acute generalized exanthematous pustulosis following use of ticlopidine

31
British Journal of Dermatology 2000; 142: 560–591. Correspondence Penicillamine-induced elastosis perforans serpiginosa and cutis laxa in Wilson’s disease Sir , We present an unusual and striking case of elastosis perforans serpiginosa and cutis laxa in a 36-year-old man previously on long-term, high-dose penicillamine for Wilson’s disease. The patient may also have elastolytic involvement of the upper respiratory tract, a rarely reported feature. He originally presented with jaundice at the age of 4 years and by age 8 years progressive dysarthria and clumsiness of the hands had appeared. Wilson’s disease was diagnosed and he was treated with the chelating agent dimercaprol. In 1982 the treatment was changed to penicillamine given long-term in a dose of 2–3 g daily. In 1995 he presented with itchy, papular lesions on the left arm, due to penicillamine-induced perforating elastosis. Penicillamine was discontinued in January 1996, and trientine dihydrochloride (triethylene tetramine dihydrochloride), an alternative copper chelator, was commenced. The papular lesions resolved initially but then returned 6 months later on the neck, shoulders and upper arms. Trientine was therefore discontinued and he was maintained on zinc sulphate (up to 600 mg daily),which reduces copper absorption in the intestine. Treatment with topical clobetasol propionate flattened the lesions, and small areas treated with triamcinolone 10 mg/mL injections resolved almost completely. There has also been some spontaneous improvement following the withdrawal of chelation therapy, with fewer new lesions appearing. Subse- quently, trientine has been recommenced because of neurological deterioration; new lesions have been partially controlled by the topical steroid therapy. On examination of his skin in 1996 there was generalized cutis laxa (Fig. 1a) with perforating elastolytic nodules on the neck and elastosis perforans serpiginosa over the shoulders (Fig. 1b). General examination revealed dysphonia, dysar- thria due to pseudobulbar palsy, upward gaze palsy, reduced speed of tongue movements, and erect gait with truncal rigidity. Ophthalmological examination revealed no elastolytic changes such as angioid streaks in the retina, and no Kayser– Fleischer corneal deposits of copper. Investigations revealed a normal full blood count, biochem- istry, autoantibodies and immunoglobulins. Caeruloplasmin, urine copper, serum copper and a magnetic resonance imaging brain scan were consistent with Wilson’s disease, in the decoppered state. A barium swallow, performed in 1995 because of his difficulty in swallowing, demonstrated pharyngeal and tongue weakness with aspiration and ineffective cough reflex. We feel that this may in part be caused by the elastolytic effects of penicillamine on the upper respiratory tract and oropharynx and also because of pseudo- bulbar palsy, as penicillamine is known to cause elastolysis of many tissues including the respiratory tract. Histology of a skin biopsy from the upper arm and a nodule on the neck revealed a perforating channel from the dermis through the epidermis with a surrounding inflammatory infiltrate, and horseshoe-shaped multinucleate giant cells phagocytosing abnormal elastic fibres. Elastin van Gieson stain showed abnormal elastic fibres with a ‘lumpy-bumpy’ or ‘bramble- bush’ appearance, which are typically seen in elastolysis due to penicillamine (Fig. 1c). 560 q 2000 British Association of Dermatologists Figure 1. (a) Cutis laxa over the back. (b) Elastosis perforans serpiginosa on the shoulder. (c) Elastic van Gieson stain (original magnification 400). ‘Lumpy-bumpy’ or ‘bramble-bush’ elastic fibres.

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Page 1: Acute generalized exanthematous pustulosis following use of ticlopidine

British Journal of Dermatology 2000; 142: 560±591.

Correspondence

Penicillamine-induced elastosis perforans serpiginosaand cutis laxa in Wilson's disease

Sir, We present an unusual and striking case of elastosisperforans serpiginosa and cutis laxa in a 36-year-old manpreviously on long-term, high-dose penicillamine for Wilson'sdisease. The patient may also have elastolytic involvement ofthe upper respiratory tract, a rarely reported feature.

He originally presented with jaundice at the age of 4 yearsand by age 8 years progressive dysarthria and clumsiness ofthe hands had appeared. Wilson's disease was diagnosed andhe was treated with the chelating agent dimercaprol. In 1982the treatment was changed to penicillamine given long-termin a dose of 2±3 g daily. In 1995 he presented with itchy,papular lesions on the left arm, due to penicillamine-inducedperforating elastosis. Penicillamine was discontinued inJanuary 1996, and trientine dihydrochloride (triethylenetetramine dihydrochloride), an alternative copper chelator,was commenced. The papular lesions resolved initially butthen returned 6 months later on the neck, shoulders andupper arms. Trientine was therefore discontinued and he wasmaintained on zinc sulphate (up to 600 mg daily),whichreduces copper absorption in the intestine. Treatment withtopical clobetasol propionate flattened the lesions, and smallareas treated with triamcinolone 10 mg/mL injectionsresolved almost completely. There has also been somespontaneous improvement following the withdrawal ofchelation therapy, with fewer new lesions appearing. Subse-quently, trientine has been recommenced because ofneurological deterioration; new lesions have been partiallycontrolled by the topical steroid therapy.

On examination of his skin in 1996 there was generalizedcutis laxa (Fig. 1a) with perforating elastolytic nodules on theneck and elastosis perforans serpiginosa over the shoulders(Fig. 1b). General examination revealed dysphonia, dysar-thria due to pseudobulbar palsy, upward gaze palsy, reducedspeed of tongue movements, and erect gait with truncalrigidity. Ophthalmological examination revealed no elastolyticchanges such as angioid streaks in the retina, and no Kayser±Fleischer corneal deposits of copper.

Investigations revealed a normal full blood count, biochem-istry, autoantibodies and immunoglobulins. Caeruloplasmin,urine copper, serum copper and a magnetic resonanceimaging brain scan were consistent with Wilson's disease,in the decoppered state. A barium swallow, performed in1995 because of his difficulty in swallowing, demonstratedpharyngeal and tongue weakness with aspiration andineffective cough reflex. We feel that this may in part becaused by the elastolytic effects of penicillamine on the upperrespiratory tract and oropharynx and also because of pseudo-bulbar palsy, as penicillamine is known to cause elastolysis ofmany tissues including the respiratory tract. Histology of askin biopsy from the upper arm and a nodule on the neckrevealed a perforating channel from the dermis through the

epidermis with a surrounding inflammatory infiltrate, andhorseshoe-shaped multinucleate giant cells phagocytosingabnormal elastic fibres. Elastin van Gieson stain showedabnormal elastic fibres with a `lumpy-bumpy' or `bramble-bush' appearance, which are typically seen in elastolysis dueto penicillamine (Fig. 1c).

560 q 2000 British Association of Dermatologists

Figure 1. (a) Cutis laxa over the back. (b) Elastosis perforans

serpiginosa on the shoulder. (c) Elastic van Gieson stain (original

magnification � 400). `Lumpy-bumpy' or `bramble-bush' elasticfibres.

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Penicillamine is a copper chelator used at high dosages inWilson's disease, and may cause rashes in up to 60% ofpatients. An acute hypersensitivity eruption may appearwithin the first 10 days of treatment, and immunologicaldisorders such as pemphigus foliaceous have been reported,although these are more commonly seen in patients withrheumatoid arthritis treated with penicillamine at lowerdosages.1 At high doses, penicillamine disrupts elastic fibreformation and causes penicillamine dermopathy,2 cutis laxa,3

pseudoxanthoma elasticum-like skin changes4 and elastosisperforans serpiginosa.3,4 These conditions can sometimesoccur at the lower dosages used in rheumatoid arthritis.5

Elastolytic changes may also be seen in other tissues such asthe upper respiratory tract,6 the joint capsules,7 the lungs,aorta and adventitia of the viscera.5 The histological featureseen consistently in patients with elastolysis due to penicilla-mine is `lumpy-bumpy'8 or `bramble-bush'9 -like elastic fibres,which appears to be quite specific.

The underlying mechanism is possibly direct inhibition ofcross-linkage of collagen fibres by penicillamine.10 In addi-tion, the enzyme lysyl oxidase, required for cross-linking ofcollagen fibres, is dependent on the presence of copper andtherefore may be inhibited by removal of copper from thetissues by penicillamine.11 Further support for the impor-tance of copper in the formation of elastic tissues comes fromthe very rare X-linked recessive genetic copper deficiency,Menke's disease, where cutis laxa is also common.11 Elastosisperforans serpiginosa occurs when there is sufficient build upof abnormal elastic fibres to cause a foreign body reaction andtransepidermal elimination of those fibres.

The alternative copper chelator, trientine, appears to be lesslikely to cause elastolysis, and the changes caused by thepenicillamine may regress when the treatment is switched totrientine, although this was not the case in our patient. Thetrace metal zinc may also be helpful in the treatment ofWilson's disease by reducing intestinal absorption of copper,allowing temporary discontinuation of penicillamine.

In conclusion, our patient demonstrates very well theelastolytic effects caused by long-term, high-dose penicilla-mine used as a copper chelator in Wilson's disease. Thecombination of cutis laxa and elastosis perforans serpiginosaas well as possible elastolytic effects on the oropharynx andupper respiratory tract is unusual and rarely reported.

V.A.HIL L

C.A.SEY MOUR*P.S.MORTIM ER

Department of Dermatology and*Division of Cardiological Sciences(Metabolic Medicine),St George's Hospital,Blackshaw Road,Tooting, London SW17 0QT, U.K.

References

1 Marsden RA, Vanhegan RI, Walshe M et al. Pemphigus foliaceus

induced by penicillamine. Br Med J 1976; 2: 1423±4.

2 Coulson IH, Marsden RA. Penicillamine dermopathy. Br J

Dermatol 1985; 113 (Suppl.): 87±8.

3 Amichai B, Rotem A, Metzker A. d-penicillamine-induced

elastosis perforans serpiginosa and localized cutis laxa in apatient with Wilson's disease. Israel J Med Sci 1994; 30: 667±9.

4 Meyrick Thomas RH, Kirby JDT. Elastosis perforans serpiginosa

and pseudoxanthoma elasticum-like skin change due tod-penicillamine. Clin Exp Dermatol 1985; 10: 386±91.

5 Burge S, Ryan T. Penicillamine-induced pseudo-pseudoxanthoma

elasticum in a patient with rheumatoid arthritis. Clin Exp

Dermatol 1988; 13: 255±8.6 Babu Manohar M, Boldy DAR, Bryan RL et al. Penicillamine-

induced changes in elastic tissue of the upper respiratory tract.

J Laryngol Otol 1993; 107: 62±4.

7 Dalziel KL, Burge SH, Frith PA et al. Elastic fibre damageinduced by low dose d-penicillamine. Br J Dermatol 1990; 123:

305±12.

8 Bardach H, Gebhart W, Neibauer G. `Lumpy-bumpy' elastic fibresin the skin and lungs of a patient with a penicillamine-induced

elastosis perforans serpiginosa. J Cutan Pathol 1979; 6: 243±52.

9 Hashimoto K, McEvoy B, Belcher R. Ultrastructure of peni-

cillamine-induced skin lesions. J Am Acad Dermatol 1981; 4:300±15.

10 Siegel RC. Collagen cross-linking effect of d-penicillamine on

cross-linking in vitro. J Biol Chem 1977; 252: 254±9.

11 Seymour CA. Trace metal disorders. In: Oxford Textbook ofMedicine (Weatherall DJ, Ledingham JGG, Warrell DA, eds), 3rd

edn, Vol. 2. Oxford: Oxford University Press, 1996: 1417±19.

A case of cutaneous polyarteritis nodosa associatedwith ulcerative colitis

Sir, Cutaneous manifestations are common in ulcerativecolitis (UC) and Crohn's disease (CD). Among them, however,cutaneous vasculitis, which includes leucocytoclastic vascu-litis and cutaneous polyarteritis nodosa (CPN), has rarelybeen reported.1 As far as we know, there have been only tworeports which described the association of CPN with UC.2,3

Here we report a case of CPN in a patient with a 7-yearhistory of UC. A 69-year-old woman was referred inSeptember 1994 with a 2-week history of recurrent painfulerythematous nodules on both legs, a small ulcer on the leftleg, myalgia of the calves, and arthralgia of the knees andankles. Biopsy from an erythematous nodule over the leftmedial malleolus showed panarteritis in the subcutis andmuscle. Small and medium-sized arteries showed narrowingor obliteration of their lumina due to intimal proliferationwith an infiltrate of lymphocytes and histiocytes (Fig. 1).Direct immunofluorescence testing showed IgG and IgAdeposits in the wall of involved vessels.

Laboratory tests revealed haemoglobin 87 g/dL, leucocytecount 13 � 109/L, platelet count 319 � 109/L, erythrocytesedimentation rate 68 mm in the first hour, C-reactive protein(CRP) 33 mg/L and rheumatoid factor of 209 IU/mL. Testsfor antinuclear antibody, p-ANCA, c-ANCA, hepatitis Bsurface antigen and antibody, and hepatitis C antibody wereall negative, and serum C3, C4 and CH5O were all normal orelevated. Test for nerve conduction velocities in the legsshowed mononeuritis multiplex. Coeliac angiography showedno microaneurysms.

In 1987, the patient presented with bloody diarrhoea and

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abdominal pain that was subsequently diagnosed by afibreoptic colonoscopy combined with biopsy, in June 1988at another hospital, as UC. After successful initial therapy, thepatient had been maintained on oral prednisolone 10 mg andsulphasalazine 15 g daily. On admission to our hospital, afibreoptic study was performed again and revealed a healingstage of UC, showing small shallow ulcers in the rectum,pseudopolyps, oedematous mucosa and diffuse erythema inthe descending colon, and erosions in the transversecolon.

Based on the clinical and histological findings, althoughthe latter showed a later stage of necrotizing vasculitis withlittle infiltrate of neutrophils, a diagnosis of CPN was estab-lished. After admission, the patient developed a punched-out3-cm ulcer, surrounded by a halo of livedo reticularis, fromwhich the skin biopsy was performed. Moreover, her myalgiaand arthralgia worsened with elevated CRP of 192 mg/L.Prednisolone 40 mg and cyclophosphamide 50 mg daily wereintroduced with immediate resolution of the leucocytosis andelevated CRP.

The relationship between CPN and UC is debatable.Immune complex mediated reactions are felt to be thepathogenesis of necrotizing vasculitis,4 and elevated rheuma-toid factor has been reported in the progressive form of CPN.5

Likewise, circulating immune complexes and other immuno-logical disturbances have been described in UC.6,7 The presentcase also showed an elevated rheumatoid titre, which mightreflect the immunological derangement. Therefore, we specu-late that CPN is an immunological complication of UC andcan be included as one of its extra-intestinal manifestations.

The association of CPN and CD may be more common thanexpected. In the present case, skin biopsy was important indiagnosing CPN rather than pyoderma gangrenosum (PG), asthe pattern of skin lesions looked very much like early lesionsof PG, a common skin manifestation of UC.

Y.MATSU MUR A

K.MIZUN O

K.OHTA

H.OK AM OTO

S.IMA MUR A

Department of Dermatology,Graduate School of Medicine,Kyoto University,54 Shogoin Kawara-cho,Sakyo, Kyoto, Japan

References

1 Gregory B, Ho VC. Cutaneous manifestations of gastrointestinal

disorders. Part II. J Am Acad Dermatol 1992; 26: 371±83.2 Chiu G, Rajapakse CNA. Cutaneous polyarteritis nodosa and

ulcerative colitis. J Rheumatol 1991; 18: 769±70.

3 Volk DM, Owen LG. Cutaneous polyarteritis nodosa in a patient

with ulcerative colitis. J Pediatr Gastroenterol Nutr 1986; 5: 970±2.4 Soter NA. Cutaneous necrotizing venulitis. In: Fitzpatrick's Derma-

tology in General Medicine (Freedberg IM, Eisen AZ, Wolff K, et al.,

eds), 5th edn, Vol. 2. New York: McGraw-Hill, 1999: 2044±53.

5 Chen KR. Cutaneous polyarteritis nodosa: a clinical and histo-pathological study of 20 cases. J Dermatol 1989; 16: 429±42.

6 Halstensen TS, Mollnes TE, Brandtzaeg P. Persistent complement

activation in submucosal blood vessels of active inflammatorybowel disease: immunohistochemical evidence. Gastroenterology

1989; 97: 10±19.

7 Shafir M, Martinelli G, Bekesi JG et al. Immunoglobulins (Ig) in

circulating immune complexes (CIC) in cancer and inflammatorybowel disease (IBD). Eur J Surg Oncol 1986; 12: 351±7.

Hypertrophic osteoarthropathy associated withpyoderma gangrenosum

Sir, Pyoderma gangrenosum (PG) is a rare, destructive inflam-matory skin disease which may be idiopathic or occur inassociation with systemic disease such as ulcerative colitis,Crohn's disease, polyarthritis, monoclonal gammopathy or

Figure 1. Necrotizing artery withinfiltration of mononuclear cells in the

subcutis. Intimal proliferation and almost

complete obliteration of lumen are noted.

(Haematoxylin and eosin, originalmagnification � 200.)

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other conditions.1 Hypertrophic osteoarthropathy (HOA) is asyndrome characterized by excessive proliferation of skin andbone at the extremities.2 It may be associated with severalunderlying disorders such as cyanotic heart disease, hepaticdiseases or intestinal diseases.3 As yet, an association betweenPG and HOA has not been reported. We report a patient withHOA following PG.

