A Case Report of Majocchi's Granuloma Associated with Combined Therapy of Topical
Steroids and Adalimumab
Wan-Yi Chou, MD (as the first author)
1 Department of Dermatology, China Medical University Hospital, Taichung, 40402,
Taiwan
2 China Medical University, Taichung, 40402, Taiwan
E-mail: [email protected]
Chih-Jung Hsu, MD (as the corresponding author)
1 Department of Dermatology, China Medical University Hospital, Taichung, 40402,
Taiwan
2 China Medical University, Taichung, 40402, Taiwan
2 Yude Road, Taichung, 40447, Taiwan (R.O.C.) E-mail: [email protected] Telephone numbers: +886-975-682-117 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
This case was presented at the Fourth Joint Case Discussion Meeting in Taiwan, Central Division on December 28, 2014, Cheng-Hsin Building Room 112, Chung Shan Medical University, No.110, Sec. 1, Jianguo N. Rd., South Dist., Taichung City 402, Taiwan (R.O.C.) 17 18 19 20 21
A Case Report of Majocchi's Granuloma Associated with Combined Therapy of Topical
Steroids and Adalimumab
ABSTRACT
Introduction Currently tumor necrosis factor alpha (TNF-alpha) inhibitors are widely
used for many autoimmune disorders. However, they cause an immunocompromised status that sometimes leads to many cutaneous side effects including atypical infections. Herein, we report the first case of adalimumab-related Majocchi’s granuloma.
A 43-year-old Taiwanese male patient with chronic plaque-type psoriasis developed numerous tender nodules one month after having adalimumab injection. The nodules responded poorly to bacterial folliculitis treatment. After repeated skin biopsies for pathology and tissue fungal culture, Majocchi’s granuloma was confirmed. Adalimumab was withheld and 12 weeks of terbinafine treatment was given. On completion of
treatment, the nodular skin lesions and dystrophic nail lesions improved dramatically.
ConclusionsThe information, including time span, clinical features, histological findings, and improvement following withdrawal of adalimumab and taking an oral antifungal agent, indicates that Majocchi’s granuloma was adalimumab-related. Psoriasis 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
patients are more susceptible to dermatophyte infection due to local and systemic
immunosuppressant therapy. It is important to perform a thorough examination for latent dermatophyte infection, including skin and nail lesions, before treatment with TNF-alpha inhibitors and during traditional psoriasis treatment. When atypical presentation together with treatment failure is noted in psoriasis patients prescribed biologics, clinicians should investigate evidence of dermatophyte infection and provide proper treatment. Sometimes multiple skin biopsies and tissue fungal cultures are required to establish a correct
diagnosis.
Abbreviations: TNF-alpha = tumor necrosis factor alpha, PASI = psoriasis area severity index, KOH = potassium hydroxide, PAS = periodic acid–Schiff, GMS = Grocott's Methenamine Silver, PCR = polymerase chain reaction, S100A8 = S100 calcium binding protein A8, p38 MAPK = p38 mitogen-activated protein kinase, CARD9 = caspase
recruitment domain–containing protein 9, STAT = signal transducers and activator, IL =
interleukin, MHC = major histocompatibility complex, ICAM-1 = intercellular adhesion
molecule 1, IFN-γ= interferon gamma. 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55
Keywords: psoriasis, tumor necrosis factor alpha (TNF-alpha) inhibitors, adalimumab, Majocchi’s granuloma, dermatophyte, Microsporum gypseum
56 57
INTRODUCTION
Currently tumor necrosis factor alpha (TNF-alpha) inhibitors are widely used for many kinds of autoimmune disorders.1 Among them, adalimumab (HUMIRA®, AbbVie
Inc, North Chicago) is used worldwide in treating plaque-type psoriasis, psoriatic
arthritis, rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, Crohn's disease, and ulcerative colitis.2 Because of the immunocompromised status of patients
who use TNF-alpha inhibitors, risk management plans including tuberculosis and viral hepatitis tests must be done before prescription. Our objective was to relate a case of Majocchi’s granuloma induced by adalimumab, which has not been previously reported. Clinicians should know the possible infection risk and treat infections immediately.
