**5.8. Autoimmune diseases**

### *5.8.1. Rheumatoid ulcers*

**5.5. Mixed ulcer**

**5.6. Pyoderma gangrenosum**

288 Wound Healing - New insights into Ancient Challenges

disorders [8, 12] (**Figure 4**).

**Figure 4.** Pyoderma gangrenosum.

**Figure 5.** Livedoid vasculopathy and tiny ulcerations.

**5.7. Vasculitis**

Patients with mixed etiology ulcers have combined venous and arterial disease. Often further complicating factors such as DM, rheumatoid arthritis (RA), or lymphedema also exist [42].

Pyoderma gangrenosum is a neutrophilic dermatosis. Clinically it starts with sterile pustules that rapidly progress and turn into painful ulcers with purplish‐blue, undermined borders [42, 45]. It may be associated with inflammatory bowel disease, rheumatic, or myeloproliferative

Cutaneous vasculitis may present as palpable purpura, urticaria, nodule, bullae, livedo reticularis, necrotic areas, or skin ulceration. Vasculitic leg ulcers are often painful, multilocular Approximately 10% of individuals with RA develop leg ulcers [41] (**Figure 6**). The cause of leg ulcerations in RA is multifactorial, including vasculitis, venous insufficiency, paraproteine‐ mias, medications, superficial ulcerating rheumatoid necrobiosis, pyoderma gangrenosum, and Felty's syndrome [45–48](**Figure 6**).

**Figure 6.** Rheumatoid ulcer.

### *5.8.2. Scleroderma*

The prevalence of lower extremity ulcers in scleroderma is 3.6% and various parts of the leg can be affected [49]. These ulcers are painful and relatively refractory to standard treatment methods. Antiphospholipid antibody, fibrotic skin, vascular compromise, coagulation abnor‐ malities, and tissue calcium deposition may have a role in their pathogenesis [45, 46, 48].

### *5.8.3. Systemic lupus erythematosus (SLE)*

Leg ulcers of SLE are usually painful, sharply marginated, or punched out that located over the malleolar, supramalleolar, or pretibial areas [50]. Vasculitis, antiphospholipid antibody, thrombosis of vessels, venous insufficiency, lupus profundus, and drug‐induced lupus syndrome have been associated with leg ulcerations.

### *5.8.4. Sjögren syndrome*

Leg ulcerations of Sjögren syndrome have been associated with cryoglobulinemia, anticardio‐ lipin antibody, and vasculitis [46, 51].

### *5.8.5. Dermatomyositis*

Leg ulcers of dermatomyositis have been reported to involve calcinosis cutis and vasculitis [46].

### *5.8.6. Mixed connective tissue disease (MCTD)*

MCTD is an overlap syndrome combining features of SLE, RA, systemic sclerosis, and dermatomyositis together with the presence of antibodies to U1‐RNP. Chronic leg ulcers are not rare in MCTD and they have been reported to be due to subcutaneous calcification, vasculitis, vasospasm (Raynoud's phenomenon), vascular thrombosis, and antiphospholipid antibodies [46, 52, 53].

### **5.9. Infections**

Numerous infections can precipitate ulcerations on the lower legs. Ecthyma, atypical myco‐ bacterial infections, late syphilis, cutaneous leishmaniasis, actinomycoses, nocardioses, human immunodeficiency virus (HIV) infection, herpes simplex, and cytomegalovirus infections must be considered [41, 43, 54]. In addition, all chronic wounds may be secondarily contaminated with bacteria. Tissue culture will help elucidate the cause [4].

### **5.10. Metabolic diseases**

Various metabolic factors such as diabetes mellitus, amyloidosis, hyperhomocysteinemia, prolidase deficiency, oxalosis, calciphylaxis, and gout can play a role for the lower leg ulcera‐ tions.

Necrobiosis lipoidica is a rare, chronic granulomatous disease of the skin. Clinical presentation characterized by atrophic, indurated plaques with a yellowish center and telangiectasies [42]. The lower legs, especially the shins, are the most common sites of involvement. During the course, ulcerations may occur. Necrobiosis lipoidica frequently occurs in association with diabetes mellitus (**Figure 7**).

