SKIN - July - IDR - 1134 proof returned SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 333 IN-DEPTH REVIEW Treatment of Pyodermatitis-Pyostomatitis Vegetans: A Systematic Review and Meta-Analysis Landon K. Hobbs, BS1*, Alina G. Zufall, BA1*, Shadi Khalil, MD, PhD2, Richard H. Flowers, MD1 1Department of Dermatology, University of Virginia School of Medicine, Charlottesville, VA 2Department of Dermatology, University of California San Diego, San Diego, CA *Contributed equally as first authors Pyodermatitis-pyostomatitis vegetans is a rare mucocutaneous disorder often associated with inflammatory bowel disease (IBD) that can be extremely difficult to treat. Due to is rarity, no standardized trials exist comparing the efficacy of different medications, and recommendations for treatment of this disease are limited and not evidence-based. Pyodermatitis vegetans (PDV) was first described by the French dermatologist Francois Hallopeau in 1898 as a distinct disease of vegetating plaques of the skin which he termed “pyodermite vegetante.”1 In 1949, McCarthy described three cases of PDV with mucosal-dominant disease as “pyostomatitis vegetans.”2 Clinically, PDV is ABSTRACT Background: Pyodermatitis-pyostomatitis vegetans (PDV-PSV) is a rare muco-cutaneous disorder characterized by vegetating and pustular plaques and is often associated with inflammatory bowel disease (IBD). The purpose of this study was to systematically identify and analyze reports of PDV-PSV to determine the most effective treatment. Methods: Reports of PDV-PSV were identified using the OVID-Medline database from inception through November 2019. Publications were excluded if no new patient case was included, if there was not clinical and histological evidence of PDV, PSV, or PDV-PSV, or if no treatment was discussed. Results: The final sample was comprised of 74 publications plus an additional patient from the authors’ institution, corresponding to 95 total patients. The basis of the review and analysis is limited to case reports and case series, which likely only report the cases with positive outcomes. Statistical analysis revealed that oral corticosteroids (OCS), 6-mercaptopurine/azathioprine, oral calcineurin inhibitors (OCNI), 5-aminosalicylic-acid (5-ASA), and biologics (BIO) were the most effective treatments for PDV- PSV. Topical medications, colchicine, oral dapsone, and other antibiotics were ineffective treatments, with topical medications being the least effective option. When OCS are used, they work best when used as initial treatment to induce remission. 5-ASA and BIO are most effective when used as maintenance therapies after initial remission. Conclusions: Thus, first line therapy for PDV-PSV should begin with OCS with transition to steroid- sparing agents including OCNI, BIO, and 5-ASA if indicated. INTRODUCTION SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 334 characterized by erythematous pustules that become exudative vegetative plaques with well-defined elevated borders.3 Pyostomatitis-vegetans (PSV) similarly presents with sterile pustules on mucosal sites which erode and coalesce into “snail track” ulcers.4 Histological analysis of these lesions reveals eosinophilic or neutrophilic microabscesses and infiltrates, epidermal hyperplasia and often focal acantholysis.1,3,5 The spectrum of disease is referred to as pyodermatitis-pyostomatitis vegetans (PDV- PSV), with patients presenting with cutaneous symptoms only, mucosal symptoms only, or both cutaneous and mucosal symptoms. Since 1949, PDV-PSV has been documented in association with IBD in 80% of cases.1,5,6 Treatment is often directed at underlying IBD, though cutaneous and mucosal disease can prove refractory. The purpose of this review was to determine the most effective treatment options for PDV- PSV based on the success of medications used for patients with PDV-PSV found in the literature. The demographics of this population are presented, as well as the medications attempted for treatment. Medications are compared to determine which are most effective for the treatment of PDV-PSV. Search strategy and Inclusion