Scleroderma skin ulcers definition, classification and treatment strategies our experience and review of the literature

. Background: Skin ulcers (SU) are one of the most frequent manifestations of systemic sclerosis (SSc). SSc-SU are very painful, often persistent and recurrent; they may lead to marked impairment of patient’s activities and quality of life. Despite their severe impact on the whole SSc patient’s management, the proposed definition, classification criteria, and therapeutic strategies of SSc-SU are still controversial. Objective: The present study aimed to elaborate a comprehensive proposal of definition, classification, and therapeutic strategy of SSc-SU on the basis of our long-term single center experience along with a careful revision of the world literature on the same topic. Methods: A series of 282 SSc patients (254 females and 28 males; 84% with limited and 16% diffuse cutaneous SSc; mean age of 51.5±13.9SD at SSc onset; mean follow-up 5.8±4.6SD years) enrolled during the last decade at our Rheumatology Unit were retrospectively evaluated with specific attention to SSc-SU. The SSc-SU were classified in 5 subtypes according to prominent pathogenetic mechanism(s) and localization, namely 1. digital ulcers (DU) of the hands or feet, 2. SU on bony prominence, 3. SU on calcinosis, 4. SU of lower limbs, and 5. DU presenting with gangrene. This latter is a very harmful evolution of both DU of the hands and feet needing a differential diagnosis with critical limb ischemia. Results: During the follow up period, one or more episodes of SSc-SU were recorded in over half patients (156/282, 55%); skin lesions were often recurrent and difficult-to-heal because of local complications, mainly infections (67.3%), in some cases associated to osteomyelitis (19.2%), gangrene (16%), and/or amputation (11.5%). SSc-SU were significantly associated with lower patients’ mean age at the disease onset (p=.024), male gender (p=.03), diffuse cutaneous subset (p


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Introduction
Systemic Sclerosis (SSc) is a connective tissue disease, characterized by diffuse microangiopathy, collagen hyperproduction by altered fibroblasts with fibrosis of the skin and internal organs, and multiple immune system alterations (1)(2)(3).The pathogenetic role of microvascular involvement seems to be crucial as suggested by the natural course of the disease; actually, various vasculopathic manifestations characterize the SSc since its prodromic phases: Raynaud's phenomenon almost invariably precedes the SSc clinical onset (1-3), while scleroderma renal crisis and pulmonary arterial hypertension are among the most harmful scleroderma complications, finally scleroderma skin ulcers (SSc-SU) are commonly recorded in up-to 50% of patients (1)(2)(3).SSc-SU represent a burdensome, very painful, often persistent and recurrent SSc complication (4)(5)(6)(7)(8); they may lead to marked limitations in everyday personal and occupational activities with deleterious impact on the patients' quality of life (5).In some individuals, SSc-SU may be complicated by infections and severe gangrene needing amputation (5,9).Despite their severe clinical impact on the whole patient's managing, the proposed definition/classification criteria and therapeutic guidelines of SSc-SU are still controversial (4)(5)(6)(7)(10)(11)(12)(13)(14)(15).The present study aimed to draw up a proposal of definition, classification, and therapeutic strategy of SSc-SU on the basis of our long-term single center experience along with a thorough revision of the world literature on this debated issue.

Patients and Methods
We retrospectively evaluated the epidemiological and clinico-serological data derived from our SSc patients' population enrolled during the last decade at our University-based Rheumatology Unit (282 patients; 254F, 28M) and classified according to ACR/EULAR criteria (16).All SSc patients were routinely evaluated at baseline and at least every 6 months with regards to both cutaneous and visceral organ involvement according to previously reported methodologies (1,17); clinico-serological and instrumental data, as well as ongoing therapies were regularly reported in clinical records, together with unplanned visits due to the appearance/worsening of clinical symptoms, including SSc-SU that were regularly assessed according to the following criteria.

SU definition/classification.
The Tab. 1 shows our proposal of definition and classification of SSc-SU; the classification is mainly based on the different localization of cutaneous lesions, likely due to different pathogenetic mechanisms.According to the definition currently used in the wound care field (18), chronic (lasting >6 weeks) cutaneous ulcers complicating the SSc can be defined as 'loss of ACCEPTED MANUSCRIPT

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substance involving epidermis, basement membrane, and dermis; the latter can be variably involved, considering that the more severe lesions may affect deeper skin layers, i.e.
subcutaneous tissue, muscle, ligament, and bone' (Fig. 1).The SSc-SU encompass all cutaneous ulcerative lesions, while the term digital ulcers (DU) refers to lesions localized to fingertips, toe tips, and/or close to the nails.Overall, SSc-SU more frequently develop at the acral zones of the hands and feet; they may be multiple, recurrent, and/or relapsing.Therefore, SSc-SU can be classified as:  14; Fig. 1-2).

