PYODERMA GANGRENOSUM: ASSOCIATIONS REVISITED C.B. KO, M.R.C.P., S. WALTON, M.R.C.I'., AND E.H. WYATT, F.R.C.P.
tans, and syphilitic gumma. Patients were aged between 30 and 80 years witb a mean age of 62 years. Tbere were ten women and four men.
Abstract Fourteen cases of pyoderma gangrenosum were seen over a period of 24 years at tbe Hull Royal Infirmary Dermatology Department. Several associated conditions were found. Seven cases were associated witb rheumatoid artbritis of wbicb five were sero-positive, including one witb Felty's syndrome. One case was associated witb botb ulcerative colitis and psoriasis; one witb polycythemia rubra vera; two patients bad diverticular disease including one wbo also bad rbeumatoid artbritis; one had positive sypbilis serology. In tbree cases tbere was no significant associated disease identified. Ten out of tbe fourteen cases were women, indicating a female preponderance by a ratio of about 2F:1I\/1; a figure similar to tbat stated by Seitzinger.^ Tbe age of presentation ranged from 30 to 80 years.
Eleven patients had associated conditions (Table 1). Seven had rheumatoid arthritis of which five were seropositive, including one with Felty's syndrome. One had both ulcerative colitis and psoriasis. The same patient later developed colonic carcinoma and underwent a panproctocolectomy. One patient had polycythemia rubra vera, which progressed to aleukemic leukemia 12 years later. Two patients had symptomatic diverticular disease, one of whom also had associated rheumatoid arthritis. Colonic biopsies in both patients showed nonspecific chronic inflammatory change, and the diagnosis of ulcerative colitis was excluded. In one patient a reactive syphilis serology was found. A Wassermann reaction titer of 44441/0 (Kolmer) became non-reactive 3 months after systemic penicillin. She was a 30-year-old woman who presented with an acute onset of widespread pyoderma gangrenosum over her scalp, face, trunk, and limbs associated with a feeling of malaise, pyrexia of 42°C, and a reactive syphilis serology (venereal disease reference laboratory test, Kahn test, Wassermann reaction, and Reiter protein complement fixation test). Biopsy of one of tbe lesions showed nonspecific inflammatory changes with no evidence of spirochetes on silver staining. The patient responded rapidly to systemic penicillin and prednisolone and a topical steroid. Witbin 3 months her pyoderma gangrenosum bealed up completely, and all her syphilis serology became nonreactive. Review of her record showed her to be free from any recurrence of pyoderma gangrenosum for over 20 years after that episode. Three patients had no significant underlying disease. The feature of pathergy was demonstrated in patient 4, who developed pyoderma gangrenosum following injury to his forearm; patient 6, who developed lesions on his penis after circumcision for paraphimosis; and patient 12, following surgical repair of his epigastric hernia.
Pyoderma gangrenosum is a rare, ulcerative, necrotizing cutaneous disorder of unknown etiology. The lesions usually present as a painful nodule or pustule that breaks down to form a progressively enlarging ulcer witb a raised, render, undermined edge. It is often reported in association with a systemic disease such as inflammatory bowel disease, polyarthritis, hematologic malignancy, polycythemia rubra vera, and other conditions.'"'' Fourteen cases were diagnosed over a period of 24 years at the Hull Royal Infirmary Department of Dermatology, which serves a population of around half a million people. The small number of cases collected emphasizes the rarity of the condition. Materials and Methods Tbe records of patients with pyoderma gangrenosum wbo presented to tbe Dermatology Department at Hull Royal Infirmary between 1967 and 1991 were reviewed. Tbe initial diagnosis was made clinically. In 12 out of tbe 14 patients (except patients 3 and 9 in Table 1), a skin biopsy was taken to exclude otber causes of ulceration including postoperative gangrene, ectbyma gangrenosum, Meleney's synergistic gangrene, insect bite (witb particular reference to brownrecluse spider), factitious ulceration, fungal/atypical mycobacterial infections, cutaneous amebiasis. Sweet's syndrome, bowel by-pass syndrome, bromoderma, erythema multiforme, superficial tbrombopblebitis, pempbigus vege-
From the Departments of Dermatology, Hull Royal Infirmary and The General Infirmary, Leeds, United Kingdom.