Criteria A systematic review was conducted up to November 2019, using the search terms “pyostomatitis vegetans” and “pyodermatitis vegetans” in the PubMed/Medline database. All reports were analyzed by two independent reviewers to determine which met inclusion criteria. Review papers were used to find any reports missed in the initial literature search. Reports were included in the review if there was a new patient case, clinical and histological evidence of PDV, PSV, or PDV- PSV, and treatment was discussed. A diagnosis of PDV-PSV was confirmed by one dermatologist based on the clinical and histological description of PDV-PSV in each report. The exclusion criteria included any report that did not meet the above criteria, which included all review papers, reports without evidence of PDV-PSV, or those with cases that did not discuss treatment options. An additional case from the authors’ institution was also included for meta- analysis. Data Extraction and Preparation Using the PRISMA guidelines for extracting and assessing data, data from each paper was collected by two independent reviewers and is summarized in Table 1, along with the ratings of the quality of evidence of each paper. No methods were used to assess the risk of bias, as this review and analysis consists only of case reports and case series. Data collected included patient demographics, including sex, age, and ethnicity, presence and type of concomitant inflammatory bowel disease, histological description of PDV-PSV (including immunofluorescence results), complete blood count results prior to initiating treatment (including presence of eosinophilia), inflammatory markers (Erythrocyte Sedimentation Rate (ESR) or C- reactive Protein (CRP)) prior to initiating treatment, and all medications attempted with associated response. Treatment responses were separated into three categories depending on the type of response: partial response, complete response, and no response. Partial response was defined as incomplete resolution of lesions, with the disease described as: “relapsing intermittently,” “having slight clinical improvement,” METHODS SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 335 Table 1. Summary of findings in 95 reported cases Report Rating of QoE Demographic IBD PDV/ PSV Response to Treatment No Response Partial Response CR-I CR-M CR-D Abellaneda 20117 5 35M, Spanish UC PDV- PSV AZA, MTX, DAP, COL, RET, 5-ASA, MSC OCS AZA + 5-ASA Ahn 20048 5 33F, Korean UC PDV- PSV DAP, COL, OSC DAP, COL, OSC 5-ASA Al-Rimawi 19989 5 7M UC PSV OCS, 5-ASA, CHL 5F Chronic colitis PSV T-CS/CNI, OCS Atarbashi-Moghadam 201610 5 39F CD PSV 5-ASA, AZA Ayangco 200211 5 22F, White CD PSV T-CS/CNI 5-ASA Ballo 198912 5 39F UC PSV ABX, T-CS/CNI, MSC OCS 5-ASA Bens 200313 5 35F CD PSV BIO MTX Bertlich 201914 5 51F UC PDV- PSV AZA + OCS + T- CS/CNI BIO, OCS, T- CS/CNI Bianchi 20014 5 48F UC PDV ABX 5-ASA Brinkmeier 200115 5 32F, White None PDV- PSV DAP, 5-ASA OCS, T- CS/CNI, OCS + RET, OCS + OCNI Calobrisi 199516 5 65M, White UC PSV T-CS/CNI total colectomy Canpolat 201117 5 64M UC PDV OCS, ABX 5-ASA Carvalho 201618 5 79F None PDV ABX + OCS Cataldo 198119 5 48M, White CD PSV T-CS/CNI OCS Chan 199120 5 23M, White UC PSV FES, T- CS/CNI, OCS, ABX 5-ASA 17F, White UC PSV 5-ASA, T- CS/CNI, FES Chaudhry 199921 5 63M UC PSV T-CS/CNI, ABX Clark 20163 4 22F UC PSV 5-ASA, T- CS/CNI 30M UC PDV- PSV OCS, DAP, AZA, NYS, PTR 29M CD PSV OCS, DAP SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 336 54M CD PSV OCS, T-CS/CNI, DAP, OCNI, MM BIO 44F UC PDV- PSV OCS, T- CS/CNI, PTR 21M UC PDV- PSV DAP, T- CS/CNI 58M CD PDV- PSV OCS, T-CS/CNI, DAP, MSC Dodd 201722 5 30F CD PDV- PSV BIO, AZA OCS, T- CS/CNI BIO + DAP Dupuis 201623 5 48M Colitis PDV- PSV OCS Ficarra 199324 5 45F, Italian CD PDV- PSV Zinc OCS Forman 196525 5 45F UC PDV- PSV ACTH, ABX 44F UC PDV- PSV DAP DAP ABX, T- CS/CNI Gonzalez-Moles 200826 5 84F None PSV T-CS/CNI + NYS Hansen 198327 5 37M, White UC PSV OCS OCS + 5-ASA Harish 200628 5 35M UC PDV OCS 5-ASA Healy 199429 5 27M, White UC PSV DAP, OCS, T- CS/CNI, AZA 5-ASA 24F, White None PSV CHL Kajihara 201330 5 78M None PDV