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JCR: Journal of Clinical Rheumatology:
doi: 10.1097/RHU.0000000000000100
Case Reports

Successful Management of Refractory Pediatric-Onset Complex Aphthosis With Lenalidomide

Kalampokis, Ioannis MD, MPH*; Rabinovich, C. Egla MD, MPH

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From the *Department of Immunology and †Division of Pediatric Rheumatology, Department of Pediatrics, Duke University Medical Center, Durham, NC.

The authors declare no conflict of interest.

Correspondence: C. Egla Rabinovich, MD, MPH, Division of Pediatric Rheumatology, Department of Pediatrics, Duke University Medical Center, Box 3212, Durham, NC 27710. E-mail: egla.rabinovich@duke.edu.

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Abstract

Abstract: Clinicians are frequently confronted with patients presenting with oral aphthous ulcers or orogenital aphthae. Patients with complex aphthosis are characterized by the nearly constant presence of more than 3 oral aphthous ulcers or recurrent orogenital aphthae but do not satisfy the criteria for Behçet disease. We report a severe case of pediatric-onset complex aphthosis with poor response and/or significant toxicity to first-line medications. Lenalidomide, a second-generation immunomodulatory drug, induced a complete disease remission within few days of therapy. The patient has been treated for nearly 3 years with significant subjective and clinical improvement and no adverse effects. Thereby, lenalidomide may represent a well-tolerated and effective medication for patients with complex aphthosis who are intolerant or not responsive to first-line agents. Nevertheless, in view of the rare but serious potential adverse effects of lenalidomide such as teratogenicity and cancer, a clinical trial is necessary to assess the true risk-to-benefit ratio for the use of lenalidomide in patients with complex aphthosis.

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CASE REPORT

A 17-year-old white male adolescent presented with a long history of recurrent oral aphthae and chronic mucocutaneous candidiasis. Family history was negative for recurrent aphthous stomatitis (RAS), complex aphthosis (CA), and autoimmune or autoinflammatory diseases. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, which presents with early-onset chronic mucocutaneous candidiasis, was excluded after testing negative for AIRE (autoimmune regulator) mutations. The oral aphthae had been constantly present since early childhood with numbers waxing and waning in a rather predictable pattern. Typically, 40 to 50 painful oral ulcers extending from the lips to the oropharynx and interfering with speech and food intake would last for 10 days, resulting in a 10-kg weight loss. This would be followed by a 3-week period with decrease in the numbers of ulcers and partial regain of the lost weight; at the end of these 3 weeks, a new cycle would start. At the age of 16 years, he had 3 brief self-resolving episodes of mono-ocular field loss; at the time, he had normal brain imaging and neuro-ophthalmology assessment, and the presumptive diagnosis of retinal vasospasm was made. The clinical picture was further complicated by laboratory abnormalities of unclear significance such as positive p-ANCA and anti-CBir1. Endoscopic assessment of his gastrointestinal tract with biopsy ruled out inflammatory bowel disease. The patient has been antinuclear antibody–positive on multiple occasions (1:160 to 1:2560, speckled and/or nucleolar pattern). Anti–double-stranded DNA and anti-Smith antibody were negative, serum complement levels were normal, and there were no other laboratory features suggestive of systemic lupus erythematosus or mixed connective tissue disease. Other underlying conditions were ruled out including cyclic neutropenia, autoinflammatory syndromes, Sweet syndrome, nutritional deficiencies, gluten-sensitive enteropathy, and viral infections (HIV, herpes simplex virus). Pathergy test was negative. The patient did not satisfy the criteria for Behçet disease (BD), and he was assigned the diagnosis of CA.

Previous treatments never fully resolved his lesions and had variable effectiveness in reducing his symptoms. These included topical and systemic corticosteroids (doses of 40–60 mg daily induced a brief partial response), colchicine (0.6 mg twice daily for 3 months), dapsone (100 mg for 2 weeks, and then the patient experienced a major disease flare), and fluconazole (used as needed for candidiasis). The patient refused tumor necrosis factor α (TNF-α)–blocking therapy. He responded best to high-dose oral corticosteroids, although they did not completely clear his lesions even at high doses (60 mg of prednisone daily); colchicine was not tolerated because of gastrointestinal adverse effects (abdominal pain, cramping, diarrhea), whereas dapsone was ineffective in the short term.

The patient was treated with 5 mg of lenalidomide monotherapy daily, resulting in clinical improvement within 2 days and complete symptom resolution within 5 days. He remains on the medication for almost 3 years, and no recurrences or new symptoms have developed. His dose was gradually decreased to 5 mg every 3 days without loss of therapeutic effect. Importantly, not only did his mouth ulcers resolve, but also his growth parameters improved dramatically. No adverse effects have been reported. Monitoring of complete blood counts and liver function tests every 2 to 3 months during treatment (every 2 weeks during the first month of treatment) showed no evidence of myelosuppression or hepatotoxicity.