Treatment.
The treatment schedule of SSc-SU was individually tailored according to the patient's clinical conditions and the severity of cutaneous lesion(s), including its possible complications (infection, osteomyelitis, and gangrene) (5,19).In the presence of multiple SU, the characteristics of each lesion were carefully evaluated.In all cases the therapeutic strategy of SSc-SU was based on systemic and local pharmacological treatments, including analgesia for both chronic and procedural pain, as well as on non-pharmacological measures (Fig. 3, Tab.2).

systemic treatment.
Systemic therapy was individually decided by evaluating the severity/activity of the whole SSc.

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Besides local analgesia necessary for procedural pain due to local SU debridement, local nonpharmacological treatment was regularly performed according to wound bed preparation (WBP) procedures: a complex of multistep operations based on the notion that the efficacy of evaluation and treatment of chronic wounds requires holistic care by multidisciplinary approach (27)(28).In the last years we have gradually adapted these knowledge to the specific features and difficulties of SSc-SU.The main principles of WBP are summarized in the acronym TIME (Fig. 3-4; Fig. 3, Tab.2), recalling to the most important aspects of ulcer evaluation and management: necrotic tissue, infection/inflammation, moisture balance, and epithelization, in order to accelerate the spontaneous SU healing and to facilitate the effectiveness of systemic and local therapeutic measures (27)(28).
More in detail the TIME includes (Fig. 4): T is for necrotic tissue: altered cells and bacterial load represent a strong obstacle to the healing process, thus their removal by means of debridement is crucial.Necrotic tissues frequently overshadow the underlying wound bed for a careful assessment, while bacteria compete for scarce local resources necessary for wound healing such as nutritional factors.Different kind of debridement can be performed: chemical, autolytic, mechanical (less selective), biological, and sharp/surgical.We usually employed the sharp debridement because it is the most selective.
The infection complicating the SU is clinically diagnosed by the presence of lesion redness, warmth of the skin surrounding the wound, edema, worsening pain and tenderness, foul smell, and/or purulent drainage.The SU infection should be confirmed by laboratory investigations; considering the difficulties of the tissue biopsy, an adequate deep wound swab may be sufficient.Wound debridement reducing the bacterial burden, including the biofilm, is mandatory.Moreover, the presence of underlying osteomyelitis requires extended systemic antibiotic and surgical management.
-M is for moisture balance: the moisture balance is useful to control of the wound and surrounding area; correct moisture balance has been proven to accelerate wound healing in terms of re-epithelization, granulation tissue formation, and prevention of surrounding skin maceration, without increasing the infection rate.In clinical practice this balance is favored by the use of the wide array of "advanced" moisture retentive dressing (occlusive, semiocclusive, absorptive, and hydrating dressing) according to the moisture status of the wound bed.

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-E is for epithelization: wound healing can be defined in the case of complete progression of the edges and wound contraction.Otherwise, in the case of discontinuation of healing process, every step of the TIME procedure should be re-considered.

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A correct education of all SSc patients for an appropriate life-style is particularly advisable, with specific instructions for individuals with severe Raynaud's phenomenon and/or complicating SSc-SU (37).Therefore, all SSc patients should be recommended to wear a hat, mittens or gloves, scarf, coat with snug cuffs, and warm socks and shoes during cold weather; moreover, to use hand and foot warmers in mittens, boots, socks, or pockets, warm up car before driving in cold weather, wear gloves or mittens when taking food out of the refrigerator or freezer.In general, it is also important to learn handling anxiety, when present, by mean of physical activity, yoga, tai chi, or meditation.Considering that some drugs can trigger Raynaud's attacks, it is necessary to avoid medicines that contain ergotamine, appetite suppressants, betablockers, and hormonal contraceptives; in addition, all patients were strongly advised to stop smoking (29, 30, 37, 38; Fig. 3; Tab. 2).
For a correct management of SSc patients, an individually tailored rehabilitation and/or occupational therapy programs was also included when opportune.These physical therapies were selected on the bases of prevalent clinical manifestation(s), considering the impact on the patient's quality of life.