OCS + T- CS/CNI + COL OCS + COL Kalman 201331 5 41F CD PSV OCS BIO Khader 201632 5 21M UC PDV OCS Kim 201533 5 27M CD PDV- PSV COL; OSC, DAP (high dose) OCS, DAP (low dose) Kitayama 201034 5 51F, Japanese UC PDV- PSV OCNI, OCS, AZA 5-ASA Knapp 201635 5 10M UC PSV ABX AZA OCS T-CS/CNI + AZA Ko 200936 5 47M None PDV- PSV ABX, T-CS/CNI OCS (high dose) OCS (low dose) 24F None PDV- PSV OCS OCS Konstantopoulou 200537 5 19M UC PDV- PSV ABX, T-CS/CNI DAP OCS + ABX Leibovitch 200538 5 29M UC PDV- PSV ABX OCS, T- CS/CNI 5-ASA, OCS SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 337 Li 201839 5 25M None PDV- PSV OCS 5-ASA Lopez 201240 5 35M UC PDV- PSV MSC T-CS/CNI, NYS, 5-ASA Lourenco 201041 5 63F UC PSV OCS, DAP Maseda 201742 5 49M CD PDV ABX Markiewicz 200743 5 30M, White UC PSV 5-ASA Marks 196244 5 20M UC PDV- PSV ABX, DAP ABX OCS, ACTH Matias 201145 5 47F None PDV ABX OCS (low dose) + DAP OCS (higher dose) McCarthy 19632 5 27M, White UC PSV T-CS/CNI Mehravaran 19975 5 43F None PDV- PSV OCS+AZA OCS Merkourea 201346 5 58M CD PSV 5-ASA (“low dose”) Mesquita 201247 5 12M None PDV- PSV OCS + AZA DAP Mijandrusic-Sincic 201048 5 23F CD PSV BIO 32F UC PSV AZA Mizukami 201949 5 29F UC PSV OCS DAP Molnar 201150 5 16M CD PSV OCS, AZA+BIO Moloney 201151 5 50F UC PDV- PSV DAP DAP + AZA + 5-ASA Naish 197052 5 26M, Black UC PSV OCS Nayak 201753 5 33F UC PDV- PSV OCS OCS Neville 198554 5 47F, Black CD PSV OCS 5-ASA + OCS Nico 201255 4 63F UC PSV OCS OCS 33M Colitis PSV OCS T-CS/CNI 33F UC PSV OCS 34M UC PSV OCS Niezgoda 201856 5 69M UC PSV OCS + OCNI Nigen 200357 5 22F None PDV- PSV DAP T-CS/CNI, ABX OCS 57F None PDV- PSV ABX OCS O'hagan 199858 5 65F None PDV- PSV OCS T-CS/CNI + AZA Pazheri 201059 5 15F CD PSV T-CS/CNI Peuvrel 200860 5 28M None PSV OCS OCS Ruiz-Roca 200561 5 51F UC PSV ABX, T-CS/CNI Saghafi 201162 5 30F None PSV OCS SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 338 Shah 201363 5 63M UC PSV DAP Soriano 199964 5 49M, White UC PDV- PSV 5-ASA, T- CS/CNI T-CS/CNI + 5- ASA 5-ASA Stingeni 201565 5 17M UC PSV OCS AZA Storwick 199466 5 42F UC PDV- PSV OCS T-CS/CNI, ABX Thornhill 199267 5 26F, White UC PSV OCS + 5-ASA DAP 51M, White None PSV OCS ABX + DAP 33F, Greek None PDV- PSV OCS ABX, DAP, AZA Tursi 201668 5 42F UC PSV OCS, DAP BIO, ABX Uzuncakmak 201569 5 16M UC PDV OCS, ABX Van Hale 198570 5 23F UC PDV- PSV ABX, DAP, MSC OCS, T- CS/CNI Colectomy 24F UC PDV- PSV AZA T-CS/CNI, IV ALB, MSC DAP Wang 201371 5 42F UC PDV- PSV ALB, OCS Werchniak 200572 5 30F UC PDV NYS T-CS/CNI 5-ASA Wolz 201373 5 21M, White UC PDV- PSV T-CS/CNI + DAP DAP 58M, White CD PDV- PSV OCS + DAP DAP Wray 198474 5 58M, White UC PSV 5-ASA OCS T-CS/CNI 52M, White None PSV T-CS/CNI + 5- ASA Yasuda 200875 5 37M UC PDV- PSV T-CS/CNI Total colectomy T-CS/CNI Index patient 5 51F, Hispanic UC PDV- PSV MTX, T-CS/CNI, ABX, MSC RET, MM, ABX, T- CS/CNI DAP, OCS, ABX Empty Box: not mentioned or specified in primary paper Abbreviations: 5-ASA, sulfasalazine/sulphasalazine, aminosalicylates, mesalamine; ABX, antibiotics (piperacillin4, metronidazole4,17,37,41, amoxicillin clavulanate17,18,38,67, dicloxacillin38, ciprofloxacin41,42, clarithromycin42, vancomycin37, penicillin44, di-iodohydroxyquinoline44, streptomycin44, doxycycline61, sulfonamides25,67, and tetracycline20,21); ACTH, adrenocorticotropic hormone; ALB, albumin; AZA, azathioprine, mercaptopurine; BIO, biologic (infliximab3,14,22,31,41, adalimumab22,48,50, and golimumab68); CD, Crohn’s disease; CHL, chlorhexidine mouthwash; COL, colchicine; CR-D, complete response-discontinuation; CR-I, complete response—initial; CR-M, complete response— maintenance; DAP, dapsone; F, female; FES, ferrous sulfate; M, male; MM, mycophenolate mofetil; MSC, miscellaneous (intravenous immunoglobulin7, aurothiomalate7, acyclovir12, ketoconazole3, “antifungals40,” topical imiquimod, vitamin therapy70, diphenhydramine elixer70, and viscous lidocaine70); MTX, methotrexate; NYS, nystatin; OCS, systemic corticosteroids; OCNI, oral calcineurin inhibitors; PTR, petrolatum; QoE, quality of evidence; RET, retinoids; T-CS/CNI, topical corticosteroids or topical calcineurin