Prevalence of Firmicutes in Lesions of Hidradenitis Suppurativa in Obese

Letters

Acquisition, analysis, or interpretation of data: Rothschild, Duhon, Riaz, Jetty, Figure. Bilateral Palmar Planar Xanthoma Goldenberg Glueck, Wang. Drafting of the manuscript: Rothschild, Duhon, Riaz, Jetty, Glueck, Wang. Critical revision of the manuscript for important intellectual content: Rothschild, Duhon, Riaz, Jetty, Glueck, Wang, Goldenberg. Statistical analysis: Wang. Obtained funding: Glueck. Administrative, technical, or material support: Glueck, Goldenberg. Study supervision: Glueck. Conflict of Interest Disclosures: None reported. Funding/Support: This study was supported in part by the Lipoprotein Research Fund (this is a fund of the Jewish Hospital-Mercy Health which provides support for The Cholesterol, Metabolism, and Thrombosis Center). Role of the Funder/Sponsor: The Jewish Hospital-Mercy Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. 1. Blom DJ, Byrnes P, Jones S, Marais AD. Dysbetalipoproteinaemia—clinical and pathophysiological features. S Afr Med J. 2002;92(11):892-897. 2. Hachem SB, Mooradian AD. Familial dyslipidaemias: an overview of genetics, pathophysiology and management. Drugs. 2006;66(15):1949-1969. 3. Cho EJ, Min YJ, Oh MS, Kwon JE, Kim JE, Kim CJ. Disappearance of angina pectoris by lipid-lowering in type III hyperlipoproteinemia. Am J Cardiol. 2011; Numerous yellowish maculopapular lesions on the palms. Note the 107(5):793-796. pathognomonic macular yellowish discoloration of the palms, which is limited 4. Cruz PD Jr, East C, Bergstresser PR. Dermal, subcutaneous, and tendon to the creases. xanthomas: diagnostic markers for specific lipoprotein disorders. J Am Acad Dermatol. 1988;19(1 Pt 1):95-111. 5. Eto M, Saito M. [Familial type III hyperlipoproteinemia]. Nihon Rinsho. 2013;71 (9):1590-1594. and how many patients are investigated, given their usually subtle presentation of yellow-orange macules involving the palm creases. These are considered pathognomonic of FD, but Prevalence of Firmicutes in Lesions of Hidradenitis may be confused with planar xanthoma seen in cholestasis dis- Suppurativa in Obese Patients The role of bacteria in the pathogenesis of hidradenitis sup- eases, which are usually white plaques that extend beyond the purativa (HS) remains controversial. Firmicutes is the largest palmar creases.4 Since FD has important cardiac5 and derma- bacterial phylum, and it contains several important and well- tologic manifestations that respond well to treatment,3 iden- known genera, such as Staphylococcus and Streptococcus. tification of FD is critical. Recognition by all physicians, especially dermatologists, Figure. Percentages of Bacterial Species Cultured From Hidradenitis of the rare diagnostic and pathognomonic physical sign of PCXs Suppurativa Lesions Grouped by Phylum of apoE2/2 dysbetalipoproteinemia, opens the door to early di-

agnosis, documentation, and therapy; all focused on resolu- CoNS tion of both cutaneous xanthomas and atherosclerotic le- Staphylococcus aureus sions. The dermatologist is the gatekeeper for early diagnosis Enterococcus MRSA and treatment. Firmicutes Streptococcus anginosus Bacteroidetes Group B streptococci Matan Rothschild, MD Peptostreptococcus Proteobacteria Greg Duhon, MD Viridans streptococci Actinobacteria Rashid Riaz, MD Prevotella Vybhav Jetty, MD Bacteroides Proteus Naila Goldenberg, MD Bacterial Species Escherichia coli Charles J. Glueck, MD Acinetobacter Ping Wang, PhD Pseudomonas Morganella Author Affiliations: Cholesterol, Metabolism, and Thrombosis Center, Klebsiella MMA-Jewish Hospital, Cincinnati, Ohio. Corynebacterium Corresponding Author: Matan Rothschild, MD, Cholesterol, Metabolism, and Actinomyces Thrombosis Center, MMA-Jewish Hospital, 2135 Dana Ave, Suite 430, Cincinnati, 0 5 10 15 20 25 30 OH 45207 ([email protected]). Prevalence, % Accepted for Publication: May 22, 2016. Published Online: September 7, 2016. doi:10.1001/jamadermatol.2016.2223. Shown are the relative frequencies of the bacterial species cultured in our cohort, demonstrating an overall predominance of staphylococci, Proteus, and Author Contributions: Drs Rothschild and Glueck had full access to all of the Corynebacterium species. Bars of the same color represent bacteria within the data in the study and takes responsibility for the integrity of the data and the same phylum. CoNS indicates coagulase-negative staphylococci; accuracy of the data analysis. MRSA, methicillin-resistant Staphylococcus aureus. Study concept and design: Rothschild, Glueck, Wang.

