Clinical and Experimental Dermatology 1992; 17: 437 440.
Pyoderma gangrenosum—response to topical nitrogen mustard E.TSELE, R.C.H.YU AND A.C.CHU Unit of Dermatology, Hammersmith Hospital, Royal Postgraduate Medical School Accepted for publication 20 December 1991 Summary We report a 69-year-old Caucasian male patient with long-standing pyoderma gangrenosum; the lesions preceded the appearance of an IgA monoclonai gammopathy by' 2 years. A number of systemie treatments, inciuding high dose steroids and immunosuppressive agents, were poorly tolerated and resulted in serious side-effects. The skin and haematologicai conditions, however, were kept under control for 2 years with regular piasmapheresis. Pyoderma gangrenosum recurred as vaseuiar access became exhausted but new iesions heaied compieteiy with topical appiication of 20% nitrogen mustard.
Pyoderma gangrenosum is an uicerative skin condition of unknown aetioiogy with characteristic ciinicai features and non-specific histopathoiogy. It may or may not be associated with an underiying benign or maiignant disease. Pyoderma gangrenosum most commonly appears in patients with inflammatory bowei disease (IBD) or arthritis. The arthritis can be sero-negative with or without IBD, or rheumatoid arthritis-like. The atypical or buiious form of pyoderma gangrenosum is usuaiiy seen in patients with ieukaemie or pre-ieukaemic conditions. Pyoderma gangrenosum has been repeatediy reported in association with monoeionai gammopathy. In the vast majority of eases the paraprotein is of IgA type. In isolated reports, IgG' or IgM^ have been found. We deseribe a male patient who developed monoclonal IgA gammopathy 2 years after the appearance of pyoderma gangrenosum. The patient initially presented enormous therapeutic problems but eventually responded to a novel use of topical nitrogen mustard. Case report A 61-year-old Caucasian male presented in February 1983 with red, painful, ulcerating nodules in his buttocks, calves and thighs. On examination there were several large indurated, ulcerative nodules in his calves. The surrounding tissue Correspondence: Dr F.Tsele, Unit of Dermatology, Hammersmith Hospital, Du Cane Road, T^ondon W12 ONN, UK,
was oedematous and gave a dusky purple erythematous hue. Investigations were normal or negative at this stage and included: full blood count, ESR, urea and electrolytes, liver enzymes, ANA, rheumatoid factor, plasma electrophoresis and urinary Bence-Jones protein. Skeletal survey was normal. A barium meal, sigmoidoscopy and barium enema excluded bowel disease. A skin biopsy from the edge of the ulcer showed a dermal abscess which extended right down to the subcutaneous fat. There was intense cellular inflltrate, predominantly neutrophilic with admixture of some lymphocytes. Direct immunofiuorescence was negative to IgM, IgA, and IgG but there was C,i deposition around the vesseis. The histologicai appearance was compatibie with a ciinicai diagnosis of pyoderma gangrenosum. In his past medicai history, the patient made a complete recovery from acute renai faiiure and haemoiytic anaemia foiiowing mycopiasma pneumonia in i976. He gave no history of inflammatory bowel disease or arthritis. His pyoderma gangrenosum was largely controlled by the use of topical steroids and intermittent courses of systemic steroids until October 1985, when there was a sudden deterioration in this condition. The exacerbation was associated with the identification of a monoclonal IgA paraproteinaemia, kappa-chain type. He started treatment with oral prednisolone 60 mg/day with some response. However, after 12 months he developed osteoporotic bone pain, hypertension and cushingoid features. Over the subsequent year a number of therapeutic agents were attempted hut were stopped for various reasons (Table 1). In 1987 he was commenced on weekly plasmapheresis to which he responded favourably with a faii in his paraprotein ievei and compiete heaiing of his pyoderma gangrenosum. Eor 2 years his paraproteinaemia and pyoderma gangrenosum were both well eontroiied with piasmapheresis oniy. He received no other systemic agent. Vaseuiar access beeame diflicult from i989 and piasmapheresis couid oniy be done on a monthiy basis. He began developing pyoderma lesions around the venepuncture sites and this elinieal deterioration coineided 437
438
E.TSELE, R.C.H.YU AND A.C.CHU Table 1. Therapeutic agents used in our patient Treatment modality
Outcome
Topical steroids