inhibitor; UC, Ulcerative colitis. SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 339 “improved but still present,” “regressed,” or “still mildly active.” Cases with complete response required evidence of good control of the disease after initiating or discontinuing the medication. Response of the disease to treatment in these cases was described as: “having marked or significant improvement,” “resolution,” “relief,” or being “well- controlled.” Complete response was further subdivided into three categories: resolution while on—initial (CR-I); response while on— maintenance (CR-M); and remission after discontinuation (CR-D). Drugs were split into initial and maintenance categories if one drug resulted in the resolution of lesions (CR-I) then a second drug was added immediately after to maintain remission (CR-M). If a treatment resulted in resolution of PDV-PSV while on the drug, but lesions recurred after discontinuation, then this medication was considered CR-I. A treatment required only intermittently for relapse control resulting in complete control was also considered CR-I. Drugs directed at underlying IBD were generally included in the CR-M category, as patients often remained on these medications indefinitely. Medications that resulted in sustained clearance of PDV-PSV after their discontinuation were considered CR-D. Medications were included in this category if the authors stated that there was “complete remission” after drug discontinuation or sustained clearance was noted after follow-up, with follow-up times ranging from 15 days to 20 years (mean= 26.4 months, median=12 months). The medications used to treat PDV-PSV were divided as follows: oral corticosteroids (OCS), topical medications (T-CS/CNI), colchicine (COL), azathioprine/6- mercaptopurine (AZA), 5-aminosalicylic-acid (5-ASA) derivatives, oral calcineurin inhibitors (OCNI: tacrolimus and cyclosporine), biologics, oral dapsone (DAP), other antibiotics (ABX), and miscellaneous medications (MSC). Topical corticosteroids and topical tacrolimus were combined into a topical medications category (T-CS/CNI) due to their limited systemic effects. Oral dapsone and other antibiotics were separated because dapsone is most commonly used for its anti-neutrophilic and general anti- inflammatory mechanisms. Other antibiotics used to treat PDV-PSV included: piperacillin4, metronidazole4,17,37,41, amoxicillin clavu-lanate17,18,38,67, dicloxacillin38, cipro-floxacin41,42, clarithromycin42, vancomycin37, penicillin44, diiodohydroxyquinoline44, strep-tomycin44, doxycycline61, sulfonamides25,67, and tetracycline.20,21 All biologic medications were combined into one category, as they were all TNF alpha blocking agents (infliximab3,14,22,31,41, adalimumab22,48,50, and golimumab68). Drugs in the miscellaneous category were not included in the statistical analysis because all were used only once. This included intravenous immunoglobulin7, aurothiomalate7, acyclovir12, ketoconazole3, “antifungals40,” topical imiquimod, vitamin therapy70, diphenhydramine elixer70, and viscous lidocaine.70 Statistical Analysis Each medication was compared across different subgroups to determine if any medications were more successful in patients with certain characteristics. These subgroups included: sex (male versus female), type of inflammatory bowel disease (ulcerative colitis (UC) versus Crohn’s disease (CD)), presence of colitis, presence of eosinophilia, presence of elevated inflammatory markers (ESR or CRP), and subtype of PDV-PSV (PDV only versus PDV only versus PDV- PSV). This was done using 2x2 chi square tests to compare the number of times each treatment was successful versus unsuccessful within each subgroup. P-values were adjusted to account for running multiple tests using the Holm method. SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 340 In this review, 128 related articles were identified using the search criteria discussed above (Figure 1). After the initial abstract screening 38 articles were excluded. An additional 23 reports were excluded because they did not meet the inclusion criteria for this review. Six additional