Generalized pustular psoriasis following withdrawal of oralcyclosporin treatment for palmo-plantar pustulosis

B. D. De Silva,* E. C. Benton and M. J. TidmanUniversity Department of Dermatology, The Royal Infirmary of Edinburgh, Scotland

Summary We report the cases of two patients who developed generalized pustular psoriasis on thewithdrawal of oral Cyclosporin treatment for persistent palmoplantar pustulosis. Thiscomplication does not appear to have been reported previously.

Introduction

Cyclosporin A (CsA) is an established treatment in themanagement of severe plaque psoriasis1 and has beenused for generalized pustular psoriasis.2 Although notspecifically licensed for this condition, CsA has beenshown to be effective in the treatment of persistentpalmoplantar pustulosis (PPP) when used in doses inthe range 2.5–6 mg/kg/day.3,4

We report two cases of generalized pustular psoriasisoccurring after the withdrawal of CsA therapy for PPP.This phenomenon does not appear to have been reportedpreviously.

Case reports

Case 1

A 51 year-old female smoker had a 15-year history ofPPP with a marked perimenstrual exacerbation. She hadsevere functional impairment, at times being houseboundor having to use a wheelchair because of involvement of theentire surface of the palms and soles (Fig. 1) together withthe nail changes of acrodermatitis continua. Cessation ofsmoking did not improve the condition

Hospital admission always led to a remarkably swiftimprovement in her symptoms often within a few days.She had been treated with superficial radiotherapy, but a

good initial response was followed by rapid relapse. Atrial of topical PUVA was inadequate because of geogra-phical difficulties with attendance. Oral etretinate waspartially succesful over a period of 5 years but had to bewithdrawn because of persistently raised fasting lipidlevels. She was diagnosed as diabetic in 1990 but thiswas well controlled by diet and oral hypoglycaemicagents. Her PPP gradually worsened and treatmentwith oral CsA was therefore begun in March 1995 at adose of 2.5 mg/kg/day. This was well tolerated and thePPP cleared completely. Renal function and blood pres-sure remained within acceptable limits. Unfortunately, inAugust 1996 she developed profound gingival hyper-plasia (Fig. 2) necessitating withdrawal of CsA. Within2 weeks she had developed generalized pustular psoriasisrequiring urgent hospital admission.

On examination she was pyrexial, pale and unwell.Her skin showed generalized erythema with sheets ofpustules (Figs 3 and 4). Blood tests showed hypocalcae-mia (corrected calcium 1.96 mmol/L), hypoalbuminae-mia (albumin 27 g/L) and a hypochromic microcyticanaemia (7.8 g/dL) with a low serum iron.

The anaemia, which was exacerbated by menorrha-gia responded to oral iron. A pelvic ultrasound scanrevealed no abnormalities. Endometrial biopsy showedno evidence of atypia and urine tracking showed normalovarian production of oestradiol and progesterone con-sistent with ovulatory cycles. In view of her history ofperimenstrual exacerbation of PPP an attempt was madeto induce a ‘chemical menopause’ using the luteinizinghormone releasing hormone analogue, Naferelin, intra-nasally. This quickly controlled menstruation and helpedto correct the anaemia.

Clinical dermatology • Concise report

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Correspondence: Dr B. D. De Silva, University Department of Dermatology,The Royal Infirmary of Edinburgh, Lauriston Place, Edinburgh EH3 9YW,UK. Tel.: þ 44 131 5362056. Fax: þ 44 131 2298769.

Accepted for publication 29 September 1998

Pustular psoriasis after cyclosporin withdrawal • B. D. De Silva et al.

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Figure 1 PPP of the sole.

Figure 2 Gingival hyperplasia due to CsA.

Figure 3 Generalized pustular psoriasis (Case 1).

Figure 4 Close up of Fig. 3 to show sheets of pustules.

The pustular psoriasis settled over a period of 3 weekswith oral methotrexate (7.5 mg/week) and the calciumand albumin returned to within normal limits. She hassubseqeuntly been stabilized on a dose of 15 mg/weekwith modest benefit.

