pyoderma gangrenosum: a review

Clinica l r e v i e w

Pyoderma gangrenosum: A review Sonya Martin Schwaegerle, M.D.,* Wilma F. Bergfeld, M.D.,** David Senitzer, Ph.D.,*** and Robert T. Tidrick, M.D. Cleveland, OH, and Bronx, NY

Pyoderma gangrenosum is a poorly understood disease characterized by exacerbations and remissions of morphologically unique skin ulcers. It frequently is thought to be the cutaneous manifestation of an underlying systemic disease. In this review of pyoderma gangrenosum, the characteristics of the disease are described and a differential diagnosis is formulated. Associations with systemic diseases are made through a review of the literature. The pathophysiology of pyoderma gangrenosum and probable causes are considered, and special consideration is given to the immunologic mechanisms that may be operative in the disease. Finally the currently available therapeutic alternatives are reviewed. (J AM Acid DERMATOL 1988;18:559-68.)

Pyoderrna gangrenosum is an uncommon, ul- cerating skin disease of unknown cause that is frequently the cutaneous manifestation of a systemic disease. Currently the diagnosis of pyoderma gangrenosum must be made on the basis of the clinical evaluation of the patient, focusing spe- cifically on the appearance of the cutaneous lesions. Arriving at such a diagnosis on the basis of clinical observation and history is at best imprecise and exclusion of various other disease processes figures prominently in making the diagnosis. Un- fortunately the lesions of pyoderma gangrenosum do not exhibit a specific histopathology. Other laboratory findings also have been variable and inconsistent. Thus the clinical picture presented by the patient remains the cornerstone for the diagnosis of this disease.

Clinical findings. The characteristic lesions of pyoderma gangrenosum begin as small erythematous papules that spread concentrically. The early

From the Departments of Pathology* and Dermatology,** The Cleve- land Clinic, and Transplantation Immunology,*** Montefiore Medical Center.

Reprint requests to: Dr. Sonya Martin Schwaegerle, Department of Pathology, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44106-4775.

lesions are similar to those of erythema nodosum, erythema multiforme, some bacterial infections (for example, folliculitis), and the cutaneous manifestations of malabsorption and malnutrition. 1 These lesions undergo prompt evolution into ten- der pustules surrounded by indurated erythematous skin. Their rapid development continues as the central portion of the lesions undergoes necrosis and ulceration. The appearance of the ulcerated lesions, with their pus-covered centers and ragged, undermined violaceous edges, is one of the hall- marks of the disease (Fig. 1). 2.6 The large, fully developed ulcers of pyoderma gangrenosum must be differentiated from the so-called factitious ul- cerations and from deep mycoses.

Although the lesions most often are found on the lower extremities, especially on the anterior tibial surface, they are commonly found elsewhere on the body. 7 Lesions may be single or multiple, developing simultaneously or in sequence. They frequently become quite large and adjacent lesions may coalesce to form huge areas of confluent ulceration. Some minor local trauma or irritation is thought to incite some of these early lesions, 4,6 which often develop over bony prominences.

Exquisite painfulness of the ulcers is a striking characteristic of the disease, as is the atrophic,

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Fig. 1. Characteristic ulcer of pyoderma gangrenosum consists of central necrosis and ulceration with ragged undermined, violaceous edges.

Fig. 2. "Parchment" (cigarette paper scarring typically seen with healing of ulcers of pyoderrna gangrenosum).

"parchment" scarring that is the end result of healing (Fig. 2). 2 Frequently there is hyperpigmen- tation at the periphery of the healed ulcers and focal depigmentation within the scar itself?