articles were included from reference lists of PDV-PSV review papers. For the final review, 74 reports were used, which included 72 case reports and 2 case series. This corresponded to 94 unique patients. No prospective or retrospective cohort trials were found for PDV-PSV. With the addition of a patient from the authors’ institution, 95 total patients were used in this review an analysis. There was no evidence of duplicate cases. Demographics of the study population are summarized in Table 2. Seventy-six patients (80%) had concomitant IBD. The median age was 35 (IQR=24) years old and 47 (49%) of the patients were female. The median number of treatments per patient was 2 (IQR=2), with a median follow-up time of up to 12 months (IQR=20). Several treatments were found to be effective (with greater than 75% of patients having a complete response to the medication), including OCS, AZA, 5-ASA, OCNI, and BIO. T-CS/CNI, Colchicine, oral dapsone, and other antibiotics appeared to have lowest efficacy in treating the disease (Table 3). OCS were the most commonly used treatment, used in 79 of 95 patients (83%). OCS also demonstrated strong efficacy with a complete response achieved in 80% (63/79) patients. OSC was Table 2. Characteristics of the PDV-PSV patients Characteristics Values Total number of patients 95 Female, n (%) 47 (49%) Median age in years (IQR) 35 (24) Ethnicity White/Caucasian, n (%) 18 (19%) Other, n (%) 8 (8%) Unspecified, n (%) 69 (73%) Associated with IBD/chronic colitis, n (%) 76 (80%) UC, n (%) 55 (72%) IBD presented before PDV- PSV, n (%) 56 (74%) Location of muco-cutaneous lesions PSV only, n (%) 46 (48%) PDV-PSV, n (%) 39 (41%) PDV only, n (%) 10 (11%) Peripheral eosinophilia, n (%) 30 (32%) Elevated inflammatory markers, n (%) 23 (24%) Median follow up time in months (IQR) 12 (20) Achieved complete response, n (%) 86 (91%) Median number of treatments, n (IQR) 2 (2) Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IBD, inflammatory bowel disease; IQR, interquartile range; PDV, pyodermatitis vegetans; PDV-PSV, pyodermatitis-pyostomatitis vegetans; PSV, pyostomatitis vegetans; UC, ulcerative colitis. determined to be most successful when used as initial therapy, achieving CR-I in 49% (31/63) of patients achieving complete remission. Topical therapies were used in nearly half of patients (45/95, 47%), but were often unsuccessful, resulting in complete resolution of lesions in only 49% (22/45) of cases. AZA was used by 19 patients (22%) and found to be effective, resulting in CR in 12 (80%) patients. AZA therapy was not found to be more successful in one subgroup of CR over another. RESULTS SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 341 Table 3. Total number of patients per response category by medication class Number of within each Response Category (total patients = 95) Number of Patients within each Complete Response (CR) Subgroup Medication Total patients (%) No Response (%) Partial Response (%) Complete Response (%) CR-I (% of CR) CR-M (% of CR) CR-D (% of CR) OCS 79 (83%) 10 (13%) 6 (9%) 63 (80%) 31 (49%) 23 (23%) 9 (14%) T-CS/CNI 45 (47%) 10 (22%) 12 (27%) 23 (51%) 6 (26%) 11 (48%) 6 (26%) DAP 36 (38%) 10 (28%) 5 (14%) 21 (58%) 7 (33%) 13 (62%) 1 (5%) 5-ASA 31 (33%) 5 (16%) 1 (3%) 25 (81%) 3 (12%) 21 (84%) 1 (4%) ABX 29 (31%) 10 (34%) 4 (14%) 15 (52%) 3 (20%) 7 (47%) 5 (33%) AZA 19 (20%) 5 (26%) 2 (11%) 12 (63%) 4 (33%) 5 (42%) 3 (25%) BIO 9 (9%) 2 (22%) 0 (0%) 7 (78%) 1 (14%) 5 (71%) 1 (14%) COL 6 (6%) 1 (17%) 1 (17%) 4 (67%) 3 (75%) 1 (25%) 0 (0%) OCNI 4 (4%) 0 (0%) 0 (0%) 4 (100%) 2 (50%) 2 (50%) 0 0%) Partial response was defined as incomplete resolution of lesions. Complete response required evidence of good control of the disease after initiating or discontinuing the medication. Abbreviations: 5-ASA, sulfasalazine/sulphasalazine, aminosalicylates, mesalamine; ABX, antibiotics; AZA, azathioprine, mercaptopurine; BIO, biologics; COL, colchicine; CR, complete response; CR-D, complete response-discontinuation; CR-I, complete response – initial; CR-M, complete response – maintenance; DAP, dapsone; OCNI, oral calcineurin inhibitors; OCS, systemic corticosteroids; NR, no response; PR, partial response; T-CS/CNI, topical corticosteroids or topical calcineurin inhibitor. 