Ulcerative Pyoderma Gangrenosum and Leukocytoclastic Vasculitis in a Hypothyroid Woman: A Case Report

Background. Skin ulcers, especially of the lower extremities, encompass a myriad of causes that a clinician must analyze.Case Report. A 45-year-old hypothyroid woman presented with a 6-year history of recurrent widespread eruptions of rashes and ulcers on her skin. She was diagnosed to have pyoderma gangrenosum and leukocytoclastic vasculitis. She was successfully managed with a novel combination of azathioprine and methotrexate. Conclusion. Pyoderma gangrenosum is an unusual wounding disease that makes the diagnosis and management challenging. In addition, occurrence of these 2 distinct entities together and their association with preexisting hypothyroidism is new to the scientific literature and hence discussed here. 

Skin ulcers, especially of the lower extremities, encompass a myriad of causes that a clinician must analyze. Unlike most leg ulcers managed by surgical intervention, pyoderma gangrenosum (PG) may even worsen with debridement.¹ High suspicion is required to identify this condition, and the management often involves multiple disciplines.

A 45-year-old woman presented to SMS Medical College and Hospital, Jaipur, India, with a 6-year history of widespread eruptions of rashes and skin ulcers on her extremities recurring 4 to 5 times per year. According to the patient, the rashes began as tiny deep-red spots occurring over her limbs associated with swelling of the feet and mild-to-moderate fever. They were nonpruritic and healed in 2 to 3 weeks’ time, leaving behind hyperpigmentation spots. When these rashes recurred a month later, she also developed spontaneous ulceration of skin over the right buttock. The ulcer started as a pus-filled boil that progressed to a large, unusual, eroded area in a 5- to 7-day span. Similar ulcers followed at multiple sites over the lower and upper extremities. The ulcers were extremely painful and nonhealing, appeared unsightly, and restricted her routine activities. She had received treatment suggestive of antibiotics, corticosteroids, dapsone, and immunosuppressive drugs (azathioprine and cyclophosphamide) from multiple hospitals. Although she found partial relief to her illness with medications, such episodes of rashes followed by ulcers repeatedly occurred again for the past 6 years, without a complete symptom-free period. She presented to the authors’ institution in November 2014 with a similar episode of skin rashes and ulcers of 10 days’ duration. 

The patient had a 7-year history of hypothyroidism and was taking L-thyroxine 50 mg/day orally; her medical history was otherwise insignificant. There was no history of drug intake prior to the onset of lesions, weight loss, or any other systemic complaint. Family history was insignificant, and she was a mother of 3 who had started menopause recently. On general examination, she was obese (body mass index 31.18), pale, and vitally stable.  Ambulation was difficult due to movement-restricting, painful ulcers. On examination, there were multiple ulcers predominantly over the posterior and lateral aspects of the lower limbs and buttocks. They were 5 cm to 10 cm in diameter with irregular margins, undermined edges, and tender on palpation; the floor was covered by necrotic slough and eschar and the base was formed by muscles. There were numerous nonblanchable purpura seen on the normal skin between the ulcers, some of which showed central hemorrhagic vesiculation (Figure 1). There was no significant lymphadenopathy, and the peripheral pulses were felt normally. There were multiple healed cribriform scars and postinflammatory hyperpigmentation in the surrounding lesion-free skin. Hair, nails, and mucosa were normal. No clinical signs of thyroid disease were noted. 

Routine hemogram, urine analysis, lipid profile, and hepatic and renal function tests were within normal limits. Erythrocyte sedimentation rate at first hour was 58 mm, and C-reactive protein was positive. She was biochemically euthyroid except for borderline elevation in antithyroid peroxidase antibody titer (35.7 IU/mL). Thyroid ultrasound (USG) showed a multinodular goiter. Pathergy test was negative. Other investigations to rule out underlying infective, systemic, or malignant pathology were also negative, which included microbial cultures of pus, blood, urine, and throat swab; stool for occult blood; peripheral blood smear; serology (human immunodeficiency virus, Australian antigen, hepatitis C, herpes simplex, venereal disease research laboratory, antinuclear antibody, antineutrophil cytoplasmic antibody [ANCA], rheumatoid factor, antiphospholipid antibodies, immunoelectrophoresis); chest x-ray; abdominal USG; contrast-enhanced computed tomography of the thorax and abdomen; lower extremity doppler; endoscopy of gastrointestinal tract; and jejunal biopsy. Dual-energy x-ray absorptiometry scan for bone density was normal.

Histopathology of the ulcer margin showed epidermal ulceration with neutrophilic infiltration. Dermis revealed necrosis, collagenolysis, dense neutrophilic infiltrate, and granulation tissue with no evidence of vasculitis (Figure 2A). Histopathology of the purpuric lesion showed mild hyperkeratosis, neutrophilic infiltrate with fragmentation of nuclei, and nuclear debris around the dermal blood vessels and within the vascular wall. Endothelial swelling, fibrinoid degeneration of the vessel wall, and extravasation of erythrocytes were noted (Figure 2B). Tissue sections on special staining (periodic acid–Schiff, Grocott-Gomori’s methenamine silver, Giemsa, Ziehl-Neelsen, Fite-Faraco) were negative for fungi, acid-fast bacilli, and parasites. Direct immunofluorescence showed no antibody or immune complex deposition. Fine needle aspiration cytology of the thyroid nodule revealed clusters and sheets of benign follicular cells admixed with thick basophilic colloid. A diagnosis of ulcerative PG and leukocytoclastic vasculitis (LCV) with multinodular colloid goiter was made (Figure 2). 

