Skin disorders in diabetes mellitus

847© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210 847

Skin disorders in diabetes mellitus

SummaryDiabetes mellitus is one of the most common diseases in industrialized Western countries with about 300 million affected patients worldwide. The hyperglycemic state of diabetes mellitus leads to changes in almost every human cell type and organ. Skin changes are considered the most common manifestations of diabetes mellitus. As skin changes can manifest before onset of diabetes mellitus, they may have a diagnostic relevance. Other cutaneous manifestations develop during the course of diabetes mellitus and may be associated with complications in internal organs or may occur as an adverse effect of antidiabetic therapy. In particular, the presence of the diabetic foot syndrome is associated with significantly increased morbidity and mortality of diabetes patients as well as with markedly elevated di-rect and indirect costs for the health care system. In this article the most common skin diseases of patients with diabetes mellitus as well as their pathophysiology and current treatment are reviewed.

Introduction

Diabetes mellitus ranks among the most common diseases in Western industrial nations. With a worldwide prevalence of 6.4 % in the year 2010, it affected appro-ximately 285 million adults, a number expected to rise to 324 million by the year 2025 [1, 2]. Nosologically, diabetes mellitus has traditionally been divided into two pathophysiologically different subtypes. Type 1 diabetes mellitus primarily affects children and adolescents whose endogenous insulin production disappears due to autoimmune destruction of pancreatic β cells, so they frequently require ear-ly insulin replacement. On the other hand, type 2 diabetes mellitus, characterized by insulin resistance and lack of insulin dependence in the early stages, shows in-creasing incidence with age and correlates with the body mass index (BMI). Other subtypes of diabetes mellitus include congenital pancreatic β cell deficiency and insulin signal transduction disorders as well as diabetes mellitus in the context of exocrine pancreas disorders and syndromic polyendocrinopathies [2, 3].

Epidemiologically, approximately 30 % of all diabetics show skin lesions du-ring their lifetime [1]. Although predominantly occurring during the course of the disease, skin disorders may occasionally also precede diabetes mellitus or indicate a hereditary or acquired syndrome associated with diabetes mellitus. In general, there is no clear correlation between incidence or extent of diabetic skin lesions and the severity of the diabetic state. Nevertheless, certain skin diseases or ma-nifestations may be indicative of extracutaneous diabetic complications such as

Submitted: 17.4.2014Accepted: 17.6.2014

CME-ArticleDOI: 10.1111/ddg.12424

Paraskevi Gkogkolou, Markus BöhmDepartment of Dermatology, University Hospital Münster, Germany

Section Editor Prof. Dr. Jan C. Simon, Leipzig

Conflict of interestNone.

Approximately one third of all diabetics develop skin lesions during the disease

course.There may be a correlation between

certain diabetic skin manifestations and extracutaneous diabetic complications

such as neuropathy or vasculopathy.

CME Article

848 © 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210

diabetic neuropathy or vasculopathy [2]. Clinically most relevant are those skin disorders that show greater morbidity and mortality in diabetic patients and thus entail greater health care costs. In Germany, direct health care costs linked to dia-betes mellitus amounted to an estimated 42 billion EUR in 2007 [4]. Finally, skin lesions may also be result of anti-diabetic therapy.

Pathophysiology of diabetes mellitus with particular focus on the skin

Through various pathomechanisms, diabetes mellitus damages skin function in a complex fashion. Studies on in vitro cell culture systems have shown that diabetes mellitus exerts negative effects on nearly every cell parameter, not only directly through pathologic glucose levels but also indirectly by the formation of so-called advanced glycation end products (AGEs). Not only do pathologic glucose levels inhibit the proliferation, migration, and protein biosynthesis of keratinocytes and fibroblasts [5], they also cause apoptosis of endothelial cells and inhibit nitric oxide (NO) synthesis by blocking the enzyme nitric oxide synthase (NOS), thus resulting in decreased vasodilation in vivo [5]. Moreover, pathologic glucose levels suppress chemotaxis and phagocytosis in various cell types of the innate immune system [1, 5]. AGEs arise from non-enzymatic reactions (glycation) of glucose with proteins, li-pids and nucleic acids [1, 6]. AGEs interact with and thus impair the biologic func-tion of a number of intracellular and extracellular proteins such as type 1 collagen, superoxide dismutase 1, or epidermal growth factor receptor. Further, AGEs also bind to RAGE (receptor for AGEs), resulting in activation of the canonical nuclear factor κB (NF-κB) signaling pathway, which induces proinflammatory cytokines [6]. Pathologic glucose levels as well as AGEs bring about increased intracellular oxidative stress, including the formation of reactive oxygen species (ROS). This ef-fect is caused, on the one hand, by the depletion of protective antioxidant enzymes such as glutathione or mitochondrial superoxide dismutase, on the other hand by the induction of ROS-generating enzymes such as nicotinamide adenine dinucleo-tide phosphate oxidase [6].

