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Successful Re-Treatment of Generalized Granuloma Annulare with AdalimumabMichael Zaycosky, DO, MS / Jeffrey Collins, DO / Jere Mammino, DOOrlando Dermatology Residency / KCU GME / Orlando, FL

IntroductionThe first case of granuloma annulare (GA) was described by Calcott Fox as “ringed

eruptions of the fingers” in 1895.2 Today, the cause of this dermal inflammatory process is still not well understood.3

GA has been associated with some medications, trauma, diabetes mellitus, thyroid diseases, tuberculosis, borreliosis, and malignancies. It is also believed that there is some association between GA and some infectious agents, e.g., hepatitis C virus, human immunodeficiency virus, and Epstein–Barr virus.1,4

It exists in several forms. Localized GA is the most common, it presents on the distal extremity as an erythematous, non-scaly, annular plaque. Generalized GA, which makes up less than 25% of total cases presents as scattered erythematous papules and plaques on the trunk and extremities.5 While localized GA is typically self-limiting and more of a cosmetic concern, generalized GA rarely resolves spontaneously and can be recalcitrant to treatment.6 Though more than 30 treatments have been described in the literature no well-established treatment protocols exist.7 This article will focus on the use of adalimumab as a successful treatment option for generalized GA.

Case ReportA 45 year old female presented to the office with a 9 month history of

progressively enlarging rash on her lower legs (Figure 1 and 2). Patient denied any associated symptoms or precipitating factors, including fevers, chills, pain, pruritis, joint aches, or recent infections. Past medical history was limited to seasonal allergies which she took loratadine daily.

Cutaneous examination revealed a Fitzpatrick type 3 patient with scattered erythematous to violaceous annular plaques and papules on her bilateral lower legs. There was no overlying scale or ulceration and the remainder of the skin exam was unremarkable. She was clinically diagnosed with generalized granuloma annulare and agreed to a confirmatory punch biopsy. This revealed necrobiotic centers of degraded matrix surrounded by infiltrate of macrophages and lymphocytes consistent with granuloma annulare.

Over the course of the next several months, the patient was treated with topical steroids, dapsone, pentoxifylline, and isotretinoin with minimal improvement. During this period, affected area spread to include her abdomen and arms. Blood work performed during this period included a complete blood count, comprehensive metabolic profile, lipid panel, hepatic panel, and qualitative beta hCG. Due to the limited response of the prior medications, the use of adalimumab was discussed, along with a lengthy discussion regarding the risk and benefits, and the patient was agreeable to trial the medication.

Prior to starting therapy with adalimumab screening for hepatitis B, hepatitis C, and tuberculosis were performed, all of which were negative. The patient was started on an initial subcutaneous dose of adalimumab 80mg followed by 40mg doses every 2 weeks. Within 4 weeks of starting therapy, there was significant fading of existing plaques with no new plaques noted. At 12 weeks there was limited post inflammatory hyperpigmentation, which was resolved completely at the 9 month visit. At this point, the adalimumab dosing began to be tapered slowly over an 8 month period.

Our patient remained clear for 7 months off adalimumab when she presented to the office with small pink annular plaques on both lower legs. Screening blood work was repeated and the patient was started on loading dose of adalimumab once again. Response was near identical to the first dosing with fading of plaques and no new areas at 3 month follow up. At the time of this case report being written, the patient remains clear and is in the tapering phase receiving adalimumab 40mg every 3 weeks.

Clinical Photographs

• Figures 1 and 2: Clinical photographs taken on initial presentation

DiscussionThere have been numerous treatments for generalized granuloma annulare all

with varying limited success. This case supports the recent article of 7 patients who had similarly impressive clearance with adalimumab in GA.7 Our case further illustrates successful re- challenging of adalimumab after disease recurrence.

Granuloma annulare can exist in many forms but is most commonly a self-limited, benign cutaneous disease that classically presents as annular plaques located on the extremities of young people.2 While benign, these lesions can cause significant cosmetic distress to the patient and cause social withdrawal. The cause of GA is unknown but insect bite reactions, sun exposure, trauma, tuberculin skin testing, PUVA therapy, and viral infections have all been proposed as the initiating factor.8

Localized GA is the most common form followed by generalized but other subtypes exist including subcutaneous, perforating, and patch. Localized GA typically presents as well defined annular papules or plaques on arms, legs, hands, or feet.1,2

50% of patients will have more than one plaque and the face is almost never involved.5 Generalized GA is more widespread with papules and plaques coalescing together to involve large areas most commonly on the trunk and extremities. Cosmetically this can cause significant distress and social withdrawal. These areas usually spontaneously clear but can take up to a decade for complete resolution. 9

Differential diagnosis for GA can be broad and vary widely depending on the specific morphology of the lesion and its anatomical location. It is commonly mistaken for tinea corporis, but can be differentiated by the absence of scale. Arthropod bites can be a confounding diagnosis especially in the early papular state. Other differential diagnoses include annular lichen planus, cutaneous sarcoidosis, tuberculoid leprosy or erythema annulare centrifugum.10

Tumor necrosis factor (TNF) is released by a variety of cells including macrophages and T lymphocytes in response to a variety of stimuli. TNF has numerous biologic effects including antiviral and antitumor activity. 11 Tumor necrosis factor-alpha (TNF-α) is the prototypical member of a family of cytokines which are involved in pro-inflammatory responses, pro-apoptosis, cell activation, and granuloma formation in both infectious and noninfectious states.12 The concentration of TNF-α is elevated in several rheumatic diseases, such as psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, Crohn's disease.13

Treatment of GA with adalimumab has been reported several times in the literature, 7,10,14 the importance of this case study is showing its tremendous efficacy when retreating the patient after complete cessation of the medication. Further studies are needed to elucidate effective treatment protocols including dosing and length of taper. If further studies continue to show similar dramatic resolution of GA, we suspect that adalimumab will rapidly rise towards first line therapy of generalized GA. Practically, cost and insurance will be large barriers towards faster adoption. Although a benign condition, it can have devastating psychosocial and cosmetic effects on patients and for this reason treatment options need further exploration.