Case 2

The second patient was a 41-year-old female smokerwith a 14-year history of unrelenting and progressivelymore severe PPP with changes of acrodermatitis con-tinua of Hallopeau (Fig. 5). In addition to severe func-tional impairment her condition was complicatedlatterly by recurrent episodes of cellulitis. Topical therapywas unhelpful as was systemic PUVA and the introduc-tion of oral tetracyclines on two separate occasions led towidespread erythema with pustulation. Etretinate andsusequently acitretin both led to severe abnormalities ofliver function (alanine transaminase >800 U/L) withinweeks of their introduction

CsA was started in January 1994 at a dose of 3 mg/kg/day with an initial excellent response. However, after6 months of continuing deterioration the dose was

increased to 5 mg/kg/day. Renal function and bloodpressure remained stable. Unfortunately, any subsequentattempt to reduce the dose of CsA led to a flare of PPP. Itwas decided therefore to withdraw CsA and substituteoral methotrexate, repeated liver function tests havingbeen satisfactory and a liver biopsy showing steatosisonly. However, within 2 weeks of stopping CsA thepatient developed severe widespread pustular psoriasisresulting in a prolonged hospital admission. During thistime she had a swinging pyrexia with no focus ofinfection, normochromic anaemia (Hb 7.8 g/dL),reactive thrombocythaemia (platelets >1000 × 109/L),hypoalbu-minaemia (albumin 28 g/L) and deranged liverfunction tests. After 8 weeks of intensive treatment thegeneralized pustular psoriasis stabilized on 15 mg/week ofmethotrexate with improvement in the haematological andbiochemical parameters. However, despite a subsequentincrease to 20 mg/week of methotrexate she continued tohave painful acral pustulation, swelling and intermittentcellulitis of the forearms. This was eventually controlled bydual therapy with methotrexate (up to 15 mg/week) andCsA (5 mg/kg). She remains on CsA (5 mg/kg) but it hasbeen possible to withdraw the methotrexate.

Discussion

PPP is a chronic relapsing and remitting disorder ofpalms and soles characterized by sterile pustulation.Histologically ‘neutrophil stuffed’ pustules beneath thestratum corneum are characteristic. It is more commonin females than in males. A high prevalence of cigarettesmoking has been found in patients with PPP5 and thismay be due to a direct effect of nicotine on the release ofneutrophil migration factors (chemoattractants).

Treatment for PPP is difficult and potent topicalsteroids, tar, oral tetracycline, topical or systemicPUVA, retinoids and cyclosporin A have all been usedwith varying levels of success.

CsA has been shown to be effective in double-blindcontrolled trials in the treatment of PPP.3,4 CsA has alsobeen used to treat generalized pustular psoriasis.2 Thetwo subjects of this case report, both with progressivedisabling disease, were treated with CsA following unac-ceptable side-effects of other therapy. Relapse, i.e. areturn to a pretreatment level of disease, is common oncessation of CsA treatment.1 However, these two patientsillustrate the phenomenon of rebound generalized pust-ular psoriasis on withdrawal of CsA. This has beendescribed in relation to the treatment of chronic plaquepsoriasis6,7 but not, as far as we are aware, in thetreatment of PPP. This rebound would seem to be similarto that which is seen on withdrawal of potent topical or

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Figure 5 Acrodermatitis continua and involvement of the palm (Case 2).

oral steroid therapy in patients with psoriasis. Therefore,the possibility of a rebound phenomenon occurring oncessation of CsA for the treatment of PPP must beconsidered. It may be helpful, if it is possible, to withdrawCsA gradually in order to prevent this rebound, or if CsAmust be stopped abruptly, to institute another systemictreatment in anticipation.

References

1 Griffiths CEM. Systemic and local cyclosporine to treatpsoriasis. J Am Acad Dermatol 1990; 23: 1242–7.

2 Meinardi M, Weterhof W, Bos JD. Generalized pustularpsoriasis (Von Zumbusch) responding to cyclosporin A.Br J Dermatol 1987; 116: 269-70.

3 Reitamo S, Errko P, Remitz AJ. Cyclosporin forpalmoplantar psoriasis. J Autoimmunity 1992; 5 (Suppl):285–7.

4 Meinardi MMHM, de Rie MA, Bos JD. Oral cyclosporin A iseffective in clearing persistent PPP. Acta Derm Venereol1990; 70: 77–9.

5 O0Doherty CJ, MacIntyre C. Palmoplantar pustulosis andsmoking. Br Med J 1985; 291: 861–5.

6 Cacoub P, Artru L, Canesi M et al. Life threateningpustular erythroderma in a patient with psoriasisand psoriatic arthritis (Letter). Lancet 1988; II:219–20.

7 Heidenheim M, Oxholm A, Da Cunha Bang F.Generalized pustular psoriasis in relation to thewithdrawal of cyclosprin A (Letter). Br J Dermatol 1990;120: 719.

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