Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2023;13(1):e2023019 1 Digital Ulcers: Multidisciplinary Approach and Dermatological Management Michela Starace1,2, Gionathan Orioni1,2, Aurora Alessandrini1,2, Francesca Bruni1,2, Carlotta Baraldi1,2, Cosimo Misciali1,2, Bianca Maria Piraccini1,2 1 Dermatology Unit- IRCCS Azienda Ospedaliero-Universitaria di Bologna 2 Department of Experimental, Diagnostic and Specialty Medicine Alma Mater Studiorum University of Bologna, Italy Key words: digital ulcer, multidisciplinary approach, dermatology, diabetes, ischaemic wound Citation: Starace M, Orioni G, Alessandrini A, et al. Digital Ulcers: Multidisciplinary Approach And Dermatological Management. Dermatol Pract Concept. 2023;13(1):e2023019. DOI: https://doi.org/10.5826/dpc.1301a19 Accepted: June 9, 2022; Published: January 2023 Copyright: ©2023 Starace et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Gionathan Orioni, IRCCS Azienda Ospedaliero-Universitaria di Bologna; Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale (DIMES) Alma Mater Studiorum – Università di Bologna, Via Massarenti 1, 40138 Bologna, Italy. Telephone number +390512144838 E-mail: gionathan.orioni@studio.unibo.it Introduction: Digital ulcers represent a current public health issue, due to the relevant difficulties in their management and their tendency to become chronic, non-healing lesions. Objectives: Our case series represents an opportunity to discuss the main comorbidities of digital ulcers and to present an evidence-based treatment protocol that has proved highly effective in our clinical practice. Methods: We collected the clinical data about clinical features, associated diseases and diagnostic therapeutical procedures of 28 patients with digital ulcers referred to our Wound Care Service at S. Orsola-Malpighi Hospital. Results: Digital ulcers were divided into 5 categories, based on the causative agent: peripheral artery disease: 5/16 females and 4/12 males, diabetes-associated wounds: 2/16 females and 1/12 males, mixed wounds: 4/12 males, pressure wounds: 3/16 females and 2/12 males, and immune-mediated diseases associated with wounds: 6/16 females and 1/12 males. Each group received specific management, based on the characteristics of the ulcer and the underlying comorbidities. Conclusions: The clinical evaluation of digital wounds requires a thorough knowledge of their aetiopathogenesis. A multidisciplinary approach is necessary to achieve a precise diagnosis and correct treatment. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2023;13(1):e2023019 Introduction With the increase in life expectancy, more and more patients are suffering from chronic diseases and an increasingly inno- vative and personal approach, which includes the collabora- tion between specialists from various branches of medicine and surgery, is now part of a comprehensive care plan [1]. Limb chronic ulcers have an increasing incidence, due to the higher prevalence of chronic vascular and metabolic dis- eases, such as peripheral artery disease (PAD) and diabetes mellitus, which play the main role in their aetiology. Within the category of limb chronic ulcers, digital ulcers (DU) represent a small but peculiar group, due to their diffi- cult management and their scarce tendency to heal. We present an observational study of 28 patients with DU referred to our Wound Care Service, focusing on multi- disciplinary and dermatological management. Methods We collected the clinical data of patients with DU referred to the Wound Care Service (a tertiary referral center) of the Dermatology Unit of the S.Orsola-Malpighi Hospital over a period of 18 months, from January 2020 to June 2021. Only patients presenting with non-healing digital ulcers of the limbs, present for at least 6 weeks, were enrolled. Demographic and clinical data were collected, including associated comorbidities and their therapy and previous ul- cerative episodes in other cutaneous areas. Diagnosis of the disease that caused the DU was based on clinical history, laboratory evaluation and histopathological study, when necessary. Management of these conditions was based on the main International Guidelines for the management of peripheral artery disease in patients with foot ulcers and di- abetes [2-4] and on the evidence-based protocol for diabetic foot ulcers [5]. All the digital wounds were assessed for excluding any signs of local or surrounding infection. In particular, the presence of at least 3 or more STONEES criteria (Size is big- ger, Temperature elevated, Os, New breakdown, Exudate, Erythema, Smell) lead to a systemic antibiotic treatment. The presence of