5-ASA was used by 31 (33%) patients and found to be effective, with 25 (81%) patients achieving CR. BIO were used by 9 (9%) patients and also found to effective, resulting in CR in 7 (78%) patients. 5-ASA and BIO were statistically most successful when used as maintenance therapies with 21/25 (84%) and 5/7 (71%) patients achieving a complete response when the therapies were used as maintenance, respectively. OCNI were only used by four (4%) patients, but were still found effective, achieving complete response in 100% of patients. ABX were used in 29 (31%) patients and found to be poorly effective, achieving complete response in only 15 (52%) individuals. DAP was used by 36 (38%) patients and was also found to be ineffective, with 21 (58%) patients achieving any complete response. COL was used by 6 (6%) patients and was found to be ineffective, despite 4/6 (67%) patients achieving complete response. A comparison of the medications’ success within subgroups was analyzed by Chi- squared test. No medications were found to be more successful when treating males versus females, patients with UC versus CD, patients with colitis versus without colitis, patients with versus without eosinophilia prior to initiating therapy, patients with versus without elevated inflammatory markers prior to initiating therapy, and patients with PDV versus PSV versus PDV-PSV. Pyodermatitis-pyostomatitis (PDV-PSV) is a rare mucocutaneous dermatosis characterized by pustular and vegetating lesions of the skin and oral mucosa. In the literature, 80% of cases of PDV-PSV were associated with IBD, though gastrointestinal symptoms may not initially be present. Therefore, the presence of PDV-PSV should trigger further investigation for underlying IBD.16,35 The proposed mechanism and disease process of PDV-PSV remains unknown. While the name “pyoderma” suggests skin infection, no consistent pathogenic bacteria, fungi, or viruses have DISCUSSION SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 342 been discovered.48 Thus, PDV-PSV is thought to result from an abnormal inflammatory response to unknown factors. Due to the high proportion of PDV-PSV cases associated with IBD, these factors are hypothesized to be antigens shared by bacteria in both the gut and the skin. Multiple treatment options exist for PDV- PSV, primarily targeting underlying IBD and the pathologic cutaneous inflammatory response. Unfortunately, due to the rarity of PDV-PSV, no controlled trials exist comparing different treatment modalities. Healey et al published an initial treatment algorithm for only PSV in 1994.29 Consequently, drugs like biologics and calcineurin inhibitors, more commonly used now than 26 years ago, were not represented. The present review of treatment data from 95 cases provides updated evidence regarding the most effective therapies. Multiple therapies are often required with widely varying levels of success. In the present review, many patients had success with oral corticosteroids when used initially, either followed by steroid-sparing maintenance therapy or when used intermittently for relapse control. Improvement in skin and oral lesions generally correlated with treatment of underlying IBD, likely because of shared pathogenesis involving overactive inflammatory response.1,5,11,15,16,29,61,65,66 The results suggest that a patient, with or without IBD, may see benefit with a course of OCS as the initial intervention. In patients with active IBD, 5-ASA may be helpful in managing both the IBD and mucocutaneous symptoms. 