The pathomechanisms outlined above lead to diabetic micro- and macroan-giopathy, which subsequently cause tissue hypoxia and thus eventually also nerve damage [1]. As a consequence of diabetic neuropathy, sensorimotor and autonomic nerve function is impaired, resulting in decreased nociception, greater vulnerabi-lity for exogenous trauma, reduced circulation, anhidrosis, and xeroderma [7, 8].

Skin complications in diabetes mellitus

Diabetic foot syndrome

Diabetic foot syndrome is one of the most significant diabetic complications; its therapy poses an interdisciplinary challenge [7, 8]. In their lifetime, 15–25 % of all diabetics are affected by diabetic foot syndrome. The amputation rate in these patients amounts to approximately 25 % and nearly 50 % of all diabetics die wit-hin three years of undergoing such an operation [1, 7]. Europe-wide, annual costs incurred by diabetic foot syndrome have been estimated at 4 500–16 835 € per patient, depending on concomitant peripheral artery disease or infection [9].

The pathogenesis of diabetic foot syndrome is complex and, apart from diabetic micro- and macroangiopathy as well as neuropathy, also includes coexis-ting skeletal deformities (hallux valgus, claw toes) and wearing of inappropriate

In diabetics, some skin disorders show considerably greater morbidity and

mortality.

Pathologic glucose levels as well as the formation of reactive oxygen species

and AGEs interact in the molecular pathogenesis of diabetic skin lesions.

AGEs interact with intracellular as well as extracellular proteins and also bind

to RAGE, resulting in a proinflammatory cellular immune response.

Depletion of antioxidant enzymes and induction of ROS-generating enzymes

result in increased oxidative stress in diabetes mellitus.

Diabetic micro- and macroangiopathy as well as diabetic neuropathy are a

crucial mainstay in the pathogenesis of diabetic skin lesions.

In their lifetime, 15–25 % of all diabetics suffer from diabetic foot syndrome.

CME Article

849© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1210

footwear [7, 10]. Diabetic foot syndrome is usually preceded by minimal trauma [8, 10]. On the cellular level, all phases of wound healing are affected. Chemotaxis and phagocytosis in cells of the innate immune system are impaired, production of antimicrobial peptides is reduced, and migration and proliferation of epidermal keratinocytes as well as matrix synthesis by fibroblasts are hampered [5]. An in-crease in proinflammatory cytokines such as tumor necrosis factor (TNF) on the one hand, and a reduction of growth factors on the other, both contribute to the impaired wound healing process [8] (Figure 1).

Clinically, diabetic foot syndrome is characterized by an ulcer, which is predo-minantly located at pressure sites secondary to diabetic neuropathy and resultant decreased nociception [8]. Protrusions of the second and third metatarsal head and inappropriate weight bearing result in hyperkeratoses and subsequently in a well-demarcated ulcer with hyperkeratotic margins, showing only minor tenden-cy to form granulation tissue (Figure 2). This ulcer has to be differentiated from a purely neuropathic ulcer (malum perforans), because in the latter, neuropathy plays an essential pathogenetic role, whereas circulation remains normal. Here, the foot is typically warm, pedal pulses are palpable, and there is hypohidrosis [7]. The danger of osteomyelitis rises with increasing ulcer depth [7]. By contrast, in neuroischemic ulcers, the foot is cold, pedal pulses are not palpable, and there is atrophy of the skin and its appendages. Intermittent claudication may be missing due to concomitant neuropathy.