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DISCUSSION

Clinicians are often confronted with patients presenting with orogenital aphthae. A diagnostic classification scheme for patients with recurrent aphthous ulcers has been proposed.1 Patients with recurrent attacks of minor, major, or herpetiform aphthae with distinct ulcer-free periods are diagnosed with RAS. Individuals with nearly constant presence of more than 3 oral aphthous ulcers or with recurrent orogenital aphthae should be further evaluated to rule out BD; when BD is excluded, they are labeled as having CA. In fact, some investigators consider CA as a forme fruste of BD.2 Therefore, the diagnosis of CA represents the part of the aphthous ulcer continuum between RAS and BD. The international criteria for BD have never been validated in children. Furthermore, children usually present with several years (up to a decade or more) of oral ulcers before the development of the full triad (oral ulcers, genital ulcers, and eye disease). Therefore, some pediatric patients with CA represent patients who will eventually satisfy the criteria for BD. Complex aphthosis is divided into primary (idiopathic) and secondary to another underlying disease such as cyclic neutropenia, certain autoinflammatory syndromes (such as Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome), Sweet syndrome, nutritional deficiencies (such as iron, zinc, or vitamin B12), gastrointestinal disorders (such as inflammatory bowel disease or gluten-sensitive enteropathy), or viral infection (such as HIV).1

Although the clinical features of CA have been defined, the etiology underlying its pathogenesis remains unclear. Because CA is considered an incomplete form or even a precursor of BD, it may be that factors playing a role in the pathogenesis of BD are also involved in the pathogenesis of CA. Behçet disease is proposed to be triggered by environmental factors in genetically susceptible individuals.3 Multiple studies have demonstrated a strong association with HLAB51.4 Other genes, both major histocompatibility complex and non-major histocompatibility complex associated, have been implicated such as a TNF-α promoter polymorphism5 that failed to be confirmed in follow up genome-wide association studies.4 However, genome-wide association studies confirmed a previously reported association of interleukin 23 receptor (IL-23R) polymorphisms and BD.6 Potential environmental triggers include bacteria (especially oral streptococci such as Streptococcus sanguis), viruses, and heat shock proteins (HSPs)6; molecular mimicry has been implicated particularly in the context of the homology between bacterial HSP65 and the human HSP60. A variety of other immunologic abnormalities have been described, including but not limited to polyclonal expansion of γδ T cells,7 up-regulation of cytokines (such as IL-6),8,9 and TH1 and/or TH17 polarized T-cell phenotypes along with an altered TH1/TH17 ratio.9,10

Management of patients with CA can be very challenging. The medications used for the management of CA fall into 2 groups based on the method of administration: topical and systemic. Topical agents such as corticosteroids and antimicrobials reduce only the symptoms of ulcerations at best but do not prevent recurrences. Although systemically administered agents are more effective than topical agents in preventing recurrences, their long-term use is limited by the occurrence of significant adverse effects that outweigh clinical benefit. One such systemic medication is thalidomide, which has shown efficacy in RAS and BD. However, its use is limited by the high incidence of adverse effects, specifically peripheral neuropathy. Lenalidomide, a derivative of thalidomide, is much more potent than thalidomide with minimal neurotoxicity.11–13 We hypothesized that lenalidomide will be well tolerated and effective in controlling our patient’s symptoms and prevent recurrences.

Lenalidomide, a second-generation immunomodulatory drug developed by modifying the backbone of thalidomide, is currently approved by the US Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome and multiple myeloma. It is rapidly absorbed following oral administration; 30% is bound to plasma protein, and two thirds of the absorbed drug is excreted unchanged in the urine with a half-life of 3 hours.14,15 The high incidence of neurotoxicity associated with the use of thalidomide16 frequently renders the drug poorly tolerated, thus limiting its use. Lenalidomide is associated with a higher risk of myelosuppression when compared with thalidomide and also has the unique adverse effect of drug-induced hepatitis. Immunomodulatory drugs have a variety of immune system effects, some of which may explain the effectiveness of lenalidomide in our case as well as in a previously reported case with BD.17 Tumor necrosis factor α and IL-6 are important inflammatory mediators in BD; thalidomide inhibits their production by human monocytes ex vivo.13 The fact that lenalidomide has anti–TNF-α and anti–IL-6 activities similar to thalidomide13 but with a more favorable adverse effect profile led us to use it in our patient.