A 19-year-old woman was admitted in April 1996 becauseof large painful areas of ulceration involving both legs.Acneiform pustules had developed 2 years previously, andbecame confluent and ulcerated on her legs. The clinicalcourse had been chronic, with painful exacerbations. She hadbeen treated with antituberculosis medication and antifungalmedication for possible lupus vulgaris or sporotrichosis, butnew pustules and ulceration had developed and slowlyenlarged.

Examination revealed large, well demarcated, crustedulcers containing several pustules with bullous bordersand surrounding hypopigmented atrophic scars on boththighs (Fig. 1). She had had tenderness and swelling of

the proximal left index finger and both lower legs for6 months. Initial blood count showed leucocytosis (whitecell count 16´0 � 109/L), anaemia (haemoglobin 7´7 g/dL)and elevated erythrocyte sedimentation rate (97 mm in thefirst hour) and alkaline phosphatase (493 IU/L).

Skin biopsy demonstrated a dense neutrophilic infiltratewith abscess formation in the dermis and subcutaneous fat,without evidence of vasculitis. Tissue cultures for bacteria,acid-fast bacilli and fungi were negative. A diagnosis of PGwas made. Simple X-ray showed a longitudinal periostealreaction on the tibia and on the proximal phalanx of theleft index finger (Fig. 2a). Multiple hot-spots were revealedon skeletal scintigraphy (Fig. 2b). Secondary HOA wasconsidered, and various studies were performed to find anunderlying condition associated with PG or HOA. Thefollowing tests were negative or normal: colonoscopy,gastroscopy, serum protein electrophoresis, serum and urineimmunoelectrophoresis, chest X-ray, echocardiography,abdominal ultrasound, antineutrophil cytoplasmic antibodies,cryoglobulins and antinuclear antibody.

She was treated with systemic prednisolone 1 mg/kg dailyfor 2 weeks, with gradual improvement. Two months later,the cutaneous lesions had healed and the dosage ofprednisolone was reduced. After discharge, she was treatedwith prednisolone 10±20 mg daily, minocycline 200 mgdaily and dapsone 100 mg daily for 18 months. During thisperiod, new cutaneous lesions did not develop and periostealreactions were markedly reduced on simple X-ray and skeletalscintigraphy.

Our patient had typical clinical and pathological featuresconsistent with PG. She had been suffering from PG for2 years before HOA developed. A varying frequency ofassociated systemic diseases such as inflammatory boweldisease, different types of arthritis, immunological abnor-malities, monoclonal gammopathy, malignant disease,chronic active hepatitis, thyroid disease, chronic obstructivepulmonary disease and systemic lupus erythematosus hasbeen reported in patients with PG.4,5

Many patients with HOA are asymptomatic and unaware ofthe deformity of their digits, although pain is prominent in thelegs as a result of lower limb dependency.2 HOA may beclassified as primary, in which there is no underlying disease,or secondary to a variety of serious thoracoabdominalconditions such as cyanotic heart disease, pulmonary fibrosis,infection, malignancy or inflammatory bowel disease.2,3,6

Periosteal proliferation of the tubular bones is the hallmark ofHOA.6 Correction of underlying conditions can produce rapidregression of the syndrome.2

Coexistence of PG and the synovitis, acne, pustulosis,hyperostosis, osteitis (SAPHO) syndrome has beenreported.7,8 In our patient, there was no evidence of acne,hyperostosis or synovitis, and the SAPHO syndrome can beexcluded. Idiopathic PG without associated disease had beenpresent for 2 years, and treatment of the skin lesionsproduced dramatic regression of the periosteal reaction.This suggests that PG could be a condition associated withHOA.

Figure 1. A large haemorrhagic crusted ulcer with an irregularpustular bullous border is evident on the thigh.

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M-H.HAN

G-J.KOH

J-K.KOH

K-C.MOON

Department of Dermatology,Asan Medical Center,College of Medicine,University of Ulsan,388-1 Poongnap-dong,Songpa-gu, Seoul 138-040,Korea

References

1 Wolff K, Stingl G. Pyoderma gangrenosum. In: Dermatology in

General Medicine (Freedberg IM, Eisen AZ, Wolff K et al., eds), 5th

edn. New York: McGraw-Hill, 1999; 1140±8.

2 Martinez LM. Hypertrophic osteoarthropathy. In: Primer on the

Rheumatic Diseases ( John HK, Cornelia MW, eds), 11th edn.Atlanta: Arthritis Foundation, 1997; 370±2.

3 Martinez LM. Hypertrophic osteoarthropathy. Curr Opin Rheumatol1997; 9: 83±6.

4 Powell FC, Su D, Perry HO. Pyoderma gangrenosum: classificationand management. J Am Acad Dermatol 1996; 34: 395±409.

5 Callen JP. Pyoderma gangrenosum. Lancet 1998; 351: 581±5.

6 Pineda C, Fonseca C, Martinez LM. The spectrum of soft

tissue and skeletal abnormalities of hypertrophic osteoarthro-

pathy. J Rheumatol 1990; 17: 626±32.7 Rosner IA, Richter DE, Huettner TL et al. Spondyloarthropathy

associated with hidradenitis suppurativa and acne conglobata. Ann

Intern Med 1982; 97: 520±5.

8 Claudepierre P, Clerc D, Cariou D et al. SAPHO syndrome andpyoderma gangrenosum: is it fortuitous? J Rheumatol 1996; 23:

400±2.

CD8-positive mycosis fungoides presenting ascapillaritis

Sir, We report two patients with mycosis fungoides (MF)presenting as a capillaritis. Both patients had a CD8+ immuno-phenotype and both exhibited T-cell clones in the skinconfirming the diagnosis of cutaneous T-cell lymphoma (CTCL).

Patient 1, a 33-year-old man, presented in 1997 withhyperpigmentation and a purpuric eruption of the thumb,thenar eminence and wrist of the right arm that clinicallyresembled lichen aureus (Fig. 1a). Skin histology showedfocal lichenoid change at the dermoepidermal junction and a

Figure 2. (a) X-ray of the hand reveals a longitudinal periosteal reaction in the metacarpals of the thumb, index and ring fingers and in the

proximal phalanx of the index finger. (b) Bone scintigraphy shows multiple hot-spots in the extremities and vertebrae.

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Figure 1. (a) A purpuric eruption resembling lichen aureus is seen on the thumb, thenar eminence and wrist (patient 1). (b) A purpuric eruption

is seen below the breast (patient 2).

Figure 2. Photomicrographs showing(a) a predominantly lymphocytic infiltrate

with focal lichenoid change at the

dermoepidermal junction, and (b) extension

into the panniculus (patient 1; haematoxylinand eosin; original magnification:

a � 100, b � 60).

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predominantly lymphocytic infiltrate with mild cytologicalatypia of the mononuclear cells (Fig. 2a). The infiltrate wasperivascular in the superficial dermis, but was also present inthe panniculus (Fig. 2b). It was associated with red blood cellextravasation and haemosiderin deposition at both sites(Perl's stain). Immunotyping of the infiltrate showed thatthe atypical cells were CD3+ and CD8+ but CD4±. T-cellreceptor (TCR) gene analysis studies from the skin showed aT-cell clone, but studies on the blood were negative. Full bloodcount was normal, and human T-cell lymphotropic virus type 1(HTLV-1) antibodies were negative. There was no evidence ofextracutaneous disease. The patient was diagnosed as havingMF, and treated with radiotherapy, two fractions of 400 cGyat 800 kV. There was no evidence of recurrence at follow-up1 year later.

Patient 2, a 24-year-old woman, presented in 1997 with a5-year history of a progressive erythematous eruption below

her left breast. Most lesions were purpuric, with some areasshowing telangiectasia and slight scarring (Fig. 1b). Therewas no evidence of lymphadenopathy or organomegaly. Skinhistology showed a heavy lymphoid infiltrate extending tothe level of the subcutis, with a small number of atypicalmononuclear cells, slight epidermotropism, telangiectasia,scarring and red cell extravasation (Fig. 3a). Immunotypingof the infiltrate showed that the cells were CD3+ and CD8+(Fig. 3b) but CD4±. TCR gene analysis of blood, SeÂzary cellcount, T-cell subsets and HTLV-1 were all normal or negative.TCR gene analysis of the skin, however, demonstrated a T-cellclone, confirming a diagnosis of MF. The lesions were treatedwith superficial radiotherapy, two cycles of 400 cGy at 80 kV,with good effect.

MF may present with a wide range of cutaneousmanifestations including eczematous or psoriasiform erup-tions. Less common presentations include bullous, pustular,

Figure 3. Photomicrographs showing

(a) a heavy lymphoid infiltrate with slight

epidermotropism and red cell extravasation

(haematoxylin and eosin), and (b) apredominance of CD8+ cells (patient 2;

original magnification: both � 60).

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granulomatous, hypopigmented, hyperkeratotic and verruc-ous forms.1 Our two patients demonstrate that MF maypresent with purpuric lesions, and although this, too, is anuncommon feature of early MF, a review of the literatureshows that similar cases have previously been reported.

Purpura as a component of MF was first recorded in theFrench literature in 1876 by Bazin.2 The first report in theEnglish literature was by Gordon in 1950. His patient was a65-year-old man who initially presented with purpuricpatches over the trunk which progressed to lichenoid lesions3 years later, followed by erythroderma 2 years thereafter, bywhich time histology confirmed MF.3 McDonald also reportedthat petechiae were found in a small number of his patientswith MF, and that they correlated with disease activity. Henoted that the histological changes in these purpuric areaswere typical of those observed in MF.4 The first case of lichenaureus reported by Farrington5 `evolved' into MF approxi-mately 5 years later.6 Barnhill and Braverman reported threepatients with capillaritis who were confirmed to have MF afterserial skin biopsies and an average follow-up period of8´4 years.7 These reports, together with their own experienceof two purpuric presentations of MF, prompted Toro et al. toexamine the skin biopsies of 56 patients with persistentpigmented purpuric dermatitis (PPPD), to determine thefrequency of MF-like histological configurations.8 They foundthat in 29 of these patients, there were histological featurestypically seen in MF, such as epidermal alignment oflymphocytes along the dermoepidermal junction, with a fewnecrotic keratinocytes. These cases were then evaluated forclonality of the T-cell population using a polymerase chainreaction for g-chain rearrangements. They demonstratedclonal rearrangements in eight of the 12 specimens oflichenoid PPPD studied, and postulated that the lichenoidvariants of PPPD may be biologically related to MF. Ackermanet al. compared the histological features of lichenoid purpurawith plaque-stage MF, noting many similarities between thetwo, and concluding that it is sometimes impossible todifferentiate between them histologically. However, theyestablished that some features were characteristic of MF:lymphocytic atypia; the presence of eosinophils; lympho-cytes obscuring the dermoepidermal junction. They notedthat vascular stasis is a feature more typical ofcapillaritis.9

Capillaritis therefore has an important place in thedifferential diagnosis of early MF, and TCR gene analysismay be needed to distinguish the two conditions. In our casesthe diagnosis was particularly difficult as most cases of MFexhibit a CD4+ helper cell phenotype. However, approxi-mately 6% exhibit a cytotoxic phenotype10 and these casesmay be over-represented in childhood.11 The possibility thatpurpura is commoner in CD8+ MF requires further study.

M.AMEEN

A.DARVA

M.M.BLACK

D.H.MCGIBBON

R.RUSSELL-JONES

St John's Institute of Dermatology,St Thomas' Hospital,London SE1 7EH, U.K.

References

1 Lambroza E, Cohen SR, Phelps R et al. Hypopigmented variant of

mycosis fungoides: demography, histopathology and treatment of

seven cases. J Am Acad Dermatol 1995; 32: 987±93.2 Brehmer-Andersson E. Mycosis fungoides and its relation to

SeÂzary's syndrome, lymphomatoid papulosis and primary cutane-

ous Hodgkin's disease: a clinical, histopathologic, and cytologicstudy of fourteen cases and a critical review of the literature. Acta

Derm Venereol (Suppl.) (Stockh) 1976; 75: 1±142.

3 Gordon H. Mycosis fungoides. Br J Dermatol 1950; 62: 177±8.

4 McDonald CJ. Mycosis fungoides: a malignant cutaneous lym-phoma. Conn Med 1969; 33: 37±41.

5 Farrington J. Lichen aureus. Cutis 1970; 6: 1251±3.

6 Waisman M, Waisman M. Lichen aureus. Arch Dermatol 1976;

112: 696±7.7 Barnhill RL, Braverman IM. Progression of pigmented purpura-

like eruptions to mycosis fungoides: report of three cases. J Am

Acad Dermatol 1988; 19: 25±31.

8 Toro JR, Sander CA, LeBoit PE. Persistent pigmented purpuricdermatitis and mycosis fungoides: stimulant, precursor or both.

Am J Dermatopathol 1997; 19: 108±18.

9 Ackerman AB, White WL, Guo Y, Ignacio U. Differential

Diagnosis in Dermatopathology, Vol. 4. Philadelphia: Lea &Febiger, 1994; 70±3.

10 Agnarsson BA, Vonderheid EC, Kadin ME. Cutaneous T cell

lymphoma with suppressor/cytotoxic (CD8) phenotype: identifi-cation of rapidly progressive and chronic subtypes. J Am Acad

Dermatol 1990; 22(4): 569±77.

11 Whittam LR, Orchard GE, Calonje E et al. CD8 positive juvenile

cutaneous T-cell lymphoma. Br J Dermatol 1998; 139 (Suppl.):82.

Intraoperative detection of 5-aminolaevulinicacid-induced protoporphyrin fluorescence inlymphonode metastases after oral administration

Sir, Since the study by Kennedy et al.,1 it has been reportedthat photodynamic therapy (PDT) with endogenous proto-porphyrin IX (PpIX) produced from exogenous 5-aminolae-vulinic acid (ALA) is useful to treat non-melanoma skincancers.2±5

ALA is a compound used for PDT, although it is not itself aphotosensitizer. Its great advantage is that the photosensitiz-ing effects disappear within 24 h.3 However, ALA can also begiven systemically,6 with the result that the photodynamictechnique is useful not only for therapy but also in diagnosis.For evaluating tumour location, detecting early lesions ortumour spread, confirmation of residual tumour afterexcision, etc., photodynamic diagnosis (PDD) with ALA hasbeen reported for bladder carcinoma,7 aerodigestive tractcarcinoma,8 early stage lung carcinoma5 and brain tumours.5

In the field of dermatological oncology, intraoperativeintervention employing PDD with ALA for basal cellcarcinoma has been reported,9,10 although the label `PDD'may be unsuitable because the procedure depends on theobservation of fluorescence, rather than a dynamic oxygen-dependent reaction. Herein, we report a case of delayed lymph

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node metastases following a wide resection of poorlydifferentiated squamous cell carcinoma, and the novel useof fluorescence detection with ALA-induced PpIX.

The patient was a 77-year-old woman who complained

of a thumb-sized mass in the left inguinal region 2 yearsafter a wide excision of poorly differentiated squamous cellcarcinoma (stage I by Union Internationale Contre leCancer, 1987) on her left foot. The lesion was suspiciousof delayed lymph node metastases because the computedtomogram showed multiple masses up to 2´5 cm indiameter. In view of the potential requirement for radicalgroin lymph node dissection, PDD was planned, concur-rent with the surgical procedure. Three hours before theoperation, 15 mg/kg of 5-aminolaevulinic acid hydrochlor-ide was administered orally to the patient. Intraoperatively,ALA-induced endogenous PpIX in the lesions was detectedas fluorescence under a Wood's lamp in a darkenedoperating room. Of four palpable enlarged lymph nodes,two showed strong fluorescence (Fig. 1a±c), and intra-operative histopathological examination confirmed lymphnode metastases of squamous cell carcinoma. The othertwo nodes with no fluorescence revealed reactive lympha-denopathy without tumour cells. None of the otherextirpated lymph nodes during the radical groin nodedissection demonstrated fluorescence, and none showedany involvement by tumour cells on histopathologicalexamination postoperatively. During the operation, noother fluorescence was seen in the operative field includingthe area surrounding the positive lymph nodes.

Our case demonstrated the possibility of effective intra-operative diagnosis. Intraoperative fluorescence detectioneasily and quickly helped to distinguish lymph nodemetastasis of squamous cell carcinoma from enlargedlymph nodes due to non-specific inflammation. However,this technique may not be useful to judge micrometastasisor to detect evidence of metastasis at all sites within alymph node because it is only possible to observe surfacefluorescence.

It has been reported that some patients having systemicALA administration suffer from mild, transient nausea and/ortransient abnormalities of liver function, and that a dosagelower than 60 mg/kg (oral) or 30 mg/kg (intravenous) doesnot result in any neurological symptoms.5 In our experience,oral administration with more than 20 mg/kg to Orientalsincluding Japanese caused nausea, vomiting and liver dys-function. We used a Wood's lamp, which is essential for theclinical diagnosis of porphyria, in order to excite PpIX. Thislight source is a conventional device and has a spectrumbetween 320 and 400 nm. When using a Wood's lamp, it isnecessary for the examiner to be dark-adapted in order to seethe contrast clearly. Intraoperatively, achieving this situationwas time-consuming and therefore disadvantageous. Deve-lopment of better optical equipment may overcome thisdrawback and may permit a more obvious contrast betweenpositive and negative fluorescence.