Figure 1 Schematic illustration of the pathophysiology of diabetic foot syndrome with ulceration showing the impact of high glucose levels on essential cutaneous cell types. Abbr.: A, adipocytes; AT-II, angiotensin II; AT-II-R, angiotensin II receptor; COL, collagen; CTGF, connective tissue growth factor; E, endothelial cells; F, fibroblasts; FN, fibronectin; HA, hyaluronic acid; hBD2, human beta-defensin 2; IL, interleukin; K, keratinocytes; MCP-1, monocyte chemotactic protein; MΦ, monocytes, macrophages; N, neural cells; NG, neutrophilic granulocytes; O2

−, superoxide anion; PAI-1; plasminogen-activator inhibitor 1; TNF, tumor necrosis factor.

CME Article


Diabetic foot syndrome is classified according to guidelines issued by the German Diabetes Society and recommendations by the Work Group Foot of the German Dermatologic Society (DDG) (Table 1). Coexisting infections and angio-pathy have a negative effect on prognosis [8].

Treatment of diabetic foot syndrome requires an interdisciplinary approach [7, 8]. Besides regular wound debridement to remove dead tissue, application of topical antiseptic agents (for example hydrophilic polyhexanide gel) as well as wound dres-sings geared towards the respective wound healing phase, the general diabetic state should be optimized and acral perfusion enhanced. Initially, a vascular workup should be performed, followed, if indicated, by recanalization procedures such as percutaneous transluminal angioplasty, stent placement, or peripheral arterial bypass [1, 8, 10]. The risk for amputation may be reduced by revascularization. However, if such a procedure is surgically not feasible, treatment with alprostadil or iloprost may be administered, in order to improve arterial circulation [7]. In case of contraindications to surgical debridement under general anesthesia, biosurgical debridement using medicinal maggots represents an alternative [10]. Large defects may be closed with split-thickness skin grafts, and graft survival can be facilitated by using vacuum therapy. If there are any signs of infection, a thorough workup

Figure 2 Diabetic foot syndrome with plantar ulceration.

Table 1 Classification of diabetic foot according to Wagner and Armstrong.

Grade according to Wagner

0 1 2 3 4 5

Stage according to Armstrong

Pre- or post- ulcerative

lesion

Superficial wound

Wound extends to the level of tendons

or capsules

Wound extends to the level of bones

and joints

Necrosis of parts of the

foot

Necrosis of the entire

foot

A Without infection and ischemia

B With infection

C With ischemia

D With infection and ischemia

Diabetic foot syndrome is classified according to Wagner and Armstrong; infection and angiopathy exacerbate

the prognosis.

CME Article


should be implemented (deep swabs, diagnostic imaging (MRI), if osteomyelitis is suspected) followed by the administration of systemic antibiotics according to antibiogram [10]. Further measures include bedrest and orthopedic shoes to reduce local pressure [7, 8, 10]. Bone deformities may be surgically corrected.

Other therapeutic options supposed to facilitate wound healing in diabetic foot syndrome include the local application of growth factors such as epidermal growth factor, basic fibroblast growth factor, platelet-derived growth factor, gra-nulocyte macrophage colony-stimulating factor (GM-CSF) as well as “artificial skin” (autologous transplantation of fibroblasts and/or keratinocytes) [10]. Am-putation of the affected foot as last resort in case of failure of the aforementioned measures should preferably be performed by sparing weight bearing structures [7].

Charcot foot

Although Charcot foot (acroosteolysis ulceromutilans, diabetic neuropathic osteoar-thropathy) does not primarily affect the skin, dermatologists should be familiar with this disorder, as it may imitate erysipelas/cellulitis, deep vein thrombosis, or an acute gout attack [11]. In case of delayed diagnosis, the risk for foot amputation is high [7].