at least three NERDS criteria (Nonhealing, Exu- date Increase, Red friable granulation, Debris) was followed by a topical antimicrobial therapy [3]. The evaluation of pain associated with the DU was per- formed using the VAS (visual analogue scale). All patients with pain equal or superior to 5 on the VAS scale, despite ad- equate medication and non-responder to paracetamol, were managed by our Pain Therapy Service. Despite the cause of the DU, mechanical debridement of the necrotic tissues was performed in all cases. In three cases, the use of local medications was preceded by a total surgi- cal debridement of necrotic tissue. In the other patients, an ambulatorial mechanical debridement was performed. Gauze soaked in iodine was used as the main antiseptic medication. Results From January 2020 to June 2021, we treated 28 patients with DU, 12 males and 16 females (Table 1). Median age was 72.6 years (range 38-97 years): average age of males was 68.3 years, that of females 75.9 years. The toes were the most common site of DU (24 patients), with 16 patients having ulcers of several digits (ranging from 2 digits to 4); finger ulcers were present in 4 patients, one of them having DU in 3 fingers, the other 3 in one finger. The diseases detected as causes of DU were as follows: peripheral artery disease (PAD): 9 cases, all with DU of the toes; type 2 diabetes mellitus with poor glycaemic control: 3 patients, all with DU of the toes; association of PAD with type 2 diabetes mellitus: 4 patients, 3 with DU of the toes and 1 of a finger; pressure ulcers with toe involvement: 5 patients; vasculitis: 3 patients with DU of the toes; systemic sclerosis (SSc) in 4 patients, 3 with DU of the fingers and 1 of a toe. PAD-Associated DU The 9 patients with PAD were evaluated by specific imag- ing investigation (color duplex ultrasound, computed tomo- graphic angiography, magnetic resonance angiography) and then referred to a vascular surgeon for possible revascular- ization. Only 4 cases were revascularized, while in the other 5 the procedure was not possible due to the poor general conditions and the high anaesthetic risk. The topical medica- tion of the DU after debridement in all these patients was an Iodine-based antiseptic dressing or a soft silicon foam dress- ing, in order to diminish the risk of bacterial superinfection of necrotic tissue (Figure 1a). All the cases that underwent revascularization showed a better outcome compared to the other cases, with a significant reduction in healing times. No correlations with any lymphatic drainage impairment were found in this group of patients after specific imaging investigation. Diabetes-Associated DU Seven patients presented type 2 diabetes mellitus in poor glycaemic control, associated with the presence of DU. In 3 cases diabetes was identified as the primary cause of the ulcerative lesions, as laboratory and technical evaluations excluded other comorbidities: these patients were referred to the Diabetology service for a review of their metabolic sta- tus and chronic hypoglycaemic therapy and underwent local medications with gauze soaked in iodine to accelerate wound healing. A better clinical outcome was achieved only after the diminishment of these patients’ plasma glucose values. Original Article | Dermatol Pract Concept. 2023;13(1):e2023019 3 In 4 patients, type 2 diabetes was associated with arteri- opathy of the large vessels of the lower limbs that required prompt revascularization (Figure 1b). Surgery increased the chances of wound healing in these patients. Obesity and metabolic syndrome are often present in patients with diabetes II and PAD, as they recognize a sed- entary lifestyle as a common denominator, associated with unbalanced nutrition. However, no direct correlations were found between these factors and the development of digital ulcerative lesions. Pressure DU Five patients with pressure ulcers of the feet developed toe lesions as an effect of continuous forces directed to the distal pulp, causing progressive skin ischemia above bone prom- inences4. These patients were bedbound due to progressive neurological diseases, such as multiple sclerosis with spinal involvement (4 cases) or a severe form of motor-sensitive polyneuropathy of the lower limbs (1 case). In these cases, mechanical debridement of the eschar followed by topical therapy with iodine gauzes was associated with a physiatrist consultation that lead to the prescription of plantar orthosis and anti-decubitus mattresses. All the procedures allowed wound healing with restoration of the physical integrity of the toe skin (Figure 1c). Immune-Mediated Disease-Associated DU