Correspondence *Naval Medical Center San Diego, Suite 301, 34800 Bob Wilson Drive, San Diego, CA 92134, USA

Email alissa.quin@med.navy.mil

The case

A 20-year-old woman presented to her gastroenterologist with fevers and right-labial pain and swelling. She had a 10-year history of Crohn's colitis (involving the distal 45 cm of the colon), perirectal abscesses and fistulizing disease, and had undergone a diverting ileostomy 16 months earlier. She was admitted to a medical ward. Although she complained of mild lower abdominal pain, her ileostomy and rectal output were stable. Soon after admission, she developed painful, erythematous nodules in her pretibial region, with associated lower-extremity edema. (Figure 1). The patient's medical history was also notable for asthma, and she was a nonsmoker. She was on no medications during remission of her Crohn's disease owing to a history of interstitial pneumonitis whilst on 6-mercaptopurine, intolerance to methotrexate and thalidomide, and a loss of response to infliximab. She had no family history of malignancy or IBD.

Figure 1 The pretibial region of the patient before initiation of adalimumab, showing the presence of erythematous nodules and lower-extremity edema.

 

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On physical examination, the patient looked ill: she had a temperature of 96 °F, her blood pressure was 107 mmHg over 58 mmHg, and her pulse rate was 86 beats per minute. Her abdomen was soft, nontender and nondistended with normoactive bowel sounds, and her stoma appeared normal. The right labium was swollen and erythematous. Laboratory investigations revealed that the patient had anemia (hemoglobin 9.9 mg/dl), leukocytosis with a left shift (white blood count 13,600 cells per l), and normal blood chemistry results. Dermatologic examination confirmed that the patient's pretibial lesions were consistent with a diagnosis of erythema nodosum. The patient requested that a biopsy sample be taken to confirm the diagnosis; histologic examination of the biopsy sample revealed granulomatous septal panniculitis, which was consistent with the diagnosis of erythema nodosum (Figure 2).

Figure 2 An excisional biopsy sample taken from the patient, which reveals septal granulomatous panniculitis (inflammation of the superficial fascia of the subcutaneous fat tissue).

(A) Low-power view (magnification x100; hematoxylin and eosin stain). (B) High-power view (magnification x400; hematoxylin and eosin stain).

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Examination under anesthesia revealed an abscess on the right labium, which was treated by incision and drainage. Proctoscopy to 20 cm revealed severe inflammation of the sigmoid colon and the presence of a fistula between the anterior dentate line and the labial abscess, for which a seton was placed. Postoperative MRI revealed extensive perianal fistulizing disease, which involved both buttocks, the distal vagina and right labium, with thickening of the sigmoid colon wall.

After obtaining negative pregnancy and intradermal tuberculin test results, adalimumab therapy was initiated. This treatment was chosen for several reasons. First, the patient had had a previous therapeutic response to infliximab. Second, a steroid-sparing regimen was preferred, because the patient had a 9-year history of steroid use. Third, adalimumab offered a long-term treatment option for controlling the patient's underlying Crohn's disease. An initial loading dose of 160 mg of adalimumab was administered by subcutaneous injection: within 24 h there was a marked reduction in both the leg pain and edema. The patient was discharged after 9 days on amoxicillin 875 mg and clavulanate 125 mg twice daily. In week 2, she received subcutaneous adalimumab 80 mg, and thereafter 40 mg subcutaneous adalimumab was given every other week on an ongoing basis. At the week 4 follow-up, the patient's erythema nodosum had completely resolved (Figure 3). Repeat MRI 3 months after discharge showed some improvement in the patient's fistulizing and sigmoid disease. Unfortunately, 8 months after discharge, the fistulizing disease had progressed, and the frequency of the 40 mg subcutaneous adalimumab injections was increased to once weekly. No further improvement occurred. The patient underwent a permanent ileostomy with proctocolectomy 9 months after discharge, and is currently asymptomatic and off medications.

Figure 3 The pretibial region of the patient 4 weeks after treatment with adalimumab, showing resolution of erythematous nodules and lower-extremity edema.

 

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Discussion of diagnosis

Erythema nodosum is a secondary manifestation of multiple diseases, which means that a detailed evaluation to discover the underlying etiology is essential. Such evaluation should include a thorough history, physical examination and guided laboratory investigations. The annual incidence of erythema nodosum is 1–5 cases per 100,000 individuals,¹ and women aged 15–40 years are most commonly affected. Cases of erythema nodosum tend to exhibit geographic and seasonal clustering indicative of the underlying disease process.

