Clinical and Experimental Dermntology W)2; 17: 49-52.
Recalcitrant pyoderma gangrenosum^—two cases successfully treated with cyclosporin A G.M.KAVANAGH, J.S.ROSS, E.CRONIN, N.P.SMITH AND M.M.BLACK St Johns Dermatology Centre. St Thomas' Hospital. lAimbeth Palace Road, London SEI 7EH, UK Accepted for publication 15 May 1991
Summary The successful use of cyclosporin A (CSA) in organ transplantation is now well established.' In recent years its usefulness has extended to the treatment of cutaneous autoimmune disorders,' including pyodern^a gangrenosum (P.G.)." ' We report two further cases of recalcitrant P.G., hoth associated with rheumatoid arthritis (R.A.) which responded to low dose CSA.
Case reports Case ]
A 48-year-oId woman with a past history of vitiligo., mild eczema and sero-ncgative R.A. was admitted because of joint pains and a bleeding leg ulcer. Previous treatment for her R.A. had included non-stcroidal anti-inflammatory agents., penicillamine and salicylates. Her current therapy was ferrous sulphate for iron deficiency anaemia, the cau.se of which was not determined. In 1978 she developed a rapidly extending, necrotic ulcer on the left buttock. .\ diagnosis of P.G. was made on clinical and histological grounds and the ulcer healed over the subsequent 10 months on minocycline (300 mg/day).'* Over the following decade she suffered recurrent lesions of P.G. on the legs and temple. Each relapse appeared to respond to minocycline until January 1989 when a lesion of P.G. on the lower leg failed to heal despite treatment with minocycline 300 mg/day for over 3 weeks. Prednisolone (1 mg/kg/day) was introduced successfully and the ulcer healed completely after 4 months. Another ulcer developed in July 1989 and progressed despite initial treatment with minocycline (200 mg/day) and then prednisolone (1 mg/kg/day) in combination with azathioprine (3 mg/kg/day). As there was no improvement after 1 month, the azathioprine was stopped and CS.'\ introduced at 4 mg/kg/day (the prednisolone was gradually reduced to zero over the following 5 weeks). Healing commenced within 1 week and was virtually
complete at 3 months when she de\eloped a flu-like illness with nausea and vomiting. Although this was thought to be a viraemia rather than a side effect of CSA therapy; CSA was discontinued. Within 6 weeks ulceration of her leg had recurred and was extending again. CSA was introduced as before, maintaining 12-h between serum trough CSA levels 180 450 ng/ml (as measured by radioimmunoassay). Improvement was again seen after 3 weeks of therapy, and continued for 4 months when her ulcers suddenly became painful, larger and bled significantly despite continued CSA therapy. As on previous occasions, hot weather appeared to have precipitated the relapse. She was rc-admitted for review of therapy and bed rest. Relevant investigations revealed a hypochromic, microcytic anaemia (haemoglobin U) gm/dl). The patient's urea and creatinine were within normal limits and 24-h urinary creatinine clearance was 60 mls/min (creatinine clearance pre-CSA was 74 mls/min). TJver function tests were normal. After a further 6 weeks of CSA therapy (4 mg/kg/day) both ulcers had healed completely and she remains in remission 6 months later on a maintenance dose of CSA 2 5 mg/kg/day. Her blood pressure has been normal throughout. Case 2 A 69-year-old lady presented in October 1989 with a 2month history of rapidly enlarging, painful ulcers on her lower legs. She had longstanding sero-negativc rheumatoid arthritis which was well controlled on non-stcroidal anti-inHammatory agents. Left ventricular failure thought to be ischaemic in aetiology had been treated successfully with diuretics in the past. Physical examination revealed a symmetrical, deforming arthritis predominantly affecting the hands, feet and knees. She had several large ulcers on the lower legs, all of which had a necrotic, purulent base and purplish undermined edges. A clinical diagnosis of P.G. was made, but a biopsy was refused. Investigations for associated gastro-intestinal and systemic diseases were normal. The patient was admitted and commenced on predni-
50
G.M.KAVANAGH et al. (a)
(h)
Fij^urc 1. The left lateral lower leg ulcer of patient 2 before (a) and alter (b) 4 months of CSA therapy.