Y.ITOH

Y.NINOMIYA

T.HENTA

S.TAJIMA

A.ISHIBASHI

Department of Dermatology,National Defence Medical College,3-2 Namiki,Tokorozawa,Saitama, 359-8513 Japan

Figure 1. (a) Photograph shows the resected lymph nodes whichwere involved by squamous cell carcinoma. (b) Photograph shows

strong pinkish-red fluorescence of protoporphyrin IX in the lesion,

under a Wood's lamp in the operating room. (c) Through a cut-off

filter to eliminate wavelengths less than 600 nm, the colour offluorescence is observed as vivid red.

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References

1 Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with

endogenous protoporphyrin: basic principle and present clinical

experience. J Photochem Photobiol B 1990; 6: 143±8.

2 Fijan S, Honigsmann H, Ortel B. Photodynamic therapy of

epithelial skin tumours using delta-aminolaevulinic acid and

desferrioxamine. Br J Dermatol 1996; 133: 282±8.

3 Pass HI. Photodynamic therapy in oncology: mechanisms andclinical use. J Natl Cancer Inst 1993; 85: 443±56.

4 Wolf P, Kerl H. Photodynamic therapy with 5-aminolevulinic

acid: a promising concept for the treatment of cutaneous tumors.

Dermatol 1995; 190: 183±5.

5 Peng Q, Warloe T, Berg K et al. 5-aminolevulinic acid-based

photodynamic therapy: Clinical research and future challenges.

Cancer 1997; 79: 2282±308.

6 Loh CS, MacRobert J, Bedwell J et al. Oral versus intravenousadministration of 5-aminolevulinic acid for photodynamic

therapy. Br J Cancer 1993; 68: 41±51.

7 Kriegmair M, Stepp H, Steinbach P et al. Fluorescence cystoscopy

following intravesical instillation of 5-aminolevulinic acid: a newprocedure with high sensitivity for detection of hardly visible

urothelial neoplasias. Urol Int 1995; 55: 190±6.

8 Regula J, MacRobert AJ, Gorchein A et al. Photosensitization and

photodynamic therapy of oesophageal, duodenal, and colorectaltumors using 5-aminolevulinic acid induced protoporphyrin: a

pilot study. Gut 1995; 36: 67±75.

9 Fritsch C, Becker-Wegerich PM, Menke H et al. Successful surgery

of multiple recurrent basal cell carcinomas guided by photo-dynamic diagnosis. Aesth Plast Surg 1997; 21: 437±9.

10 Wennberg AM, Gudmundson F, Stenquist B et al. In vivo detection

of basal cell carcinoma using imaging spectroscopy. Acta DermVenereol 1999; 79: 54±61.

Low specificity of cytokeratin 20 in the diagnosis ofextramammary Paget's disease

Sir, Ito et al.1 recently discussed the utility of cytokeratin 20(CK20) in evaluating perianal Paget's disease based on theproposed high specificity of CK20 for gastrointestinal car-cinoma. They state that according to Moll et al.2 theexpression of CK20 is confined to normal and carcinomatousgastrointestinal epithelium and that Merkel cells also expressCK20. However, review of the literature including the studyby Moll et al.2 shows a wider distribution of CK20. Othernormal cells besides gastrointestinal epithelial cells andMerkel cells that significantly express CK20 include urothelialumbrella cells, taste bud cells and thymic reticulum cells.2

CK20 is expressed in Merkel cell carcinoma2 and carcinomasof the liver,3 pancreas, biliary system and alimentary canal.2

CK20-positive tumours outside the digestive system include:transitional cell carcinomas,2 ovarian carcinomas,2,4 endo-metrial carcinomas,5 Mullerian testicular papillary seroustumours4 and small cell carcinoma of the salivary gland.6

Rarely, small cell carcinomas of the lung and cervix;6

adenocarcinomas of the lung, breast, prostate and paranasalsinuses;2 and squamous cell carcinomas2 express CK20.These immunohistochemical findings therefore considerablyexpand the list of primary tumours that should be sought asthe possible underlying cause of CK20-positive extramammary

Paget's disease. Weak expression of CK20 that escapes detec-tion by immunohistochemistry may be detected by molecularmethods.5

Such widespread distribution of CK20 indicates thatCK20 positivity may be less specific for gastrointestinalcarcinoma than is proposed by Ito et al.1 Finally, a panel ofimmunostains consisting of CK7, CK20, gross cystic diseasefluid protein-15, lysozyme and Leu-M1 may be more usefulthan CK20 alone in evaluating perianal Paget's disease.7

M.L-C.WU

J.GUITART*Departments of Pathology,Pathology Laboratories,Feinberg 7th Floor,Northwestern Memorial Hospital,251 East Huron Street, Chicago,IL 60611, U.S.A.*Dermatology,Northwestern University Medical School,Chicago, IL, U.S.A.E-mail: [email protected]

References

1 Ito Y, Watanabe S, Usui Yet al. Expression of cytokeratin antigen 20

in perianal Paget's disease. Br J Dermatol 1999; 140: 1169±70.

2 Moll R, Lowe A, Laufer J, Franke WW. Cytokeratin 20 in human

carcinomas: a new histodiagnostic marker detected by monoclonalantibodies. Am J Pathol 1992; 140: 427±47.

3 Schirmacher P, Dienes HP, Moll R. De novo expression ofnonhepatocellular cytokeratins in Mallory body formation.

Virchows Arch 1998; 432: 143±52.

4 Carano KS, Soslow RA. Immunophenotypic analysis of ovarian andtesticular Mullerian papillary serous tumors. Mod Pathol 1997; 10:

14±20.

5 Zemer R, Fishman A, Bernheim J et al. Expression of cytokeratin-20

in endometrial carcinoma. Gynecol Oncol 1998; 70: 410±13.

6 Chan JK, Suster S, Wenig BM et al. Cytokeratin 20 immuno-

reactivity distinguishes Merkel cell (primary cutaneous neuro-

endocrine) carcinomas and salivary gland small cell carcinomasfrom small cell carcinomas of various sites. Am J Surg Pathol 1997;

21: 226±34.

7 Nowak MA, Guerriere-Kovach P, Pathan A et al. Perianal Paget'sdisease: distinguishing primary and secondary lesions using

immunohistochemical studies including gross cystic disease fluid

protein-15 and cytokeratin 20 expression. Arch Pathol Lab Med1998; 122: 1077±81.

Congenital papular xanthoma

Sir, The term `papular xanthoma' was introduced byWinkelmann1 in 1981 to describe a xanthomatous eruptionwith the following characteristics. Lesions are asymptomatic,generalized, discrete, yellow, 2±15 mm papulonodules. Theyhave no tendency to merge into plaques or to become red±brown in colour. No visceral involvement occurs, lipidmetabolism is normal, and the dermal infiltrate is composedof predominantly foamy cells with some Touton giant cellsbut no non-lipidized histiocytes, and few inflammatory cells.

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Birbeck granules are absent. Initially, all cases of papularxanthoma reported were in adult men,2,3 but there have beenseveral reports of papular xanthoma in children since 1990.4

Congenital papular xanthoma has not been described, and wereport a Korean boy with this condition.

A 13-month-old Korean boy presented with numerousasymptomatic yellow papules mainly on the head and neck(Fig. 1a), but also some on the trunk and extremities. Somelesions were present at birth on the cheek and forehead. Hewas born by natural spontaneous delivery at 40 weeksgestation and weighed 2920 g at birth. His developmentalhistory was normal and the family history was unremarkable.Since 5 months of age the lesions had gradually spread, butshowed no tendency to coalesce. Mucosal and ophthalmo-logical involvement was not noted. Total serum cholesterolwas 192 mg/dL (normal 114±203) and serum triglycerideswere 93 mg/dL (normal 30±100). Serum lipoproteinelectrophoresis was within the normal range. Two skinbiopsies from the scalp (Fig. 1b) demonstrated a dermalinfiltrate composed mainly of cells with a large, foamycytoplasm and a centrally located, round to oval nucleus. Afew mononuclear cells were noted. One specimen showedonly foamy cells, but the other also had a few Touton giantcells (Fig. 1b). There were no definite non-lipidized histiocytesin the infiltrates. Oil red O staining was strongly positive inthe cytoplasm of foamy cells, but S-100 and periodic acid-Schiff (PAS) staining was negative. Electron microscopyrevealed the foamy cells to show morphological features ofmacrophages, with numerous large electron-dense lipidvacuoles packed in the cytoplasm (Fig. 1c). No Birbeckgranules, comma-shaped bodies or laminated bodies werefound.

The term `papular xanthoma' describes a normolipidaemicpapular to papulonodular cutaneous xanthomatosis usuallywith multiple lesions. The skin lesions of adult papularxanthoma seem to be persistent, and no case has beenreported with spontaneous regression. Caputo et al.4 reported10 cases of papular xanthoma in children with similarclinical and histopathological features as reported in adults,but with a self-healing course within 1±5 years. Clinically,papular xanthoma in children consists of 1±10 mm, yellowpapulonodules involving the head, face, trunk and extremi-ties, with sparing of mucosae, palms, soles and flexuralareas except for the axillae. Caputo et al. observed that theskin lesions gradually flattened and developed transienthyperpigmentation in weeks to months, and finally slightanetoderma-like scars in 60% of cases. Our patient had a fewyellow papules at birth, an apparently undescribed situation.For 13 months after birth, the lesions spread in distributionwithout any sign of regression, although the histopatho-logical and immunohistochemical findings were similar tothose of previously reported cases of papular xanthoma. Mostauthors suggest that the foamy histiocytes are derived frommonocytes/macrophages on the basis of immunohisto-chemical findings (OKT6±, OKM1+, Leu M3+).4 However,Fonseca et al.5 reported them to have the phenotype of dermaldendrocytes (factor XIIIa+, MAC 387±, CD1a±). Ultrastruc-turally, Caputo et al.4 demonstrated the morphology ofmacrophages, with numerous variably sized lipid vacuolesin the cytoplasm, as demonstrated in our case. Sanchez et al.2

suggested that laminated bodies are cytoplasmic markers ofpapular xanthoma, like other non-X histiocytoses, but thesewere not found in our patient or in other reported cases.4,6

The differential diagnosis of papular xanthoma includes

Figure 1. (a) Multiple discrete 2±5 mm diameter flat-topped yellow papules are evident on the face and scalp. (b) Most cells in the dermis are

large, with foamy cytoplasm and a round to oval nucleus. Inset, Touton giant cell (haematoxylin and eosin; original magnification � 200). (c)

Electron micrograph of foam cells showing characteristics of macrophages, with numerous large lipid vacuoles packed in the cytoplasm (originalmagnification � 5000).

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juvenile xanthogranuloma, xanthoma disseminatum, histio-cytosis X, generalized eruptive histiocytoma and benigncephalic histiocytosis.4,7,8 One of the most importantdifferential diagnoses is the micronodular form of juvenilexanthogranuloma, which is clinically indistinguishable.7

Caputo et al.4 suggested the diagnosis of papular xanthomato be confirmed histologically by the absence of a purehistiocytic phase, the presence of inflammatory cells, and thescarcity or absence of Touton giant cells. In juvenilexanthogranuloma, a pure histiocytic phase clinically manifestas an erythematous papule appears at the initial stage. In ourpatient, only yellow papules without erythematous lesionswere detected from birth. There were no clinical features tosuggest the pure histiocytic phase of juvenile xantho-granuloma, although this was not confirmed histologically.Sanchez et al.2 and Horiuchi and Ito9 suggested the use ofiron staining and PAS staining for differential diagnosis, butthese were negative in our case. Papular xanthoma maysometimes be difficult to differentiate clinically from thechronic progressive form of histiocytosis X.7 The presence ofpure foamy cells on histological examination ruled out othernon-X histiocytoses.

Besides histiocytic syndromes, cutaneous xanthomatosesmust be considered in the differential diagnosis. Normo-lipidaemic xanthoma occurs primarily in xanthoma dissemi-natum and juvenile xanthogranuloma or secondarily byaltered lipoprotein, underlying lymphoproliferative diseasesand local tissue alteration.10 In most reported cases, papularxanthoma is normolipidaemic and occurs primarily, but ithas occasionally been reported as secondary to other dis-orders.10±13 Chen et al.6 suggested the term `primary papularxanthoma' to describe papular xanthoma without anyunderlying disease, as in our case.

S-H.KIM

K-J.KOH

J-H.CHOI

K-J.SU NG

K-C.MOON

J-K.KOH

Department of Dermatology,Asan Medical Center,College of Medicine,University of Ulsan,388-1 Poongnap-Dong,Songpa-Gu,Seoul 138-736, Korea

References

1 Winkelmann RK. Cutaneous syndromes of non-X histiocytosis.

Arch Dermatol 1981; 117: 667±72.

2 Sanchez RL, Raimer SS, Peltier F et al. Papular xanthoma: a

clinical, histologic, and ultrastructural study. Arch Dermatol1985; 121: 626±31.

3 Bundino S, Zina AM, Aloi F. Papular xanthoma: clinical, histo-logical and ultrastructural study. Dermatologica 1988; 177: 382±5.

4 Caputo R, Gianni E, Imondi D et al. Papular xanthoma inchildren. J Am Acad Dermatol 1990; 22: 1052±6.

5 Fonseca E, Contreras F, Cuevas R. Papular xanthoma in children:

report and immunohistochemical study. Pediatr Dermatol 1993;10: 139±41.

6 Chen CG, Chen CL, Liu HN. Primary papular xanthoma ofchildren: a clinicopathologic, immunohistopathologic and ultra-

structural study. Am J Dermatopathol 1997; 19: 596±601.

7 Gianotti F, Caputo R. Histiocytic syndromes: a review. J Am AcadDermatol 1985; 13: 383±404.

8 Zelger BW, Sidoroff A, Orchard G et al. Non-Langerhans cell

histiocytoses. A new unifying concept. Am J Dermatopathol 1996;

18: 490±504.

9 Horiuchi Y, Ito A. Normolipidemic papuloeruptive xanthomatosis

in an infant. J Dermatol 1991; 18: 235±9.

10 Geordt S, Kretzschmar L, Bonsmann G et al. Normolipidemicpapular xanthomatosis in erythrodermic atopic dermatitis. J Am

Acad Dermatol 1995; 32: 326±35.

11 Sato A, Tanahashi Y, Maie O et al. Xanthoma secondary to

reticulohistiocytic infiltration. Arch Dermatol Res 1976; 112:

1294±7.

12 Sueki H, Whitaker D, Buchsbaum M et al. Generalized papularxanthomatosis in mycosis fungoides. J Am Acad Dermatol 1992;

26: 828±32.

13 Caputo R, Monti M, Berti E et al. Normolipidemic eruptive

cutaneous xanthomatosis. Arch Dermatol 1986; 122: 1294±7.

Normolipaemic xanthomas in association with humanimmunodeficiency virus infection

Sir, We report a case of the association of normolipaemicxanthomas with human immunodeficiency virus (HIV)infection. A 42-year-old homosexual male with acquiredimmune deficiency syndrome (AIDS) developed asymptomaticyellow papules and plaques on the forehead and cheeks(Fig. 1a). AIDS had been diagnosed 3 years previously on thebasis of an episode of Pneumocystis pneumonia and positiveHIV-serology. Since then his general health had been good,although he had required treatment for facial seborrhoeicdermatitis. At the time of presentation to dermatology his HIVviral load was , 400,000 copies/mL and CD4 count0´31 � 109/L on triple antiretroviral therapy of ritinovir,lamivudine and stavudine.

Fasting lipid and lipoprotein profiles, complement studies,plasma glucose, liver and thyroid function were normal. Anon-clonal rise in IgA of 448 IU (normal 50±267) withnormal IgG and IgM was found. No serum paraprotein orurinary light chains were detected. Twenty-four-hour urinarymicroalbumin excretion (a marker of general increasedvascular permeability1) was within normal limits. Biopsy ofone of the forehead lesions (Fig. 1b) confirmed the clinicaldiagnosis of plane xanthoma with nodular groups of foamyhistiocytes in the reticular dermis. No Touton giant cells,refractile material or altered collagen were seen; neutrophils,leucocytoclasis and eosinophils were absent and perivascularlymphocytes sparse. Monoclonal antibody studies demon-strated immunoglobulins of all classes in association with thedermal foam cells.

Topical application of 90% trichloroacetic acid to thelesions resulted in some improvement. Normolipaemiccutaneous xanthomas can be divided into three groups,types I±III.2,3 Type I are found in association with alteredlipoprotein content or structure, type II with benign ormalignant lymphoproliferative disorders, and type III with nodetectable underlying systemic disease or lipoprotein abnorm-ality (for example, those cases following erythroderma, where

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increased vascular permeability to lipoprotein enhancesdermal lipid deposition).

Smith et al.4 reported three cases of xanthomas associatedwith AIDS. All lesions were facial and all patients normo-lipaemic, with an IgA gammopathy. However, in contrast toour case, these cases also showed extracellular nuclear dust,with phagocytosed nuclear debris and hyalinization ofcollagen fibres.

A number of factors may be relevant to the pathogenesis ofxanthomas in HIV infection. HIV infection may be considereda lymphoproliferative disorder with virus-induced T-cell deathbeing accompanied by rapid B-cell proliferation and immuno-globulin production. These immunoglobulins may interferewith lipoprotein metabolism, by enhancing their uptake bydermal macrophages (a type II mechanism). The facialseborrhoeic dermatitis may enhance vascular permeabilityand facilitate lipoprotein deposition (a type III mechanism).