Charcot foot is considered an inflammatory syndrome likely caused by mul-tiple pathogenetic factors such as mixed (sensorimotor and autonomic) diabetic neuropathy, exogenous trauma, and perturbations in bone metabolism [11]. Neu-ropathy gives rise to an increase in peripheral blood flow, bone metabolism, and bone degradation, subsequently leading to bone destruction, dislocation, and de-formity [11]. Although patients with non-diabetic neuropathies may also develop Charcot foot, diabetic neuropathy by far represents the most common cause for this disease, which may involve bones, joints as well as soft tissues. Initially, the affected foot is warm, swollen, and erythematous. Pain is slight to moderate and pulses are typically palpable [7, 11]. In later stages, the metatarsals collapse resul-ting in the typical rocker bottom foot (Figure 3), which may lead to ulceration in areas exposed to inappropriate weight bearing. Besides history and clinical presen-tation, diagnostic imaging is vital. Conventional X-rays of the foot show fractures

Local application of growth factors as well as autologous cell grafts are new methods in the treatment of diabetic

ulcers.

Figure 3 Charcot foot with typical rocker bottom deformity (photography kindly provided by Dr. T. Budny).

Concomitant vascular and orthopedic care may be crucial in improving the long-term prognosis in diabetic foot

syndrome patients.

Charcot foot may imitate erysipelas/cellulitis, deep vein thrombosis, or an

acute gout attack.

Charcot foot is considered an inflam-matory syndrome resulting in bone

destruction and deformity due to in-creased bone metabolism.

CME Article


and dislocations, however, in early stages, MRI is the method of choice due to its greater sensitivity and specificity [7, 11] and its ability to differentiate osteomyeli-tis. Bone scans using Technetium-99m or labeled (radioisotopes) white blood cells as well as positron emission tomography scanning may also be useful, particularly in the diagnostic differentiation of osteomyelitis [11].

Aimed at preventing further progression and fractures, swift and complete off-loading of the foot using a total contact cast is the most vital therapeutic measure [7, 8]. Following the acute healing process, which may take up to several months, offloading by means of prescriptive orthopedic shoes should be continued [11].

Infectious disorders

Bacterial and mycotic skin infections occur more frequently in diabetic than he-althy individuals. In case of skin or soft tissue infections, diabetics exhibit a fi-vefold increase in complication risk compared to non-diabetics [12]. On the one hand, neuropathy pathogenetically predisposes diabetics to not notice mechanical trauma, giving rise to indolent portals of entry. On the other hand, the diabetic sta-te promotes greater pathogen growth at the portal of entry and causes disturbance in both the innate and the adaptive immune response [5]. Recurrent or recalcitrant skin infections should therefore always raise the suspicion for diabetes mellitus [1].

Bacterial skin infections are common in diabetics [1]. They typically include erythrasma, impetigo, folliculitis, multiple abscesses, furuncle, and carbuncle. Ery-sipelas and cellulitis often show a more severe clinical course (Figures 4, 5) [1, 12]. Treatment options comprise local antiseptic or antibiotic agents and, in case of progressive soft tissue involvement or systemic signs of infection, the timely use of systemic antibiotics according to antibiogram.

Malignant (or necrotizing) otitis externa represents a particular bacterial skin infection in diabetes mellitus. It is caused by Pseudomonas aeruginosa, may lead to osteitis or meningitis, and takes a lethal course in approximately 50 % of cases [13]. Necrotizing fasciitis affects diabetics more frequently than non-diabetics,

Figure 4 Erysipelas. Sharply demarcated, hyperthermic, swollen erythema. Secondary findings: xeroderma and onychomycosis representing portal of entry for bacteria.

Recurrent bacterial skin infections should always raise the suspicion for

diabetes mellitus.

Malignant otitis externa caused by Pseu-domonas aeruginosa may lead to ostei-tis or meningitis and takes a lethal cour-

se in approximately 50 % of patients.

If Charcot foot is clinically suspected, conventional X-rays and MRI are indica-

ted to ascertain the diagnosis.

In case of skin infections, diabetics exhi-bit a fivefold increase in complication

risk and a fourfold increase in hospitali-zation risk compared to non-diabetics.

CME Article


the former often displaying a fulminant course associated with high mortality. The most common causal pathogens are Staphylococcus aureus, Streptococcus pyogenes, anaerobic Streptococcus and Bacteroides species. Mixed infections are common [2]. Within 24–48 hours, the initial erythema develops into a violaceous, poorly demarcated discoloration with occasional blisters, followed by extensive deep tissue destruction. Despite optimal therapy including swift administration of systemic antibiotics, surgical debridement, and ICU monitoring, the mortality rate is 20–30 % [2].