solone (1 mg/kg/day). Ulceration progressed despite three weeks of therapv. CSA was therefore commenced at a dose of 4 mg/kg/day. Improvement was observed within 5 days, and continued over the following 4 months as the dose of prednisolone was gradually reduced to 01 mg/kg/ day. Indomethacin was also continued on an intermittent basis. One ulcer healed after 4 months of CSA therapy (see Fig. la and b), and all leg ulcers had healed at 9 months. She remains in remission 6 months later on CSA 1 mg/ kg/day. Therapy has been complicated by gastric ulceration and the development of hypertension which is well
controlled on nifedipine. Renal function remains stable despite a creatinine clearance of 50 ml/min. Discussion Pyoderma gangrenosum is a painful, ulcerating condition of unknown aetiology. It is characterized by progressively enlarging cutaneous ulceration with raised, undermined borders and a purulent base. P.G. has been associated with a variety of systemic diseases including inflammatory bowel disease, sero-positive rheumatoid arthritis, sero-negative polyarthritis, malignancies of the haemo-
RECALCITRANT PYODERMA GANGRENOSUM poetic system, chronic active hepatitis and systemic lupus crythcmatosis.** The frequency with which arthritis has been reported to occur in association with P.G. varies from 20 to 57%,'" but there does not appear to be any correlation between skin disease and joint disease activity.'" In a recent controlled trial assessing efficacy of low dose CSA in treatment of R.A., substantial benefit was reported at 12 weeks." Most authors consider P.G. to he an expression of altered humoral or cellular immunity. Reported humoral abnormalities include hyper/hypoglohulinemia, and occasional dysprotcinacmis.'' The evidence implicating a disturbance in cellular immune function is more convincing and includes abnormalities in skin graft rejection, cutaneous anergy and reduced T cell reactivity.'' Defects in neutrophil chemotaxis and phagocytosis have also been described.'' The mainstay of treatment for P.G. to date has been with immunosuppressive agents such as systemic corticosteroids. However, many patients respond poorly and side effects have been reported in up to 50% of patients.'^ Various steroid sparing agents such as azathioprine''' and 6-mcrcaptopurine"' have also been tried with some success. Sulphonamide drugs,'' clofazimine"* and minocycline'* have been suggested as therapeutic options in view of their effects on neutrophil function. CSA influences both humoral and cellular immunity,''' with its primary mechanism of action on the suppression of interlcukin-2 synthesis which is critical for T helper cell activation and cytotoxic T cell expansion.^" Not only sparing but amphfication of T lymphocyte suppression has been reported during CSA therapy-' while production of antibodies to T-cell dependent antigens is also inhibited.''^ The efficacy of CSA is therefore in keeping with the postulated pathogenesis of P.G. and the known actions of this drug. Renal dysfunction and hypertension are the two most significant side effects of treatment. In short-term, lowdose therapy these are reversible when CSA is discontinued."' With regard to long-term therapy, the occurrence of clinically silent renal dysfunction remains a concern. Patients with R.A. seem to be more susceptible to nephrotoxicity,-' and 'new onset' hypertension has heen reported to occur in 25% of patients with auto-immune disease.^"* These two cases demonstrate that there is a role for CSA in recalcitrant P.G. Potential toxicity may be minimi/.ed by regular monitoring. Both patients currently remain in remission on low dose CSA (1-2 5 mg/ kg/day). The need for long-term CSA to maintain remission in these patients remains speculative. Recent successful use of intralesional C.SA in psoriasis-' raises the possihility of benefit from local application in diseases such as P.G., whilst reducing recognized side effects.'-
51
References 1. W'cil C. Cyclosporin A: Review of results in organ and bone transplantation in man. Medicinal Research Reviews 1984; 4: 2216. 2. Ciupta AK, Brown MD, KIlis CN, Rocher IJ., I'isher GJ. Haadsfraartl (), (hooper KD, Voorhees JJ. (Jvelosporinc in Dermatology. Journal of the American .-Icadeiny of Dermalology Vm\ 21: 1245-55. i. C.uricy RK, Macfarlane .'\W, \ ickcrs CFH. Pyoderma gangrenosum treated with Cyclosporin A. British Jiniriud of Dermatology 4. Shelly KD, Shelly WB. (lyclnsporine Therapy for pyoderma gangrenosum associated with scierosing cholangitis and ulcerative coWth. Journal of the American Academy of Dermatology IMSS; 18: 1084 i. 5. Penmetcha M, Navaratrani AK. Pyoderma gangrenosum: Response to Cyclosporin A. Internulional Journal of Dermatology
i
6. Magid VIL, Gold MH. Treatment of recalcitrant pyoderma gangrenosum with ilyc\o
Recalcitrant pyoderma gangrenosum^—two cases successfully treated with cyclosporin A G.M.KAVANAGH, J.S.ROSS, E.CRONIN, N.P.SMITH AND M.M.BLACK St Johns Dermatology Centre. St Thomas' Hospital. lAimbeth Palace Road, London SEI 7EH, UK Accepted for publication 15 May 1991
Summary The successful use of cyclosporin A (CSA) in organ transplantation is now well established.' In recent years its usefulness has extended to the treatment of cutaneous autoimmune disorders,' including pyodern^a gangrenosum (P.G.)." ' We report two further cases of recalcitrant P.G., hoth associated with rheumatoid arthritis (R.A.) which responded to low dose CSA.