Finally, opportunistic infection should be considered, ascutaneous xanthoma-like lesions have been reported inpatients with atypical visceral leishmaniasis complicatingHIV infection.5 Thus, the association between normolipaemicxanthomas and AIDS now seems to be established, but thepathogenesis remains obscure.

H.M.RAM SAY

M.C.GAR RID O*A.G.SM IT H

Department of Dermatology,Central Outpatients,*Department of Histopathology,North Staffordshire Hospital,Stoke-on-Trent, ST4 7PA, U.K.

References

1 Deckert T, Feldt-Rasmussen B, Borch-Johnson T et al. Albuminuriareflects widespread vascular damage: the Steno hypothesis.

Diabetologica 1989; 32: 219±26.

Figure 1. (a) Plane xanthomas are

demonstrated around the right eye as is

residual seborrhoeic dermatitis around theala nasae. (b) Skin biopsy from forehead.

Groups of foamy histiocytes are seen in the

reticular dermis (haematoxylin and eosin,

original magnification � 100).

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2 Parker F. Normocholesterolemic xanthomatosis. Arch Dermatol1986; 122: 1253±7.

3 Marcoval J, Moreno A, Bordas X et al. Diffuse plane xanthoma:

Clinicopathologic study of 8 cases. J Am Acad Dermatol 1998; 39:439±42.

4 Smith KJ, Yeager J, Skelton HG. Histologically distinctive papular

neutrophilic xanthomas in HIV-1+ patients. Am J Surg Pathol 1997;

21: 545±9.5 Hamour AA, Skelly R, Jowitt SN et al. Visceral leishmaniasis (kala-

azar) in two patients with HIV-1 infection: atypical features and

response to therapy. J Infect 1996; 36: 217±20.

Cutaneous squamous cell carcinoma withzosteriform metastases in a human immunodeficiencyvirus-infected patient

Sir, Cutaneous metastases are uncommon, often occur as alate phenomenon and are associated with a poor prognosis.They normally appear as round to oval nodules with a firmrubbery consistency, and very rarely present in a zosteriformdistribution. We report a human immunodeficiency virus(HIV)-infected patient who had a cutaneous squamous cellcarcinoma (SCC) with zosteriform metastases.

A 56-year-old HIV-infected man first presented to the skindepartment in 1995. He had had a considerable amount ofsun exposure in the past, having worked in the Caribbean andHawaii. On examination, he had widespread sun-damagedskin with numerous actinic keratoses and a more prominentkeratotic lesion on his right eyelid which proved to be an SCC.Over the next 3 years he had eight SCCs, one basal cellcarcinoma and several bowenoid actinic keratoses excisedfrom the upper torso and face. Six of the SCCs arose over theanterior chest wall. As well as continued surgical proceduresit was decided to start acitretin 25 mg daily but the patientdiscontinued it after 3±4 months.

He was diagnosed HIV-positive in 1985 but was otherwisewell; he had no AIDS-defining diagnosis, had never takenantiretroviral medication (patient's choice) and his CD4 countwas 100 cells/mm3 (1995) with an HIV-1 viral load of116,400 RNA copies/mL (1997). In October 1997 he deve-loped a persistent left axillary swelling, clinically felt to belymphadenopathy. An ultrasound-guided biopsy demon-strated metastatic SCC on cytology; cultures for mycobacteriaand fungi were negative. A computed tomographic scan ofthe chest revealed multiple enlarged lymph nodes in the leftaxilla with abnormal areas of bony destruction in the lowerthoracic vertebrae, compatible with bony metastases.

Shortly after hospital admission, he developed a painfulerythematous skin eruption on the left side of his chest(Fig. 1a) and an oedematous left arm (found to be secondaryto a left axillary vein thrombosis, and successfully treatedwith heparin). Some of the lesions were vesicular and aclinical diagnosis of herpes zoster was made, but there was noimprovement despite 2 weeks of intravenous aciclovir fol-lowed by oral valaciclovir. Six weeks later, the whole areabroke down and ulcerated (Fig. 1b). Swabs for viral culture

were negative. Histology of a skin biopsy revealed large pale-staining epithelial cells with pleomorphic nuclei and mitosesinfiltrating throughout the dermis and subcutaneous fat,consistent with a poorly differentiated invasive SCC.

He was commenced on antiretroviral treatment and chemo-therapy (cisplatin and 5-fluorouracil) with some improvementof his skin lesions; however, his general condition deterioratedand he died a few weeks later.

Zosteriform skin metastases have been described in associ-ation with various neoplasms including breast carcinoma,melanoma and cutaneous SCC in two immunosuppressed

Figure 1. A zosteriform vesicular eruption over the chest (a) thatsubsequently broke down and ulcerated (b).

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renal transplant patients.1±3 The clinical appearance includesvesicles and bullae in most cases, so can easily be confusedwith herpes zoster infection, thus leading to a delay indiagnosis and treatment. The mechanism by which tumourcells spread and form zosteriform lesions remains unknown,but proposed theories include lymphatic spread, koebnerizationat the site of previous zoster infection, surgical implantationof tumour cells and neural spread via the dorsal root ganglia.A recent study4 looking at risk factors for the development ofSCC in HIV-infected patients found that fairer skin type,history of sun exposure and later stage of HIV disease werethe most important risk factors. Human papillomavirus wasnot found in most of the SCCs examined in that study. This isthe first report of zosteriform metastases to occur in an HIV-infected patient. It is well documented that cutaneous SCCsbehave more aggressively in immunosuppressed renal trans-plant patients, and it is likely that our patient's immuno-suppressed state also encouraged metastatic potential.5 Thiscase highlights the importance of including cutaneous meta-stases within the differential diagnosis of non-healing zosteri-form eruptions, especially in patients with a known underlyingneoplasm.

L.A.FEARFIELD

M.NELSON*N.FRAN CIS²C.B.BU NK ER

Departments of Dermatology and*Genitourinary Medicine,Chelsea and Westminster Hospital,London SW10 9NH, U.K.²Department of Histopathology,Charing Cross Hospital,Imperial School of Medicine,London W6 8RF, U.K.

References

1 Matarasso SL, Rosen T. Zosteriform metastasis: case presentation

and review of the literature. J Dermatol Surg Oncol 1988; 14: 774±8.

2 Buecker JW, Ratz JL. Cutaneous metastatic squamous-cell carcin-oma in zosteriform distribution. J Dermatol Surg Oncol 1984; 10:

718±20.

3 Shafqat A, Viehman GE, Myers SA. Cutaneous squamous cell

carcinoma with zosteriform metastasis in a transplant recipient.J Am Acad Dermatol 1997; 37: 1008±9.

4 Maurer TA, Vin Christian K, Kerschmann RL et al. Cutaneous

squamous cell carcinoma in human immunodeficiency virus-

infected patients. Arch Dermatol 1997; 133: 577±83.5 Leigh IM, Glover MT. Cutaneous warts and tumours in immuno-

suppressed patients. J R Soc Med 1995; 88: 61±2.

Combined ultraviolet A1 radiation and acitretintherapy as a treatment option for pityriasis rubrapilaris

Sir, We read with interest the recent correspondence byKaskel et al.1 suggesting bath-psoralen ultraviolet A (PUVA)for the treatment of pityriasis rubra pilaris (PRP). We report apatient with PRP who was resistant to oral and systemic

corticosteroids, but successfully treated with ultraviolet A1(UVA1) phototherapy in conjunction with oral acitretin.

A 63-year-old female patient presented with an itchingerythematous eruption that became generalized despitetopical and systemic corticosteroid therapy. On admissionshe had developed suberythroderma consisting of keratoticfollicular papules and plaques which were most pronouncedon the extensor surfaces but spared clear islands of normalskin (`nappes claires') (Fig. 1a). Her palms and soles showederythema, keratoderma and oedema. Skin biopsies fromdifferent sites confirmed the clinical diagnosis of PRP.

After the patient tolerated photoprovocation with 45, 90and 135 J/cm2 UVA1 on involved as well as on clear skin, westarted whole body UVA1 phototherapy with 30 J/cm2 (UVA1Medisun-24000 system, Schulze & BoÈhm GmbH, HuÈ rth,Germany main spectrum: 340±400 nm). Doses were thenincreased to 60 J/cm2 on day 2, 90 J/cm2 on days 3±7 and100 J/cm2 on days 8±15 (total number of treatments: 15; fivetreatments per week; cumulative UVA1 dose: 1340 J/cm2).Additionally, we started her on 25 mg oral acitretin daily(Neotigasonw; Roche, Grenzach-Whylen, Germany). Pruritusstopped within days and the suberythroderma improveddramatically shortly after UVA1 phototherapy was started;the patient retained only slight erythema (Fig. 1b) aftercompletion of UVA1 phototherapy. After 6 months she is

Figure 1. Pityriasis rubra pilaris before (a) and after (b) ultravioletA1 radiation phototherapy.

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still taking alternating doses of 10 and 20 mg acitretin daily,but remains stable, without pruritus and just with milderythema.

UVA1 phototherapy has been shown to be effective in thetreatment of atopic dermatitis,2 urticaria pigmentosa,3 local-ized scleroderma,4 pansclerotic morphoea,5 chronic handeczema6 and cutaneous T-cell lymphoma.7 PRP is a skindisease of unknown aetiology to date. Systemic treatmentoptions include oral corticosteroids, immunosuppressantssuch as cyclosporin and azathioprine and retinoids.8 Thetopical application of calcipotriol has been reported to bebeneficial.9 Response to PUVA therapy has been variable,8

and recently extracorporeal photochemotherapy has beenreported to be effective in a small number of patients.10

As oral corticosteroids were not effective in our patient andbecause of the potential side-effects of other systemic treat-ment options such as methotrexate11 or immunosuppres-sants,8 we decided to use UVA1 phototherapy. Although thecurrently stable condition of our patient is certainly main-tained by the oral acitretin, we believe that the immediaterelief of pruritus and the fast onset of clearing of thesuberythroderma were induced by UVA1 phototherapy. Wetherefore suggest that initial UVA1 phototherapy combinedwith acitretin as maintenance therapy is added to thetreatment options for PRP.

R.A.HER BST

M.VOGELBRUCH

A.EHNIS

P.KIEHL

A.KAPP

J.WEISS

Photodermatology Unit,Department of Dermatology and Allergology,Hannover Medical University,Ricklinger Strasse 5,D 30449 Hannover, GermanyE-mail: [email protected]

References

1 Kaskel P, Grundmann-Kollmann M, Schiller PI et al. Bath-PUVAas a treatment for pityriasis rubra pilaris provoked by ultraviolet

B. Br J Dermatol 1999; 140: 769±70.

2 Krutmann J, Czech MD, Diepgen T et al. High-dose UVA1 therapy

in the treatment of patients with atopic dermatitis. J Am Acad

Dermatol 1992; 26: 225±30.

3 Stege H, SchoÈpf E, Ruzicka T, Krutmann J. High dose UVA1 forurticaria pigmentosa. (Letter.) Lancet 1996; 347: 64.

4 Kerscher M, Dirschka T, Volkenandt M. Treatment of localised

scleroderma by UVA1 phototherapy. (Letter.) Lancet 1995; 346:

1166.

5 Gruss C, Stucker M, Kobyletzki G et al. Low dose UVA1phototherapy in disabling pansclerotic morphoea of childhood.

Br J Dermatol 1997; 136: 293±4.

6 Schmidt T, Abeck D, Boeck K et al. UVA1 irradiation is effective in

treatment of chronic vesicular dyshidrotic eczema. Acta DermVenereol 1998; 78: 318±19.

7 Kobyletzki G, Dirschka T, Freitag M et al. Ultraviolet-A1 photo-

therapy improves the status of the skin in cutaneous T-cell

lymphoma. Br J Dermatol 1999; 140: 768±9.

8 Albert MR, Mackool BT. Pityriasis rubra pilaris. Int J Dermatol1999; 38: 1±11.

9 Van de Kerkhof PC, Steijlen PM. Topical treatment of pityriasis

rubra pilaris with calcipotriol. Br J Dermatol 1994; 120: 675±8.

10 Hofer A, Mullegger R, Kerl H, Wolf P. Extracorporal

photochemotherapy for the treatment of erythrodermic pityriasisrubra pilaris. Arch Dermatol 1999; 135: 475±6.

11 Duncan KO, Imaeda S, Milstone LM. Pneumocystis carinii

pneumonia complicating methotrexate treatment of pityriasisrubra pilaris. J Am Acad Dermatol 1998; 39: 276±8.

Pemphigoid nodularis associated with nifedipine

Sir, Bullous eruptions secondary to nifedipine administrationinclude bullous fixed drug eruption, phototoxic bullouseruption, erythema multiforme and pemphigus foliaceus.1,2

We report a case of probable nifedipine-induced pemphigoid.Only one other case has previously been mentioned, as anunpublished observation.2

A 70-year-old man with hypertension was commenced onnifedipine 10 mg twice daily in 1995. Three months later hedeveloped a pruritic eruption on his back, which spread tocover his trunk, limbs, face and scalp. There was involvementof his mouth, with ulceration which healed without scarring,but other mucosal areas were spared. His other medicationsincluded ranitidine and bendrofluazide, and he was latercommenced on amlodipine 10 mg daily. However, when thedose of nifedipine was increased a year later to 20 mg twicedaily, his skin condition deteriorated.

On examination, although he had given a history ofoccasional blisters, there was evidence only of excoriatedpapules and nodules (Fig. 1a). Nikolsky's sign was negative,and the lesions healed with crusting, leaving hyperpig-mentation. There was no cutaneous scarring, but involve-ment of the nail beds of several fingers and toes resulted indystrophy and the formation of pterygium unguis (Fig. 1b,c).

Skin biopsy revealed a subepidermal cleft accompanyingbulla formation and regeneration of the basal layer, with aperivascular mononuclear inflammatory infiltrate composedof lymphocytes, histiocytes and eosinophils. Direct immuno-fluorescence (IMF) of perilesional skin revealed bright linearbasement membrane zone (BMZ) staining with IgG and C3.Indirect IMF using human skin substrate detected circulatinganti-BMZ IgG antibodies to a titre of 1 : 800, which showedepidermal binding on split-skin substrate. Western blotting ofthe patient's serum using an epidermal extract detectedantibodies to the 230-kDa pemphigoid antigen. Thesefindings supported a diagnosis of pemphigoid. He was initiallycommenced on topical clobetasol propionate and minocycline100 mg daily rather than systemic steroids, in view of hishistory of hypertension, and he initially showed a goodresponse to treatment. The amlodipine was initially stopped,followed by nifedipine 4 months later, and substituted bycoamilofruse and enalapril. With the cessation of nifedipine,his skin showed considerable improvement, together with afall in indirect IMF titre to 1 : 100. He has not, however,cleared completely, and continues to require treatment withminocycline 100 mg daily and topical clobetasol propionate.

These histopathological and IMF findings fulfilled thecriteria for bullous pemphigoid (BP). There were, however,some unusual clinical features. His cutaneous lesions were

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more typical of nodular prurigo and would therefore fit thecriteria for pemphigoid nodularis, a rare distinct clinicalvariant of BP.3 There was also involvement of the face andscalp, which are usually spared by BP, and the formation ofpterygium unguis is a feature more typical of lichenplanus or its variants. Other cases of drug-induced BPhave also shown unusual clinical features, such as

pemphigus-like lesions with a positive Nikolsky's sign,4

and bullous erythema multiforme.5 Drug-induced BP can beacute and self-limiting, with resolution following withdrawalof the offending drug, or persistent, in which the drug appearsto have initiated idiopathic BP, and this was observed in ourpatient.6 IMF studies may reveal tissue-bound and circulatinganti-BMZ antibodies,4,7 and the antigen in drug-induced BPhas been identified as identical to that in idiopathic BP,6 as inour case.

Systemic and topical drugs reported to have triggeredBP include frusemide, penicillamine, penicillin and itsderivatives, angiotensin-converting enzyme inhibitors suchas captopril and enalapril, nalidixic acid, salicylazosulpha-pyridine, ibuprofen, phenacetin, topical fluorouracil andpsoralen-ultraviolet A (PUVA) therapy.4±6

There are several theories to explain the pathogenesis ofdrug-induced BP. Bean et al. postulated that drugs may bindto molecules in the lamina lucida and act as haptens,inducing the formation of anti-BMZ antibodies.7 Kashiharaet al. later suggested that drugs may structurally modifymolecules and uncover hidden epitopes, thereby stimulatingan autoimmune response.4 Many drugs which trigger BPcontain sulphur or sulphydryl groups, e.g. penicillamine,captopril and frusemide. These are metabolized into thiols,which have been shown to provoke subepidermal splitting aswell as acantholysis.8 With respect to PUVA-induced cases, ithas been shown that there is a transient alteration in thiolconcentration of skin exposed to UV radiation, therebysupporting such an association.9

Ruocco et al. first demonstrated biochemical acantholysison in vitro cultured normal human skin explants to variousdrugs in the absence of autoantibodies.8 Brenner et al. haveused this technique to look specifically at the effect ofnifedipine on human skin explants, and were able todemonstrate that nifedipine may cause acantholysis andsubepithelial splitting in vitro.2 They concluded, as othershave done previously, that skin susceptibility to drugssuch as nifedipine may be genetically determined, withsome nifedipine-treated patients developing an acantholyticreaction and others a subepidermal bullous eruption, as thetype of splitting was donor-specific.