CASE REPORT
A 43-year-old Taiwanese businessman with chronic plaque-type psoriasis developed numerous mildly tender skin nodules one month after receiving adalimumab. He had been diagnosed as having plaque-type psoriasis for two years with thick, scaling plaques on the scalp, neck, lower back, and all four limbs. Nail changes including nail pitting, leukonychia, oil stains, distal ungual crumbling, and subungual hyperkeratosis were also 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74
found (Figure 1A). Initially, topical steroids, Daivobet® ointment (calcipotriol with
betamethasone, LEO Pharma, Ballerup Denmark), oral methotrexate, acitretin and narrow-band ultraviolet radiation B were the main therapy. During treatment, a short period of tinea infection presented as annular erythematous scaly patches and plaques with central clearing on the right forearm, face, and neck. This was confirmed by septated hyphae observed on microscopic examination with 10% potassium hydroxide (KOH). Most of the annular lesions were located on previous psoriatic plaque areas. The tinea corporis was gone after the patient received topical ketoconazole treatment for one month. No remnant annular lesions were seen. However, many psoriatic plaques persisted despite many kinds of traditional psoriatic treatment. His PASI (psoriasis area severity index) score was as high as 24.4. Thus, adalimumab was prescribed at the standard dosage and intervals.
Chronic psoriatic plaques improved gradually, manifesting decreased thickness and scaling. Three months later, most psoriatic plaques were barely visible except for two palm-sized plaques on the lower legs. However, several acute skin eruptions appeared on the nape of the neck one month after the first dose of adalimumab. These lesions
presented as erythematous, mildly tender nodules, and the locations roughly 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91
corresponded to the previous tinea corporis sites (Figure 1B). Even though these lesions were non-pruritic, the patient tried to reduce the lesions by scratching sometimes. These new skin eruptions progressed during the course of treatment with the biologic agent and extended rapidly to the face and four limbs.
We prescribed oral minocycline and topical benzoyl peroxide for one month under an initial diagnosis of folliculitis or furunculosis, but lesions still increased. Skin biopsy was prescribed due to the poor response to treatment. Biopsies were performed three times because the initial pathological diagnosis was inconclusive. The first biopsy showed a ruptured epidermal infundibular-type cyst involving the hypodermis with suppurative abscess formation. However, inflamed ruptured epidermal cysts appeared neither in a cluster nor spread out over a short period of time.
Two subsequent biopsies were arranged. The pathology of the second biopsy demonstrated a small locus of clustered and partially yellow-pigmented fungal hyphae surrounded by suppurative granulomatous inflammation in the deep reticular dermis. The third biopsy revealed destroyed hair follicles containing some septated fungal hyphae surrounded by mild, deep folliculitis and fibrotic granuloma formation. These
intrafollicular fungal spores and hyphae were confirmed using periodic acid–Schiff 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108
(PAS) and Grocott's Methenamine Silver (GMS) stains. Microsporum gypseum complex grew in the soft tissue culture (Figure 1C). However, both fingernail and toenail fungal cultures yielded negative results.
Adalimumab was discontinued after a diagnosis of Majocchi’s granuloma was
established. By this time, the patient had already received adalimumab bi-weekly for five months. All other psoriatic treatment was suspended, including the topical steroid, Daivobet® ointment, and narrow-band ultraviolet radiation B. Meanwhile, we initiated a
systemic antifungal therapy of terbinafine (250 mg) once daily. After 12 weeks of treatment with systemic terbinafine, cutaneous nodules had almost disappeared, and all the nails were almost normal except for minimal pitting (Figure 1D). We performed cryotherapy and prescribed topical 1% butenafine hydrochloride cream for the few remaining lesions on the scalp and thighs. The patient felt no discomfort during the entire treatment course.
DISCUSSION
Adalimumab-induced deep fungal infections, including pulmonary and
disseminated histoplasmosis, coccidioidomycosis, aspergillosis, and blastomycosis, have 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125
rarely been reported.3 One casereported a patient with rheumatoid arthritis and severe
asthma who developed an invasive Trichophyton rubrum infection after she received infliximab (REMICADE®) and long-term prednisolone.4 Herein, we report the first case
of Majocchi's granuloma associated with a combined therapy of topical steroids and adalimumab.