Several diseases and conditions are associated with erythema nodosum: sarcoidosis (11–25% of cases); Behçet's disease; connective-tissue disorders; pregnancy (2–5%); use of oral contraceptives and other medications (3–10%) including sulfonamides, bromides, omeprazole, isotretinoin, zafirlukast and montelukast; infections (particularly tuberculosis, coccidiomycosis and streptococcal infection); lymphoma, leukemia, pancreatitis, Whipple's disease, and IBD (1–4%).^{1, 2} Idiopathic erythema nodosum is, therefore, a diagnosis of exclusion (37–60% of cases).¹ The etiology of erythema nodosum is unclear, but is thought to represent a vigorous, systemic immune response to various antigens, the nature of which depend on population and geography.² Deposition of immune complexes and a delayed hypersensitivity reaction have been implicated in the pathogenesis of erythema nodosum.¹

Clinically, erythema nodosum presents as symmetric, painful, subcutaneous nodules in the pretibial region, which range from 1–5 cm in diameter. Rarely, the nodules can involve the face, thighs, upper extremities, and trunk. The nodules are initially erythematous, and can evolve to a violaceous and finally a yellow or greenish color. Typically, the nodules resolve without scarring, ulceration or atrophy over a period of 2–6 weeks. Erythema nodosum can recur in patients with IBD who experience a flare of intestinal symptoms.³ Polyarthralgia, fever, and malaise can accompany and even precede the appearance of the nodules.

Histologically, erythema nodosum must be differentiated from other disorders such as acute febrile neutrophilic dermatosis (Sweet's syndrome), erythema induratum, Behçet's disease, necrobiosis lipoidica, lupus panniculitis, and nodular fat necrosis.^{1, 2} For patients who have atypical features of erythema nodosum, histologic examination of excisional biopsy samples narrows the differential diagnosis, by revealing septal granulomatous panniculitis (inflammation of the superficial fascia of the subcutaneous fat tissue).⁴ Typically, there is no associated vasculitis.¹ The composition of the nodule infiltrate depends on the age of the lesion.¹ Early-stage lesions are characterized by the presence of neutrophils, edema and hemorrhage. By contrast, late-stage lesions are characterized by lymphocytes, fibrosis, periseptal granulation tissue and the hallmark Miescher's radial granulomas (i.e. histiocytes aggregated around a central, stellate cleft).

Erythema nodosum is the most common cutaneous manifestation of IBD, and occurs in 10–15% of patients with IBD.⁴ Erythema nodosum occurs more commonly in patients who have colonic involvement and/or arthritis⁵ and, typically, parallels disease activity but not severity.³ The incidence of erythema nodosum in patients with Crohn's disease is 15% and in patients with ulcerative colitis is 10%.⁶ The prevalence of erythema nodosum is elevated in Hispanic patients with IBD (odds ratio of 3.3 compared with non-Hispanic white individuals).⁷

Treatment and management

Treatment of erythema nodosum is primarily supportive, and aimed at modifying the underlying disease. Bed rest, anti-inflammatory medications, potassium iodide, hydroxychloroquine, colchicine, and oral or intralesional steroids have been used to hasten the disease course and relieve symptoms.^{1, 2} In cases that are related to IBD, such as the patient described here, treatment of the underlying disease often accelerates the resolution of erythema nodosum. As such, 5-aminosalicylates, steroids and immunomodulators can be appropriate agents to use.

Tumor necrosis factor (TNF)-blocking therapies used to treat patients with IBD can also treat erythema nodosum. Specifically, retrospective case data have demonstrated that the chimeric monoclonal antibody infliximab, given by intravenous infusion, has proven effective in the treatment of erythema nodosum.⁸ Inhibition of TNF has been effective in the off-label treatment of numerous inflammatory dermatologic conditions, including psoriasis, sarcoidosis, hidradenitis suppurativa, cicatricial pemphigoid, Behçet's disease, pyoderma gangrenosum, multicentric reticulohistiocytosis, aphthous stomatitis, subcorneal pustular dermatosis (Sneddon–Wilkinson disease), SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis) syndrome, pityriasis rubra pilaris, eosinophilic fasciitis, panniculitis, necrobiosis lipoidica diabeticorum, dermatomyositis, graft versus host disease, toxic epidermal necrolysis, erythema annulare centrifugum, and scleroderma.⁹ Experience suggests that other biologic therapies might also have a role in the treatment of such conditions.

Adalimumab, a recombinant, humanized mono-clonal antibody against TNF, binds soluble and membrane-bound TNF with high affinity and neutralizes its activity by preventing it from binding to cell-surface receptors.¹⁰ Like infliximab, adalimumab has been shown in vitro to induce apoptosis in monocytes.⁹ Adalimumab has been shown to be an effective treatment for Crohn's disease in patients who are infliximab-naive, and those who have lost their response to or are intolerant of infliximab.^{10, 11, 12} At 4 weeks follow-up¹² and also at 6 months follow-up,¹⁰ remission was achieved in 36–54% of adalimumab-treated patients with Crohn's disease. Injection-site reactions are the most common adverse event experienced by patients taking adalimumab.¹¹ Although long-term safety data are not available for adalimumab in Crohn's disease, the severe complications linked to other anti-TNF therapies—lymphoma, demyelinating disorders, and drug-induced lupus—have so far not been reported. The risk of tuberculosis reactivation remains, however, as with other TNF antagonists.