Nifedipine is widely used in the treatment of cardiovasculardiseases, and its side-effects are mainly as a result of itsvasodilating properties. Clinicians should also be aware of itspotential adverse cutaneous reactions.

M.AMEE N

K.E.HA RM AN

M.M.BLACK

St John's Institute of Dermatology,St Thomas' Hospital,Lambeth Palace Road,London SE1 7EH, U.K.

References

1 Alcalay J, David M, Sandbank M. Cutaneous reactions to nifedipine.Dermatologica 1987; 175: 191±3.

2 Brenner S, Ruocco V, Bialy-Golan A et al. Pemphigus andpemphigoid-like effects of nifedipine on in vitro cultured normal

human skin explants. Int J Dermatol 1999; 38: 36±40.

Figure 1. Excoriated papules and nodules are evident on the upper

back (a), and pterygium unguis of the fingernails (b) and toenails (c)is seen.

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3 Cliff S, Holden C. Pemphigoid nodularis: a report of three cases andreview of the literature. Br J Dermatol 1997; 136: 398±401.

4 Kashihara M, Danno K, Miyachi Y et al. Bullous pemphigoid-like

lesions induced by phenacetin: report of a case and an immuno-pathologic study. Arch Dermatol 1984; 120: 1196±9.

5 Alcalay J, David M, Ingber A et al. Bullous pemphigoid mimicking

erythema multiforme: an untoward side-effect of penicillins. J Am

Acad Dermatol 1988; 18: 345±9.6 Pazderka Smith E, Taylor TB, Meyer LJ, Zone JJ. Antigen

identification in drug-induced bullous pemphigoid. J Am Acad

Dermatol 1993; 29: 879±82.

7 Bean S, Good R, Windhorst D. Bullous pemphigoid in an 11 year oldboy. Arch Dermatol 1970; 102: 205±8.

8 Ruocco V, Luca M, Pisani M et al. Pemphigus provoked by

d-penicillamine: an experimental approach using in vitrotissue culture. Dermatologica 1982; 164: 236±48.

9 Danno K, Horio T. Histochemical staining of sunburn cells for

sulfhydryl and disulphide groups: a time course study. Br J Dermatol

1980; 102: 535±9.

Acute generalized exanthematous pustulosis followinguse of ticlopidine

Sir, Ticlopidine is a platelet aggregation inhibitor widely usedfor secondary prevention of cerebrovascular accidents inpatients predisposed to thrombosis. In addition to haemato-logical side-effects such as purpura and ecchymosis, bonemarrow aplasia, and jaundice and cholestatic hepatitis, thisdrug may induce numerous cutaneous adverse drug reac-tions: pruritus, urticaria, exanthemata, hyperhidrosis, lupuserythematosus and vasculitis;1 to the best of our knowledge,acute generalized exanthematous pustulosis (AGEP) followinguse of ticlopidine has not previously been reported.

A 66-year-old woman, with a previous history of ischaemicheart disease, started oral ticlopidine (Tiklid, Sanofi WinthropIndustrie, Ambares, France) 250 mg daily, to prevent throm-bosis, in March 1998. She was on no other medication, andthere was no personal or family history of psoriasis. After3 weeks, she was referred to our department with an acute,febrile (39 8C), pruritic rash. This began on the trunk andsubsequently spread to the extremities; the face, palms andsoles were spared and there was no mucosal involvement.Examination showed several hundred superficial, small(1±3 mm diameter), non-follicular pustules on an erythe-matous base (Fig. 1), with maceration at the axillae andgroins. Laboratory findings revealed leucocytosis (white cellcount 29´4 � 109/L) with a polymorphonuclear count of21´1 � 109/L; the erythrocyte sedimentation rate was43 mm in the first hour. Blood culture was sterile, andnegative results were obtained in fungal and bacterialcultures from the pustules, and serological tests for cyto-megalovirus, Epstein±Barr virus, parvovirus B19 and Cox-sackie virus. Skin biopsy demonstrated subcorneal pustuleswith neutrophils and a perivascular inflammatory cellinfiltrate in the papillary dermis.

Ticlopidine was stopped with rapid and complete resolutionof fever and rash within 1 week; widespread desquamationpersisted for 10 days. After 4 weeks, patch tests with 5% and

10% ticlopidine in distilled water and petrolatum produced anintense positive reaction at 72 h, with a pustular eruptionon an erythematous base. Patch tests with 5% and 10%ticlopidine in distilled water and petrolatum were negative in10 consecutive controls.

In 1980, Beylot et al. described a new pattern of cutaneousadverse drug reaction, which they termed AGEP, character-ized by a febrile, pustular eruption in response to drugadministration.2 There have been several further reports;although most cases have been drug-related,3 AGEP has alsobeen described in association with viral infection, psoralen-ultraviolet A therapy and hypersensitivity to mercury.4 Thepathogenesis is still obscure: it has been suggested that AGEPmight represent a type IV delayed hypersensitivity reaction,5

but production and release of neutrophil chemotactants suchas interleukin (IL)-1 and IL-8, or activation of complement,could be involved.6

Diagnostic criteria of AGEP include: a febrile eruption ofmyriads of sterile, small, non-follicular pustules on anerythematous base with possible oedema, purpura or target-shaped lesions; leucocytosis with polymorphonuclear count. 7 � 109/L; sudden onset after viral infection or drugingestion in patients with no history of psoriasis; shorttime to onset of pustular eruption after administration ofcausative drug (from 2 or 3 days for antibacterial-inducedforms to 18 days with other drugs); self-limiting course,with spontaneous healing after suspension of therapy withcausative agent; histopathological findings of intra-epidermal or subcorneal pustules sometimes associatedwith dermal oedema, focal necrosis of keratinocytes, orvasculitis.2,4

AGEP must be distinguished from generalized pustularpsoriasis of von Zumbusch, subcorneal pustulosis of Sneddon±Wilkinson and septicaemic pustulosis. Patch testing with thesuspected agent is positive in approximately half of the cases:it seems to be useful in the investigation of the aetiology ofdrug-induced AGEP,7,8 as rechallenge with the same sub-stance is not ethical. However, a negative test does notexonerate the drug.8 Our case satisfies the criteria for AGEP:

Figure 1. Confluent, milky-white pustules may be seen on theabdomen.

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the patient had a negative family and personal history ofpsoriasis, and other criteria, such as the clinical andhistological features, and the rapid resolution of the pustulareruption after discontinuation of ticlopidine, were very sug-gestive. Patch tests performed with the suspected causativedrug were positive.

S.P.CA NNAVOÁ

F.BORGIA

F.GUA RN ER I

M.VACCARO

Institute of Dermatology,University Hospital,Via Consolare Valeria-Gazzi,98125 Messina, ItalyE-mail: [email protected]

References

1 Litt JZ, Pawlak WA. Drug Eruption Reference Manual. New York:

Parthenon, 1997; 430.

2 Beylot C, Bioulac P, Doutre MS. Pustoloses exantheÂmatiques aigues

geÂneÂraliseÂes. AÁ propos de 4 cas. Ann Dermatol Venereol 1980; 107:37±48.

3 De Coninck AL, Strubarq AS, Pipeleers-Marichal MA et al. Acute

generalized exanthematous pustulosis induced by paracetamol: a

case with severe hemodynamic disturbances. Dermatology 1996;193: 338±41.

4 Roujeau JC, Bioulac-Sage P, Bourseau C et al. Acute generalized

exanthematous pustulosis: analysis of 63 cases. Arch Dermatol

1991; 127: 1333±8.5 Demitsu T, Kosuge A, Yamada T et al. Acute generalized

exanthematous pustulosis induced by dexamethasone injection.

Dermatology 1996; 193: 56±8.6 Ogoshi M, Yamada Y, Tani M. Acute generalized exanthematic

pustulosis induced by cefaclor and acetazolamide. Dermatology

1992; 184: 142±4.

7 Jan V, Machet L, Gironet N et al. Acute generalized exanthematouspustulosis induced by diltiazem: value of patch testing. Dermatology

1998; 197: 274±5.

8 Kuchler A, Hamm H, Weidenthaler-Barth B et al. Acute generalized

exanthematous pustulosis following oral nystatin therapy: a reportof three cases. Br J Dermatol 1997; 137: 808±11.

Is systemic autoimmune disease a risk factor forterbinafine-induced erythema multiforme?

Sir, Terbinafine is a frequently used systemic antimycoticdrug, with tinea unguium as its most frequent indication.Most side-effects are related to the gastrointestinal system(nausea, diarrhoea, taste disorders and hepatitis). Variousterbinafine-induced cutaneous manifestations have beendescribed, including erythema, urticaria, acute generalizedexanthematous pustulosis, erythema annulare centrifugum,fixed drug eruption, psoriasis and erythema multiforme (EM).We report three patients who developed EM during treatmentwith terbinafine (Lamisilw, Novartis) 250 mg daily foronychomycosis. In each case there was a typical clinicalpresentation of EM with histological confirmation of thediagnosis. Remarkably, each of the three patients had apre-existing systemic autoimmune disease.

The first patient was a 60-year-old man with systemic

lupus erythematosus (LE) (anti-DNA+, SSA+), who had acutecutaneous LE lesions and was being treated with prednisolone15 mg daily and hydroxychloroquine 400 mg daily. Fourweeks after starting terbinafine for onychomycosis, hedeveloped a severe cutaneous eruption that was diagnosedas EM. Terbinafine was stopped and the dose of prednisolonewas raised to 40 mg daily. The eruption faded rapidly.

The second patient was a 71-year-old man with subacutecutaneous LE of 2 years duration (antinuclear factor, ANF+,SSA+, SSB+). He developed an extensive cutaneous eruptionsome days after starting terbinafine for onychomycosis. Adiagnosis of EM was made. There was no other medication.The lesions were controlled with systemic corticosteroids.

The third patient was a 49-year-old woman who developedurticarial weals and target lesions, typical for EM, 8 weeksafter starting terbinafine for onychomycosis. Concomitantmedication was methotrexate 5 mg weekly for rheumatoidarthritis (rheumatoid factor titre 1 : 128, ANF+). Treatmentwith oral corticosteroids (methylprednisolone 32 mg daily)rapidly cleared the lesions.

Our patients each suffered from a systemic autoimmunedisease and developed EM while taking terbinafine 250 mgdaily for tinea unguium. EM lesions developed between 1 and8 weeks after starting treatment. In the literature, we found13 reports of EM, two cases of Stevens±Johnson syndromeand two of Lyell's syndrome associated with terbinafine.1±8

Two of the described EM patients had systemic LE.3,4 We areaware of another case of terbinafine-induced EM in a patientwith LE (Novartis data, on file). The incidence of EM duringterbinafine treatment has been estimated at 13´5 in100,000.1

In conclusion, six of 17 patients known to have developedEM during terbinafine treatment suffered from a systemicautoimmune disease (systemic LE or rheumatoid arthritis).This suggests that systemic autoimmune disease constitutes arisk factor for the development of terbinafine-induced EM.Interestingly, three cases of terbinafine-induced or exacer-bated LE have also been described recently.9±11

V.GOETEYN

J.M.NA EYA ERT

J.LA MB ERT*L.MON BA LIU*

F.VERMA ND ER²

Department of Dermatology,University Hospital Ghent,De Pintelaan 185, 9000 Ghent,Belgium*Department of Dermatology,University Hospital Antwerp,Belgium²OLV Ter Linden Knokke-Heist,BelgiumE-mail: [email protected]

References

1 Gupta AK, Lynde CW, Lauzon GJ et al. Cutaneous adverse effects

associated with terbinafine therapy: 10 case reports and a reviewof the literature. Br J Dermatol 1998; 138: 529±32.

2 Barbaud A, Trechor P, Reichert S et al. Is terbinafine responsiblefor EM induced by Lamisilw tablets? Australas J Dermatol 1997;

20: 247±8.

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3 Todd P, Halpern S, Munro DD. Oral terbinafine and erythemamultiforme. Clin Exp Dermatol 1995; 20: 247±8.

4 Hall M, Monka C, Krupp P, O'Sullivan D. Safety of oral terbinafine.

Arch Dermatol 1997; 133: 1213±19.5 Tramaloni S, Castanet J, Chichmanian RM et al. ErytheÁme

polymorphe seÂveÁre au cours d'un traitement par terbinafine.

Therapie 1995; 50: 594±5.

6 McGregor JM, Rustin MH. Terbinafine and erythema multiforme.Br J Dermatol 1994; 131: 578±8.

7 Carstens J, Wendelboe P, Sogaard H et al. Toxic epidermal

necrolysis and erythema multiforme following therapy with

terbinafine. Acta Derm Venereol (Stockh) 1994; 74: 391±2.8 Rzany B, Mockenhaupt M, Gehring W, SchoÈpf E. Stevens±

Johnson syndrome after terbinafine therapy. (Letter.) J Am Acad

Dermatol 1994; 30: 509.

9 Murphy M, Barnes L. Terbinafine-induced lupus erythematosus.Br J Dermatol 1998; 138: 708±9.

10 Brooke R, Coulson IH, Al-Dawoud A. Terbinafine-induced

subacute cutaneous lupus erythematosus. Br J Dermatol 1998;

139: 1132±3.11 Holmes S, Kemmett D. Exacerbation of systemic lupus

erythematosus induced by terbinafine. (Letter.) Br J Dermatol

1998; 139: 1133.

Intranasal betamethasone induced acne and adrenalsuppression

Sir, It has long been recognized that systemic and topicalcorticosteroids can provoke and exacerbate acne. Inhaledsteroids have also been reported to cause acne,1 but as far aswe know, this problem has never been reported withintranasal steroids. We report a patient with late-onset acnewho was subsequently found to have adrenal suppression dueto chronic use of betamethasone sodium phosphate (Betnesol,Medeva, Leatherhead, U.K.) nasal drops.

A 51-year-old bank manager presented in November 1997with a 1-year history of acne, which had failed to respond tosystemic antibiotics. He gave a history of severe adolescentacne but this had been clear for the past 10 years. This late-onset acne differed from his adolescent pattern, consistingmainly of small papules. He had a medical history of severeallergic rhinitis, nasal polyps and mild asthma. At present-ation, his only medication was betamethasone nasal drops(eight drops per day, equivalent to 240 mg of betamethasoneper day) which he had been using since 1995. He had neverreceived systemic steroids. Clinical examination revealednumerous small papules and pustules, a few nodular lesionsand extensive scarring on his back, chest, upper arms andabdomen. Systemic examination was unremarkable. Becauseof the recurrence of acne, he was referred for endocrineassessment. Full blood count, urea and electrolytes, liverfunction tests, thyroid function tests, gonadal and adrenalandrogens were normal. However, his cortisol level wasundetectable at baseline and only slightly increased 30 minafter adrenocorticotrophic hormone stimulation (250 mgintramuscular Synacthen, Alliance, Chippenham, U.K.)(Table 1). A diagnosis of adrenal suppression due to

intranasal betamethasone was made. He was advised togradually discontinue his steroid nasal drops and was referredto an ear, nose and throat surgeon for nasal polypectomy.Further investigations including bone densitometry revealedno other systemic complications. The patient declined oralisotretinoin for his acne due to fear of side-effects. His acne,however, cleared after a course of narrow-band ultraviolet Bradiation, and follow-up at 1 year showed no evidence ofrecurrence. Further adrenocorticotrophic hormone stimu-lation tests at 3 months and 1 year showed improvement ofhis adrenal function (Table 1).

Glucocorticoid hormones, both topically and systemically,provoke acneiform eruptions, although the pathogenesis ofthis is not fully understood. Steroid-induced acne consistspredominantly of small uniformly sized papules and pustuleswith few comedones. Our patient presented with acne in hisfifth decade; its onset and clinical pattern suggested asecondary cause. The discovery of significant but asympto-matic adrenal suppression and the improvement of his acneafter discontinuation of betamethasone nose drops supportthe argument that this patient's acne was due to chroniccortisol excess.

Inhaled beclomethasone diproprionate of more than1500 mg/day has previously been shown to cause suppres-sion of the hypothalamic/pituitary/adrenal axis.2 However,high-dose intranasal beclomethasone was thought to be safeon a short-term basis.3 To date, there has been no formalstudy on the safety of intranasal betamethasone, althoughthere are two case reports of adrenal suppression due to thissteroid.4,5 Our patient had been on betamethasone for morethan 2 years before adrenal suppression was diagnosed;significant systemic absorption is likely to have occurredbecause of chronically inflamed and enlarged nasal mucosa.Betamethasone is also readily absorbed from the gastro-intestinal tract and unlike some newer steroids, is notdegraded by the liver.

We report this case to highlight two points: first,patients who present with late-onset acne should bethoroughly questioned, examined and investigated for asecondary cause of acne. Secondly, intranasal betametha-sone drops, when used for prolonged periods of time, cancause adrenal suppression. Physicians should be aware ofthis possibility and arrange for the appropriate assessmentof adrenal reserve to ensure patient safety in circum-stances when an intact hypothalamic/pituitary/adrenal axisis important.