Twelve out of the 14 patients had lesions of pyoderma gangrenosum on their legs, whilst the remainder had involvement of other body sites including one with buccal mucosal involvement (Table 1).
Address for correspondence: E.H. Wyatt, F.R.C.P., Hull Royal Infirmary, Anlaby Road, Hull HU2 3JZ, U.K. 574
Pyoderma Cangrcnosuni Ko, Walton, and Wyatt
Table 1. Patients with Pyoderma Gangrenosum Patient Age (years) Sex
Prednisolone and azathioprine
Healed; 5 months
Sero-negative rheumatoid artbritis colonic diverticular disease None Sero-negative arthritis
Topical steroids Azathioprine and topical steroids Initially dapsone. None later prednisolone. azathioprine and minocycline Prednisolone and Psoriasis and ulcerative colitis Breast, hand. azathioprine complicated by a colonic Ca. abdomen, and legs Prednisolone Face, abdomen. Polycythemia rubra vera penis, and leg azathioprine Topical steroids Leg Diverticular disease Prednisolone and Hand, lower back. Sero-positive rheumatoid azathioprine legs arthritis Prednisolone, Legs Sero-positive rheumatoid azathioprine. arthritis cyclophosphamide Prednisolone and Hands and legs Sero-positive rheumatoid azathioprine arthritis (Felty's Syndrome) Generalized and buccal Prednisolone and Sero-positive rheumatoid mucous membrane cyclophospbamide arthritis ischemic lesions cardiomyopatby Prednisolone and Abdomen and tbigh None azathioprine Prednisolone, Reactive serology for syphilis Generalized penicillin, topical steroids — Under breasts. Sero-positive rheumatoid perineum, groin arthritis Right breast Left foot and rigbt ankle Forearm, buttocks. and legs
Healed; 1 year Healed; 1 year Relapses for 3 years to date
Relapses for 8 years. none over last 2 years Relapses over 10 years Healed; 8 months Relapses over 2 years (then moved away) Healed; 1 year
Healed; 1 year Rapid downhill course
Healed; 6 years Healed; 3 months
Died shortly following diagnosis of skin lesions before any treatment was started
immune coinplex disease have also been reported.''••' , Other investigators have suggested alternative theories such as dysfunction of neutrophils and monocytes and defects in humoral and cellular immunity.'-'' The diversity of pathogenetic mechanisms put forward by various investigators reflects our present incomplete understanding of the disease. In Brunsting's original description, pyoderma gangrenosum was associated with ulcerative colitis in four out of five cases,^ and subsequent series have found a prevalence ranging widely from 7 to 60%.*"^ It is not clear if there was any referral bias to account for this great variation in prevalence. In our series of 14 patients, only one had ulcerative colitis. This figure is similar to the series by Holt et al.^ and Hickman and Lazarus.** Powell et al.'^ found that pyoderma gangrenosum is most often associated with sero-negative symmetrical polyarthritis, which often resembles the arthritis of rheumatoid disease. In his series of 86 patients, 37% had arthritis, but only four of those were
The pathogenesis of pyoderma gangrenosum is still unclear ever since Brunsting et al.^ first described the disease in 1930. Local infection does not appear to be an etiologic factor,' even though Brunsting initially suggested this may be the case. Its association with various autoimmune diseases and its response to immunosuppressive therapy suggest an immunologic basis for the disease. Fernandez et al.'' studied three cases of pyoderma gangrenosum and found them all to have high levels of circulating immune complexes, which subsequently dropped to normal values as their skin lesions disappeared following treatment with prednisolone. Only one of our patients (patient 11) had raised levels of circulating immune complexes. Staining for immunoreactants (IgG, IgA, IgM, fibrin, and complement) in the involved skin was done in 3 out of the 14 patients (patients 4, 11, and 14) and was completely negative. Immunoglobulin deposits and vasculitis consistent with 575
International journal of Dermatology Vol. 31, No. 8, Atigust 1992
series of patients with pyoderma gangrenosum, seropositive rheumatoid arthritis was the commonest association unlike other reported studies.^'^