To our knowledge, this case represents the first pediatric-onset patient with CA treated with lenalidomide reported in the literature. Lenalidomide therapy induced a complete disease remission over the course of few days that has been sustained for nearly 3 years. Disease remission was accompanied by significant improvements in the patient’s growth parameters and subjective improvement in his quality of life. In view of the patient’s extensive involvement and continuous nature of his symptoms, we could almost certainly exclude the possibility of spontaneous improvement unrelated to lenalidomide therapy. Therefore, we conclude that the use of lenalidomide in this case of CA was safe and effective. Lenalidomide may represent a safe and effective drug for CA patients where first-line medications have failed or were not tolerated. Nevertheless, safety concerns remain, especially in the pediatric population where the effects of long-term lenalidomide use are unknown. The increased risk of malignancy is of main concern, especially following the May 2012 FDA warning for increased risk of secondary malignancies. In view of the established risk of teratogenicity with thalidomide and the recent company reports of teratogenic effects of lenalidomide on primates, strict adherence to contraception methods is mandatory during therapy, with strict FDA guidelines in place to prevent pregnancies. Furthermore, lenalidomide is currently much more expensive than thalidomide in most countries, and whether the increased cost is justified by the increased drug potency and the decreased incidence of adverse effects needs to be formally evaluated. Anti–TNF-α agents are another high-cost treatment option for patients with CA; however, the parenteral route of administration often limits their use, especially in pediatrics. In the future, a clinical trial should evaluate the safety, clinical efficiency, and cost-effectiveness of lenalidomide in the management of patients with CA.

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REFERENCES

1. Letsinger JA, McCarty MA, Jorizzo JL. Complex aphthosis: a large case series with evaluation algorithm and therapeutic ladder from topicals to thalidomide. J Am Acad Dermatol. 2005; 52 (3 pt 1): 500–508.

2. Jorizzo JL, Taylor RS, Schmalstieg FC, et al. Complex aphthosis: a forme fruste of Behcet’s syndrome? J Am Acad Dermatol. 1985; 13: 80–84.

3. Pineton de Chambrun M, Wechsler B, Geri G, et al. New insights into the pathogenesis of Behcet’s disease. Autoimmun Rev. 2012; 11: 687–698.

4. de Menthon M, Lavalley MP, Maldini C, et al. HLA-B51/B5 and the risk of Behcet’s disease: a systematic review and meta-analysis of case-control genetic association studies. Arthritis Rheum. 2009; 61: 1287–1296.

5. Amoura Z, Dode C, Hue S, et al. Association of the R92Q TNFRSF1A mutation and extracranial deep vein thrombosis in patients with Behcet’s disease. Arthritis Rheum. 2005; 52: 608–611.

6. Mizuki N, Meguro A, Ota M, et al. Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet’s disease susceptibility loci. Nat Genet. 2010; 42: 703–706.

7. Accardo-Palumbo A, Giardina AR, Ciccia F, et al. Phenotype and functional changes of Vgamma9/Vdelta2 T lymphocytes in Behcet’s disease and the effect of infliximab on Vgamma9/Vdelta2 T cell expansion, activation and cytotoxicity. Arthritis Res Ther. 2010; 12: R109.

8. Akman-Demir G, Tuzun E, Icoz S, et al. Interleukin-6 in neuro-Behcet’s disease: association with disease subsets and long-term outcome. Cytokine. 2008; 44: 373–376.

9. Ben Ahmed M, Houman H, Miled M, et al. Involvement of chemokines and TH1 cytokines in the pathogenesis of mucocutaneous lesions of Behcet’s disease. Arthritis Rheum. 2004; 50: 2291–2295.

10. Kim J, Park JA, Lee EY, et al. Imbalance of TH17 to TH1 cells in Behcet’s disease. Clin Exp Rheumatol. 2010; 28 (4 suppl 60): S16–S19.

11. Kotla V, Goel S, Nischal S, et al. Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol. 2009; 2: 36.

12. Chaulet C, Croix C, Alagille D, et al. Design, synthesis and biological evaluation of new thalidomide analogues as TNF-alpha and IL-6 production inhibitors. Bioorg Med Chem Lett. 2011; 21: 1019–1022.

13. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999; 163: 380–386.

14. Celgene Corporation. Revlimid (lenalidomide) 5 mg, 10 mg, 15 mg and 25 mg capsules prescribing information USA. Available at: http://www.revlimid.com/pdf/REVLIMID_PI.pdf. Accessed February 2013.

15. Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer. 2004; 4: 314–322.

16. Mileshkin L, Stark R, Day B, et al. Development of neuropathy in patients with myeloma treated with thalidomide: patterns of occurrence and the role of electrophysiologic monitoring. J Clin Oncol. 2006; 24: 4507–4514.

17. Green J, Upjohn E, McCormack C, et al. Successful treatment of Behcet’s disease with lenalidomide. Br J Dermatol. 2008; 158: 197–198.

Keywords:

complex aphthosis; aphthous ulcers; orogenital aphthae; genital ulcers; lenalidomide; thalidomide

© 2014 by Lippincott Williams & Wilkins, Inc.

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