Initially the patient responded but he failed to do so later Good response but later cusbingoid features osteoporotic bone pain and hypertension developed No response No response Abnormal liver function tests Haemolytic anaemia Skin pigmentation T^ack of respon.se Neutropenia Neutropenia Neutropenia Effective EfFective
Systemic steroids Erythromycin Rifampicin Clofazimine Dapsone Minocycline Aspirin 4- dipyridamole Azathioprine Cblorambucil Melphalan Plasmapheresis Topical nitrogen mustard
with fluctuation of IgA paraprotein ieveis. In June 1990, all venous access failed and a persistent ulcer in his right ankle extented posteriory. It was at this point that topicai nitrogen mustard in aqueous soiution (20%) was appiied daiiy. The patient was provided with the iyophiiiized powder and instructed to diiute it in tap water and apply it to the uicer himseif using gauze swabs and wearing poiythene gioves. The uicer heaied compieteiy after 3months continuous daiiy treatment and remains healed ever since (Eig. 1 a and b). The treatment was well tolerated and no sensitization was observed. Discussion Pyoderma gangrenosum is usually associated with inflammatory, autoimmune or neopiastic diseases. Although in 40-50% of cases there is no underlying cause identified,' any patient with pyoderma gangrenosum must be thoroughly investigated. When an associated disease is found, the treatment is primarily directed to this and its control usuafly results in the clearing of the skin lesions. In some cases, pyoderma gangrenosum can foilow a protracted course and become resistant to therapy. Numerous therapeutie modalities have been used so far (Tables 1 and 2), the mainstay being oral steroids. The diversity in the mode of action of these agents simpiy reflects our inabiiity to understand the basic pathogenetic mechanism. Our patient initiaiiy responded very well to topieai steroids with occlusive bandages. Periodic exacerbations remitted with short courses of orai steroids. The detection of the monoeionai gammopathy foiiowed a severe deterioration of his pyoderma. The skin eondition
seemed to heraid the paraproteinaemia by 2 years. In 1983, Powell et al.^ reported eight patients with pyoderma gangrenosum and monoeionai gammopathy. In seven of these patients, the skin iesions preceded, as in our patient, the onset of the paraproteinaemia. Seven patients had IgA and one had IgM paraprotein. One patient deveioped muitipie myeioma and died 6 months later. A number of topical and systemic treatments used in our patient proved either of no benefit or harmful (Table 1). Among them two alkyiating agents, meiphaian and chiorambucil, were stopped because of neutropenia. Moiier et al.^^ has given meiphaian to a patient with pyoderma gangrenosum and IgA monoclonal paraproteinaemia with very good results. Another alkyiating agent, cyciophosphamide, has been used successfuiiy in the treatment of two patients with pyoderma gangrenosum.'"'''' One of them'^ aiso had an inconsistent poiycional eievation of IgA. Prior to the immunosuppressive treatment, piasmapheresis was tried but faiied to control the pyoderma. In our patient, piasmapheresis kept both the skin and IgA ieveis in the latest episode under controi. When the pyoderma recurred, we considered the use of cyciosporin A, which has been used in the treatment of pyoderma gangrenosum with exceiient resuits since 1985.'^ Our patient refused eyelosporin A, however, because of the severe adverse effects he had experienced with other systemic drugs. This is the first report of pyoderma gangrenosum treated with topieai nitrogen mustard. Nitrogen mustard is used in the treatment of eutaneous T-ceii iymphoma where it has proved to be most effective in the eariy stages of the disease. It was aiso used in the treatment of singie system eutaneous Langerhans eell histiocytosis(LCH) by
NITROGEN MUSTARD FOR PYODERMA GANGRENOSUM
439
Table 2. Other therapeutic modalities used for pyoderma gangrenosum BcnzoyI peroxide"" Hyperbaric oxygen'' Sodium cromoglycate' Intralesional steroids** Sulphasalazine' Sulphapyridine'" Pulse treatment witb methyl prednisolone" Cyclosporin A'^ Vancomycin, mezlocillin''
paraproteinaemia by 2 years. The management of this patient has been very difiicuit and a number of systemic treatments have either been unsuccessfui or have resuited in serious side-effects. Piasmapheresis on a weekiy basis kept both pyoderma gangrenosum and IgA gammopathy under control for 2 years, but difficulty with vaseuiar access reduced the frequency of the treatments and the pyoderma gangrenosum reeurred. Finaiiy, topieai nitrogen mustard resuited in compiete heaiing of the skin iesions.