Compared with infliximab, adalimumab offers the benefits of decreased immunogenicity and subcutaneous administration (an induction course of 160 mg in week 0 and 80 mg in week 2, followed by maintenance doses of 40 mg every other week). Experimental assays demonstrate that only 6–12% of patients develop anti-adalimumab antibodies, which will hopefully result in minimal adverse reactions and a sustained response to therapy.¹¹ The drug is currently approved by the US FDA for the treatment of rheumatoid and psoriatic arthritis and Crohn's disease. Limited case reports have shown adalimumab to be safe during pregnancy and lactation; it is a pregnancy category B drug.¹³

Until now, adalimumab has had limited applications in the treatment of dermatologic conditions. In 2007, a 79-year-old patient with idiopathic, chronic erythema nodosum who failed to respond to conventional therapy was reported to improve with adalimumab 40 mg by subcutaneous injection every other week.¹⁴ Adalimumab has also been used for the treatment of sarcoidosis and multicentric reticulohistiocytosis.⁹ With regard to cutaneous manifestations of Crohn's disease, however, there has been documented use of adalimumab for the treatment of recalcitrant pyoderma gangrenosum, but not erythema nodosum.¹⁵

Conclusions

Erythema nodosum is a common extraintestinal manifestation of IBD that is best treated by controlling the underlying etiology. In this patient, the diagnosis of erythema nodosum was made on the basis of the presence of active Crohn's disease, the lack of medication use and infectious or inflammatory etiologies, and histologic examination of a skin-biopsy sample. For patients whose disease is refractory to conventional medications or for those patients who cannot tolerate conventional medications, adalimumab provides further treatment options. The case described here provides further evidence that adalimumab is of use—albeit as a bridge to surgery in this patient—in the treatment of fistulizing Crohns' disease with erythema nodosum.

Acknowledgments

The views expressed in this article are those of the authors and do not reflect the official policy or position of the US Department of the Navy, US Department of Defense, or the US Government.

References

1. Requena L and Sánchez YE (2007) Erythema nodosum. Semin Cutan Med Surg 26: 114–125 | Article | PubMed | ChemPort |
2. Schwartz R and Nervi S (2007) Erythema nodosum: a sign of systemic disease. Am Fam Physician 75: 695–700 | PubMed |
3. Trost L and McDonnell JK (2005) Important cutaneous manifestation of inflammatory bowel disease. Postgrad Med J 81: 580–585 | Article | PubMed | ChemPort |
4. Weinstein M et al. (2005) Erythema nodosum as a presentation of inflammatory bowel disease. Can Med Assoc J 173: 145–146 | Article |
5. Tavarela Veloso F (2004) Review article: skin complications associated with inflammatory bowel disease. Aliment Pharmacol Ther 20 (Suppl 4): 50–53 | Article |
6. Kethu SR (2006) Extraintestinal manifestations of inflammatory bowel diseases. J Clin Gastroenterol 40: 467–475 | Article | PubMed |
7. Nguyen GC (2006) Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort. Am J Gastroenterol 101: 1012–1023 | Article | PubMed | ISI |
8. Barrie A and Plevy S (2006) Treatment of immune-mediated extraintestinal manifestations of inflammatory bowel disease with infliximab. Gastroenterol Clin North Am 35: 883–893 | Article | PubMed |
9. Graves JE et al. (2007) Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept (part 2 of 2). J Am Acad Dermatol 56: e55–79 | Article | PubMed |
10. Papadakis KA et al. (2005) Safety and efficacy of adalimumab (D2E7) in Crohn's disease patients with an attenuated response to infliximab. Am J Gastroenterol 100: 75–79 | Article | PubMed | ISI | ChemPort |
11. Sandborn W et al. (2004) An open-label study of the human anti-TNF monoclonal antibody adalimumab in subjects with prior loss of response or intolerance to infliximab for Crohn's disease. Am J Gastroenterol 99: 1984–1989 | Article | PubMed | ChemPort |
12. Hanauer SB et al. (2006) Human anti-tumor necrosis factor monoclonal antibody (Adalimumab) in Crohn's disease: the CLASSIC-I Trial. Gastroenterology 130: 323–333 | Article | PubMed | ChemPort |
13. Vesga L et al. (2005) Adalimumab use in pregnancy. Gut 54: 890 | Article | PubMed | ChemPort |
14. Ortego-Centeno N et al. (2007) Refractory chronic erythema nodosum successfully treated with adalimumab. J Eur Acad Dermatol Venereol 21: 409–410 | Article |
15. Fonder MA et al. (2006) Adalimumab therapy for recalcitrant pyoderma gangrenosum. J Burns Wounds 5: e8 | PubMed |

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Subject areas under which this article appears: Inflammatory bowel disease