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Table. Differences in Growth of Bacterial Species From Hidradenitis Suppurativa Lesions Grouped by BMIa

Prevalence, No. (%) Variable BMI <30 BMI ≥30 P Value Phylumb (n = 42) (n = 131) Firmicutes 27 (64.3) 113 (86.3) .002 Bacteroidetes 6 (14.3) 21 (16.0) .79 Proteobacteria 15 (35.7) 41 (31.3) .59 Actinobacteria 19 (45.2) 43 (32.8) .14 Abbreviations: BMI, body mass index Bacteria by phylum (n = 47) (n = 142) (calculated as weight in kilograms Firmicutes divided by height in meters squared); Staphylococcus aureus 3 (6.4) 42 (27.5) .002c CoNS, coagulase-negative staphylococci; MRSA, CoNS 15 (31.9) 27 (19.0) .07 methicillin-resistant Staphylococcus MRSA 6 (12.8) 12 (8.5) .38 aureus. Streptococcus anginosus 1 (2.1) 12 (8.5) .19c a Shown is the percentage of cultures Group B streptococci 6 (12.8) 11 (7.8) .30 that grew specific bacterial species in obese (BMI Ն30) vs nonobese Viridans streptococci 2 (4.3) 3 (2.1) .60c (BMI <30) patients with hidradenitis Enterococcus 1 (2.1) 26 (18.3) .004c suppurativa. P values were Peptostreptococcus 0 6 (4.2) .34c calculated using the χ2 statistic unless otherwise noted. Prevalence Bacteroidetes odds ratios, 95% CIs, and P values Prevotella 4 (8.5) 16 (11.3) .79c are adjusted for age (continuous) Bacteroides 1 (4.3) 6 (4.2) >.99c and ethnicity (African American, white, or other). Proteobacteria b Compared with a reference BMI of Proteus 6 (12.8) 38 (26.8) .049 less than 30, the adjusted Acinetobacter 4 (8.5) 5 (3.5) .23c prevalence odds ratios of cultivation Escherichia coli 3 (6.4) 8 (5.6) >.99c in obese patients were 3.1 (95% CI, 1.3-7.1) for Firmicutes, 1.5 (95% CI, Pseudomonas 2 (4.3) 3 (2.1) .60c 0.5-4.4) for Bacteroidetes, 0.8 Klebsiella 0 4 (2.8) .57c (95% CI, 0.4-1.8) for Proteobacteria, Actinobacteria and 0.6 (95% CI, 0.3-1.2) for Actinobacteria. Corynebacterium 17 (36.2) 39 (27.5) .26 c P value was calculated using the Actinomyces 2 (4.3) 1 (0.7) .15c Fisher exact test.