Four patients, 3 with DU of the fingers and 1 of a toe suf- fered from SSc (Figure 1d). A skin biopsy of the DU showed in all cases skin calcinosis. These patients were managed through the close collaboration of rheumatologists. One patient with DU of the toe was affected by rheu- matoid arthritis and 2 by systemic lupus erythematous. A biopsy of the perilesional skin showed leukocytoclastic vas- culitis with fibrinoid necrosis of the vessel walls and promi- nent polymorphonuclear cell infiltration. Table 1. Clinical characteristics of the patients with digital ulcers. Patient Age Sex Number of wounds Localization Aetiology 1 50 F 2 toe Diabetes II 2 70 M 2 toe Diabetes II and PAD 3 95 F 4 toe PAD 4 80 M 3 finger SSc 5 64 M 2 toe PAD 6 81 F 1 toe PAD 7 50 M 1 finger Diabetes II and PAD 8 82 F 1 toe Pressure ulcer 9 82 F 4 toe Vasculitis 10 83 M 2 toe Diabetes II 11 58 M 1 toe PAD 12 81 M 1 toe Diabetes II and PAD 13 83 F 1 toe Vasculitis 14 46 M 3 toe Pressure ulcer 15 69 M 1 toe Diabetes II and PAD 16 97 F 5 toe PAD 17 89 F 2 toe Diabetes II 18 92 F 4 toe PAD 19 84 F 2 toe Pressure ulcer 20 56 F 1 toe SSc 21 64 F 3 toe Vasculitis 22 80 F 2 toe PAD 23 80 M 3 toe Pressure ulcer 24 83 F 2 toe Pressure ulcer 25 58 M 1 toe PAD 26 58 F 1 finger SSc 27 38 F 1 finger SSc 28 80 M 2 toe PAD M: Male; F: Female; PAD: peripheral artery disease; SSc: systemic sclerosis. 4 Original Article | Dermatol Pract Concept. 2023;13(1):e2023019 and on the respective aetiologies. The multidisciplinary man- agement of the different cases represents the standard model to get better the outcome of patients suffering from multiple comorbidities. PAD-Associated DU The term peripheral arterial disease defines the lower ex- tremity artery disease, including obstruction at the aortoil- iac, femoropopliteal and infrapopliteal arterial segments [5]. Studies have shown an increased risk of cardiovascular mor- tality, as well as of morbidity from myocardial infarction The clinical suspicion of autoimmune disease in this group of patients derived from suggestive anamnestic data collection and from the execution of skin biopsies of the ul- cerative lesions. A subsequent rheumatological evaluation confirmed the clinical suspicion. Discussion Our literature search could not identify any studies that col- lected such a large number of cases regarding DU of both fin- gers and toes, making a subdivision based on clinical aspects Figure 1. Clinical images of patients with digital ulcers of different aetiology. A 92-year-old female patient with two recently occurring ischemic ulcers at her right first toe, in the context of peripheral artery disease (A); a 50-year-old female patient with extensive necrosis at her distal phalanx of the right first toe, in the context of poorly controlled diabetes mellitus (B); an 82-year-old female patient with a well-demarcated pressure ulcer at the fourth finger of her left foot (C); an 80-year-old male patient with a necrotic ulcer at the distal phalanx of the fourth finger of his left hand, in the context of systemic sclerosis (D). Original Article | Dermatol Pract Concept. 2023;13(1):e2023019 5 must be carried out [19]. It is important to assess the pedal pulses, and unless a pulse is clearly palpable, all patients with foot ulcers should undergo non-invasive vascular testing, to determine if the patient would benefit from re- vascularization. In an observational study, shorter time to revascularization (<8 weeks) was associated with a higher possibility of healing of ischaemic foot ulcers [20]. In ad- dition, it is mandatory that every patient be evaluated for proper orthotics, and appropriate footwear should be pre- scribed that adequately protects the foot from trauma in- duced by shoes and alleviates pressure, considering the fact that pressure and pain sensation are often impaired in these patients [21]. Pressure DU Prolonged bed rest caused by paraplegia and various central nervous system diseases plays an important role in the forma- tion of pressure acral lesions, which follow prolonged skin ischemia and are especially located above bony prominences. The first signs of ischemia are the formation of calluses at the level of the toepads. If not recognized and treated, they lead to the formation of painless and difficult-to-treat chronic ul- cers. The application of physical means such as intermittent pneumatic compression devices and the evaluation from ex- pert physiotherapists is necessary in these patients, in order to prevent the extension of the wound and the arising of other similar lesions in other toes [22]. In people suffering from advanced neurological con- ditions, spasticity