Although most patients with pyoderma gangrenosum have some associated systemic disease, published reports indicate that up to 50% of patients with pyoderma gangrenosum have underlying ulcerative colitis, providing the strongest association between pyoderma gangrenosum and a systemic disease process. 2,4's~L Other frequent cutaneous lesions of ulcerative colitis, seen in ap-

proximately 34% of all patients, ~ include urticaria, erythema nodosum, and erythema multiforme.tZ

It is estimated that at least 22% of all patients suffering from Crohn's disease exhibit skin lesions in the form of granulomatous fistulas, abscesses, or ulcers, j3~4 Although in reviewing a series of 138 patients, McCallum and Kinmont t5 found 43% of the patients to suffer from skin complications of Crohn's disease, less than 3% were reported to exhibit the vasculitis-type lesions of erythema nodosum or pyoderma gangrenosum. 9'~6~ These lesions may be divided into those resulting from

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Fig. 3. Parafollicular infiltration of inflammatory cells is seen in pyoderma gangrenosum. (Hematoxylin-eosin stain; x 10.)

direct extension of disease, vascular reactions, and malabsorption syndromes. In both ulcerative colitis and Crohn's disease, the appearance of pyoderma gangrenosum is nearly always preceded by the inflammatory bowel disease. Exacerbations of the skin lesions tend to parallel recurrences of the intestinal inflammation.~6 Only very rarely has an acute flare of cutaneous lesions been observed in a patient whose inflammatory bowel disease was quiescent. 3 Although the incidence of inflammatory bowel disease (both ulcerative colitis and Crohn's disease) is distributed approximately evenly between the sexes, ~s it is interesting to note that male patients reportedly suffer from associated cutaneous manifestations twice as frequently as do female patients--a finding that is currently unexplained2

The third most common disease associated with pyoderma gangrenosum is rheumatoid arthritis with or without concomitant inflammatory bowel disease. 5,t~,~9-24 This association is particularly difficult to sort out since inflammatory bowel disease and pyoderma gangrenosum each have their own arthritic components. The problem is complicated further by the difficulty of distinguishing between true arthritis and arthralgias. Although a few patients exhibit rheumatoid arthritis z'5'z" or ankylos- ing spondylitis, in many patients the arthritis shows negative findings on serologic examina- tion. 25 This type of arthritis is mainly monoartic- ular, involves large joints, and does not result in

permanent joint damage or deformity. A number of such cases have undergone spontaneous regres- sion after colectomy. ~

Chronic active hepatitis, "-627 some gastroin- testinal diseases, malignant/proliferative diseases, monoclonal gammopathy and myeloma,~.2~-29 blood dyscrasias, 3~ and sarcoidosis ~z also have been linked to pyoderma gangrenosum? "3~

In 20% to 30% of patients with pyoderma gangrenosum, no associated disease process can be identified at the time the cutaneous lesions first appear. 17,23.34 In many of these cases, the underlying cause of the skin lesions becomes evident after a variable period of time.

Histology, The microscopic study of lesions of pyoderma gangrenosum has yielded variable and nonspecific findings. The pathology includes necrosis and ulceration of the epidermis and dermis, particularly in parafollicular zones (Fig. 3), a heavy infiltration of acute inflammatory cells at the margins of the lesions, and a significant infiltration of chronic inflammatory cells at the base (Fig. 4).s's9'll't4'z2'25'35 The precise histopathology of the lesions is variable in different areas, with predominant lymphocytic infiltration, endothelial swelling, and fibrinoid necrosis of blood vessels in the peripheral (erythematous) zone, and a denser, mixed lymphocytic/neutrophilic infiltrate and early abscess formation centrally. 36 Perivas- cular cuffing of lymphocytes and plasma cells is a consistent finding. A major controversy exists



Dermatology

Fig, 4. Heavy infiltrations of inflammatory cells are seen at margins and bases of lesions. (Hematoxylin-eosin stain; • 10.)

with respect to vascular involvement. Some investigators emphatically deny that there is any de- gree of involvement of vasculaturer'22; others have reported finding an intensely hemorrhagic, nec- rotizing vasculitis. 89"14'36"3"I Indeed Samitz believes that the histologic finding of "dilated and engorged blood vessels w i t h . . , edematous, fibrillated and fragmented wails" is central to a diagnosis of pyoderma gangrenosum? -9 Epidermal acanthosis is seen in the area immediately adjacent to the ulcer.