**Figure 7.** Necrobiosis lipoidica.

*5.8.3. Systemic lupus erythematosus (SLE)*

290 Wound Healing - New insights into Ancient Challenges

lipin antibody, and vasculitis [46, 51].

*5.8.6. Mixed connective tissue disease (MCTD)*

with bacteria. Tissue culture will help elucidate the cause [4].

*5.8.4. Sjögren syndrome*

*5.8.5. Dermatomyositis*

antibodies [46, 52, 53].

**5.10. Metabolic diseases**

diabetes mellitus (**Figure 7**).

**5.9. Infections**

tions.

syndrome have been associated with leg ulcerations.

Leg ulcers of SLE are usually painful, sharply marginated, or punched out that located over the malleolar, supramalleolar, or pretibial areas [50]. Vasculitis, antiphospholipid antibody, thrombosis of vessels, venous insufficiency, lupus profundus, and drug‐induced lupus

Leg ulcerations of Sjögren syndrome have been associated with cryoglobulinemia, anticardio‐

Leg ulcers of dermatomyositis have been reported to involve calcinosis cutis and vasculitis [46].

MCTD is an overlap syndrome combining features of SLE, RA, systemic sclerosis, and dermatomyositis together with the presence of antibodies to U1‐RNP. Chronic leg ulcers are not rare in MCTD and they have been reported to be due to subcutaneous calcification, vasculitis, vasospasm (Raynoud's phenomenon), vascular thrombosis, and antiphospholipid

Numerous infections can precipitate ulcerations on the lower legs. Ecthyma, atypical myco‐ bacterial infections, late syphilis, cutaneous leishmaniasis, actinomycoses, nocardioses, human immunodeficiency virus (HIV) infection, herpes simplex, and cytomegalovirus infections must be considered [41, 43, 54]. In addition, all chronic wounds may be secondarily contaminated

Various metabolic factors such as diabetes mellitus, amyloidosis, hyperhomocysteinemia, prolidase deficiency, oxalosis, calciphylaxis, and gout can play a role for the lower leg ulcera‐

Necrobiosis lipoidica is a rare, chronic granulomatous disease of the skin. Clinical presentation characterized by atrophic, indurated plaques with a yellowish center and telangiectasies [42]. The lower legs, especially the shins, are the most common sites of involvement. During the course, ulcerations may occur. Necrobiosis lipoidica frequently occurs in association with Calciphylaxis is an uncommon disorder, classically associated with renal disease and secon‐ dary parathyroidism [55]. Clinical presentation may begin as microlivedo that develop into painful ulcerations.

### **5.11. Hematologic diseases**

Several forms of anemia (thalassemia, sickle cell anemia, hereditary spherocytosis, glucose 6 phosphate dehydrogenase deficiency), and hypercoagulable disorders (antiphospholipid antibody syndrome, antithrombin III, protein C or S deficiency, essential thrombocythemia, thrombotic thrombocytopenic purpura, polycythemia, or abnormal clotting factors such as factor V Leiden, factor II mutant) have been associated with lower leg ulceration [54].

### **5.12. Neoplasia**

Many tumor types such as basal cell carcinoma, squamous cell carcinoma, and melanoma may present with skin ulceration. Basal cell carcinomas arising from venous ulcers appear as exuberant granulation tissue rolling onto the wound edges [4]. In addition, malignancy that presents as Marjolin's ulcers is most commonly associated with chronically inflamed, or scarred skin. Skin biopsy is necessary to identify ulcerated malignant tumors on the leg.

### **5.13. Medications**

Hydroxyurea is a cytostatic drug used in various myeloproliferative disorders. A rare com‐ plication is the development of painful ulcers, usually localized on the malleoli or in neigh‐ boring regions [42, 54]. The coumarin derivatives, nifedipine, diltiazem, barbiturates, and erythropoietin in very rare cases, may trigger ulcer development [42].