Majocchi’s granuloma (Majocchi granuloma, granuloma trichophyticum, nodular granulomatous perifolliculitis), first described in 1883, may develop on any hair-bearing area, most often the scalp, face, forearms, hands, and legs.5 It is an uncommon, deep
fungal folliculitis related to cutaneous dermatophyte infection.6 The fungi disrupt hair
follicles and spread into the dermis producing a granulomatous inflammation.7
Causative fungi for Majocchi’s granuloma are Trichophyton rubrum, Trichophyton
mentagrophytes, Trichophyton epilans, Trichophyton violaceum, Microsporum audouinii, Microsporum gypseum, Microsporum ferrugineum, and Microsporum canis. The most
common one is Trichophyton rubrum.8 Dermatophytes typically spare underlying living
tissue by not invading deeper structures or disseminating into the blood stream, even in severely immunocompromised hosts, because they require keratin from hair, skin, and nails for survival. Moreover, competition for iron by serum proteins such as transferrin or 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142
activation of the complement system may prevent tissue invasion and dissemination of dermatophytes.8 Both immunocompetent and immunocompromised patients may develop
Majocchi’s granuloma with different clinical presentations (Table 1).5,6,8-10 In
immunocompetent patients, trauma such as scratching or leg shaving, and local
immunosuppression such as topical steroid use are predisposing factors of Majocchi’s
granuloma. Topical steroids are potent inhibitors of T-lymphocyte proliferation that
modify the functions of epidermal/dermal cells and leukocytes, are well known agents
that increase the risk of dermatophyte infection.11
Why did our patient develop majocchi’s granuloma? First, before developing
Majocchi’s granuloma, our patient received potent topical steroids and Daivobet®
ointment, which would lead to local immunosuppression. Second, adalimumab was
administered for better control due to inadequate clinical response to topical agent and
phototherapy, which might cause systemic immunosuppression. Adalimumab, a
TNF-alpha inhibitor, suppresses cell-mediated immunity and inflammatory response, and
might broke the defenses against invasion by dermatophytes.1
Dermatophyte species and Candida spp. share common cell wall carbohydrates and
are recognized by the same innate immune mechanisms such as Dectin-1 and Dectin-2, 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159
and induce similar adaptive response.12 Antimicrobial mechanisms include innate
immunity, adaptive immunity, and phagocytosis. We list these mechanisms and immune
deficiencies associated with dermatophyte and Candida infection in table 212-19. The
following are three possible mechanisms of TNF-alpha inhibitor related dermatophyte
and Candida infection.
First, S100 calcium binding protein A8 (S100A8), the antimicrobial peptide, is
upregulated in psoriatic skin and exerts antifungal activity. TNF-alpha and interleukin
(IL) -17A induced S100A8 mRNA and protein via p38 mitogen-activated protein kinase
(MAPK) pathway. Significantly decreased in S100A8 mRNA at treatment day 14 are
seen in psoriasis patient received adalimumab.13
Second, transforming growth factor beta 1, interferon gamma (IFN-γ), IL-6, and IL-22
induce podoplanin-expression in keratinocytes, which might be significantly involved in
the pathogenesis of psoriatic hyperproliferative epidermis. IFN-γ, IL-6, and IL-22
upregulate the podoplanin expression in both signal transducers and activator (STAT)-1-
and STAT-3-dependent manner.20 Patients with deficiencies in innate (dectin-1, CARD9,
IL12RB1) or adaptive immunity (interleukin (IL)17-F, IL-17 receptor, STAT1, STAT3,
antibodies to Th-17 cytokines) that disrupt the Th-17 pathway, cannot clearance 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176
superficial Candida or Dermatophyte infections.14 Though TNF-alpha inhibitors suppress
the activity of psoriasis via increasing phospho-STAT4 and 6,16 no previous studies report
the relationship between TNF-alpha inhibitors and STAT 1 and 3. The exact interaction
between TNF-alpha inhibitors and STAT 1 and 3 requires further study.
Third, peripheral mononuclear cells release IFN-gamma in response to dermatophyte
compound stimulation with elevated serum levels of TNF-alpha.17 TNF-alpha inhibitors
decrease the TNF-alpha level, and might impair the response to dermatophyte infection.
Whether psoriasis patients have a higher incidence of dermatophyte infection
remains a debated issue. Authors who found increased incidence of dermatophyte
infection pose a hypothesis that morphological abnormalities in psoriatic nails (e.g.