Etiology and pathophysiology. The cause of pyoderma gangrenosum has remained an enigma since Brunsting et al 2 first described the clinical entity in 1930. Various proposals to explain the mechanisms underlying the disease have been put forth since that time; however, there has been a relative paucity of evidence to give substance to any of the theories.

During the past 50 years both streptococcal and staphylococcal organisms have been cultured from the ulcers of many patients with pyoderma gangrenosum. This has led numerous investigators to postulate a primary bacterial component as the causative agent in pyoderma gangrenosum. De- lescluse et a133 expanded on this and proposed that pyoderma gangrenosum might result from the specific sensitization of a patient to the streptococcal organisms, resulting in a poststreptococcal syndrome similar to that seen in poststreptococcal glo- merulonephritis. They also suggested that pyoderma gangrenosum might represent a "Koebner phenomenon," that is, a local inflammatory re-

sponse resulting from a streptococcal infection. Since cultures of early lesions have consistently failed to reveal any organisms, ~ it is now widely held that organisms cultured from wound exudates and biopsy specimens represent a secondary in- vasion by bacteria rather than a primary pathogen.

McKay 38 has suggested that intravascular coagulation with deposition of platelets and clotting proteins in small blood vessels may contribute to the development of pyoderma gangrenosum.

Recently the focus of attention has turned to a possible immunologic basis for pyoderma gangrenosum, but investigators have been frustrated in their attempts to define precisely an immunologic mechanism because no consistent abnormalities in either laboratory values or histologic studies have been found. Assays to evaluate the immunologic status of patients with pyoderma gangrenosum have included the erythrocyte sedimentation rate (Westergren method), which is elevated in some patients s'35'39 but normal in others. 3s Significant titers of antibodies by latex fixation are identified in a few patients, 5 as are titers of antinuclear antibody (ANA), antideoxyribonucleic acid (anti- DNA), and antiextractable nuclear antigen (anti- ENA). 5'2~'35 Significant titers of rheumatoid factor (RF) are found in some persons s,3s but are absent in others. 22,35 Quantitative immunoglobulins also are inconsistent since they are decreased, ~ normal, 2z or diffusely increased 2a,35 in different patients. ~,28

Monoclonal gammopathies have been found in

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Pyoderma gangrenosum 563

a number of patients] s,40 most of whom are older. 29 These gammopathies are monoclonal, with IgG, IgA, o r I g M , 29,41 o r biclonal, z9 Monoclonal gammopathy in patients with pyoderma gangrenosum may be related to altered immune competence 29 and has been associated with a number of immune dysfunctions, including in vitro inhibition of neutrophil function, 42 decreased neutrophil chemotaxis, delayed migration and abnormal bactericidal ability, 25 and deficient monocyte phagocytosis.

An alternative theory is that immune activity in patients with pyoderrna gangrenosum and a monoclonal gammopathy might be compromised by paraproteins, which block surface receptors of neutrophils or monocytes. '13 Clinically there is overlap between paraproteinemias and multiple myeloma, with progression from the benign to the malignant state in a significant number of patients. ~

Samitz 89 found the clinical and histologic findings in pyoderma gangrenosum compatible with those of the Arthus and Shwartzman reactions and suggested that the immunologic mechanisms underlying pyoderma gangrenosum might be ex- plained on the basis of these reactions. Simply stated, the Arthus reaction involves formation of immune complexes in tissues with subsequent ac- tivation of the complement cascade. This in turn results in the release of proteolytic lysosomal en- zymes, which are directly responsible for damage to tissues and blood vessels. The techniques of direct and indirect immunofluorescence are used currently for identifying the presence of antigen- antibody complexes in tissues. Analysis by immunofluorescence of specimens from patients with pyoderma gangrenosum has yielded variable results, with some investigators obtaining no staining 33'44 and others obtaining positive vascular and perivascular fluorescence. 4546 Powell et a111'19,36 found perivascular deposition of immune reactants in 61% of patients examined, in- volving both superficial and deep vessels in the peripheral zone, corresponding with the area undergoing active destruction. Specimens from the central necrotic and ulcerated areas showed negative findings. These findings would suggest that the specific site from which the biopsy specimen is taken may be critical in identifying immune complexes in tissues. Technical inaccuracies or

evanescence of the immune complexes also might help to explain the failure of the technique to dem- onstrate such complexes in many c a s e s . 89

