response in fluoresceinisothiocyanate (FITC)-primed mice. �, Core peptide; �, bovine serumalbumin.

2. Moreland LW, Bucy RP, Tilden A, Pratt PW, LoBuglio AF, Khazaeli M, Everson MP, Daddona P, Ghrayeb J, Kilgarriff C. Use of a chimeric monoclonal anti-CD4 antibody in patients with refractory rheumatoid arthritis. Arthritis Rheum. 1993; 36:307–18.

3. van der Lubbe PA, Dijkmans BA, Markusse HM, Nassander U,Breedveld FCA. A randomized, double-blind, placebo-controlledstudy of CD4 monoclonal antibody therapy in early rheumatoidarthritis. Arthritis Rheum. 1995; 38: 1097–106.

4. Vandenbark AA, Hashim G, Offner H. Immunization with a synthetic T-cell receptor V-region peptide protects against experimental autoimmune encephalomyelitis. Nature 1989; 341: 541–4.

5. Howell MD, Winters ST, Olee T, Powell HC, Carlo DJ, Brostoff SW.Vaccination against experimental allergic encephalomyelitis withT cell receptor peptides. Science 1989; 246: 668–70.

6. De Magistris MT, Alexander J, Coggeshall M, Altman A, Gaeta FC,Grey HM, Sette A. Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. Cell 1992; 68: 625–34.

7. Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, SmolenJS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H. Randomised double-blind comparison of chimeric monoclonal antibody totumour necrosis factor alpha (cA2) versus placebo in rheumatoidarthritis. Lancet 1994; 344: 1105–10.

8. Feldmann M, Brennan FM, Chantry D, Haworth C, Turner M,Abney E, Buchan G, Barrett K, Barkley D, Chu A. Cytokine production in the rheumatoid joint: Implications for treatment.Ann. Rheum. Dis. 1990; 49: 480–6.

9. Manolios N, Collier S, Taylor J, Pollard J, Harrison LC, Bender V.T-cell antigen receptor transmembrane peptides modulate T-cellfunction and T cell-mediated disease. Nat. Med. 1997; 3: 84–8.

10. Back O, Groth O. The cellular infiltrate of the contact sensitivityreaction to picryl chloride in the mouse. Acta Derm. Venereol. 1983;63: 304–7.

11. Gollner GP, Muller G, Alt R, Knop J, Enk AH. Therapeutic application of T cell receptor mimic peptides or cDNA in the treatment of T cell-mediated skin diseases. Gene Ther. 2000; 7:1000–4.

Nicholas Manolios,1 Nghi T Huynh1 and Simon Collier2

1Department of Rheumatology, Westmead Hospital and2Sydney Eye Institute, University of Sydney, Sydney,

NSW, Australia

Dear Editor,

Re: Multiple corticosteroid allergies. Australas. J. Dermatol.2001; 42: 62–3

I agree with Dr Dallimore that treatment of perioral dermati-tis requires the avoidance of all forms of topical corticosteroids.The article could perhaps have emphasized that the hydro-cortisone and clotrimazole cream treatment was onlyprescibed for the first 2 weeks to help ease the acute flare ofthe patient’s perioral dermatitis, after ceasing the mometasonecream. I was not the treating dermatologist, but my postulationis that the patient may have accidentally contaminated herperioral skin with some of the corticosteroids used to treat hervulval dermatitis and hence the prolonged period of activeperioral dermatitis despite oral tetracycline.

Elizabeth ChowSkin and Cancer Foundation, Ashley Lane, Westmead,

NSW, Australia

Letters to the Editor 227

Book Reviews

Dubois’ Lupus Erythematosus, 6th edn. Edited by Daniel JWallace and Bevra Hannahs Hahn. Lippincott Williams &Wilkins, Philadelphia, 2002. 1348 pages, including index.A$503.80. ISBN 0-7818-2464-3.

This enormous tome, which is now in its sixth edition, wasfirst published in 1966. There are now two editors and multi-ple authors writing a variety of chapters on all aspects of lupuserythematosus (LE) through history, definition and epidemi-ology, pathogenesis, clinical and laboratory features, and thenmanagement and prognosis. There is a separate section on cu-taneous LE written by Richard Sontheimer with coauthors,which substantially comprises the aspects of this book thatwould be of interest to dermatologists. The two chapters underthe section on cutaneous LE are 69 pages long, with some diagrams and plenty of references, which are up to date. Apartfrom a few colour photographs of mediocre quality at the be-ginning of the book, all the rest of the illustrations and photographs throughout the book are in black and white. Thatis a pity, particularly as it reduces the ability to highlight subtle variations in the cutaneous signs and histopathologyof LE.