Table 1. Serial cortisol levels

Serum cortisol level in mmol/L

0 min

30 min

after adrenocorticotrophic hormone

At presentation , 27 763 months 156 260

1 year 178 407

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J.L.BONG²J.M.C.CON NELL*

R.LE V ER

Department of Dermatology,*Department of Medicine and Therapeutics,Western Infirmary,Dunbarton Road,Glasgow, U.K.²Correspondence: Dr. J.L.Bong,Department of Dermatology,Queen's Medical Centre,Nottingham NG7 2UH, U.K.

References

1 Monk B, Cunliffe WJ, Layton AM, Rhodes DJ. Acne induced byinhaled corticosteroids. Clin Exp Dermatol 1993; 18: 148±50.

2 Smith MJ, Hodson ME. Effects of long term inhaled high dose

beclomethasone diproprionate on adrenal function. Thorax 1983;38: 676±81.

3 Harris DM, Martin LE, Harrison C, Jack D. The effect of intra-nasal

beclomethasone diproprionate on adrenal function. Clin Allergy

1974; 4: 291±4.4 Daman Willems CE, Dinwiddie R, Grant DB et al. Temporary

inhibition of growth and adrenal suppression associated with the

use of steroid nose drops. Eur J Pediatr 1994; 153: 632±4.

5 Flynn MD, Beasley P, Tooke JE. Adrenal suppression with intranasalbetamethasone drops. J Laryng Otol 1992; 106: 827±8.

Treatment of haemodialysis-associated pseudoporphyriawith N-acetylcysteine: report of two cases

Sir, Pseudoporphyria refers to a syndrome that isclinically and histologically indistinguishable from porphyriacutanea tarda (PCT), despite normal levels of porphyrinexcretion.1,2 So far, there is no specific treatment forpseudoporphyria complicating haemodialysis for chronicrenal failure. We report the treatment of two patients withoral N-acetylcysteine.

A 32-year-old woman with chronic renal failure had beenreceiving maintenance haemodialysis for 10 years. She didnot consume alcohol and had negative serological tests forhuman immunodeficiency virus (HIV) and hepatitis B and Cviruses. She was having treatment with lisinopril andmetoprolol when she presented with lesions suggestive ofPCT (skin fragility, blistering, and erosions on sun-exposedareas). Histopathological examination revealed subepidermalbullae, thickening of vascular walls and a minimal peri-vascular lymphocytic infiltrate. Plasma porphyrin levels werenormal. Urine porphyrin quantification could not beperformed because of anuria. Direct immunofluorescencestudy of a cutaneous blister was negative. Other laboratoryfindings were as follows: serum iron level 73 mg/dL (normal50±150); ferritin 320 ng/mL (normal 20±200); haemo-globin 12´8 g/dL (normal 11´5±15´7); alanine aminotrans-ferase 30 IU/L (normal , 53); aspartate aminotransferase24 IU/L (normal , 53); g-glutamyltransferase 38 IU/L(normal , 53); and alkaline phosphatase 157 IU/L(normal 60±310). Screening for autoantibodies to double-stranded DNA was negative. The lesions did not improve in

spite of avoidance of sun exposure. N-acetylcysteine (Zambon;Brussels, Belgium) 200 mg four times daily was then started.The blisters disappeared during the first month and theerosions during the second month. A transient discon-tinuation of the drug led to recurrence of the lesions.N-acetylcysteine was restarted at the same dose, and againthe patient's skin cleared. Twelve months after reintroductionof the drug, there was no further recurrence of thelesions.

The second patient, a 38-year-old woman, had undergonehaemodialysis for 7 years. She was suffering from blisterswhich were located on the dorsal surface of her hands. Shetook no photosensitizing drug. Histopathological examinationof a skin biopsy specimen and absence of measurableporphyrins in the serum led to the diagnosis of pseudo-porphyria. Laboratory studies yielded the following values:serum iron level 32 mg/dL; ferritin 580 ng/mL; haemoglobin11´8 g/dL; alanine aminotransferase 19 IU/L; aspartateaminotransferase 26 IU/L; and alkaline phosphatase157 IU/L. HIV and hepatitis B and C virus serologies werenegative. She was treated with N-acetylcysteine 600 mgtwice daily. The blisters and erosions healed after 1 month ofN-acetylcysteine therapy. There was no recurrence of lesionsduring a 6-month follow-up.

The exact pathogenesis of pseudoporphyria complicatinghaemodialysis remains unclear.1,2 Dermal microangiopathicchanges and decreased subcutaneous oxygenation duringhaemodialysis might facilitate frictional blistering.2 Anotherpossible pathogenetic mechanism is the use of photosen-sitizing drugs. As a consequence of its unclear pathogenesis,there is so far no specific therapy for blistering associated withhaemodialysis. Several data suggest that haemodialysispatients are particularly prone to oxidative stress.3±5 Theyhave an imbalance between the disulphide and reduced formsof thiol compounds as well as decreased levels of gluta-thione,4,5 a potent antioxidant. The hypothesis that reactiveoxygen species may contribute to the skin damages ofhaemodialysis, namely through local ischaemia, iron over-load and exposure to ultraviolet radiation, prompted us topropose treatment with oral N-acetylcysteine, a glutathioneprecursor metabolized in the gut wall and liver,6 which werecently showed to be effective in a man with HIV-relatedPCT.7 The cutaneous lesions rapidly healed in both haemo-dialysed patients after the introduction of N-acetylcysteine totreatment which was otherwise unchanged. Furthermore,transient discontinuation of the medication in one patient ledto a recurrence of blistering. Controlled investigationsevaluating the role of possible bias (such as sun exposure oralcohol intake) are needed to confirm our results. As the side-effects of oral N-acetylcysteine are mild, consisting of nausea,vomiting and diarrhoea, we conclude that N-acetylcysteinemay offer a safe therapeutic option for pseudoporphyriacomplicating haemodialysis.

J.VADOUD-SEY ED I

G.DE DOBBELEER

T.SIMONART

Department of Dermatology,Erasme University Hospital,808 Route de Lennik,B-1070 Brussels, Belgium

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References

1 Gilchrest B, Rowe JW, Mihm M. Bullous dermatosis of hemo-

dialysis. Ann Intern Med 1975; 83: 480±3.

2 Shelley WB, Shelley ED. Blisters of the fingertips: a variant ofbullous dermatosis of hemodialysis. J Am Acad Dermatol 1989; 21:

1049±51.

3 Mimic-Oka J, Simic T, Djukanovic L et al. Alteration in plasmaantioxidant capacity in various degrees of chronic renal failure. Clin

Nephrol 1999; 51: 233±41.

4 Hulberg B, Andersson A, Arnadottir M. Reduced, free and total

fraction of homocysteine and other thiol compounds in plasmafrom patients with renal failure. Nephron 1995; 70: 62±7.

5 Ross EA, Koo LC, Moberly JB. Low whole blood and erythrocyte

levels of glutathione in hemodialysis and peritoneal dialysis

patients. Am J Kidney Dis 1997; 30: 489±94.6 Holdiness MR. Clinical pharmacokinetics of N-acetylcysteine. Clin

Pharmcokinet 1991; 20: 123±34.

7 Binet H, van Simonart T, Vooren JP et al. Porphyria cutanea tarda in

a HIV-infected patient: treatment with N-acetyl-cysteine. Int JDermatol 1998; 37: 718±19.

Severe course of chronic urticaria, arthralgia, feverand elevation of erythrocyte sedimentation rate:Schnitzler's syndrome without monoclonalgammopathy?

Sir, Chronic recurrent urticaria associated with malaise,intermittent fever, arthralgia, elevation of erythrocytesedimentation rate (ESR) and IgM monoclonal gammo-pathy has been designated Schnitzler's syndrome.1,2 Wereport a 57-year-old man who had had severe recurrenturticaria, joint and bone pain and intermittent fever since1994. In January 1997, he was admitted for furtherevaluation of his symptoms, which included general fatigueand weight loss. Examination revealed small, moderatelypruritic urticarial lesions especially on the upper trunkand extremities as well as the perisacral, periumbilical andperiaxillary regions. The weals lasted less than 24 h, andleft no residual pigmentation. The patient also evidencedgeneralized axillary and inguinal lymphadenopathy. Biopsy ofthe urticarial skin lesions revealed perivascular infiltrates oflymphomononuclear cells and granulocytes throughout thedermis, accompanied by mild leucocytoclasis, which iscompatible with an urticarial vasculitis. Biopsy of an axillarylymph node showed reactive, non-specific lymphadenitis withmassive B- and T-zone activation, without evidence ofmalignant lymphoma (no expression of BCL-2 oncoprotein);bone marrow histology revealed reactive changes, but againno infiltration or tumoral proliferation.

Laboratory tests yielded the following results: ESR94 mm in the first hour (normal 3±8); C-reactive protein133 mg/L (normal , 6); white cell count 13´4 � 109/L(normal 5±10 � 109) with 78% neutrophils, 15% lympho-cytes, 3% monocytes, 1% eosinophils and 1% basophils;platelets 572 � 109/L (normal 130±400 � 109); haemo-globin 11´7 g/dL (normal 14±18); erythrocytes

4´53 � 1012/L (normal 4´50±5´50 � 1012). Protein electro-phoresis: albumin 52% (normal 58±70), a1-globulin 4´2%(normal 1´5±4), a2-globulin 14´2% (normal 5±10), g-globulin19´5% (normal 10±19); serum IgM concentration 6´5 g/L(normal 0´6±2´8), IgG 17 g/L (normal 8´0±18), IgA 1´7 g/L(normal 0´9±2´8) and IgE 267 KU/L (normal , 100);antinuclear antibody titre 1 : 80.

On several occasions during the next 2 years, serumimmunofixation electrophoresis did not demonstrate mono-clonal gammopathy; only once, faint bands indicatedmonoclonal elevation of the IgM k type. Urine immuno-fixation electrophoresis was always negative. Extensive X-rayexamination yielded no evidence of plasmocytoma; bonescintigraphy showed only a moderate circumscribed inflam-mation of the left hand. Based on these findings, we favouredthe diagnosis of Schnitzler's syndrome despite the absence ofmonoclonal gammopathy.

Different treatment modalities, including various anti-histamines and corticosteroids at different doses (15±60 mgdaily), temporarily given in combination with azathioprine50 mg three times daily, colchicine 1 mg daily and thecytostatic agent trofosfamide 100 mg daily, were not suf-ficient to control the patient's symptoms. Interferon alfa-2a(3 � 9 million IU subcutaneously weekly) combined withparacetamol (2±3 g daily) and six cycles of plasmapheresisachieved only initial improvement. Treatment with oralcorticosteroids and non-steroidal anti-inflammatory drugshas now provided limited symptomatic relief, but the patienthas developed reactive depression due to the chronicity of hisdisease and is now also receiving the antidepressantparoxetine, which has not improved his urticarial lesions (ithas no antihistamine effect).

Chronic urticaria associated with fever, arthralgia andmonoclonal IgM gammopathy was first described bySchnitzler et al.1,2 and was subsequently reported by othergroups.3±9 In more than 30 cases in the literature,monoclonal IgM gammopathy was clearly evident in most,and is thus one of the criteria defining Schnitzler's syndrome.Several cases have been reported with combined monoclonalgammopathies involving IgM and IgA4 or IgM and IgG.5 Inaddition, one case featuring the clinical symptoms ofSchnitzler's syndrome was reported to occur with isolatedIgG monoclonal gammopathy.3 Our patient showed thetypical clinical signs of Schnitzler's syndrome, including asevere intractable course with elevation of the ESR and theserum IgM concentration, although no clear evidence ofmonoclonal IgM gammopathy was found after several check-ups. We, therefore, suggest that the spectrum of Schnitzler'ssyndrome be broadened to include cases displaying the typicalsevere course with or without varying types and degrees ofmonoclonal gammopathy. Management of this rare entity is achallenge for the physician.

R.HU SA K

S.NESTORIS

S.GOERD T

C.E.ORFANOS

Department of Dermatology,University Medical Centre Benjamin Franklin,The Free University of Berlin,Hindenburgdamm 30, 12200 Berlin,Germany

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References

1 Schnitzler L, Schuber B, Boasson J et al. Urticaire chronique, leÂsions

osseuses, macrogloblineÂmie IgM: maladie de WaldenstroÈm? Bull SocFr Dermatol Syphiligr 1981; 88: 363.

2 Schnitzler L, Hurez D, Verret JL. Urticaire chronique±osteÂo-

condensation±macroglobulineÂmie. Cas princeps. EÂtude sur 20

ans. Ann Dermatol Venereol 1989; 116: 547±50.3 Nashan D, SundenkoÈtter C, Bonsmann G et al. Chronic urticaria,

arthralgia, raised erythrocyte sedimentation rate and IgG para-

proteinaemia: a variant of Schnitzler's syndrome? Br J Dermatol

1995; 133: 132±4.4 Machet L, Vaillant L, Machet MC et al. Schnitzler's syndrome

(urticaria and macroglobulinemia) associated with pseudo-

xanthoma elasticum. Acta Derm Venereol (Stockh) 1992; 72: 22±4.

5 Verret L, Leclech C, Rousselet MC et al. Schnitzler syndrome andWaldenstroÈm disease. Fatal outcome of the original case. Ann

Dermatol Venereol 1993; 120: 459±60.

6 Borradori L, Rybojad M, Puissant A et al. Urticarial vasculitisassociated with a monoclonal IgM gammopathy: Schnitzler's

syndrome. Br J Dermatol 1990; 123: 113±18.

7 Baty V, Hoen B, Hudziak H et al. Schnitzler's syndrome: two

case reports and review of the literature. Mayo Clin Proc 1995; 70:570±2.

8 Berdy SS, Bloch KJ. Schnitzler's syndrome: a broader clinical

spectrum. J Allergy Clin Immunol 1991; 87: 849±54.

9 Lautenschlager S, Itin PH. Schnitzler Syndrom. Hautarzt 1993; 44:781±4.

High-dose intravenous immune globulin is alsoeffective in linear IgA disease

Sir, We read with great interest the recent article by Harmanand Black1 which demonstrated a benefit of high-doseintravenous immune globulin (IVIG) in several autoimmuneblistering diseases including epidermolysis bullosa acquisita,bullous pemphigoid, nodular pemphigoid, pemphigus ges-tationis and pemphigus vulgaris. We would like to drawattention to linear IgA disease (LAD) as another bullousautoimmune dermatosis where we have observed a con-vincing response to IVIG.

A 45-year-old man presented with polymorphic lesionsincluding erythematous papules, urticarial weals, annularerythema and small blisters predominantly on both legs andthe trunk. Diagnosis of LAD was confirmed by directimmunofluorescence, which showed linear deposits of IgAat the basement membrane zone and subepidermal blisteringwith aggregates of neutrophils within the papillae in routinehistology (haematoxylin and eosin). No circulating IgAanti-endomysium antibodies were observed.

Therapy with dapsone 100 mg daily in combination withmethylprednisolone 40 mg daily for 6 months, followed bycyclosporin 250 mg daily in combination with low-dosemethylprednisolone 10 mg daily for several months gave onlyslight response. Higher doses of dapsone could not beadministered because of elevated levels of methaemoglobin.In contrast, within several days of administration of IVIG2 mg/kg body mass divided over 5 days (Sandoglobulin,Sandoz, Novartis Pharma GmbH, NuÈ rnberg, Germany) the

lesions cleared, and blistering was suppressed for a periodof 4 weeks. Readministration of IVIG at the same dose andpermanent therapy with methylprednisolone 10 mg dailywere continued for several cycles. During this treatment, onlya few erythematous episodes occurred after 4 weeks (prior tothe next cycle of therapy), and blistering was suppressedcompletely. Response of LAD to IVIG was recently alsodescribed by Khan et al.2 The way in which IVIG modulatesthe immune system in LAD might be similar to one of theknown mechanisms, such as Fc receptor blockade, anti-idiotypic antibodies or modulation of cytokines.3,4

Therefore, IVIG may be promising for sparing systemicsteroids or as a second-line treatment in LAD if classicaltherapies are ineffective or unsuitable.

M.M.KROISS

T.VOG T

M.LA NDTHA LE R

W.STOLZ

Department of Dermatology,University of Regensburg,D-93042 Regensburg,GermanyE-mail: [email protected]

References

1 Harman KE, Black MM. High-dose intravenous immune globulin

for the treatment of autoimmune blistering diseases: an

evaluation of its use in 14 cases. Br J Dermatol 1999; 140:

865±74.2 Khan IU, Bhol KC, Ahmed AR. Linear IgA bullous dermatosis in a

patient with chronic renal failure: response to intravenous

immunoglobulin therapy. J Am Acad Dermatol 1999; 40: 485±8.

3 Dwyer JM. Manipulating the immune system with immuneglobulin. N Engl J Med 1992; 326: 107±16.

4 Spellberg B. Mechanisms of intravenous immune globulin therapy.

N Engl J Med 1999; 341: 57±8.

Pustular psoriasis exacerbated by pregnancy andcontrolled by cyclosporin A

Sir, Generalized pustular psoriasis in pregnancy remains anuncommon condition.1 It is often difficult to treat astherapeutic options are limited during pregnancy. A recentreport from Saudi Arabia suggested that cyclosporin may besafely used to treat this condition in the third trimester ofpregnancy.2 We report the first British case of the successfuluse of cyclosporin to control pustular psoriasis in pregnancyfrom 25 weeks gestation.