5-ASA can also be attempted if OCS fail to result in remission for patients without associated IBD, as the data does not suggest an increased efficacy in IBD associated PDV-PSV versus skin only disease. Maintenance therapy can also be initiated if a patient is requiring frequent courses of OCS due to relapse of the disease. While topical steroids are currently considered first line treatment based on Healey’s treatment algorithm, the data clearly demonstrates PDV-PSV responds poorly to topical medications. Oral dapsone and colchicine are also commonly used but demonstrate poor efficacy for the treatment of PDV-PSV. Antibiotics were found to be ineffective medications for the treatment of PDV-PSV but should be considered if there is concern for superinfection. If the above medications fail, are poorly tolerated, or the provider or patient prefers, azathioprine or 6-mercaptopurine or an oral calcineurin inhibitor may be attempted for patients with or without associated IBD. In refractory cases, a TNF-alpha blocking biologic can be used. Given their safety and significant effectiveness as maintenance therapies, biologics can also be considered earlier in the treatment course. However, data is limited by small sample size. This review has several limitations. First, there are no prospective studies regarding the treatment of PDV-PSV due to the rarity of the disease, so this analysis is limited to case reports and case series. This lends to both publication and reporting bias. Reports were likely not written and/or published if medications used to treat PDV-PSV were ineffective, leading to a lack of negative data. Additionally, studies may have selectively reported only positive outcomes, and there was no standardized way of reporting these outcomes. Due to this lack of standardization of the magnitudes of the responses to the medications, response categories were created based on the specific phrases used in the primary literature. This made the vocabulary used in each article extremely important, as specific wording was SKIN July 2021 Volume 5 Issue 4 Copyright 2021 The National Society for Cutaneous Medicine 343 categorized as different levels of response. This use of categorization based on semantics is inherent in retrospective papers, as well as review papers. Prospective data and controlled studies would be necessary to fully compare different regimens. Furthermore, the reviewers grouped medications (such as topical medications and biologics) into classes for statistical analysis due to small sample sizes. This could mask the effects of individual agents. Finally, follow-up time varied greatly (mean=28.3 months, range=1-252 months), thus making it difficult to determine long-term effects. Some patients had no follow up or were seen as early as one-week post discontinuation of their medication(s). Some papers did not record follow up results at all. Because of this variation in follow-up reported, the maintenance of remission following discontinuation of a medication could not always be determined. When a patient is diagnosed with PDV-PSV, it is important to evaluate for underlying IBD due to the high number of associated cases. No treatments proved to be more or less effective for IBD associated PDV-PSV versus skin-only disease, but PDV-PSV improvement tended to correlate with management of associated IBD if present. Oral corticosteroids were the most commonly used and most effective medication at obtaining resolution of the mucocutaneous lesions of pyodermatitis-pyostomatitis vegetans. Based on the literature review conducted, other effective treatments include azathioprine and 6-mercaptopurine, 5- aminiosalicylic acid derivatives, oral calcineurin inhibitors, and TNF-alpha blocking biologics. It will be important to improve the evidence for the efficacy of these medications through rigorous prospective studies. Acknowledgements: No external or internal funding. All authors declare that they have no conflict of interest. All contributors did necessary work to qualify for authorship, no other contributors. Conflict of Interest Disclosures: None Funding: None Corresponding Author: Landon Hobbs, BS Department of Dermatology University of Virginia School of Medicine 1215 Lee Street Charlottesville, VA 22903 Phone: 434-924-5115 Fax: 434-244-4504 Email: lkh6k@virginia.edu References: 1. Hegarty AM, Barrett AW, Scully C. Pyostomatitis vegetans. Clin Exp Dermatol. 2004 Jan;29(1):1– 7. 2. Mccarthy P, Shklar G. A SYNDROME OF PYOSTOMATITIS VEGETANS AND ULCERATIVE COLITIS. 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