Overall, the book is a very, very detailed exposition on various manifestations of LE. The book is large and the textis very dense with extensive reviewing of the literature withinthe text, plus referencing. This, although of value to someonewith a major interest in LE, would tend to make it a ratherdifficult book to use for someone who wanted a quick answerto a relatively simple question. Because of its size, breadth anddepth of content, and cost, it is probably not likely to be ap-pealing to dermatologists in general, but would be of value ina major medical library, or possibly in a dermatological clinicthat had a special interest in LE.

Professor R Marks

Obstetric and Gynecologic Dermatology, 2nd edn. Editedby Martin M Black and Marilynne McKay. Mosby InternationalLimited, London, 2002. 241 pages, including index and appendices. Price: A$271.15. ISBN 0-723-43182-5. (Distributedin Australia by Harcourt Australia.)

This is a book of A4 size that can be recommended to dermatologists in all sections of practice, and not only thoseassociated with a women’s hospital.

The text is clearly set out and is accompanied by tables re-lating to grouped conditions, such as: ‘Viral Exanthemata inPregnancy. 1. Maternal Infection. 2. Consequences for theFetus/Neonate’. The illustrations are of best quality, and in allcases clearly display the condition, almost always on the pageaccompanying the relevant text. Most references are from thelate 1990s, and some from 2000.

Appendices are on Differential Diagnosis of Vulvar Ulcersand Pruritus (with further tables and illustrations); TopicalTherapy of Gynecological Skin Disorders; Diagnostic Tech-niques; and lastly, some pages for photocopying as patient in-formation sheets.

It is interesting that the book is printed in China: perhapsthis keeps the price reasonable for such a book on the Australian market.

Dr David S Nurse

Physical Signs in Dermatology, 2nd edn. Clifford MLawrence and Neil H Cox. Harcourt Health Sciences, Mosby, 2002. 396 pages, including index. Price: A$180.95.ISBN 0-72343184-1. (Distributed in Australia by Harcourt Australia.)

This is the ultimate book on skin signs. It is problem orientated with superb photographs. It is not for the readerlooking for mechanisms of disease or to understand the molecular basis of skin diseases. It makes no attempt to covertherapeutics. It does, however, achieve the authors’ aim ‘to encourage the reader to be analytical in evaluating clinical features of dermatological conditions and to understand howthese combine to lead to a diagnosis’. It is essentially an atlasof excellent photographs beautifully produced, but accordinglyexpensive. It would be largely directed at the American market and would suit early trainees in dermatology, togetherwith a general audience interested in descriptive dermatology.

Dr John A Brenan

228 Book reviews

CLINICAL MANAGEMENT OF CHILDREN ANDADULTS WITH EPIDERMOLYSIS BULLOSA

A symposium will be held at the Institute of Child Health, 30 Guilford Street, London WC1N 1EH, United Kingdom, for individuals and multidisciplinary teams who care for patients with EBS. The meeting will be held from 7–8 November 2002 and is sponsored by DEBRA UK. Those interested in participating should contact DEBRA UK, DEBRA House, 13 Wellington Business Park, Dukes Ride, Crowthorne, Berks RG14 6LS, United Kingdom; Tel.: 0044 7779221909; Fax: 0044 1344762777; Email: sue.glazier@btinternet.com

THIRD NATIONAL SCIENTIFIC MEETING OF THEAUSTRALASIAN HAIR AND WOOL RESEARCH

SOCIETY

The Australasian Hair and Wool Research Society presents aCutaneous Biology and Endocrinology Workshop, to be held

from 31 October to 2 November, 2002, at the Mary AikenheadConference Centre, St Vincent’s Hospital, 27 Victoria Parade,Melbourne, Australia. Please address enquiries to the Work-shop Secretariat, Mrs H Gibson, c/- Department of Derma-tology, St Vincent’s Hospital, PO Box 2900, Fitzroy, Vic. 3065,Australia; Tel: 613 9288 3127; Fax: 613 9288 3292; Email: gibsonhh@svhm.org.au

SIXTH WORLD CONFERENCE ON MELANOMA

To be held in Vancouver, British Columbia, Canada, 2–9 September, 2005. For more information please contact the Sixth WCOM Secretariat, c/o Venue West ConferenceServices Ltd., #645-375 Water Street, Vancouver, BC, V6B 5C6,Canada; Tel: 604 681 5226; Fax: 604 681 2503;Email: congress@venuewest.com; Website: http://www.worldmelanoma.com

ANNOUNCEMENTS