hyperkeratosis and onycholysis) and the use of systemic and topical immunosuppressive
drugs are predisposing factors for invasion of the nail by microorganisms. They believe
abnormal capillary units in psoriatic nail impair the defense normally supplied by healthy
hyponychium and weakens the nail defense system against invading microorganisms. In
contrast, the others who had decreased incidence think the immune response against
microbial skin infections is stronger in psoriasis. Besides, psoriatic nails have a higher
turnover and desquamation rate, and could lower the nail keratin invasion rate by fungal 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193
organism. A systemic review conducted by Klaassen KM et al. indicated that the
prevalence of onychomycosis in psoriatic patients seem to be increased when compared
with control groups and literature on healthy population, although the ultimate evidence
remains lacking.21 In addition, psoriasis patients frequently receive systemic and topical
immunosuppressive drugs that may facilitate the development of dermatophyte
infections.21
Majocchi’s granuloma usually begins as a non-pruritic solitary patch or as multiple well-circumscribed oval patches. Then it becomes clustered perifollicular papulopustules, nodules, or erythematous, granulomatous lesions.6 Onychomycosis is a huge reservoir of
dermatophytes.7 Thus, inquiry should be made about a history of tinea pedis, corporis or
onychomycosis in susceptible patients.6 Sometimes skin and nail lesions associated with
psoriasis and tinea infection share similar clinical presentation; therefore, KOH
preparation and fungal culture could be useful tools for differentiation between psoriatic nails and onychomycosis and between annular resolving psoriatic plaques and annular tinea plaques. Because KOH preparation can only detect fungi located in the stratum corneum, the result may be negative for Majocchi’s granuloma due to deeper invasion of the fungi into the dermal follicular component. In such circumstances, a skin biopsy with 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210
special staining (PAS or GMS) and tissue fungal culture may be more diagnostic.6 A
negative result on microscopy cannot exclude the diagnosis of Majocchi’s granuloma.5
Other tests, such as the trichophytin skin test and body (Mycobacteriumand anti-Trichophyton antibodies) and polymerase chain reaction (PCR)-based molecular typing, could yield variable results.7
Treatment of Majocchi’s granuloma includes removing predisposing factors (such as topical steroid use, occlusion, and leg shaving) and prescribing a combination of topical and systemic antifungal therapy.6 Most antifungals exert only fungistatic activity and only
temporarily inhibit fungal growth. Recurrence will be noted if this treatment is too short. Newer antifungal agents such as terbinafine provide fungicidal and likely immuno-stimulating activity on neutrophils.5 If onychomycosis is identified, a 12-week course of
terbinafine treatment is indicated. Dermatophytosis may respond slowly to therapy at first and have a tendency to relapse.8 Cryotherapy can be considered in refractory cases.5
In conclusion, atypical clinical behavior such as progressive and rapid development of newer lesions and treatment failure in psoriasis patients who have been prescribed biologics should alert care providers to investigate symptoms of dermatophyte infection. Longer treatment and potentially toxic antifungals may be needed if delayed diagnosis 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227
causes more extensive involvement.6 Surgical debridement may also be required in severe
cases.6,7 Sometimes multiple skin biopsies and tissue fungal cultures are needed to
establish a correct diagnosis. As a result, a thorough physical examination and additional tests for latent dermatophyte infection, including skin and nail lesions, before treatment with TNF-alpha inhibitors and during traditional psoriasis treatment are important.
The limitation of our report is that we have only one case. Therefore, the incidence of this significant adverse effect requires further investigation. The information, including time span, clinical features, histological findings, and improvement following withdrawal of adalimumab and taking an oral antifungal agent, indicates that Majocchi’s granuloma was adalimumab-related.
CONCLUSION
Psoriasis patients seems to be susceptible to dermatophyte infection due to local and systemic immunosuppresion therapy. A thorough physical examination and additional tests for latent dermatophyte infection, including skin and nail lesions, before treatment with TNF-alpha inhibitors and during traditional psoriasis treatment are important. During treatment with biologics, when acute skin lesions develop with atypical clinical 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244
morphology and persist even under ongoing biologic treatment, clinicians should investigate evidence of dermatophyte infection and provide proper treatment as soon as possible. Multiple skin biopsies and tissue fungal cultures are sometimes required to establish the diagnosis. To our knowledge, this is the first case of adalimumab-related Majocchi’s granuloma. 245 246 247 248 249
ACKNOWLEDGEMENTS
We are indebted to the assistance of Rose Kastelic, B.A., M.A. for her English editing of this manuscript. There was no financial compensation for this contribution. 250
251 252
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Figure 1A. Nail lesions before adalimumab injection: nail pitting (arrowheads), leukonychia, oil stains, distal ungual crumbling and hyperkeratosis (arrow).
Figure 1B. Clinical presentation of Majocchi’s granuoloma: multiple erythematous papulonodules developed one month after adalimumab injection.
Figure 1C. Microsporum gypseum: fungal hyphae (arrowheads) highlighted with Grocott's Methenamine Silver (GMS) stain (original magnification X400).
Figure 1D. Nail lesions after 12-week terbinafine treatment: almost all hyperkeratotic nails have returned to normal except for mild nail pitting on a few nails (arrowheads). 313 314 315 316 317 318 319 320 321 322 323