The Shwartzman reaction involves tissue damage by direct toxicity of gram-negative bacterial endotoxins.5'47 Since this reaction represents a nonspecific destruction of tissue by toxins, the basis for proposing it as a pathophysiologic mechanism in pyoderma gangrenosum is purely morphologic similarities of resultant lesions. With the frequent superimposition of bacterial infection of the un- defined pathologic process taking place, it is con- ceivable that the Shwartzman reaction does occur, but secondarily.

Ebringer et a148 proposed that a "dermonecrotic factor" might play an important role in the cause of pyoderma gangrenosum. 6 Serum contains a factor that when injected intradermally into albino guinea pigs results in the rapid development of a pustule, followed by edema and infiltration of inflammatory cells, resulting in a lesion that is morphologically similar to that seen in patients with pyoderma gangrenosum. The physical and immunologic characteristics of this dermonecrotic factor appear to correspond with those of IgG. Although present in the serum of normal persons, it has been found in increased amounts in patients with various systemic diseases. Biopsies of the lesions induced in guinea pigs indicate that damage is directed at the vasculature and connective tissue.

Samitz 8 suggested that in those cases of pyoderma gangrenosum associated with ulcerative colitis, a primary hypersensitivity reaction might be occurring whereby skin lesions and colonic lesions might be caused by a common etiologic agent or immunologic (autoimmune) mechanism-- tha t is, similarity between some factor in skin and bowel mucosa results in attack against each. Another pos- sibility is that the primary disease process is occurring in the colon and is reflected secondarily in the skin as an allergic angiitis or Shwartzman phenomenon. 4v Biologic changes in the colon (caused by bacteria, endogenous toxins, or psychic trauma) cause the colon to take on the nature of an antigen, giving rise to secondary cutaneous vasculitides. Additional support for such an immunologic mechanism for pyoderma gangrenosum resulting from ulcerative colitis has been reported by Broberger and Perlmann, 495~ who found humoral antibo-



Dermatology

dies in the lipopolysaccharide fraction of colonic mucosa, with the diseased colon serving as antigen. 8.5~-5,_

A derangement in humoral or cell-mediated immunity or neutrophil function is now being given serious consideration as the cause of the disease. Clinically as well as histologically, pyoderrna gangrenosum would appear to reflect increased activity of effector cells of immunologic response, with associated destruction of tissues. Norris and colleagues 35 have proposed that pyoderma gangrenosum involves an increased, misdirected effector- cell response against some factor in the skin. This defective effector-cell function may arise from release of immature cells into peripheral blood in response to cutaneous stimuli, desensitization of phagocytes, or altered responsiveness.

Turning to the other end of the immunologic spectrum, one might postulate that pyoderma gangrenosum is the result of decreased immunologic competence. In vivo evaluation of cell- mediated immunity with intradermal injections of purified protein derivative, Candida albicans, mumps, streptokinase-streptodornase, and sensitization with dinitrochlorobenzene have revealed a cutaneous anergy among many of the patients studied, s.22,~3 In vitro studies of cell-mediated immunity with mitogen-induced incorporation of tri- tiated thymidine in cultured Iymphocytes stimu- lated by phytohemagglutinin A showed what would appear to be a curious dissociation between production of migration inhibitory factor (MIF), which was absent, and normal blastogenesis in response to phytohemagglutinin A. 22,53-54 This would suggest a partial defect in cellular immunity in these persons.