Our patient initially developed pustular psoriasis at the ageof 16 years. Her first pregnancy was associated with a mildflare of the disease which settled spontaneously. Eight weeksinto her second pregnancy at the age of 29 years, she had afurther recurrence which initially settled with bed rest andemollients. Unfortunately, at 22 weeks she was admitted witha more extensive flare (Fig. 1). All investigations includingserum calcium were within the normal range. Bed rest,emollients and topical steroids failed to settle the disease. Oralprednisolone was therefore commenced at a dose of 40 mg

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daily. Ultrasound scans showed good fetal growth but clinicalresponse was limited. Cyclosporin (Neoralw; Novartis, Cam-berley, Surrey, U.K.) was then added to the prednisolone at adose of 3 mg/kg daily. Within days there was a markedreduction in disease activity, which was sustained despiteweaning off the prednisolone and subsequently reducing thedose of cyclosporin. At 38 weeks gestation a healthy baby girlweighing 2350 g was delivered by caesarean section.

Few data are available on the use of cyclosporin inpregnancy. These mostly refer to transplant recipients andindicate that cyclosporin is not teratogenic, and comparedwith prednisolone and azathioprine imposes no increased riskof adverse effects on the course or outcome of pregnancy.3,4

Interestingly, unpublished data (personal communication,Novartis Pharmaceuticals, 1998) have been collected on agroup of patients with autoimmune-related conditions whohave been treated with cyclosporin during 19 completedpregnancies, resulting in the delivery of 20 infants. Seven ofthese babies had been exposed to cyclosporin throughout theentire pregnancy. The daily dose was reported in eight

pregnancies and ranged from 2´5 to 9 mg/kg daily, mean5´6 mg/kg daily. The pregnancies appear to have been largelyuneventful, although one case of intrauterine growthretardation was diagnosed. The duration of pregnancy isknown for 11 of the 19 pregnancies with eight cases deliveredat term and three cases prematurely. Birth weight rangedfrom 1360 g to 3486 g, with a mean of 2737 g.

The increasing amount of data implies that cyclosporinmay be relatively safe to use during pregnancy for pustularpsoriasis and other intractable dermatoses, without the risk ofneonatal hypoadrenalism and cataracts which are associatedwith exposure to high-dose prednisolone. The main adverseeffects of cyclosporin appear to be the possibility of growthretardation and premature delivery, although affected infantsappear to progress rapidly after birth with no long-term sequelae.

T.M.FINCH

C.Y.TAN

Birmingham Skin Centre,City Hospital NHS Trust,Dudley Road,Birmingham B18 7QH, U.K.

Figure 1. (a) Exacerbation of pustular psoriasis on the lower legs at 22 weeks gestation. (b) Close-up view of a sheet of pustules on an

erythematous background.

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References

1 Ott F, Krakowski A, Tur E et al. Impetigo herpetiformis with lowered

serum level of vitamin D and its diminished intestinal adsorption.

Dermatologica 1982; 164: 360±5.2 Raddadi AA, Baker Damanhoury Z. Cyclosporin and pregnancy.

Br J Dermatol 1999; 140: 1197±8 (letter).

3 Gaughan WJ, Moritz MJ, Radomski JS et al. National Trans-plantation Pregnancy Registry: report on outcomes of cyclosporine-

treated female kidney transplant recipients with an interval from

transplantation to pregnancy of greater than five years. Am J Kid

Dis 1996; 28: 266±9.4 Baruch Y, Weiner Z, Enat R et al. Pregnancy after liver trans-

plantation. Int J Gynaecol Obstet 1993; 4: 273±6.

Photodistributed chickenpox mimicking polymorphiclight eruption

Sir, Photodistributed varicella infection is rare and the typicalpolymorphism of varicella lesions may not be present.1

Unfamiliarity with this phenomenon may lead to misdiagno-sis as a specific photodermatosis of non-infectious aetiology,e.g. polymorphic light eruption. We report an adult with arelatively monomorphic photolocalized cutaneous varicellaeruption occurring a day after an episode of subtropicalsunbathing, where the clinical features most resembled thoseof polymorphic light eruption; however, subsequent vesiclefluid analysis indicated the true diagnosis. We wish tohighlight this rare differential diagnosis of polymorphic lighteruption, as the clinical distinction is of great importancewhen therapy with a systemic steroid is considered. Ifadministered erroneously in chickenpox, this could lead tolife-threatening disseminated varicella infection;2 in addition,unsuspected chickenpox could lead to the infection of manyothers.

A 31-year-old woman presented to the dermatology out-patient department with a 2-day history of a rapidly evolving,widespread, slightly pruritic eruption on the trunk, face andlimbs. This had arisen the day she returned to the U.K. from aspring holiday in Turkey where, a day earlier, she hadsustained mild sunburn while sunbathing. There were noprevious or present constitutional features besides a mildfrontal headache present following the onset of the rash.There was no relevant past medical or drug history and thepatient denied previous unusual sunlight sensitivity or aknowledge of prior chickenpox infection. Examinationrevealed a densely distributed monomorphic, almost con-fluent eruption composed of erythematous 1±2 mm diameterpapules, with only a few vesicles, each surmounting a papule,localized to the trunk and, to a lesser extent, the face andlimbs. There were no pustules, crusts or erosions. Theeruption had a clear photodistribution, showing a strikingdemarcation with normal skin at the margins of the bathingsuit area, where there was a complete absence of lesions.There were no lesions on the scalp or oral mucosa. Theremaining physical examination was unremarkable. The

history of very recent sunbathing and the presence of apruritic, predominantly monomorphic, apparent photo-eruption following intense sunlight exposure strongly sug-gested a diagnosis of a first episode of polymorphic lighteruption. As the rash was extensive and clearly troubling thepatient considerably, treatment with a systemic steroid wasconsidered on the proviso that subsequent vesicle fluidanalysis was negative for herpes simplex or varicella zostervirus. However, a Tzank preparation from the fluid showedmultinucleated epidermal cells, suggesting the presence ofherpes, while antigen-specific immunofluorescence of thevesicle fluid then confirmed the presence of varicella zostervirus. Oral aciclovir treatment was therefore commenced,after which, over the subsequent few days, lesions alsogradually developed at sites protected from sunlight.Within 10 days the patient had made a complete recovery.

There have been only about 10 cases reported in theEnglish language literature1,3±11 of photolocalized cutaneousvaricella infection since this phenomenon was first noted byCastrow and Wolf.3 In most of these, the eruption was pre-dated by an episode of acute sun exposure or sunburnbetween 2 and 10 days previously, while the remainingepisodes occurred in individuals with chronic sun exposure.What is also apparent from these reports is that the clinicalfeatures often differ from the classical description of chicken-pox in a number of ways besides occurring in a photo-distribution.1 Firstly, the typical polymorphism of chickenpoxlesions may not be present, with most lesions being at thesame stage of development throughout the course of thedisease. Secondly, the lesions may be more densely distributedand individually larger than usual. Lastly, the classicalcentripetal spreading of lesions may not occur. However, theduration of the illness in the reported cases has notsignificantly differed from that of conventional chickenpox.

The precise mechanisms of photolocalization or photo-exacerbation in varicella are unknown, but the direct inflam-matory properties of acute exposure to ultraviolet radiation(UVR) do appear to increase capillary permeability, whichmay then lead to the deposition of viral particles at exposedsites. Furthermore, a tendency to cutaneous immune sup-pression as well as the increased temperatures often associ-ated with acute exposure to UVR from sunlight may alsoencourage viral replication in sun-exposed skin. Finally, it isalso possible that in cases associated with chronic sunexposure that virus may disperse to epidermal cells fromvirally infected melanocytes,8 or that similarly infectedlymphocytes may more readily bind to keratinocytes as aresult of the enhanced expression of intercellular adhesionmolecule-1 induced by the UVR.9

In our patient, the history of recent sun exposure, thepresence of monomorphic lesions and the photodistributionled to a differential diagnosis strongly including the possibilityof polymorphic light eruption, pointing to the need to beaware of this clinically distinct form of varicella infection andto have a low threshold for performing an immediatevesicle fluid analysis where the suspicion of such a diagnosisexists.

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G.E.N.OSBORNE

J.L.M.HAWK

St John's Institute of Dermatology,St Thomas' Hospital,London SE1 7EH, U.K.

References

1 Serrano G, Aliaga A, Bonillo J et al. Photodistribution of varicellaexanthem: report of two cases. Pediatr Dermatol 1986; 3: 215±18.

2 Dowell SF, Bresee JS. Severe varicella associated with steroid use.

Pediatrics 1993; 92: 223±8.

3 Castrow FF, Wolf JE. Photolocalized varicella. Arch Dermatol 1973;107: 628.

4 White SM, Gupta SM, Tager P et al. Photolocalized varicella in a

middle-aged adult. Cutis 1998; 62: 199±200.

5 Feder HM, Luchetti ME. Varicella mimicking a vesiculobulloussun eruption. (Letter.) J Infect Dis 1988; 158: 243.

6 Findlay GH, Forman L, Hull PR. Actinic chickenpox. Light-

distributed varicella eruption. S Afr Med J 1979; 55: 989±91.

7 Newell GB. Photolocalized varicella. J Ky Med Assoc 1978; 76:443±4.

8 Gilchrest B, Baden HP. Photodistribution of viral exanthems.

Pediatrics 1974; 54: 136±8.

9 Boyd AS, Nelder KH, Zemtsov A, Shihada B. Photolocalizedvaricella. J Am Acad Dermatol 1992; 26: 772±4.

10 Boyd AS, Nelder KH. Photolocalized varicella in an adult. JAMA

1991; 266: 2204.11 Belhorne TH, Lucky AW. Atypical varicella exanthems associated

with skin injury. Pediatr Dermatol 1994; 11: 129±32.

Melanoma follow-up: protocols and practice

Sir, The incidence and mortality of cutaneous malignantmelanoma are increasing at the rate of between 3 and 7% inEuropean countries.1 Ideally, national guidelines shouldensure that treatment and follow-up of melanoma patientsare based upon sound scientific data. In creating a moreuniform practice, the quality of melanoma managementcould be optimized.

We report an audit of compliance that facilitated thecreation of a unified melanoma follow-up policy within asubregional plastic surgery department. Melanoma follow-uphas been a contentious issue for many years.2 There has beengreat debate as to the timing,3 benefits4 and cost-effective-ness5,6 of hospital follow-up, both in the `short-term' (for 5±10 years) and longer.7 This has major implications in terms ofclinic workload, out-patient attendance costs, time availablefor new cases and patient throughput.7,8

We performed an audit of melanoma follow-up in ourhospital. Each of the consultants initially had a differentpreferred follow-up policy (Table 1a). We questioned alljunior staff and found that only one of the 10 doctors wasaware of these policies. A retrospective audit was thenconducted of the last 50 out-patient episodes when attendingfor melanoma follow-up. Of the 50 patients, 24 (48%) werenot followed up according to the consultant's preferredpolicies. Eleven cases (22%) were due to further disease and13 (26%) were due to incorrect follow-up. The results of the

audit data and a review of the published literature highlightedthe need for an agreed, combined and unified follow-up policy.The revised policy (Table 1b) was then instituted anddistributed to clinics, junior staff and consultants. Thesechanges resulted in an immediate and significant reduction inclinic costs: 9% for thick melanoma ($ 0´76 mm Breslowthickness).

The policy was then re-audited 1 year later to assess itsimpact. Fourteen patients (28%) were not followed upaccording to the new policy (cf. 48% previously). Of these,eight cases (16%) were due to further disease and six (12%)were due to incorrect follow-up (cf. 26% previously). Twotypes of error were found on implementing the revised policy:failure to check the month of diagnostic excision and failureto recognize the presence of a second primary. In eachsituation, patients were incorrectly moved to the next year'sfollow-up programme and hence were seen less frequentlythan the guidelines intended.

Well-defined follow-up policies are of great benefit in themanagement of out-patient attendance. An agreed, unifiedpolicy provides clarification for the surgeon, the patient andthe junior staff who may rotate through various consultants'clinics. It reduces unnecessary attendance, thus generatingtime for new referrals. Provision of organized guidelinesfor the patient may also reduce non-attendance rates,with obvious economic benefit. However, policies shouldnot be entirely prescriptive and must be tailored to theindividual.

The provision of a unified policy seeks to establish whatconstitutes optimum follow-up in melanoma care, although itis unlikely that this will be answered at a local level. Nationalguidelines would address this issue and improve the quality ofmelanoma management.9 By conducting this audit andcreating a unified policy, we have reduced clinic costs by9% and identified and reduced errors in follow-up by 54%.Implementation of follow-up criteria on a national scalecould, therefore, deliver economic as well as clinicalbenefits.

In the era of clinical governance, we need to adopt anevidence-based approach towards even the most routineissues. In generating cost-effective practice we will optimizecare for our patients in the next millennium.

E.HORMBREY

P.BAN WEL L

P.GILLESPIE

P.BU DN Y

Department of Plastic Surgery, StokeMandeville Hospital, Aylesbury HP21 8AL,U.K.

References

1 Armstrong B, Kricker A. Cutaneous melanoma. Cancer Surv 1994;19±20: 219±40.

2 Rapaport D, Mettlin C, Michalek A et al. Life-long screening of

patients with intermediate-thickness cutaneous melanoma forasymptomatic pulmonary recurrences: a cost-effectiveness analysis.

Cancer 1995; 80: 1052±64.

3 Basseres N, Grob J, Richard M et al. Cost-effectiveness of surveillance

of stage I melanoma. A retrospective appraisal based on a 10-year

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experience in a dermatology department in France. Dermatology1995; 191: 199±203.

4 Couilliet D, Poisson-Salomon A, Cosquer M, Guillaume J. Modalities

of follow-up after excision of stage I melanoma: practice survey in

hospitals. Ann Dermatol Venereol 1995; 122: 263±6 (in French).5 Martini L, Brandani P, Chiarugi C, Reali U. First recurrence analysis

of 840 cutaneous melanomas: a proposal for a follow-up schedule.

Tumori 1994; 80: 188±97.

6 Romero J, Stefanato C, Kopf A, Bart R. Follow-up recommendationsfor patients with stage I malignant melanoma. J Dermatol Surg

Oncol 1994; 20: 175±8.

7 Baughan C, Hall V, Leppard B, Perkins P. Follow-up in stage Icutaneous malignant melanoma: an audit. Clin Oncol 1993; 5:

174±80.

8 Anonymous. Consensus conference. Follow-up of patients surgi-

cally treated for stage I melanoma. (Review.) Ann Dermatol Venereol1995; 122: 250±391 (in French).

9 Dicker T, Kavanagh G, Herd R et al. A rational approach to

melanoma follow-up in patients with primary cutaneous mela-

noma. Br J Dermatol 1999; 140: 249±54.

Elastotic change in the subpapillary and mid-dermallayers in pseudoxanthoma elasticum-like papillarydermal elastolysis

Sir, Pseudoxanthoma elasticum (PXE)-like papillary dermalelastolysis (PXE-PDE) is a new entity characterized byPXE-like clinical features (non-follicular yellowish papulescoalescing into plaques localized on the sides of the neck andsupraclavicular regions in the elderly), and by histologicalfeatures which are the loss or decrease of elastic fibres in thepapillary dermis.1±5 Despite a preferential occurrence on sun-exposed areas, the disease has been suggested to be a disorderrelated to chronological ageing of the elastic fibres, on thebasis of histological similarities to those seen in intrinsic

ageing.6 The major features of elastic fibres found in intrinsicageing skin are loss of elastic fibres in the papillary dermis andthe presence of ultrastructurally disintegrated abnormalelastic fibres associated with immature elastic fibres. Theseelastogenic changes in chronologically ageing skin have beeninterpreted as a process of repair of elastolytic damage.7±10

However, elastotic changes in PXE-PDE have never beenreported in detail, and only elastolytic changes have beenfocused on in the literature. We describe details of two furtherpatients.

Patient 1, a 61-year-old Japanese woman, noticed asympto-matic yellow to white papules on the neck, some of whichhad coalesced to form reticulate plaques, for 3 years. Shehad no lesions in the inguinal region or axillae. Therewere no abnormal findings on routine laboratory exami-nation except slight elevation of serum triglyceride(181 mg/dL), g-glutamyltransferase (44 IU/L) and fastingblood sugar (161 mg/dL). Patient 2, an 81-year-old Japanesewoman, had had yellow papules on the neck and supra-clavicular area for 5 or 6 years. Some papules on the neckhad coalesced to form PXE-like plaques. She had no lesions inother areas. Laboratory examination revealed no abnormalfindings except positive protein in urine. Neither patient hadabnormal findings suggestive of PXE on the basis of the resultsof chest X-ray, cardiovascular investigation or ophthalmo-logical examination.