is significantly associated with the de- velopment of pressure ulcers in typical and even atypical locations  [23]. Severe spastic conditions might facilitate wound onset in various ways: increased tonus of the limbs leads to immobility and to a reduced capacity to reposition the body, with an abnormal pressure redistribution. This prolonged rigidity causes severe soft tissue injury [4, 24]. A comprehensive assessment is warranted with a focus on iden- tifying the source of pressure, contributing factors, underly- ing comorbidities, and elements affecting wound healing. Pressure redistribution targeting the duration and/or magnitude of loading is critical [25, 26]. Evidence exists that advanced support surfaces are superior to standard hospital beds in preventing and managing pressure injuries. However, no clear advantage has been identified for one specific ad- vanced support surface over another [27]. There is strong evidence that a moist wound environ- ment accelerates healing in this type of DU: occlusive dress- ings seem to be superior to more-traditional simple gauze, especially in terms of maintaining a moist wound environ- ment [28]. Ultimately the dressing selection may be guided by the characteristics of the wound, balance of moisture and exudate, bacterial control, debridement balance, ease of use, cost, and patient preference [29]. and stroke in patients with asymptomatic or symptomatic arterial disease [2]. The distal localization of the vascular ob- struction leads to the formation of chronic ulcerative lesions of the acral extremities, mainly of the lower limbs, with the appearance of necrotic eschars of the distal phalanges of the toes. These ulcers are at high risk of bacterial superinfection. The association with both uncontrolled type II diabetes mel- litus is common, therefore in these patients, the evaluation of the arterial function with imaging techniques should always be associated with laboratory monitoring of the glycaemic state, as type II diabetes comorbidity greatly impairs local wound management [6]. The symptoms and signs of PAD are variable and range from the classic symptom of claudication to other non– joint-related limb symptoms (atypical leg symptoms) or are absent [7-10]. In these cases, the DU may be the first sign that leads to the diagnosis. The vascular examination for PAD includes pulse palpation, auscultation for femoral bruits, and inspection of the legs and feet [8]. To confirm the diagnosis of PAD, abnormal physical examination findings must be confirmed with diagnostic testing [5]. Studies for anatomic imaging assessment (duplex ultrasound, computed tomography angiography [CTA], or magnetic resonance angiography [MRA], invasive angiography) are generally reserved for highly symptomatic patients in whom revascu- larization is being considered [9]. Patients with PAD associated with skin ulcers fall into a high-risk cardiovascular group, due to the signs of advanced disease10: for this category, a careful multidisciplinary evalu- ation is important in order to select patients eligible for sur- gical revascularization and to increase the chance of wound healing, as well as of reducing a progression of disease [11]. Adequate pharmacological therapy associated with a healthy lifestyle is mandatory for the chronic management of this disease and to reduce the global cardiovascular risk [12, 13]. Diabetes-Associated DU As for diabetic foot ulcers, they occur in between 12 and 25% of patients with type 2 diabetes mellitus [14] and precede 84% of all non-trauma limb amputations in this growing slice of the population [15]. A diabetic foot ulcer is defined as any skin breakdown on the foot of a diabetic person [16]. Early recognition of the skin defect and treatment prevents its progression to a chronic wound that is often recalcitrant to therapy [17-18]. When a patient with a diabetic foot ulcer is first seen, a comprehensive history and treatment plan must be put into place. Then, a laboratory evaluation based on their metabolic status, and the monitoring for any complications (e.g. heart disease, renal failure, retinopathy, neuropathy) 6 Original Article | Dermatol Pract Concept. 