Check and colleagues 5~ have reported an abnormal ratio of T-heIper to T-suppressor cells, with an overall increase in suppressor activity. It is postulated that excess T-suppressor function (or lack of T-helper function) could be a common factor underlying many of the immunologic abnormalities associated with pyoderma gangrenosum. Because of the role of T cells in regulation of antibody synthesis, relative changes in T-suppressor/T-helper activity could result in either increased 22,25 or decreased 5~ levels of immunoglobulins. Since T-helper cells are responsible for initiating the production of MIF and

MIF is a component of delayed-type hypersensitivity responses, 54 complete or partial cutaneous anergy 2z.33.57 and lack of in vitro production of MIF 22 may be caused by an imbalance in the ratio of T-suppressor to T-helper cells. 55 Also if T cells have a regulatory role with respect to neutrophil synthesis and release, as has been demonstrated with other blood cells, 58-59 abnormal T-suppressor/T-helper cell ratios may explain some of the dysfunctions of neutrophils seen in pyoderma gangrenosum? 5 Further investigation regarding the potential role of T cells in pyoderma gangrenosum is warranted. Such a defect in immune regulation would help to account for the clinical appearance of hyperresponsiveness in light of variable immunologic defects.

A number of abnormalities in neutrophil function have been described, including in vitro inhibition of neutrophil function, 4~ decreased neutrophil chemotaxis, 25,35,6~ delayed migration and abnormal bactericidal ability, zs and decreased neutrophil phagocytosis? v,~6z Norella et al 6~ postulated that intrinsic neutrophil dysfunction was responsible for diminished chemotaxis. 63 This author believed that the defective neutrophil function most likely was correlated with the clinical observation that the patients react to minor trauma with tissue destruction and are very resistant to antibiotic therapy of chronic infections. 6~

Jacobs and Goetz164 found normal neutrophil chemotaxis and enhanced "random migration" of neutrophils and monocytes due to a 160 K mo- lecular weight factor that they called "leukocyte streaking factor." This leukocyte migration- enhancing factor may contribute to an increased inflammatory response in the patient, which is manifested as an inappropriately exuberant exu- dation of leukocytes in response to a trivial stimulus. The hyperactive leukocytes persist locally and may produce tissue damage in a pattern similar to the reaction to infection. 64 In studying patients with pyoderma gangrenosum associated with chronic active hepatitis, Norris et a135 concluded that a defective modulation of antibody production by T-suppressor cells gives rise to a persistent hepatitis B antigenemia. This results in a relative stim- ulation of T-killer cells, "turned on" to destroy hepatocytes containing the hepatitis B antigen.

From the number and variety of causes that have



been proposed, it is evident that the mechanism responsible for the development of the cutaneous ulcers has yet to be elucidated. At present it is not even clear whether there is a unifying immunologic process or whether the clinical presentation of the ulcerative lesions comprising pyoderma gangrenosum simply represents the morphologically common end point of a number of different processes.

Treatment . A wide variety of therapeutic modalities have been used in attempting to treat the lesions of pyoderma gangrenosum. These treat- ments may be roughly divided into internal and external ones. The most basic external means of treating the lesions is with the use of whirlpool and topical dressings. Povidone-iodine, 0.5% sil- ver nitrate, benzoyl peroxide, hexachlorophene, and potassium permanganate have all been used with varying degrees of success. There has been a renewed interest recently in biologic dressings commonly used in the treatment of burns and other serious breaches of the protective skin barrier.

Intralesional steroids in the form of triamcinolone diacetate are currently the preferred method of treatment of early lesions. 3'31'65 Good technique in injecting into the base of the lesion 1 ml of triamcinolone diacetate per 6 mg lidocaine hydrochloride every other day for 14 days is essential; results are satisfactory only if the lesions are treated at an early stage in their development.