Review of the literature.
A throughout search in PubMed, Embase, Scopus, Web of Science, Asian Science Citration Index (ASCI), IranMedex, Scientific Information, Database (SID), PaKMediNet, IndMed, and Index

Medicus for the World Health Organization Eastern Mediterranean Region (IMEMR) regarding
SSc patients with SU/DU was done up to June 2017, using the key words scleroderma, systemic sclerosis, skin ulcers, digital ulcers, skin lesions.

Statistical analysis.
Data were expressed as mean±standard deviation (SD) unless otherwise noted.Categorical variables were analyzed by Fisher's exact test, while differences between the means were determined using the Mann-Whitney U-test for unpaired samples.p values ≤ 0.05 were considered statistically significant.
The data processing was performed using the statistical software GraphPad Prism 5.5 for Windows.

Results
The main epidemiological and clinical features of our SSc patients series evaluated in the present study are shown in the Tab.3; it includes 282 individuals (254 females and 28 males) with a mean age of 51.5±13.9SDat SSc onset and 54.6±13.5SDyears and at the beginning of

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follow-up, respectively.The patients were followed for a mean period of 5.8±4.6SDyears; at the first visit the disease duration was 3.1±5.7SDyears, while Raynaud's phenomenon duration before disease onset was 6.4±11SD years.With regards to cutaneous subset classification, 84% All SSc patients underwent systemic therapy (Tab.2; Fig. 3) with at least two drugs; namely, calcium channel blockers (86%), acetylsalicylic acid (75%), prostanoids (75%), steroids (66%), bosentan (25%), and/or immunomodulators/immunosuppressants (anti-CD20 monoclonal antibodies, mycophenolate mophetyl, cyclophosphamide) (33%).These latter were employed in patients with severe/active cutaneous and/or visceral organ involvement, mainly interstitial lung involvement, for one or more cycles.In some cases the concomitancy of non-healing, recurrent SU was also considered in the therapeutical decisions.
With regards the SU complicating over half of our SSc patients, the systemic and local treatment was invariably adjusted according to the patients' general conditions, including the concomitant comorbidities; in particular, local management of SU was decided from time to time considering the objective characteristics of each lesion (Fig. 2-3; Tab. 2).

Review of the literature
The high number of studies published during the last years on SSc-SU assessment and management indicates the growing interest on this issue, considering the negative impact of

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The comparison between the previously and more recently published studies revealed a progressive accuracy and uniformity in the proposed definition and classification criteria of SSc-SU.A number of specific issues relative to previously published studies on SSc-SU are addressed in the following paragraph.

Discussion.
The present proposal of definition, classification criteria, and treatment strategies of SSc-SU is the result of our long-term experience in this challenging scleroderma manifestation in the light of the growing knowledge on the same topic as evidenced by the review of the world literature.
The analysis of our patients' series enrolled during the last decade evidenced one or more An increasing number of clinical reports focused on clinical correlation between skin ulcers and other scleroderma manifestations with the purpose of better define the burden and the

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distinctive features of different SSc-SU variants (Tab.5).Our definition and classification criteria are quite concordant with those emerging from the analysis of more recent studies reported in the literature (14,20,47,50,(52)(53)(54). In the past years some important differences were recognizable among different Authors, particularly with regards to the definition of 'skin ulcer'; the lack of agreement among clinicians was clearly evidenced in a web-based study reporting high intra-rater reliability in grading images of SSc digital lesions [10].The frequent limitations and discrepancies among definition and classification proposals are shown in details in Table 5.
In a controlled and randomized study (44), the DU was defined as a 'loss of surface epithelization without including fissures or cracks in the skin'; similarly, other Authors defined DU as an 'area of loss of surface epithelization affecting the digital pulp or bony prominence, not including fissures or areas of calcium extrusions' (40).In other reports the definition of DU was totally lacking or simply identified as 'loss of skin epithelization' (Tab.1).
While in a recent study DU was properly defined as 'denuded area of tissue with welldemarcated borders involving loss of both the dermis and epidermis' (47).Nowadays there is a general agreement to define SU as skin lesion involving epidermal covering, basement membrane, dermis, and possibly deeper skin layers.Skin lesions detected on the bony prominence such as the volar surface of proximal interphalangeal, metacarpal joints, and/or elbows can be categorized as distinct SSc-SU more likely secondary to concurrent ischemic and traumatic mechanisms (47).Comparable considerations can be deserved for SSc-SU complicating the skin areas above subcutaneous calcinosis (13,15).Finally, there was a general agreement to avoid a number of minor skin lesions, i.e. abrasions, fissures, scars, digital pitting scars, and subungual hyperkeratosis, inconsistent with diagnosis of SSc-SU (14).
A number of studies focused on scleroderma DU of the hands without any concern for DU of the feet and lower limbs that may also represent a relevant cause of morbidity in SSc patients (56,57).In particular, DU of the feet may recognize the same SSc-related microangiopathy responsible for DU of the hands, with a variable contribution of regional macrovascular involvement; while combined arterial-venous angiopathy can be the major cause of SU of lower limbs.
Gangrene is one of the most challenging SSc complications that may be observed in a minority of patients.It may be the evolution of severe, non-healing DU of the hands or feet, or in some cases as presenting symptom at the patient's referral; this troublesome condition may need a differential diagnosis between critical ischemia of the acral districts and typical