Bibliography1 James WD, Berger TG, Elston DM, Andrew’s Diseases of the Skin. 11th ed. p. 694.

2 Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd rev. ed. Philadelphia: Elsevier Limited; 2012 p. 1563.

3 Suzuki T, et al. Subcutaneous granuloma annulare following influenza vaccination in a patient with diabetes mellitus. Dermatologica 2014; 32:55.

4 Mondhipa Ratnarathorn, Siba P Raychaudhuri, and Stanley Naguwa. Disseminated Granuloma Annulare: A Cutaneous Adverse Effect of Anti-TNF Agents. Indian J Dermatol. 2011 Nov-Dec; 56(6): 752-754.

5 Muhlbauer JE. Granuloma Annulare. J Am Acad Dermatol 1980; 3:217.

6 Thornsberry LA, English JC III. Etiology, diagnosis, and therapeutic management of granuloma annulare: an update. Am J ClinDermatol. 2013; 14(4):279-290.

7 Min MS, Lebwohl M. Treatment of recalcitrant granuloma annulare (GA) with adalimumab: A single-center, observational study. J Am Acad Dermatol. 2016; 74(1):127-131.

8 Mills A, Chetty R. Auricular granuloma annulare. A consequence of trauma? Am J Dermatopathol.1992;14:431–3.

9 Dabski K, Winkelmann RK. Generalized granuloma annulare: clinical and laboratory findings in 100 patients. J Am Acad Dermatol1989; 20:39.

10 Brodell, RT. Granuloma Annulare. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on April 22, 2016.)

11 WinthropKL: Risk and Prevention of tuberculosis and other serious opportunistic infections associated with the inhibition of tumor necrosis factor. Nature 2006, 2(11), 602-610.

12 Fayyazi A, Schweyer S, Eichmeyer B, et al. Expression of IF- Ngamma, coexpression of TNFalpha and matrix metallopro- teinasesand apoptosis of T lymphocytes and macrophages in granuloma annulare. Arch Dermatol Res. 2000;292:384-390.

13 Mirshahi A, Hoehn R, Lorenz K, Kramann C, Baatz H. Anti-tumor necrosis factor alpha for retinal diseases: current knowledge and future concepts. J Ophthalmic Vis Res. 2012;7: 39–44.

14 T Torres T, Pinto Almeida T, Alves R, Sanches M, Selores M. Treatment of recalcitrant generalized granuloma annulare with adalimumab. J Drugs Dermatol. 2011 Dec;10(12):1466-8.

15 Kui R, Gál B, Gaál M, Kiss M, Kemény L, Gyulai R. Presence of antidrug antibodies correlates inversely with the plasma tumor necrosis factor (TNF)-α level and the efficacy of TNF-inhibitor therapy in psoriasis. J Dermatol. 2016.

16 Bito T, Nishikawa R, Hatakeyama M, et al. Influence of neutralizing antibodies to adalimumab and infliximab on the treatment of psoriasis. Br J Dermatol. 2014;170(4):922-929.

17 Hsu L, Snodgrass BT, Armstrong AW. Antidrug antibodies in psoriasis: a systematic review. Br J Dermatol. 2014;170(2):261-273.

18 Anderson S, Bloom KJ, Vallera DU, et al. Multisite analytic performance studies of a real-time polymerase chain reaction assay for the detection of BRAF V600E mutations in formalin-fixed, paraffin-embedded tissue specimens of malignant melanoma. Arch PatholLab Med. 2012;136(11):1385-1391.

19 Vincent FB, Morand EF, Murphy K, Mackay F, Mariette X, Marcelli C. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis. 2013;72(2):165-178.

20 Gottlieb AB, Evans R, Li S, et al. Infliximab induction therapy for patients with severe plaque-type psoriasis: a randomized, double-blind, placebo-controlled trial. J Am Acad Dermatol. 2004;51(4):534-542.

Fig. 1 Fig. 2

TNF-α inhibitors (etanercept, adalimumab, infliximab, golimumab, and certolizumab pegol) have been used for more than a decade to successfully control the aforementioned conditions and others off label. Adalimumab is a fully human monoclonal antibody which specifically binds to membrane and soluble TNF-α with high affinity. Etanercept binds only soluble TNF-α and interestingly has more reports of treatment failure than success. This binding difference explains why TNF-α inhibitors cannot be used interchangeably.14

Neutralizing anti-adalimumab antibody formation exists in 6-50% of psoriasis patients and is correlated with loss of efficacy, clinically more severe disease and higher measured serum TNF- α levels.15-17 A correlation appears to exist as higher anti-drug antibody titers predict loss of response and treatment failure.16 The titer level seems particularly important, as patients with low titers still had the same beneficial response as patients with no drug neutralizing antibodies.18 Higher sustained TNF inhibitor doses and concomitant use of immunosuppressives like methotrexate were associated with lower anti-drug antibody formation.19 Therefore, it has been hypothesized that vacations from TNF inhibitor therapy and longer time on therapy raise the likelihood of antibody formation.19,20 In our patient, the 7 month drug holiday did not decrease clinical response.

Conclusion