DeCock and Thorne 66 reported success with the use of a 2% solution of topical sodium cromogly- cate three times a day, which inhibits mast cell degranulation. He reported few side effects. It is thought that this method of treatment holds a good deal of promise for the future, but further investigation is needed.

Corticosteroids (prednisone) have been the main systemic method of treating pyoderma gangrenosum. These drugs are thought to exert their primary effect by increasing monocyte chemotaxis and neutrophil phagocytosis. Initial doses of up to 60 to 80 mg daily may be given, with subsequent cautious tapering of dosages to maintenance levels.

Johnson and L a z a r u s 67 reported use of a pulse of 1.0 gm methylprednisolone sodium succinate intravenously in 150 ml 5% dextrose for 5 days. This was used in patients with pyoderma gangrenosum recalcitrant to conventional forms of treat-

ment. Results were good, but potential side effects severely limit the applicability of this treatment.

Sulfasalazine also is used quite widely. This drug consists of a sulfonamide plus salicylic acid; it is used in doses of 1.0 to 4.0 gm four times a day. It is useful only in pyoderma gangrenosum associated with active colonic disease. The active breakdown product of this compound is sulfapyr- idine, which has been used in doses of 4 to 8 gm daily, given in four equally divided doses, in conjunction with prednisone. 4'2~

Dapsone, 300 to 400 mg four times a day alone or 100 mg four times a day in conjunction with 18 mg daily of paraethasone, has also been used with reportedly good results. 6~

Clofazimine has been used in doses of 300 to 400 mg da i ly . 45'69-71 This drug increases neutrophil phagocytosis. Although used successfully in patients with lesions difficult to treat by more stan- dard forms of therapy, concerns remain regarding potential toxicity of the drug, especially to the small intestine.

Lynch and Bergfeld 44 reported encouraging re- suits with the use of 300 mg minocycline hydrochloride four times a day in four patients with pyoderma gangrenosum. The mechanism of action is thought to be related to the immunosuppressive, antiinflammatory properties of the drug, with dim- inution of the antigenic stimulus responsible for the production of skin lesions.

The use of hyperbaric oxygen has been advo- cated, apparently with good results. Access to fa- cilities equipped with the necessary apparatus may pose a problem.

Recently immunosuppressive agents have been used in the treatment of pyoderma gangrenosum in patients whose disease is recalcitrant to stan- dard modes of therapy. 7z-v3 Drugs used include azathioprine with or without adjuvant steroids, mercaptopurine, melphalan, cytosine arabinoside, daunorubicin, cyclophosphamide, and cyclospo- rine. 7374 The action of these drugs in pyoderma gangrenosum is not well understood; they have usually been directed at the underlying associated disease rather than at the pyoderma gangrenosum.

CONCLUSION

There is a distressing lack of understanding of pyoderma gangrenosum as a disease. Indeed it is



Dermatology

far from clear whether pyoderma gangrenosum ac- tually represents a distinct pathologic entity or whether it is merely the morphological ly similar cutaneous manifestation o f a variety of disease processes.

It would seem that an aberrant immunologic mechanism is the most likely cause in pyoderma gangrenosum. If an initial immunologic derangement resulting in increased immunologic responsiveness were present, an idiopathic autoimmunity could be responsible for the development o f the inflammatory bowel disease. In this case the pyoderma gangrenosum might be primary, resulting from the same mechanism, or secondary to the bowel disease.

On the other hand, if some type of immunologic deficiency exists initially, there might be an increased susceptibility of the patient to the causative agent (perhaps bacterial) responsible for the inflammatory bowel disease. The pyoderma gangrenosum then would represent a secondary hypersensitivity reaction. Such a mechanism of decreased immunocompetence would be compatible with the cutaneous anergy demonstrated by a number of patients.

The outlook for patients suffering from this con- dition remains guarded because there is no specific treatment for pyoderma gangrenosum in spite of the apparent plethora of treatment modalities. The more fortunate patients achieve reasonably good control of their disease with careful monitoring and judicious early application of supportive therapy. Other patients may suffer numerous exacerbations of the painful, debilitating, and ultimately disfiguring lesions.