2023;13(1):e2023019 the autoimmune disease is imperative. Adalimumab with methotrexate (MTX) has shown promise in RA-associated ulcers [39]. Improving wound bed preparation by the appli- cation of moisture-retentive dressings has been shown to be beneficial [40]. Systemic lupus erythematosus (SLE) is a systemic auto- immune connective tissue disease that can affect most or- gan systems. Ulcerations are not infrequent and, like other connective tissue diseases, they are multifactorial [41]. Vasculitis, noninflammatory thrombosis of small or large vessels, venous insufficiency, lupus profundus, lichen pla- nus overlap, and drug-induced lupus syndrome has been associated with leg ulcerations. The ulcers are usually pain- ful, sharply margined, or punched out. Adjacent skin can appear erythematous, purpuric, or rolled and violaceous. Histological examination of vasculitis ulcers in SLE shows a leukocytoclastic vasculitis with fibrinoid necrosis of the vessel walls and prominent polymorphonuclear cell infiltra- tion. Thrombocclusive histologic findings can be associated with the presence of antiphospholipid antibodies (lupus an- ticoagulant) [42]. SLE-associated leg ulcers are a therapeutic challenge, as local wound care is not always sufficient. The underlying cause of the ulceration needs to be established and treated. If vasculitis is present, systemic corticosteroids with cytotoxic agents should be utilized [37]. Conclusion The clinical evaluation of DUs requires a thorough knowl- edge of their possible causes. A careful clinical evaluation is necessary together with laboratory and imaging technique investigations. A multidisciplinary approach in the manage- ment of these wounds is the only effective way to achieve a precise diagnosis and a correct treatment, as described in  Figure 2. Immune-Mediated Disease-Associated DU Inflammatory and autoimmune systemic diseases may first become clinically evident with the appearance of an ischemic digital wound. SSc is the best described among these types of conditions [30]. Cutaneous and/or systemic vasculitis can also present with the formation of necrotic lesions involving the fingers of the limbs, both the upper and lower ones. SSc is an immune-mediated disease that represents a major clinical challenge for physicians and patients. For the patient, SSc is associated with great uncertainty of outcome and devel- opment of manifestations that are potentially lethal or can reduce quality of life [31]. The problem of digital ulcers is increasingly reco- gnised [32]. DU occur in around half of SSc cases during their disease history, and about one in five patients might have this complication at any one time [33, 34]. There is now a better appreciation of the effects of digital ulcers, which include im- paired function, pain, and loss of employment, as well as the more obvious medical complications of cellulitis, osteomy- elitis, digital infarction, and severe pain. Treatment of digital ulcers with drugs or systemic therapies needs to be com- bined with appropriate expert local care and dressings, and this treatment usually benefits from specialist nurse input. Evidence-based treatments include phosphodiesterase-5 in- hibitors and endothelin receptor antagonists, although some studies have not shown a clear treatment benefit [35, 36]. Rheumatoid arthritis (RA) is a chronic, inflammatory autoimmune disorder expressed most commonly as a sym- metrical, deforming arthropathy [37]. A well-known cause of ulceration in rheumatoid arthritis is vasculitis. Vessels of different sizes may be affected. These patients will require systemic therapy because mortality can be high [38]. Workup for the patients should include a complete his- tory and thorough physical exam, screening laboratory stud- ies and biopsies. Treatment is a challenge, but stabilizing Clinical assessment of the wound Assess the lower extremity pulses Make a doppler ultrasound exam if they are not present Start with antiseptics and/or antimicrobials topics if clinical signs of local infection are present Refer to a physiotherapist if the patient is bedbound or if a rehabilitation program is required Refer to a pain management specialist if not adeguately controlled Start systemic antibiotics and refer to an infectious disease specialist if clinical and laboratory signs of deep and progressive infection are present Exclude a concomitant involvement of large vessels with an ECD ultrasound Refer to a diabetologist for the correct metabolic management Refer to a rheumatologist for an evaluation An oncological evaluation is requiredRefer to an angiologic examination if perfusion signs are not present Exclude a bacterial superinfection using the NERDS/STONEES criteria Evaluate the degree of mobilization Evaluate the pain with the VAS scale Presence of a history of diabetes mellitus with a scarce glycemic control Make a skin biopsy if an AD and/or a secondary vasculitis history is present Exclude a paraneoplastic syndrome if an acute onset with multiple lesions are associated with a neoplastic history Figure 2. 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