References
Figure 1. Pyoderma gangrenosum in the right ankle before (a) and after (b) treatment with topical nitrogen mustard.
Wong et al.^' and, more recently, in the management of skin manifestations of multisystem LCH.'^ The meehanism of action of topieai nitrogen mustard is not weii understood. It is assumed that the drug acts iocaiiy as a cytotoxic agent. The use of the drug is often limited by the development of aiiergic contact dermatitis. In summary, we reported a maie patient in whom pyoderma gangrenosum preceded an IgA monoeionai
1. Imhof JW, Scbutter GJN, Hart HC, Zegers BJ. Monoclonal gammopathy (IgG) and ebronic ulcerative dermatitis (phagedenic pyoderma). Acta Medica Scandinavica 1969; 186: 289-292, 2. Cream JJ. Pyoderma Gangrenosum with a monoclonal TgM red cell agglomerating factor. SmHA>wr«a/o/Derma;o/or'y 1971; 84: 223-226, 3. Hickman JG, Lazarus GS. Pyoderma gangrenosum: A reappraisal of associated systemic diseases, British Journal of Dermatology 1980; 102: 235-237, 4. Powell FC, Schroeter AL, Su WPD, Perry HO. Pyoderma gangrenosum and monoclonal gammopathy. Archives of Dermatology 1983; H9: 468-472, 5. Nguyen LQ, Weiner J, Treatment of Pyoderma gangrenosum with benzoyl peroxide. Cutis 1977; 19: 842-844. 6. Thomas CY, Crouch J A, Guastello J, I Iyperbaric oxygen therapy for Pyoderma gangrenosum. Archives of Dermatology 1974- 110' 445-446. 7. De Cock KM, Thorne MG, The treatment of Pyoderma gangrenosum with sodium cromoglyeate. British Journal of Dermatology 1980; 102: 231-233, 8. Moscbella SL. Pyoderma gangrenosum: a patient successfully treated with intralesional injections of steroid. Archives of Dermatotogy 1967; 95: 121-123. 9. Perry HO, Brunsting LA. Pyoderma gangrenosum: a clinical study of 19 cases. Archives of Dermatology 1957; 75: 380-386, 10. Lorincz AT., Pearson RW. Sulfapyridine and sulphone-type drugs in dermatology. Archives of Dermatology 1962; 85: 42-56, 11. Johnson RB, T.azarus GS, Pulse therapy (therapeutic efficacy in the treatment of pyoderma gangrenosum). Archives of Dermatology 1982; 118:76-84. 12. Curley RK, MacFarlane AW, Vickers CFH, Pyoderma gangrenosum, British Journal of Dermatology 1985; 113: 601-604. 13. Kang S, Dover JS, Successful treatment of eruptive pyoderma
440
E.TSELE, R.C.H.YU AND A.C.CHU
with response to cyclophosphamide therapy. Journal of Pediatrics gangrenosum with intravenous vancomycin and mezlocillin. 1967; 71: 255-258. British Journal of Dermatology 1990; 123: 389-393, 14, Moiier H, Waldenstrom JG, Zetterval O. Pyoderma gangreno- 17. Wong E, Holden CA, Broadbent V, Atherton DJ. Histiocytosisd x presenting as intertrigo and responding to topical nitrogen sum and monoclonal (TgA) globulins healed after melphalan mustard, Clinieal and Experimental Dermatology 1986; 11: 183treatment: case report and review of the literature. Ada Medica 187. Scandinavica 1978; 203: 293-296. 15, Newell LM, Malkinson FD. Pyoderma gangrenosum: response to 18, Sheehan MP, Atherton DJ, Broadbent V, Pritchard J. Topical mecbloretbamine: an effective treatment for skin involvement in Cyclophosphamide therapy. Archives of Dermatology 1983; 119: Langerhans Cell Histiocytosis, British Journat of Dermatology 495-497, 1990; 123: 47-48 (abstract). 16, Crawford SE, Sherman R, F'avara B. Pyoderma gangrenosum
Pyoderma gangrenosum—response to topical nitrogen mustard E.TSELE, R.C.H.YU AND A.C.CHU Unit of Dermatology, Hammersmith Hospital, Royal Postgraduate Medical School Accepted for publication 20 December 1991 Summary We report a 69-year-old Caucasian male patient with long-standing pyoderma gangrenosum; the lesions preceded the appearance of an IgA monoclonai gammopathy by' 2 years. A number of systemie treatments, inciuding high dose steroids and immunosuppressive agents, were poorly tolerated and resulted in serious side-effects. The skin and haematologicai conditions, however, were kept under control for 2 years with regular piasmapheresis. Pyoderma gangrenosum recurred as vaseuiar access became exhausted but new iesions heaied compieteiy with topical appiication of 20% nitrogen mustard.