Mucocutaneous infections by Candida species, such as thrush, angular cheilitis, candidal balanoposthitis, vulvovaginitis, and paronychia as well as in-tertriginous candidiasis, also occur more frequently in diabetics (Figure 6) [13].

Figure 5 Erythrasma.

Figure 6 Intertriginous candidiasis with typical satellite lesions.

CME Article


Clinically, these infections are characterized by white oral mucosal patches that can easily be wiped away; erythema and rhagades in the corners of the mouth; interdigital erythema, scaling, and rhagades; or sharply demarcated erythematous scaly plaques in the axillae, inguinal and submammary regions with typical satel-lite lesions. Anogenital involvement usually manifests as chronic localized pruritus [13]. By contrast, it is still a matter of controversial debate whether diabetics are also more frequently affected by dermatophyte infections. With respect to therapy of mucocutaneous candidal infections, local antimycotics are the treatment of first choice. Recalcitrant cases may require systemic antimycotic treatment, however, drug interactions and contraindications have to be observed. As bacterial skin in-fections occur more frequently in diabetics, portals of entry caused by tinea pedis should always be adequately treated. Furthermore, supportive measures such as regular podiatric care as well as regular clinical foot exams are highly recommen-ded in diabetic patients [10].

Skin lesions and disorders associated with diabetes mellitus

Diabetic erythema (rubeosis diabetica)

Diabetic erythema is characterized by flush-like reddening of the face caused by abnormal vasomotor function with resultant stasis within the dermal vascular plexus. There is no known corrective therapy [13].

Diabetic purpura

Diabetics often exhibit purpuric macules, especially on the lower extremities thought to be pathogenetically caused by increased vascular fragility brought on by diabetic microangiopathy. While there is no corrective therapy, mechanical trauma should be avoided [13].

Diabetic dermopathy (Binkley syndrome)

Although diabetic dermopathy ranks among the most common skin manifestation in diabetes, it is rarely diagnosed, as lesions are asymptomatic. Clinically, it pre-sents with round to oval, hyperpigmented and partly atrophic lesions on the exten-sor surfaces of the lower extremities [2, 14]. Pathogenetically, a relationship with diabetic microangiopathy has been suggested [14]. Histopathology shows dermal hemosiderin deposits, basal hyperpigmentation of the epidermis as well as vascular thickening with hyaline deposits [13]. Remarkably, there is an association of these cutaneous diabetic manifestations with neuropathy, nephropathy, and retinopathy. Thus, the diagnosis of diabetic dermopathy should prompt targeted screening for the above-mentioned diabetic complications [1, 14]. Currently, there is no effective therapy for diabetic dermopathy [2, 14].

Diabetic bullae (bullosis diabeticorum)

This disorder is characterized by recurring, well-demarcated, tense blisters on non-inflamed skin, frequently arising on the extensor surfaces of the extremities and feet in elderly diabetes patients [13]. The pathogenesis of these skin lesions re-mains a conundrum. Blisters are located subepidermally and typically sterile [13]. Spontaneous resolution usually sets in within 2–4 weeks. For symptom control,

Diabetic dermopathy presents with round to oval, hyperpigmented, and

partly atrophic skin lesions on the ex-tensor surfaces of the lower extremities. Affected patients frequently suffer from diabetic neuropathy, nephropathy, and

retinopathy.

Tinea pedis may represent a portal of entry for potentially life-threatening

bacterial infections and should therefo-re always be treated.

CME Article


local antiseptic agents or topical corticosteroids (class II–III according to German classification) may briefly be employed [2]. It is imperative to definitively rule out other autoimmune blistering diseases, particularly bullous pemphigoid. Differen-tial diagnostic considerations in bullosis diabeticorum should therefore always prompt, possibly repeated, direct and indirect immunofluorescence tests.