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microangiopatic SSc-SU complicated by gangrene.The careful classification of these distinct conditions may be crucial for timely adequate treatment, considering also the possible concomitancy of both micro-and macroangiopathy in some cases.
A shared SSc-SU definition/classification is critical for both clinico-pathogenetic studies and therapeutic trials; therefore, the present proposal remains totally open to further improvement and revision possibly by expert consensus study.
Overall, SSc-SU are often associated with more severe disease course due to internal organ complications; they may contribute to progressive deterioration of the patient's general conditions and in some cases to worse disease outcome (17,58).Skin lesions, mainly the DU, are frequently very painful, leading to severe reduction the patient's quality of life and relevant disability; SSc-SU are among other symptoms, i.e. dyspnea, pain, muscle weakness, and dysphagia, that SSc patients perceive as the main factors affecting their level of disability (59).
Therefore, a correct treatment strategy of SSc-SU may be as relevant as that adopted for other major organ involvement; in addition, the SSc-SU treatment should be correctly combined with the whole disease management.The management of SSc encompasses a complex of therapeutical measures, including both systemic and local, pharmacological and non-pharmacological treatments (22).The pharmacological therapies include both pathogenetic and symptomatic treatments, namely immunosuppressor/immunomodulators, antifibrotics, corticosteroids, plasmapheresis, phototherapy, anti-inflammatory, vasoactive, and analgesic drugs (Tab.2; 22, 60, 61).Almost all the above therapies may be potentially useful on SSc-SU, particularly vasoactive drugs such as calcium channel blockers, prostanoids, ERA, and PDE-5 inhibitors, (22).In more severe, non-healing SSc-SU the use of more innovative treatments were employed with some benefit in small patients' series, namely grow factors, i.e.GCSF and EPO, PG, autologous and allogeneic skin grafting.However, the local treatment employing the more advanced measures, particularly the wound bed preparation procedures and advanced dressing (27,29), plays a decisive role in the majority of SSc-SU.
Recently published studies focusing on SSc treatment strategy are quite concordant as regards the importance of a multidisciplinary approach for both SSc-SU and other major organ involvement (20,22).In this respect, it is recommendable to tailor the whole therapy to each patient; moreover, the patient's education may be decisive for the adherence and efficacy of treatments, including an adequate analgesia for both chronic and procedural pain mainly due

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to skin ulcers (8,20,37).The usefulness of pharmacological, pathogenetic and symptomatic, and non-pharmacological treatments (20,22), as well as some precautionary measures and a proper life-style such as avoiding cold or smoke, may be important to prevent and treat the scleroderma skin lesions (20,22,37).
In conclusion, the progressive improvement of both systemic and advanced local treatments lead to an appreciable reduction of either the healing time of SSc-SU and the incidence of severe complications (infections, gangrene, amputation) in recently referred patients.Overall, the treatment strategy developed during the last decade represents a clear-cut advancement in term of improved patients' quality of life and reduced long-term disability (59).Clearly, the continuing refinement of SSc-SU definition and classification criteria is the precondition for suitable pathogenetic studies and therapeutical trials.

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adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis.Cell Transplant 2015;24:2297-305.

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6. Legend to the Figures.