Pyoderma gangrenosum is an uicerative skin condition of unknown aetioiogy with characteristic ciinicai features and non-specific histopathoiogy. It may or may not be associated with an underiying benign or maiignant disease. Pyoderma gangrenosum most commonly appears in patients with inflammatory bowei disease (IBD) or arthritis. The arthritis can be sero-negative with or without IBD, or rheumatoid arthritis-like. The atypical or buiious form of pyoderma gangrenosum is usuaiiy seen in patients with ieukaemie or pre-ieukaemic conditions. Pyoderma gangrenosum has been repeatediy reported in association with monoeionai gammopathy. In the vast majority of eases the paraprotein is of IgA type. In isolated reports, IgG' or IgM^ have been found. We deseribe a male patient who developed monoclonal IgA gammopathy 2 years after the appearance of pyoderma gangrenosum. The patient initially presented enormous therapeutic problems but eventually responded to a novel use of topical nitrogen mustard. Case report A 61-year-old Caucasian male presented in February 1983 with red, painful, ulcerating nodules in his buttocks, calves and thighs. On examination there were several large indurated, ulcerative nodules in his calves. The surrounding tissue Correspondence: Dr F.Tsele, Unit of Dermatology, Hammersmith Hospital, Du Cane Road, T^ondon W12 ONN, UK,
was oedematous and gave a dusky purple erythematous hue. Investigations were normal or negative at this stage and included: full blood count, ESR, urea and electrolytes, liver enzymes, ANA, rheumatoid factor, plasma electrophoresis and urinary Bence-Jones protein. Skeletal survey was normal. A barium meal, sigmoidoscopy and barium enema excluded bowel disease. A skin biopsy from the edge of the ulcer showed a dermal abscess which extended right down to the subcutaneous fat. There was intense cellular inflltrate, predominantly neutrophilic with admixture of some lymphocytes. Direct immunofiuorescence was negative to IgM, IgA, and IgG but there was C,i deposition around the vesseis. The histologicai appearance was compatibie with a ciinicai diagnosis of pyoderma gangrenosum. In his past medicai history, the patient made a complete recovery from acute renai faiiure and haemoiytic anaemia foiiowing mycopiasma pneumonia in i976. He gave no history of inflammatory bowel disease or arthritis. His pyoderma gangrenosum was largely controlled by the use of topical steroids and intermittent courses of systemic steroids until October 1985, when there was a sudden deterioration in this condition. The exacerbation was associated with the identification of a monoclonal IgA paraproteinaemia, kappa-chain type. He started treatment with oral prednisolone 60 mg/day with some response. However, after 12 months he developed osteoporotic bone pain, hypertension and cushingoid features. Over the subsequent year a number of therapeutic agents were attempted hut were stopped for various reasons (Table 1). In 1987 he was commenced on weekly plasmapheresis to which he responded favourably with a faii in his paraprotein ievei and compiete heaiing of his pyoderma gangrenosum. Eor 2 years his paraproteinaemia and pyoderma gangrenosum were both well eontroiied with piasmapheresis oniy. He received no other systemic agent. Vaseuiar access beeame diflicult from i989 and piasmapheresis couid oniy be done on a monthiy basis. He began developing pyoderma lesions around the venepuncture sites and this elinieal deterioration coineided 437
438
E.TSELE, R.C.H.YU AND A.C.CHU Table 1. Therapeutic agents used in our patient Treatment modality
Outcome
Topical steroids
Initially the patient responded but he failed to do so later Good response but later cusbingoid features osteoporotic bone pain and hypertension developed No response No response Abnormal liver function tests Haemolytic anaemia Skin pigmentation T^ack of respon.se Neutropenia Neutropenia Neutropenia Effective EfFective
Systemic steroids Erythromycin Rifampicin Clofazimine Dapsone Minocycline Aspirin 4- dipyridamole Azathioprine Cblorambucil Melphalan Plasmapheresis Topical nitrogen mustard