Studies1,2 have consistently reported bacteria from this phy- calculated as weight in kilograms divided by height in meters lum, such as Staphylococcus aureus, coagulase-negative squared). We examined the association between obesity and staphylococci, and Enterococcus species, in tissue samples bacterial culture results (by phyla) using χ2 or Fisher exact and cultures of purulent drainage from HS lesions. The asso- tests. The adjusted prevalence odds ratios (aPORs) for bacte- ciation between obesity and HS is well known, and obesity rial phyla were computed according to obesity status using has also been linked to an increase in bacteria from the Firm- multivariable logistic regression with robust variance estima- icutes phylum in gut microflora.3-5 We hypothesized that this tion, adjusting for variables (age and ethnicity) known to be a change in the microbial milieu that occurs with increasing priori predictors of obesity. body mass index (BMI) may expose patients to different bacterial species that promote a more robust inflammatory Results | The Figure shows the distribution of bacteria cul- response in the skin or hair follicles of patients with HS. This tured from HS lesions by phyla. Of the 239 patients with bac- study aimed to examine the prevalence of Firmicutes in bacterial culture data, 189 patients (79.1%) had available BMI data. terial cultures of purulent drainage from HS lesions and to Of these 189 patients, 142 patients (75.1%) were obese. After explore its potential association with BMI. adjusting for age and ethnicity, the odds of culturing Firm- icutes from HS lesions of obese patients was 3.1 (95% CI, 1.3- Methods | This study was approved by the Johns Hopkins 7.1) times higher than in nonobese patients (Table) and re- Medicine Institutional Review Boards. A waiver of informed mained significant after additional separate adjustments for consent was granted given the retrospective nature of the oral tetracycline use (aPOR, 1.35; 95% CI, 1.07-1.70) and topi- study. We conducted a cross-sectional analysis of 632 cal clindamycin use (aPOR, 1.38; 95% CI, 1.11-1.73). A larger pro- patients diagnosed as having HS between January 5, 2010, portion of obese patients with HS grew S aureus and Entero- and August 27, 2015, at The Johns Hopkins Medical Institu- coccus (Table). The proportion of cultures that grew bacteria tions. The results of the first recorded bacterial cultures of from Bacteroidetes, Proteobacteria, or Actinobacteria phyla purulent drainage from HS lesions were compared between showed no significant differences among obese and non- nonobese (BMI <30) and obese (BMI ≥30) patients (BMI was obese patients.