Necrobiosis lipoidica

Necrobiosis lipoidica may be viewed as the prototype of a diabetes-associated skin disease. Although it only occurs in roughly 0.3–1.2 % of diabetics, 10–65 % of all necrobiosis lipoidica patients suffer from diabetes mellitus [2]. However, necrobiosis lipoidica also shows greater prevalence in other immune-mediated inflammatory disorders. Clinically, it initially presents with erythematous papu-les that over time turn into mostly flat, orange-red plaques with central atrophy and telangiectasias surrounded by irregular, raised, violaceous or brown-red bor-ders (Figure 7) [15]. Although the extensor surfaces of the lower extremities are primarily affected, necrobiosis lipoidica may also involve the dorsi of the feet as well as the ankles and, in rare cases, also other areas of the body. Approximately 30 % of patients develop poorly healing ulcers, frequently following minor trau-ma [2]. Lesions are often asymptomatic but may become painful once ulceration sets in [13]. The disease is chronic and does not correlate with the extent of the diabetic state.

The pathogenesis of necrobiosis lipoidica is still only sketchily understood, but microangiopathy seems to play an essential role [15]. Histologically, the entire dermis shows necrobiotic collagen bundles extending into the subcutaneous fat with peripheral histiocytes arranged in palisades. The basement membrane is thi-ckened, dermal vessels are thrombosed [2]. Unlike granuloma annulare, necrobio-sis lipoidica affects the entire dermis.

Differential diagnostic considerations include granuloma annulare, necro-biotic xanthogranuloma, morphea, sarcoidosis [15], and, in case of ulceration, also tuberous syphilid.

Bullosis diabeticorum is a diagnosis of exclusion. Over the disease course, direct

and indirect immunofluorescence tests should be repeatedly performed, parti-cularly to rule out bullous pemphigoid.

10–65 % of necrobiosis lipoidica patients are diabetic.

Typical predilection sites are the exten-sor surfaces of the lower extremities

displaying centrifugally spreading, orange-brown, atrophic plaques with violaceous or brown-red borders. Ul-

cers following minor trauma frequently heal poorly.

Figure 7 Necrobiosis lipoidica.

Differential diagnoses of necrobiosis lipoidica include granuloma annulare,

necrobiotic xanthogranuloma, mor-phea, sarcoidosis, and, in case of ulcera-

tion, tuberous syphilid.

CME Article


Treatment of necrobiosis lipoidica is difficult and there have been no rando-mized controlled therapeutic trials [15]. In the early stages, topical high-potency corticosteroids, also under occlusion, or intralesional corticosteroids may be em-ployed. Here, the potential for aggravating preexisting atrophy has to be taken into account [13]. Smaller case series and individual case reports have shown successful treatment using bath PUVA therapy as well as topical calcineurin inhibitors. Case reports and smaller case series have suggested a certain therapeutic efficacy for pentoxifylline, antiplatelet drugs, chloroquine, clofazimine, cyclosporine, myco-phenolate mofetil, prostaglandin E1, and anti-TNF agents [13, 15]. One case series of 18 patients also showed positive effects of fumaric acid esters in necrobiosis lipoidica [16]. With respect to poorly healing ulcers, GM-CSF (granulocyte macro-phage colony-stimulating factor) may be useful.

Granuloma annulare

For decades, granuloma annulare has been considered a skin disease typically associated with diabetes mellitus, however, recent studies have questioned this correlation, as localized forms of this disorder usually arise spontaneously. Other associations include autoimmune thyroiditis, lymphoproliferative disorders as well as infectious diseases [17].

Clinically, it presents with skin-colored or livid-red dermal papules or sub-cutaneous nodules arranged in a circular fashion. Lesions may spread centrifu-gally, display central clearing and prominent borders [1]. Predilection sites are the dorsi of fingers, hands, and feet as well as elbows and knees. In the majority of cases, the disease is limited to one or only a few sites, but may rarely also occur in a disseminated fashion virtually all over the body (disseminated granuloma annu-lare) (Figure 8).

Histology shows degenerated collagen fibers at the center of the lesion, sur-rounded by macrophages in a palisade-like arrangement. The lesion usually affects the upper and mid dermis [1].