with fluctuation of IgA paraprotein ieveis. In June 1990, all venous access failed and a persistent ulcer in his right ankle extented posteriory. It was at this point that topicai nitrogen mustard in aqueous soiution (20%) was appiied daiiy. The patient was provided with the iyophiiiized powder and instructed to diiute it in tap water and apply it to the uicer himseif using gauze swabs and wearing poiythene gioves. The uicer heaied compieteiy after 3months continuous daiiy treatment and remains healed ever since (Eig. 1 a and b). The treatment was well tolerated and no sensitization was observed. Discussion Pyoderma gangrenosum is usually associated with inflammatory, autoimmune or neopiastic diseases. Although in 40-50% of cases there is no underlying cause identified,' any patient with pyoderma gangrenosum must be thoroughly investigated. When an associated disease is found, the treatment is primarily directed to this and its control usuafly results in the clearing of the skin lesions. In some cases, pyoderma gangrenosum can foilow a protracted course and become resistant to therapy. Numerous therapeutie modalities have been used so far (Tables 1 and 2), the mainstay being oral steroids. The diversity in the mode of action of these agents simpiy reflects our inabiiity to understand the basic pathogenetic mechanism. Our patient initiaiiy responded very well to topieai steroids with occlusive bandages. Periodic exacerbations remitted with short courses of orai steroids. The detection of the monoeionai gammopathy foiiowed a severe deterioration of his pyoderma. The skin eondition
seemed to heraid the paraproteinaemia by 2 years. In 1983, Powell et al.^ reported eight patients with pyoderma gangrenosum and monoeionai gammopathy. In seven of these patients, the skin iesions preceded, as in our patient, the onset of the paraproteinaemia. Seven patients had IgA and one had IgM paraprotein. One patient deveioped muitipie myeioma and died 6 months later. A number of topical and systemic treatments used in our patient proved either of no benefit or harmful (Table 1). Among them two alkyiating agents, meiphaian and chiorambucil, were stopped because of neutropenia. Moiier et al.^^ has given meiphaian to a patient with pyoderma gangrenosum and IgA monoclonal paraproteinaemia with very good results. Another alkyiating agent, cyciophosphamide, has been used successfuiiy in the treatment of two patients with pyoderma gangrenosum.'"'''' One of them'^ aiso had an inconsistent poiycional eievation of IgA. Prior to the immunosuppressive treatment, piasmapheresis was tried but faiied to control the pyoderma. In our patient, piasmapheresis kept both the skin and IgA ieveis in the latest episode under controi. When the pyoderma recurred, we considered the use of cyciosporin A, which has been used in the treatment of pyoderma gangrenosum with exceiient resuits since 1985.'^ Our patient refused eyelosporin A, however, because of the severe adverse effects he had experienced with other systemic drugs. This is the first report of pyoderma gangrenosum treated with topieai nitrogen mustard. Nitrogen mustard is used in the treatment of eutaneous T-ceii iymphoma where it has proved to be most effective in the eariy stages of the disease. It was aiso used in the treatment of singie system eutaneous Langerhans eell histiocytosis(LCH) by
NITROGEN MUSTARD FOR PYODERMA GANGRENOSUM
439
Table 2. Other therapeutic modalities used for pyoderma gangrenosum BcnzoyI peroxide"" Hyperbaric oxygen'' Sodium cromoglycate' Intralesional steroids** Sulphasalazine' Sulphapyridine'" Pulse treatment witb methyl prednisolone" Cyclosporin A'^ Vancomycin, mezlocillin''
paraproteinaemia by 2 years. The management of this patient has been very difiicuit and a number of systemic treatments have either been unsuccessfui or have resuited in serious side-effects. Piasmapheresis on a weekiy basis kept both pyoderma gangrenosum and IgA gammopathy under control for 2 years, but difficulty with vaseuiar access reduced the frequency of the treatments and the pyoderma gangrenosum reeurred. Finaiiy, topieai nitrogen mustard resuited in compiete heaiing of the skin iesions.