Case reports Case ]
A 48-year-oId woman with a past history of vitiligo., mild eczema and sero-ncgative R.A. was admitted because of joint pains and a bleeding leg ulcer. Previous treatment for her R.A. had included non-stcroidal anti-inflammatory agents., penicillamine and salicylates. Her current therapy was ferrous sulphate for iron deficiency anaemia, the cau.se of which was not determined. In 1978 she developed a rapidly extending, necrotic ulcer on the left buttock. .\ diagnosis of P.G. was made on clinical and histological grounds and the ulcer healed over the subsequent 10 months on minocycline (300 mg/day).'* Over the following decade she suffered recurrent lesions of P.G. on the legs and temple. Each relapse appeared to respond to minocycline until January 1989 when a lesion of P.G. on the lower leg failed to heal despite treatment with minocycline 300 mg/day for over 3 weeks. Prednisolone (1 mg/kg/day) was introduced successfully and the ulcer healed completely after 4 months. Another ulcer developed in July 1989 and progressed despite initial treatment with minocycline (200 mg/day) and then prednisolone (1 mg/kg/day) in combination with azathioprine (3 mg/kg/day). As there was no improvement after 1 month, the azathioprine was stopped and CS.'\ introduced at 4 mg/kg/day (the prednisolone was gradually reduced to zero over the following 5 weeks). Healing commenced within 1 week and was virtually
complete at 3 months when she de\eloped a flu-like illness with nausea and vomiting. Although this was thought to be a viraemia rather than a side effect of CSA therapy; CSA was discontinued. Within 6 weeks ulceration of her leg had recurred and was extending again. CSA was introduced as before, maintaining 12-h between serum trough CSA levels 180 450 ng/ml (as measured by radioimmunoassay). Improvement was again seen after 3 weeks of therapy, and continued for 4 months when her ulcers suddenly became painful, larger and bled significantly despite continued CSA therapy. As on previous occasions, hot weather appeared to have precipitated the relapse. She was rc-admitted for review of therapy and bed rest. Relevant investigations revealed a hypochromic, microcytic anaemia (haemoglobin U) gm/dl). The patient's urea and creatinine were within normal limits and 24-h urinary creatinine clearance was 60 mls/min (creatinine clearance pre-CSA was 74 mls/min). TJver function tests were normal. After a further 6 weeks of CSA therapy (4 mg/kg/day) both ulcers had healed completely and she remains in remission 6 months later on a maintenance dose of CSA 2 5 mg/kg/day. Her blood pressure has been normal throughout. Case 2 A 69-year-old lady presented in October 1989 with a 2month history of rapidly enlarging, painful ulcers on her lower legs. She had longstanding sero-negativc rheumatoid arthritis which was well controlled on non-stcroidal anti-inHammatory agents. Left ventricular failure thought to be ischaemic in aetiology had been treated successfully with diuretics in the past. Physical examination revealed a symmetrical, deforming arthritis predominantly affecting the hands, feet and knees. She had several large ulcers on the lower legs, all of which had a necrotic, purulent base and purplish undermined edges. A clinical diagnosis of P.G. was made, but a biopsy was refused. Investigations for associated gastro-intestinal and systemic diseases were normal. The patient was admitted and commenced on predni-
50
G.M.KAVANAGH et al. (a)
(h)
Fij^urc 1. The left lateral lower leg ulcer of patient 2 before (a) and alter (b) 4 months of CSA therapy.