rheumatoid. Stolman et al.'" has reported two patients with pyoderma gangrenosum who had classic rheumatoid arthritis and in whom skin biopsies showed features of a necrotizing vasculitis. Sero-negative arthritis associated with ulcerative colitis has also been reported previously." In our series, 7 out of the 14 patients had rheumatoid arthritis of whom five were sero-positive, including a patient with Felty's syndrome. In a series reported by Christmas et al.,'^ diabetes mellitus was found in 4 out of 10 patients. Powell et al., however, found the incidence of diabetes mellitus to be 1 % amongst his series of 86 patients with pyoderma gangrenosum.'' As diabetes mellitus occurs in up to 2% of the general population, its true association with pyoderma gangrenosum is debatable. None of our patients were found to have diabetes mellitus. Apart from inflammatory bowel disease including Crohn's disease,'' pyoderrna gangrenosum has been reported to be associated with diverticulitis.''' In our series, two patients had symptomatic diverticular disease. In both patients, inflammatory bowel disease was excluded by radiologic barium studies and colonic biopsy. Patient 6, who had associated polycythemia rubra vera, has previously been reported.'^
Pyoderma gangrenosum has also been associated with a wide variety of other diseases such as leukemia,"' monoclonal gammopathy,'^ paroxysmal nocturnal hemoglobinuria,'** non-Hodgkin's lymphoma," erythroid hypoplasia,^" myelodysplasia,^' myelofibrosis," acquired immunodeficiency syndrome,^' chronic active hepatitis,^"* primary biliary cirrhosis,^' Takayasu's disease,^'^ Wegener's granulomatosis,^^ systemic lupus erythematosus,^** Beh^et's syndrome,^** sarcoidosis,'" and gastric and duodenal ulcers.** There have also been two reports of pyoderma gangrenosum associated with solid tumors. One was in a patient with a carcinoid tumor," and the other patient had an adrenocortical carcinoma.'^ Interestingly, although pyoderma gangrenosum is a condition that primarily affects skin, there has been a report of pyoderma gangrenosum with pulmonary involvement.^^
11. 12. 13.
Pyoderma gangrenosum is a disease which is ill-understood at the present moment. Its association with a large variety of seemingly unrelated disease processes raises the question whether it actually represents a distinct pathologic entity or it is merely a morphologically similar cutaneous manifestation of all these diseases. The diagnosis of pyoderma gangrenosum is essentially clinical, as there is no specific histologic pathognomonic feature.^'' The frequent histologic finding of a vasculitic process''-''^'^^ suggests that immune complex-mediated disease may be the common denominator to explain its frequent association with rheumatoid disorders, inflammatory bowel disease, and hematologic disorders. In our
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Pyoderniii Gangrenosum Ko, Watton, ;\nd Wyatt
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Etiology of Acne
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Most acne researchers believe there are several factors involved in the development of acne lesions. Increased rate of sebum production is believed to be one of the most important factors. As a group, patients with acne secrete more sebum than normal individuals and the severity of acne is related to the degree of seborrhoea. Sebum production is directly dependent on the size and rate of growth of the sebaceous glands, which is under the control of androgenic hormones. However, there is evidence that acne is not due to increased sebum production alone. Firstly, even when acne remits spontaneously, sebum production remains higher in acne patients than in age-matched controls. Secondly, a recent survey of 20 pairs of identical and nonidentical twins showed the sebum excretion rate is under genetic control but the development of clinical acne is modified by other factors. For the most part the composition of sebum of those with and without acne is a similar complex mixture of triglycerides, mono- and diglycerides, fatty acids, wax esters, squalene and diol esters. However, it has been suggested that a reduction in the concentration of linoleic acid, an essential fatty acid (EFA), could be important in the pathogenesis of acne. As abnormal keratinization occurs in EFA deficiency states, linoleate deficiency within the follicular canal could cause the observed hyperkeratosis and follicuiar obstruction. Improvement of acne with some forms of therapy may be accompanied by a concomitant increase in sebum concentrations of linoleate. From Lever L, Marks R. Current views of the aetiology, pathogenesis and treatment of acne vulgaris. Drugs 1990; 39:681-692. 577