Skin specimens were biopsied from the lesions of eachpatient. Age- and site-matched control skin was obtainedduring surgical removal of benign skin tumours. Sampleswere fixed in 10% formalin and embedded in paraffin.Paraffin-embedded sections were stained with haematoxylinand eosin (H&E), elastica-van Gieson (EVG) and orcein. Withboth EVG and orcein staining, complete loss of elastic fibreswas seen in the papillary layer of patient 1 (Fig. 1a,c),whereas a decrease of elastic fibres was seen in a normalcontrol (a 62-year-old woman) (Fig. 1b,d). In contrast,

Table 1. Follow-up protocols before (a) and after (b) audit

Breslow(a) Before audit (b) Unified protocol

depth Mr A Mr B Mr C Mr D All consultants

(mm) Any depth , 0´5 $ 0´5 , 0´75 $ 0´75 , 0´75 0´75±2´5 . 2´5 , 0´76 $ 0´76

Year offollow-up

1 3 months 3 months 3 months 3 months 3 months 6 months 3 months 2 months 3 months 3 months

2 3 months 6 months 3 months 3 months 3 months 6 months

(dx)

3 months 3 months 3 months 3 months

3 6 months 6 months 3 months 6 months 6 months 6 months 6 months 6 months 6 months

4 6 months 1 year 4 months 6 months 6 months 6 months 6 months 6 months 6 months

5 1 year

(dx)

1 year

(dx)

6 months 6 months

(dx)

6 months 6 months

(dx)

6 months 6 months

(dx)

6 months

6 1 year 6 months 6 months 1 year

7 1 year 6 months 6 months 1 year

8 1 year 6 months 6 months 1 year9 1 year 6 months 6 months 1 year

10 1 year

(dx)

6 months

(dx)

6 months

(dx)

1 year

(dx)

dx, discharge; follow-up as for $ 0´76 mm if histology report notes `regression'; site: acral lentiginous or no Breslow depth given.

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various degrees of focal elastotic changes in the subpapillaryto mid-dermal layer were seen in patient 1 (Fig. 1a,c)compared with the age- and site-matched normal control(Fig. 1b,d). The elastic fibres accumulating appeared to bestructurally normal. Staining patterns in patient 2 with EVGand orcein were similar to those in patient 1 (not shown).Basophilic degeneration in the subpapillary dermis was notseen in either case with H&E stain (not shown).

Although Rongioletti and Rebora1,6 described the ultra-structural elastogenic changes as consisting of immatureelastic fibres in the mid-dermis and activated fibroblasts withdilated cisternae in the rough endoplasmic reticulum, ahistological picture with apparent elastotic changes hasnot been presented in the five previously described cases ofPXE-PDE, as judged by the photographs presented in theliterature.1±4,6 At a light microscopic level, we found focalelastotic changes in the subpapillary dermis of two PXE-PDEpatients. We further examined the skin specimens from ourfiles of PXE-PDE (four cases previously described5): these alsodemonstrated various degrees of elastotic changes in thesubpapillary and mid-dermal layers (not shown). An accumu-lation of elastic fibres was found focally, but not throughoutthe subpapillary and mid-dermal layers. Elastic fibresaccumulating in the subpapillary dermis appeared to bestructurally normal and mature fibres. Elastotic changesfound in the subpapillary layer were not due to solar elastosis,as the elastic fibres were structurally normal and skinspecimens stained with H&E did not show basophilicdegeneration in the subpapillary layer. We therefore thinkthat the elastotic changes in the subpapillary dermis areindependent of solar elastosis. However, as the skin specimenswere taken from sun-exposed areas such as the neck in elderlysubjects, the possibility still remains that we were unable todetect a very slight degree of basophilic degenerationoccurring in the initial stage of solar elastosis.

Elastotic change in PXE-PDE may be related to the initial

elastolytic change, and may therefore reflect the process ofrepairing tissue damage. Elastolytic changes in the papillarylayer were also seen in age- and site-matched control skin,although the degree of elastolytic damage was lower thanin PXE-PDE. The elastotic changes rather than elastolyticchanges therefore may reflect the PXE-like clinical appearance.

S.TAJIMA

Y.OHN ISH I

A.AKAG I

A.ISHIBASHI

T.SAS AK I*

Department of Dermatology,National Defence Medical College,3-2 Namiki, Tokorozawa,Saitama 359-8513, Japan*Department of Dermatology,Yokohama City University,School of Medicine,Yokohama, Japan

References

1 Rongioletti F, Rebora A. Pseudoxanthoma elasticum-like papillary

dermal elastolysis. J Am Acad Dermatol 1992; 26: 648±50.

2 El-Charif MA, Mousawi AM, Rubeiz NG et al. Pseudoxanthoma

elasticum-like papillary dermal elastolysis: a report of two

cases. J Cutan Pathol 1994; 21: 252±5.

3 Patrizi A, Neri I, Trevisi P, Varotti C. Pseudoxanthoma elasticum-like papillary dermal elastolysis: another case. Dermatology 1994;

189: 289±91.

4 Pirard C, Delbrouck-Poot F, Bourlond A. Pseudoxanthomaelasticum-like papillary dermal elastolysis: a new case.

Dermatology 1994; 189: 193±5.

5 Ohnishi Y, Tajima S, Ishibashi A et al. Pseudoxanthoma elasticum-

like papillary dermal elastolysis: report of four Japanese cases andan immunohistochemical study of elastin and fibrillin-1. Br J

Dermatol 1998; 139: 141±4.

6 Rongioletti F, Rebora A. Fibroelastolytic patterns of intrinsic

skin aging: pseudoxanthoma elasticum-like papillary dermalelastolysis and white fibrous papulosis of the neck. Dermatology

1995; 191: 19±24.

Figure 1. Histochemical staining of thelesional skin in pseudoxanthoma-like papillary

dermal elastolysis. Skin specimens taken from

patient 1 (a,c) and an age- and site-matched

normal control (b,d) were stained withelastica-van Gieson (a,b) or orcein (c,d)

(original magnification � 200).

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7 Montagna W, Carlisle K. Structural changes in aging humanskin. J Invest Dermatol 1979; 73: 47±53.

8 Braverman IM, Fonferko E. Studies in cutaneous aging. I. The

elastic fiber network. J Invest Dermatol 1982; 78: 434±43.9 Lavker RM. Structural alterations in exposed and unexposed aged

skin. J Invest Dermatol 1979; 73: 59±66.

10 Bouissou H, Pieraggi MT, Julian M et al. The elastic tissue of

the skin: a comparison of spontaneous and actinic (solar) aging.Int J Dermatol 1988; 27: 327±35.

Seasonal variation in herpes zoster infection

Sir, Seasonal patterns have been shown for a wide range ofacute cardiovascular diseases, from stroke1 to aortic rupture.2

We reviewed all patients consecutively admitted for herpeszoster infection to the Emergency Department (ED) of St AnnaHospital, Ferrara, Italy, from January 1992 to December1998. Ferrara is a town in north-eastern Italy particularlywell suited for epidemiological studies. It has a stablepopulation of approximately 150,000 inhabitants with anage, sex and socio-economic status similar to that of Italy as awhole, and the only available hospital is St Anna. Herpeszoster infection was diagnosed by clinical and laboratoryexamination, and always confirmed by the consultantdermatologist.

There were 845 cases in 826 different subjects (419 men,51%, mean age 56 ^ 19 years, 407 women, 49%, mean age61 ^ 19 years). Of these, 649 (77%) were initially identifiedin primary care by general practitioners and 196 (23%)within the ED. Day of onset of symptoms was categorized intoboth four 3-month periods by season and 12 1-monthintervals. Two methods of statistical analysis were used:x2-test for goodness of fit for data by season (winter:January to March; spring: April to June; summer: July toSeptember; autumn: October to December); and partialFourier series with up to four harmonics (12, 6, 4 and3 months) for monthly data (with chronobiological start-ing reference time from 21 December). The former methodwas aimed to compare observed vs. expected cases and tofind frequency peaks, the latter to identify rhythmicpatterns. In the seasonal analysis, a significantly higher

frequency of episodes presented in summer for the totalsample and male subgroup (P , 0´001 and 0´002, respec-tively) whereas women had a similar, but not statisticallysignificant, increased frequency of episodes in spring andsummer (Table 1). In the Fourier analysis, a circannualrhythm was found, both for the total sample and thesubgroups by gender, with significant acrophases in May±June (Table 2). Further analysis addressed to age at onset ofdisease and subjects who had more than one episode did notshow any significant difference comparing these groups withthe total sample.

To our knowledge, this is the first report on this topic in theliterature; previously, only a seasonal variation with a winterpeak has been reported for ocular herpetic infections.3 Thepeculiar pathogenetic mechanism of herpes zoster infection,its capacity to migrate after the primary infection (varicella)to the dorsal root ganglia and remain silent throughout life,makes it somewhat difficult to put forward convincinghypothetical explanations. On one hand, as both humoraland cellular immune response maintain control of possibleviral replication,4 it is possible that seasonal variations in theincidence of immunologically related diseases may be relatedto circannual variations in immune response.5 On the otherhand, although the effects of ultraviolet (UV) A on theimmune system are not fully known, there are available dataon both a possible suppressive effect mediated by reactiveoxygen species6 and a defensive action against UVB immuno-suppression via an induced haemoxygenase activity,7 and nodoubts exist regarding the immunosuppressive effect of UVB.This is due to a series of mechanisms, e.g. impairment ofnatural killer function8 and suppression of relevant functionsof phagocytic cells.9 Thus, remembering that the late spring±early summer period is characterized by a longer day lengthand more sunlight, it is also possible that sunlight exposuremay interfere with the immune response.

M.GA LL ER AN I

R.MANF RE DIN I

Department of Clinical andExperimental Medicine,University of Ferrara Medical School,via Savonarola 9,I-44100 Ferrara, ItalyE-mail: [email protected]

Table 2. Chronobiological results (partial Fourier series)

n % of rhythm P Acrophase 95% CI

All events 845 71�´7 0�´002 ±177�´3 May ±150/±205 May±June

Males 430 53�´8 0�´021 ±196�´6 June ±153/±238 May±July

Females 415 48�´2 0�´037 ±152�´3 May ±106/±202 March±June

CI, confidence interval.

Table 1. Absolute number, percentage and x2 after stratification by season

n Winter Spring Summer Autumn x2 P

All events 845 184 (21�´8%) 219 (25�´9%) 257 (30�´4%) 185 (21�´9%) 16�´9 0�´0001

Males 430 90 (20�´9%) 102 (23�´7%) 141 (32�´8%) 97 (22�´6%) 14�´6 0�´002

Females 415 94 (22�´7%) 117 (28�´2%) 116 (27�´9%) 88 (21�´2%) 6�´4 0�´093

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References

1 Manfredini R, Gallerani M, Portaluppi F et al. Chronobiological

patterns of onset of acute cerebrovascular diseases. Thromb Res

1997; 88: 451±63.2 Manfredini R, Portaluppi F, Salmi R et al. Seasonal variation in the

occurrence of nontraumatic rupture of thoracic aorta. Am J Emerg

Med 1999 in press.3 Gamus D, Romano A, Sucher E, Ashkenazi IE. Herpetic eye attacks:

variability of circannual rhythms. Br J Ophthalmol 1995; 79: 50±3.

4 Gershon AA, Steinberg SP. Cellular and humoral immune responses

to varicella-zoster virus in immunocompromised patients duringand after varicella-zoster infections. Infect Immun 1979; 25: 170±4.

5 Levi FA, Canon C, Touitou Y et al. Seasonal modulation of the

circadian time structure of circulating T and natural killer

lymphocyte subsets from healthy subjects. J Clin Invest 1988; 81:407±13.

6 Iwai I, Hatao M, Naganuma M et al. UVA-induced immune

suppression through an oxidative pathway. J Invest Dermatol1999; 112: 19±24.

7 Reeve VE, Tyrrell RM. Heme oxygenase induction mediates the

photoimmunoprotective activity of UVA radiation in the mouse.

Proc Natl Acad Sci USA 1999; 96: 9317±21.8 Miyauchi-Hashimoto H, Okamoto H, Tanaka K, Horio T. Ultraviolet

radiation-induced suppression of natural killer cell activity is

enhanced in xeroderma pigmentosum group A (XPA) model mice.

J Invest Dermatol 1999; 112: 965±70.9 Leino L, Saarinen K, Kivisto K et al. Systemic suppression of human

peripheral blood phagocytic leukocytes after whole-body UVB

irradiation. J Leukoc Biol 1999; 65: 573±82.

Photopatch testing in photosensitive patients

Sir, The British Photodermatology Group (BPG) held aworkshop on photopatch testing in November 1995, thefindings and recommendations of which were published inthe British Journal of Dermatology.1 A standard series of sixpotential photoallergens was devised, incorporating agentswhich were widely used at the time and reported to be arelatively common cause of photocontact allergy. Agents ofhistorical interest such as the antibacterial tetrachlorosali-cylanilide, which were no longer clinically relevant, wereexcluded. From September 1996, we have performed photo-patch tests on all patients with suspected photosensitivitywho have been referred to the Liverpool Photobiology Unit fordiagnostic photoinvestigation; the agents tested and proce-dure were as recommended by the BPG.1 We have conducteda retrospective review of the positive results obtained in orderto establish which allergens are most often identified asrelevant, and in which photosensitive disorders these reac-tions are occurring.

On day 0, the standard series of photocontact allergens(Table 1) is applied to the patient's back in duplicate, one setof patches for irradiation and one for control. The minimalerythema responses to ultraviolet (UV) A are also assessed.The patches are removed on the following day, and one set ofallergens is irradiated with 5 J/cm2 of broad-band UVA.Lower doses of radiation are given in those with low erythemathresholds to UVA. The readings are taken 48 h later.

Reactions are graded as follows: 0, no response; ^, doubtfulresponse; 1, mild erythema; 2, moderate erythema; 3,erythema and oedema; 4, erythema, oedema and vesicles.Grades 1 and above are regarded as positive reactions.

All 167 patients who were phototested between September1996 and December 1998 were included in the review. Afterexcluding pure contact reactions, 16 (10%) patients wereidentified who had a total of 20 photoallergic reactions,including two patients who had both photocontact andcontact allergies. Photocontact allergy occurred across therange of photosensitive conditions, and no condition appearedin the photoallergic group more often than would have beenexpected from its prevalence (Table 2). Photoallergy was seenmost commonly in polymorphic light eruption, reflecting thehigh proportion of patients with this condition undergoingphotoinvestigation. Photocontact allergy is the fourth mostcommon diagnosis made following photoinvestigation in ourunit. In most cases, the finding was of clinical relevance; thiswas established by thorough questioning of our 16 patients toconfirm a history of contact to the allergen and exposurewhich pre-dated the development or exacerbation of theirphotosensitivity. Only one had isolated photocontact allergy;in the others it complicated another disorder, the patients'photosensitive conditions being exacerbated by the appli-cation of sunscreens containing the allergen. Our figures arecomparable with a previous study in the U.S.A. whichidentified clinically relevant photocontact allergy in 11% ofphotosensitive patients.2 We observed five pure contactallergic reactions to the BPG photoallergen battery (i.e.equal reactions on both irradiated and non-irradiatedpatches), which were to Escalol 507 (two reactions), ParsolMCX (one reaction), Parsol 1789 (one reaction) andp-aminobenzoic acid (PABA, one reaction). Photosensitivityhad been suspected in these patients, and it is likely that theirconsequent increased use of sunblocks placed them at greaterrisk of developing contact allergy.

Three major groups of photoallergens exist: sunscreeningredients, fragrances and antibacterial agents, the firstgroup now being the most common and the last group havingbecome clinically irrelevant. Once photoallergens are recog-nized as such, they tend to be excluded from future products.Musk ambrette, a fragrance, is still included in the allergenbattery, as is PABA, a sunscreen ingredient which was a

Table 1. Photocontact reactions observed in patients referred for theinvestigation of photosensitivity

Photoallergen

No. of positive

photocontact

reactions

Parsol 1789 8

Benzophenone 3 5

Parsol MCX 5

Escalol 507 1Musk ambrette 1

PABA 0

Total 20

PABA, p-aminobenzoic acid.

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common photoallergen in the 1970s. Although these agentshave been excluded from products manufactured in thiscountry, patients can still come into contact with them inforeign products. PABA esters such as Escalol 507 are also inuse.

Most recent studies have reported benzophenones as themost common sunscreen allergens,2 and photocontact allergyhas been less commonly reported with the newer UVBabsorbers, the cinnamates, such as Parsol MCX, and the UVAabsorbers, the dibenzoylmethanes, such as Parsol 1789.2 The1995 BPG workshop report also concluded that photoallergywas `rare with the most widely used cinnamate, Parsol MCX'and `infrequent with Parsol 1789'.1 In contrast to this, in ourpatients the most common photoallergen was Parsol 1789,followed by benzophenone 3 and Parsol MCX, while nophotocontact reactions to PABA were observed. However, theoverall numbers were relatively small (Table 1). This studyillustrates, first, the high prevalence of sunscreen photo-allergy in photosensitive patients and, secondly, the need for

regular reviews of culprit photoallergens, with updating ofthe standard series as older allergens become less relevantand new potential photoallergens emerge. These issues arecurrently being addressed by a large multicentre U.K. study.

H.K.BELL

L.E.RHODE S

Department of Dermatology,Link 10C,Royal Liverpool Hospital,Prescot Street,Liverpool L7 8XP, U.K.

References

1 British Photodermatology Group. Workshop report. Photopatch

testingÐmethods and indications. Br J Dermatol 1997; 136:371±6.

2 DeLeo VA, Suarez SM, Maso MJ. Photoallergic contact dermatitis.Results of photopatch testing in New York. 1985. Arch Dermatol

1992; 128: 1513±18.

Photosensitive disorder

No. of

patients

No. withphotocontact

allergy

Polymorphic light eruption 53 6

Photoaggravated dermatoses (eczema or psoriasis) 34 4Chronic actinic dermatitis 12 2

Contact allergic eczema 11 2

Solar urticaria 1 1

Table 2. Photosensitive conditions associatedwith photocontact allergy