solone (1 mg/kg/day). Ulceration progressed despite three weeks of therapv. CSA was therefore commenced at a dose of 4 mg/kg/day. Improvement was observed within 5 days, and continued over the following 4 months as the dose of prednisolone was gradually reduced to 01 mg/kg/ day. Indomethacin was also continued on an intermittent basis. One ulcer healed after 4 months of CSA therapy (see Fig. la and b), and all leg ulcers had healed at 9 months. She remains in remission 6 months later on CSA 1 mg/ kg/day. Therapy has been complicated by gastric ulceration and the development of hypertension which is well
controlled on nifedipine. Renal function remains stable despite a creatinine clearance of 50 ml/min. Discussion Pyoderma gangrenosum is a painful, ulcerating condition of unknown aetiology. It is characterized by progressively enlarging cutaneous ulceration with raised, undermined borders and a purulent base. P.G. has been associated with a variety of systemic diseases including inflammatory bowel disease, sero-positive rheumatoid arthritis, sero-negative polyarthritis, malignancies of the haemo-
RECALCITRANT PYODERMA GANGRENOSUM poetic system, chronic active hepatitis and systemic lupus crythcmatosis.** The frequency with which arthritis has been reported to occur in association with P.G. varies from 20 to 57%,'" but there does not appear to be any correlation between skin disease and joint disease activity.'" In a recent controlled trial assessing efficacy of low dose CSA in treatment of R.A., substantial benefit was reported at 12 weeks." Most authors consider P.G. to he an expression of altered humoral or cellular immunity. Reported humoral abnormalities include hyper/hypoglohulinemia, and occasional dysprotcinacmis.'' The evidence implicating a disturbance in cellular immune function is more convincing and includes abnormalities in skin graft rejection, cutaneous anergy and reduced T cell reactivity.'' Defects in neutrophil chemotaxis and phagocytosis have also been described.'' The mainstay of treatment for P.G. to date has been with immunosuppressive agents such as systemic corticosteroids. However, many patients respond poorly and side effects have been reported in up to 50% of patients.'^ Various steroid sparing agents such as azathioprine''' and 6-mcrcaptopurine"' have also been tried with some success. Sulphonamide drugs,'' clofazimine"* and minocycline'* have been suggested as therapeutic options in view of their effects on neutrophil function. CSA influences both humoral and cellular immunity,''' with its primary mechanism of action on the suppression of interlcukin-2 synthesis which is critical for T helper cell activation and cytotoxic T cell expansion.^" Not only sparing but amphfication of T lymphocyte suppression has been reported during CSA therapy-' while production of antibodies to T-cell dependent antigens is also inhibited.''^ The efficacy of CSA is therefore in keeping with the postulated pathogenesis of P.G. and the known actions of this drug. Renal dysfunction and hypertension are the two most significant side effects of treatment. In short-term, lowdose therapy these are reversible when CSA is discontinued."' With regard to long-term therapy, the occurrence of clinically silent renal dysfunction remains a concern. Patients with R.A. seem to be more susceptible to nephrotoxicity,-' and 'new onset' hypertension has heen reported to occur in 25% of patients with auto-immune disease.^"* These two cases demonstrate that there is a role for CSA in recalcitrant P.G. Potential toxicity may be minimi/.ed by regular monitoring. Both patients currently remain in remission on low dose CSA (1-2 5 mg/ kg/day). The need for long-term CSA to maintain remission in these patients remains speculative. Recent successful use of intralesional C.SA in psoriasis-' raises the possihility of benefit from local application in diseases such as P.G., whilst reducing recognized side effects.'-
51
References 1. W'cil C. Cyclosporin A: Review of results in organ and bone transplantation in man. Medicinal Research Reviews 1984; 4: 2216. 2. Ciupta AK, Brown MD, KIlis CN, Rocher IJ., I'isher GJ. Haadsfraartl (), (hooper KD, Voorhees JJ. (Jvelosporinc in Dermatology. Journal of the American .-Icadeiny of Dermalology Vm\ 21: 1245-55. i. C.uricy RK, Macfarlane .'\W, \ ickcrs CFH. Pyoderma gangrenosum treated with Cyclosporin A. British Jiniriud of Dermatology 4. Shelly KD, Shelly WB. (lyclnsporine Therapy for pyoderma gangrenosum associated with scierosing cholangitis and ulcerative coWth. Journal of the American Academy of Dermatology IMSS; 18: 1084 i. 5. Penmetcha M, Navaratrani AK. Pyoderma gangrenosum: Response to Cyclosporin A. Internulional Journal of Dermatology
i
6. Magid VIL, Gold MH. Treatment of recalcitrant pyoderma gangrenosum with ilyc\o