Fig. 1. Schematic representation of skin lesions in SSc patients (see also Tab. 1).
Patients with SSc may develop a variety of cutaneous lesions: the break of basement membrane with more or less pronounced dermis involvement can represent the pathological distinctive feature of true skin ulcers (SU).
According to the definition currently used in the wound care field, chronic (lasting >6 weeks) SU complicating the SSc can be defined as 'loss of substance involving epidermis, basement membrane, and dermis; the latter can be variably involved, considering that the more severe lesions may affect deeper skin layers, i.e. subcutaneous tissue, muscle, ligament, and bone' (right: in red SU with different depth levels).
Several cutaneous lesions, generally characterized by surface loss of substance, can be frequently observed in scleroderma patients, namely abrasions and fissures, as well as digital pitting scars and sub-ungual hyperkeratosis; these manifestations are inconsistent with diagnosis of true SSc-SU (left).
SSc-SU on the whole disease outcome.Tab. 5 summarizes the main publications in the world literature regarding the SSc-SU; they represent a heterogeneous body of clinical studies on patients' series of largely variable dimensions dealing with various aspects of SSc-SU(4-7, 10-  12, 13-15, 20, 21, 39-54).Several studies focusing on distinctive features of SSc-SU spectrum referred to mono-or multicenter unselected patients series or to specific patients' populations included in therapeutical trials.The large majority of authors focused on the DU that represent the most common complication of SSc skin involvement, including consensus/registry studies; in other instances on the clinical status at the time of ulcer assessment (active or not) or on the evolutionary pattern of SSc-SU (episodic or recurrent) (4, 10, 40, 43-45, 49, 50).

Fig. 2 .
Fig. 2. Different subtypes of scleroderma skin ulcers (SSc-SU) according to proposed definition and classification criteria (see text, Tab. 1, and Fig. 1).Digital ulcers (DU) of the hands or feet are the most frequent wound skin lesions of SSc; thay may be complicated by gangrene.DU with gangrene represent a very challenging condition that may be observed in a minority of patients with severe, non-healing DU of the hands or feet, or in some cases as presenting symptom at the patient's referral.This latter occurrence needs a differential diagnosis with critical ischemia of the acral districts considering its relevant therapeutical implications (see text).Some scleroderma skin lesions inconsistent with the diagnosis of SU/DU are shown in the bottom of the figure.SU: skin ulcer; DU: digital ulcer; SU on calcinosis: the arrows point small solid calcium lumps.

Fig. 3 .
Fig. 3. Therapeutic strategies of scleroderma skin ulcers (SSc-SU).The therapeutic approach of SSc-SU should be invariably tailored to individual patient on the basis of both general clinical conditions and careful evaluation of single skin wound.In particular, a correct therapeutical strategy should always be preceded by the evaluation of the activity/severity of each SSc-SU, the presence of possible often subclinical local complications (infections, osteomyelitis, gangrene), and/or comorbidities (district macrovascular