While the localized granuloma annulare variant is typically self-limiting, treatment of disseminated forms often proves difficult, as topical corticosteroids and topical calcineurin inhibitors or cryotherapy are not very effective. Here, UVA1 or bath PUVA therapy may represent alternatives [1]. Since 8-aminoquino-line derivatives (chloroquine and hydroxychloroquine), dapsone, and clofazimine have been successfully used in various granulomatous skin disorders, they may also be employed in disseminated granuloma annulare in the context of compas-sionate use [13, 17]. There are also individual case reports on the use of tranilast and nicotinamide as well as small case series on systemic retinoids, fumaric acid esters, cyclosporine, and anti-TNF agents [2, 17]. As diabetics per se show a higher incidence of bacterial infections, the risks of immunosuppressive therapy, particularly when used off-label, always have to be thoroughly weighed against its benefits.

Scleredema adultorum of Buschke

While scleredema adultorum of Buschke in children and young women usually oc-curs as a result of infections, the disease shows a striking association with diabetes mellitus (scleredema adultorum diabeticorum) and lymphoproliferative disorders, particularly paraproteinemias, in the elderly [18]. It is clinically characterized by a rapidly progressive, typically nonpitting, induration of the skin, primarily on the upper back, neck, and arms (Figure 9). Occasionally, the skin is erythematous and

Figure 8 Disseminated granuloma annulare.

While isolated granuloma annulare is often self-limiting, treatment of disse-

minated forms is frequently protracted.

Not only is scleredema adultorum of Buschke associated with diabetes mel-litus but also with infections and lym-

phoproliferative disorders.

Initially, therapeutic options include topical corticosteroids, bath PUVA the-rapy, and topical calcineurin inhibitors.

Although granuloma annulare may be associated with diabetes mellitus, it pre-

dominantly occurs spontaneously.

CME Article


shows dilated follicular ostia (peau d‘orange sign) [18]. The mobility of the arms but also of the thorax may be restricted, potentially resulting in restrictive pulmo-nary impairment [2, 18]. Histology reveals an increase in thickened collagen bund-les and dermal mucin deposits (especially hyaluronic acid and glycosaminoglycans) [2, 18]. Important differential diagnoses include systemic sclerosis, eosinophilic fasciitis as well as scleromyxedema.

Scleredema diabeticorum poses a therapeutic challenge. Systemic corticoste-roids (for example as intravenous dexamethasone pulse therapy) alone or in com-bination with cyclophosphamide are problematic, as they facilitate infections and aggravate the diabetic state. The goal should always be optimal diabetes control as well as regular physical therapy to maintain mobility in the upper extremities and thorax [2, 18]. The therapeutic effect of PUVA, prostaglandin E1, methotrexate, and cyclosporine is uncertain [2, 18].

Diabetic cheiroarthropathy

8–50 % of all diabetes patients develop a peculiar thickening of the skin in con-junction with reduced mobility of the fingers, primarily during extension. The so-called prayer sign, i.e. the inability to completely press both palms together, and the so-called tabletop sign, i.e. the inability to completely place the palms on a table, are characteristic for this condition [19]. Accordingly, these pheno-mena are histopathologically reflected by thickened and disorganized collagen fibers as well as dermal mucin deposits, accompanied by a thickening of peri-articular structures. Diabetic microangiopathy as well as AGEs have been pro-posed as possible causes for diabetic cheiroarthropathy, giving rise to ischemia and activation of profibrotic dermal signaling pathways. Glycation of collagen and other matrix proteins changes their biomechanical properties and metabo-lism [19]. Multiple joint involvement in diabetic cheiroarthropathy is considered an important early complication in children with type 1 diabetes mellitus. Not only does diabetic cheiroarthropathy correlate with the diabetic state, affected

Figure 9 Scleredema adultorum diabeticorum.

Diabetic microangiopathy, accumulati-on of AGEs, and activation of profibrotic

signaling pathways result in diabetic cheiroarthropathy.

CME Article


patients also display a greater risk for concomitant microvasculopathy, diabetic retinopathy and/or nephropathy. Diabetic cheiroarthropathy is primarily diag-nosed on clinical grounds. Ultrasound or MRI may help verify thickening of the extensor tendons [19].