She was initially managed with systemic antibiotics along with supportive care. On histological confirmation of diagnosis, she was started on oral prednisolone 40 mg/day. In addition, she was given oral cyclosporine 100 mg/day considering her previous treatment history of poor response to other immunosuppressive drugs. As the progression of the ulcers halted and the signs of healing were seen, drugs were gradually tapered over 4 months; the dose was reduced to 10 mg/day of prednisolone and 50 mg/day of cyclosporine, and it was maintained for another 5 months. Skin lesions healed significantly. An attempt to further decrease the steroid dose resulted in reappearance of rashes and ulcer exacerbation. On increasing the doses of prednisolone and cyclosporine to initial levels, patient developed secondary hypertension. Cyclosporine was withdrawn and 100 mg/day of oral azathioprine (AZA) was added instead. However, during this episode, the response was slow and required further immunosuppression. During the course of treatment, she also developed peptic ulcer disease, requiring a cautious use of corticosteroids. The regime was boosted by adding 15 mg/week in 2 divided doses of oral methotrexate (MTX). Lesions completely healed by the end of 36 weeks of starting AZA and MTX (Figure 3). Patient continued in remission on maintenance therapy consisting of oral AZA 50 mg/day and oral MTX 7.5 mg/week, along with minimum physiologic dose of prednisolone without relapses. The doses of AZA and MTX were further reduced to 25 mg/day and 5 mg/week, respectively, during the next 6 months with insignificant exacerbations. 

Pyoderma gangrenosum is a neutrophilic dermatosis that is often diagnosed clinically.² It typically manifests as rapidly progressing, well-defined, painful ulcerations with ragged, violaceous, and undermined edges. Although histopathology and immunology are not pathognomonic in PG, they help to exclude other possible causes of skin necrosis.³ The disease should be suspected in longstanding and recurrent nonhealing ulcers that show inconsistent microbial cultures and an inadequate response to systemic antibiotics. Classically, histopathology of early lesions show perifollicular neutrophilic infiltrates and later a dense neutrophilic infiltration of dermis.⁴ Vasculitis in PG lesions is an inconsistent finding.⁵

Leukocytoclastic vasculitis is a histopathological feature of cutaneous small vessel vasculitis that clinically presents as palpable purpura, papules, or hemorrhagic vesicles over the dependent areas of the body. Lesions can sometimes ulcerate; however, large ulcers are not a feature.⁶ The commonly implicated triggers for vasculitis are drugs, infections, connective tissue diseases, and neoplasms, which in the present case were not identified.⁷

There are reports of LCV preceding PG by 1 to 4 years with further development of paraproteinemias and rheumatoid arthritis.^8-10 A vasculitic origin of PG or common immunologic aberration could be attributed as possible causes of such phenomena.⁸ Immunological Arthus or type 3 reaction is also suggested in cases of PG that are associated with positive immunofluorescence in blood vessel walls.⁹ However, in the present case, the appearance and course of LCV and PG were mostly synchronous, supported by both clinical findings and histopathology. To the best of the authors’ knowledge, this is the first description of such a concurrence. Pyoderma gangrenosum-like ulcers and purpura can also be seen in limited Wegener’s granulomatosis, which was ruled out based on negative ANCA and absence of granulomatous histopathology.¹¹

The exact etiology of PG is not defined. It is often a cutaneous marker of internal diseases with many associations described.¹² The extensive workup of the systems only revealed an associated multinodular colloid goiter of probable autoimmune etiology (elevated antithyroid titer). Endocrine disorders including thyroid diseases and antithyroid drugs like propylthiouracil have been associated with PG; the sole association of hypothyroidism with no other systemic association is not reported in the literature.^13-16 However, it is also possible the association is incidental.

Although systemic corticosteroids are the mainstay in the management of both PG and LCV, several steroid-sparing agents have been tried.¹⁷ The present patient required higher doses of corticosteroids for longer durations along with multiple immunosuppressive drugs that were needed to control the exacerbations. Simultaneous occurrence of 2 conditions, frequent recurrences with incompletely remitting episodes, and associated peptic ulcer disease in a menopausal woman made this a difficult-to-treat wound using long-term systemic corticosteroids. However, remission was achieved with an innovative combination of AZA and MTX, which were believed to have acted synergistically (MTX enhances the action of AZA by indirectly inhibiting its metabolism to inactive metabolites) to reduce the requirement of corticosteroids.¹⁸ This combination of drugs has also been tried successfully in cases of resistant rheumatoid arthritis, chronic graft-versus-host disease, dermatomyositis, and polymyositis without much adverse effects.^19-22 

Pyoderma gangrenosum is an uncommon ulcerating disease of nonsurgical etiology. Hypothyroidism is most likely a new addition to its list of systemic associations. As PG may precede, concur, or follow its systemic associations, close surveillance is required. Clinical concurrence of LCV and PG is another peculiarity of the case, suggesting a common immunologic defect of vascular origin. The management of such situations where multiple pathologies exist together are challenging and warrants trial of newer treatment strategies. While reporting a successful outcome of refractory ulcers of PG using AZA-MTX combination therapy, the authors also recommend its appraisal in other difficult-to-treat skin diseases.

From the Department of Dermatology, SMS Medical College and Hospital, Jaipur, Rajasthan, India

Address correspondence to:
Chaitra Prakash, MD
Department of Dermatology, 
SMS Medical College and Hospital, 
Jaipur 302004, Rajasthan, India
drpchaitra@gmail.com

Disclosure: The authors disclose no financial or other conflicts of interest.