Fig. 4 .
Fig. 4. Wound bed preparation according to the TIME procedures.The figure shows in details the local treatment flowcharts of SSc-SU according to the wound bed preparation by TIME procedures that are also described in the text.
dressings.Besides the above TIME procedures, we invariably utilize the active dressing; it is often required to obtain the best results of local treatment.The active, advanced of decreased patients' quality of life; while procedural pain weakens the patient's compliance during local treatment, which may result impracticable in more severe lesions.When required, patients with SSc-SU are treated for background chronic pain with long-lasting analgesic treatment, usually opioids, according to pain severity evaluated, for instance, by means of numeric rating scale (range 0-10).Procedural pain needs to be managed with timely escalation of analgesic therapy during DU debridement according to patient's pain rating at the beginning of medication and during ensuing debridement steps (8).2.2.5.Non pharmacological measures.
SSc patients showed limited cutaneous SSc, while 16% had diffuse cutaneous involvement.The detection of anti-topoisomerase antibodies (Scl-70) was positive in 33% of patients, the patients' follow-up; they were characterized by some significant correlations with SSc features.In particular, DU of the feet (52/282, 18.4%) were more frequently observed in males (p=0.026) and correlated with longer follow-up (p=.003), presence of calcinosis (p=.002), telangiectasia (p<.001), and increased value of ESR and CRP (p=.015 and p<.001, respectively); SU on bony prominence (38/282, 13.5%) correlated with diffuse cutaneous SSc subset (p=.006), While renal involvement was recorded in a limited number of patients (7%), in only 4 as typical scleroderma renal crisis.Finally, smoking habit was observed in 32% of patients (Tab.3).The occurrence of at least one episode of SU was recorded in 156 of the whole SSc series (55%).The comparison between patients with and without SU revealed that cutaneous lesions were significantly more frequent in male than female patients (p=.03); moreover, patients with SU showed a medially lower age at SSc onset (p=.024) compared to those without, as well as higher percentages of diffuse cutaneous subset, calcinosis, telangiectasia, and melanodermia (p=.015, =.002, p=.008, and <.001, respectively).Abnormally increased values of derived PAPs (>40 mmHg), and CRP were significantly more frequent in SSc patients complicated by SU (p=.036, and .011,respectively)(Tab 3).Of interest, one or more episodes of SU complicated by local infection were observed in 105/156 (67.3%) patients with SSc-SU, in some cases associated to osteomyelitis, gangrene, and/or amputation (Tab.4).The involved infectious agents were Staphylococcus Aureus in 46.6% of cases, fecal pathogens (E.coli, E. faecalis) in 29.3%, Pseudomonas Aeruginosa in 13.2%, others 10.9%.The occurrence of osteomyelitis was observed in 19.2% of patients with The analysis of SSc-SU variants evidenced that 140 patients developed at least one episode of DU of the hands, alone or in concomitancy with other types of SU; DU of the hands were the most frequent SSc-SU (140/282, 49.6%), showing some interesting correlations with other SSc clinico-serological features (Tab.3).Other SSc-SU variants were less frequently observed during

Clinical studies reporting definitions and classification criteria of scleroderma SU (review of the world literature).
28tive ulcers defined as denuded areas with defined borders and loss of epithelialization, loss of epidermis, and dermis distal to the proximal interphalangeal joint on the volar aspect of a finger.Episodic: rarely recurrent: only 1 FU visit with either ≥1 DU or new DU; the remaining FU visits have no DU and no new DU Recurrent: frequently recurrent, ≥2 FU visits with DU and/or new DU, and ≥1 visit with no DU and no new DU Chronic: ≥1 DU and/or new DU at every FU visit DU: break in the skin with loss of epithelialisation on the distal finger surface not located over subcutaneous calcifications or over extensor surfaces of joints.DU defined as ulcers on the volar aspect of the digits distal to the PIP joints thought to be caused by ischaemia and specifically excluding ulcers over calcium deposits 20 Hunzelmann N.2016 -/+Active DU defined as a loss of both epidermis and dermis in an area of at least 2-mm diameter at the distal phalanx of the fingers but not over bony prominences, encompassing the palmar (volar) area.21AhrensH.C. 2016 51 -/+ DU defined as epithelial lesions with tissue loss occurring at the fingers or the feet, they can be classified into three groups: DUs on digital pitting scars, primary DUs and DUs on calcinosis .Persistent DU defined as the loss of epithelialization of any degree of the dermis and/or the subcutaneous tissue, distal to or at the proximal interphalangeal joint of the hands or feet not due to trauma or underlying calcinosis.DU result of poor tissue perfusion over the digital pulps, around the nailfold and on extensor surfaces of the fingers or toes and may also occur in relation to calcinosis.Digital tip ischemia/ulcer defined as digital pitting scars, ulcerations or gangrene, located at finger and/or toe tips.DU defined as denuded areas with a defined border, loss of epithelialization and loss of epidermis and dermis on the volar aspect distal to the proximal interphalangeal joints.28SulimanY.A. 2017 14 review SU definded as loss of epidermal covering with a break in the basement membrane.It appears clinically as visible blood vessels, fibrin, granulation tissue and/ or underlying deeper structures (e.g., muscle, ligament, fat), or as it would appear on debridement.29 present series 2017 +/-SU defined as loss of substance involving epidermis, basement membrane, and dermis; the latter can be variably involved, considering that the more severe lesions may affect deeper skin leyers, i.e. subcutaneous tissue, muscle, ligament, and bone; classified: 1. DU of the hands and DU of the feet, 2. SU on bony prominence, 3. SU on calcinosis, 4. SU of lower limbs, and 5. SU or DU presenting with gangrene SU: skin ulcers; DU: digital ulcers; FU: follow up;