References
Figure 1. Pyoderma gangrenosum in the right ankle before (a) and after (b) treatment with topical nitrogen mustard.
Wong et al.^' and, more recently, in the management of skin manifestations of multisystem LCH.'^ The meehanism of action of topieai nitrogen mustard is not weii understood. It is assumed that the drug acts iocaiiy as a cytotoxic agent. The use of the drug is often limited by the development of aiiergic contact dermatitis. In summary, we reported a maie patient in whom pyoderma gangrenosum preceded an IgA monoeionai
1. Imhof JW, Scbutter GJN, Hart HC, Zegers BJ. Monoclonal gammopathy (IgG) and ebronic ulcerative dermatitis (phagedenic pyoderma). Acta Medica Scandinavica 1969; 186: 289-292, 2. Cream JJ. Pyoderma Gangrenosum with a monoclonal TgM red cell agglomerating factor. SmHA>wr«a/o/Derma;o/or'y 1971; 84: 223-226, 3. Hickman JG, Lazarus GS. Pyoderma gangrenosum: A reappraisal of associated systemic diseases, British Journal of Dermatology 1980; 102: 235-237, 4. Powell FC, Schroeter AL, Su WPD, Perry HO. Pyoderma gangrenosum and monoclonal gammopathy. Archives of Dermatology 1983; H9: 468-472, 5. Nguyen LQ, Weiner J, Treatment of Pyoderma gangrenosum with benzoyl peroxide. Cutis 1977; 19: 842-844. 6. Thomas CY, Crouch J A, Guastello J, I Iyperbaric oxygen therapy for Pyoderma gangrenosum. Archives of Dermatology 1974- 110' 445-446. 7. De Cock KM, Thorne MG, The treatment of Pyoderma gangrenosum with sodium cromoglyeate. British Journal of Dermatology 1980; 102: 231-233, 8. Moscbella SL. Pyoderma gangrenosum: a patient successfully treated with intralesional injections of steroid. Archives of Dermatotogy 1967; 95: 121-123. 9. Perry HO, Brunsting LA. Pyoderma gangrenosum: a clinical study of 19 cases. Archives of Dermatology 1957; 75: 380-386, 10. Lorincz AT., Pearson RW. Sulfapyridine and sulphone-type drugs in dermatology. Archives of Dermatology 1962; 85: 42-56, 11. Johnson RB, T.azarus GS, Pulse therapy (therapeutic efficacy in the treatment of pyoderma gangrenosum). Archives of Dermatology 1982; 118:76-84. 12. Curley RK, MacFarlane AW, Vickers CFH, Pyoderma gangrenosum, British Journal of Dermatology 1985; 113: 601-604. 13. Kang S, Dover JS, Successful treatment of eruptive pyoderma
440
E.TSELE, R.C.H.YU AND A.C.CHU
with response to cyclophosphamide therapy. Journal of Pediatrics gangrenosum with intravenous vancomycin and mezlocillin. 1967; 71: 255-258. British Journal of Dermatology 1990; 123: 389-393, 14, Moiier H, Waldenstrom JG, Zetterval O. Pyoderma gangreno- 17. Wong E, Holden CA, Broadbent V, Atherton DJ. Histiocytosisd x presenting as intertrigo and responding to topical nitrogen sum and monoclonal (TgA) globulins healed after melphalan mustard, Clinieal and Experimental Dermatology 1986; 11: 183treatment: case report and review of the literature. Ada Medica 187. Scandinavica 1978; 203: 293-296. 15, Newell LM, Malkinson FD. Pyoderma gangrenosum: response to 18, Sheehan MP, Atherton DJ, Broadbent V, Pritchard J. Topical mecbloretbamine: an effective treatment for skin involvement in Cyclophosphamide therapy. Archives of Dermatology 1983; 119: Langerhans Cell Histiocytosis, British Journat of Dermatology 495-497, 1990; 123: 47-48 (abstract). 16, Crawford SE, Sherman R, F'avara B. Pyoderma gangrenosum