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Dermatology

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A B S T R A C T S

Treatment of morphea with penicillin and antimalarial drugs in childhood

Nagy E, Ladanyi E. Z Hautkr 1987;62:547-9 (German)

Good results were obtained in 17 children, aged 3 to 16 years, with 1 million units intramuscular or intravenous penicillin daily for 10 consecutive days each month, combined with plaquenil, 250 nag daily every other day (in children over 10 years old; lower doses in younger children), for 6 to 18 months. Even en coup de Sabre and linear scleroderma, as well as three cases of lichen sclerosus et atro- phicus, responded to this approach.

Yehttdi M. Felman, M.D.

Cutaneous changes in hemodialysis patients (German)

Morvay M, Lubach D, Froese P, Luth B.L Z Hautkr 1987;62:891-3

One hundred eighty-eight patients undergoing long-term hemodialysis and a control group of 371 patients without kidney diseases were examined with regard to changes of the connective tissue of the skin. The following alterations were observed: increased sensibility to low temperatures and Raynaud's syndrome, 42%, Dupuytren's contracture, 22.4%, and sclerosis of the dorsum of the fingers, 17.6%. Carpal tunne{ syndrome was seen in 24.4% of the eases, significantly correlating with the duration of hemodialysis.

Yehudi M. Felman, M.D.

Fumaric acid derivatives in oral long-term treatment of psoriasis (German)

Bayard W, Hunziker 1", Krebs A, Speiser P, Joshi R. Hautarzt 1987;38:279-85

Oral treatment of psoriasis on an outpatient basis, using a prep- aration containing fumaric acid derivatives, was evaluated as initial monotherapy (3 months) and as lung-term basic therapy (12-14 months) in 13 and 11 patients, respectively. The course of the disease was analyzed in each individual case. After completion of both parts of the trial, half of the patients who had responded only poorly to conventional antipsoriatic therapy showed a significant improvement that occurred after several weeks of treatment. In four patients the

medication had to be stopped because of abdominal pain. No severe side effects, particularly renal, hepatic, or hematologic, could be established. Studies in mice and rats disclosed only a low acute toxicity of the fumaric acid derivatives used. To establish fumaric acid derivatives in the treatment of psoriasis, studies on chronic toxicity and pharmacokinetics will have to be conducted. Further clinical trials should evaluate a single fumaric acid derivative instead of mixtures.


Pemphigus vegetans of Hallopeau (German)

Gerharz M, Stadler R. Hautarzt 1987;38:371-4

The authors report the case of a 25-year-old woman with bullous lesions diagnosed as the rare pustular type of pernphigus described by Hallopeau. Direct immunofluorescence studies revealed deposits oflgG and C3 in the intercellular spaces of the epidermis; the indirect immunofluorescence technique revealed circulating antiepitbelial IgG antibodies. The skin lesions cleared completely following treatment with systemic corticosteroids and azathioprine. These findings indicate the disease first described by Hallopeau as "pyodermite vege- tante" does indeed belong to the pemphigus group, being a rare type of pemphigus vegetans.


Atopy and allergic contact dermatitis (French)

Bondeel A, Achten G, Dooms-Goossens A, Buekens P, Broeckx W, Oleffe jr. Ann Dermato/ Venereol 1987;114:203-9

A total of 3,427 nonatopic patients (mean age, 39.4 years) were compared with 935 atopic patients (mean age, 32.6 years) for the incidence of contact dermatitis. Two thirds of both groups were female. Allergic contact dermatitis was more uncommon in atopic (40.4%) than in nonatopic patients (50.7%). The difference was sta- tistically significant. The principal sources of contact allergy in both groups were topical medications and occupational allergies. Sensi- tization to nickel, paraphenylenediamine, and wood alcohols was less common in atopic patients. Other results were comparable.


pyoderma gangrenosum: a review

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