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Discussion | The results of this study reveal important differ- OBSERVATION ences in the microbiota of HS lesions in obese vs nonobese patients. Gut flora alterations are seen in obese patients,4,5 and Successful Treatment of Refractory Pityriasis HS has been associated with obesity. It is possible that altered Rubra Pilaris With Secukinumab gut or skin flora could have a pathogenic role in HS. Pityriasis rubra pilaris (PRP) is a rare inflammatory skin dis- Some of the limitations of the present study include the order of unknown cause. It is characterized by follicular use of retrospective data and the lack of a control group con- hyperkeratosis, scaly erythematous plaques, palmoplantar sisting of patients with no history of HS. Although these cul- keratoderma, and frequent progression to generalized tures were obtained from purulence extruding from HS le- erythroderma.1 Six types of PRP are distinguished, with type sions, the bacterial culture results could represent skin or gut 1 being the most common form in adults. Disease manage- flora contamination. Information about the specific ana- ment of PRP is challenging for lack of specific guidelines. Topi- tomic locations of HS cultures was not available. Because only cal emollients, corticosteroids, and salicylic acid alone or com- the first recorded culture of each patient was analyzed, it is un- bined with systemic retinoids, methotrexate, and tumor known if the culture results would change with time and fur- necrosis factor (TNF) inhibitors are considered to be most ther antibiotic therapy. The use of data obtained from swab- helpful.2,3 Unfortunately, PRP often resists conventional treat- based cultures may also represent a potential limitation because ment. We report the case of a 67-year-old man with refrac- DNA-based approaches to microbial analysis may yield more tory PRP who was successfully treated with secukinumab. information and lead to identification of organisms that are not cultivable. The use of more advanced microbiome tech- Report of a Case |A 67-year-old man presented with an acute gen- niques may be an important consideration for future studies. eralized, erythematous and scaly eruption with spared patches These data indicate that further research is needed to eluci- of unaffected skin on his chest (Figure 1A). He also had pal- date the role of specific bacterial species in the pathogenesis moplantar keratoderma, nail dystrophy, and severe pruritus. of HS and may suggest a role for targeted treatment of spe- Skin biopsy confirmed the clinical diagnosis of PRP. Before on- cific bacterial species in this disorder. set of the PRP, he had not taken any new medication, and there was no evidence for allergies or chronic skin disorders in his Alessandra Haskin, BA personal or family history. Laboratory tests ruled out any in- Alexander H. Fischer, MPH fection, atopic disposition, autoimmune disease, or cancer. Ginette A. Okoye, MD Treatment was started with acitretin, 35 mg/d, corresponding to 0.5 mg/kg of body weight. In addition, acute flares were Author Affiliations: Ms Haskin was a student at Howard University College of treated with short-term systemic corticosteroid regimens com- Medicine, Washington, DC, at the time of the study. (Haskin); Department of bined with topical class IV corticosteroids. Dermatology, The Johns Hopkins School of Medicine, Baltimore, Maryland After 5 months of treatment, he still had severe pruritus and (Fischer, Okoye). presented with erythroderma, scaling, and palmoplantar kera- Accepted for Publication: May 26, 2016. toderma. Because there were several contraindications for con- Corresponding Author: Ginette A. Okoye, MD, Department of Dermatology, ventional immunosuppressive treatments, treatment was The Johns Hopkins School of Medicine, Johns Hopkins Bayview Medical Center, 5200 Eastern Ave, Ste 2500, Baltimore, MD 21224. switched to secukinumab, a monoclonal anti–interleukin(IL)- Published Online: July 20, 2016. doi:10.1001/jamadermatol.2016.2337. 17A antibody approved for the treatment of moderate to Author Contributions: Ms Haskin and Dr Okoye had full access to all the data in severe plaque psoriasis. After giving written informed con- the study and take responsibility for the integrity of the data and the accuracy sent, the patient received 2 subcutaneous injections of of the data analysis. secukinumab, 150 mg each, once a week for 5 weeks, followed Study concept and design: Haskin, Okoye. by monthly injections. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: All authors. After 3 weeks of secukinumab treatment, the scaling Statistical analysis: Fischer. and pruritus were clearly reduced, and after 8 weeks, pruri- Conflict of Interest Disclosures: None reported. tus and erythema had completely cleared (Figure 1B). Corre- 1. Matusiak Ł, Bieniek A, Szepietowski JC. Bacteriology of hidradenitis spondingly, the typical histopathological features of PRP suppurativa: which antibiotics are the treatment of choice? Acta Derm Venereol. such as hyperplasia, acantholytic dyskeratosis, and hyper- 2014;94(6):699-702. keratosis (Figure 2A) had disappeared after 8 weeks of treat- 2. Lapins J, Jarstrand C, Emtestam L. Coagulase-negative staphylococci are the ment with secukinumab (Figure 2B). After 6 months, the most common bacteria found in cultures from the deep portions of hidradenitis suppurativa lesions, as obtained by carbon dioxide laser surgery. Br J Dermatol. palmoplantar keratoderma had also disappeared, and nail 1999;140(1):90-95. growth was normal. No clinical or laboratory adverse effects 3. Revuz JE, Canoui-Poitrine F, Wolkenstein P, et al. Prevalence and factors were registered. associated with hidradenitis suppurativa: results from two case-control studies. J Am Acad Dermatol. 2008;59(4):596-601. Discussion | The treatment options for PRP are mainly based on 4. Bervoets L, Van Hoorenbeeck K, Kortleven I, et al. Differences in gut clinical observations and are partly adopted from psoriasis microbiota composition between obese and lean children: a cross-sectional therapy because psoriasis shares some clinical and histopatho- study. Gut Pathog. 2013;5(1):10. logical features with PRP.4 In the last decade, various biologi- 5. Ferrer M, Ruiz A, Lanza F, et al. Microbiota from the distal guts of lean and obese adolescents exhibit partial functional redundancy besides clear cal therapies have improved the treatment options of psoria- differences in community structure. Environ Microbiol. 2013;15(1):211-226. sis. Some case reports have also reported successful treatment

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