Major differential diagnoses comprise Dupuytren disease, carpal tunnel syndrome, tenosynovitis, and sclerodactyly as part of systemic sclerosis. So far, there is no effective drug therapy for diabetic cheiroarthropathy. Aldose reduc-tase inhibitors have shown disappointing results. Intermittently, nonsteroidal antiinflammatory drugs may be used to control symptoms. Physical therapy to maintain joint mobility as well as optimal glycemic control may improve symp-toms [2, 19].

Acanthosis nigricans

Acanthosis nigricans very frequently occurs in diabetics with pathologically ele-vated BMI. Clinically, it presents with a gray to fawn-colored, velvety thickening of the skin and hyperpigmentation in the intertriginous areas, followed later on by papillomatous excrescences and plaques (Figure 10). While the aforementioned lesions typically exhibit only slow progression in obese diabetics (pseudoacan-thosis nigricans), any rapidly progressive acanthosis nigricans, particularly with oral mucosa involvement, should raise the suspicion for an underlying malignancy (malignant acanthosis nigricans).

Histologically, there is hyperkeratosis and papillomatosis as well as mild acan-thosis of the epidermis. As the number of melanocytes is unchanged, the brown discoloration is primarily caused by epidermal thickening. As to the pathogenesis, insulin resistance and high levels of insulin growth factor 1 (IGF 1) result in in-creased activation of the IGF 1 receptor with subsequent proliferation of epidermal keratinocytes [20]. Mechanical triggers such as friction likely play an accessory role in this disorder. Therapeutically, diabetics with acanthosis nigricans primarily benefit from weight reduction and optimal blood glucose control. In rare cases, topical or systemic retinoids, topical agents containing urea or salicylic acid,

Figure 10 Acanthosis nigricans.

Besides weight reduction and optimal blood glucose control, retinoids, topi-cal agents containing urea or salicylic

acid, calcipotriol, metformin as well as surgical procedures may be useful in

acanthosis nigricans.

Multiple joint involvement is considered an important early complication in type 1 diabetes mellitus and indicates a greater

risk for extracutaneous complications.

Nonsteroidal antiinflammatory drugs and physical therapy may lead to symp-tomatic and functional improvement in

diabetic cheiroarthropathy.

Acanthosis nigricans frequently occurs in diabetics with elevated BMI. Only in case of rapid progression and oral mucosa involvement does an under-

lying malignancy have to be taken into account.

CME Article


calcipotriol, systemic metformin, or surgical procedures may be useful (CO2 or alexandrite laser and dermabrasion) [2, 20].

Diabetic pruritus

Chronic pruritus affects 3–49 % of all diabetics and may cause considerable im-pairment of quality of life [21]. Diabetic polyneuropathy (small fiber neuropathy with damage to myelinated Ad and non-myelinated C fibers), xeroderma (aggrava-ted by age and hypohidrosis in diabetic autonomic neuropathy) as well as certain drugs (glimepiride, metformin, and tolbutamide) all have been implicated in the pathogenesis of diabetic pruritus [22]. Skin biopsies from diabetes patients have shown decreased nerve fiber density [22].

Generalized pruritus presents without any primary skin lesions but chronifica-tion may give rise to secondary clinical changes such as prurigo nodularis [21]. In diabetics with localized pruritus, skin infections, such as intertriginous candidia-sis, should be ruled out [13, 21].

Any treatment for diabetic pruritus has to be geared towards optimal pharma-ceutical control of the diabetic state. Symptomatic therapy may include high-dose antihistamines or, due to the neuropathic component of diabetic pruritus, also pain-modulating drugs such as gabapentin, pregabalin, or antidepressants [22]. Basic therapy with emollients containing urea, possibly in combination with subs-tances that mitigate pruritus (for example camphor, menthol or polidocanol), is an essential therapeutic component [21].

Vitiligo

While vitiligo affects roughly 1–7 % of type 1 diabetics, its prevalence among the normal population is only 0.5 % [23]. The majority of diabetics develop non- segmental vitiligo as manifestation of a genetically predisposed cutaneous autoimmune inflammatory disorder. Although vitiligo in diabetic patients is primarily an independent condition, the presence of further autoimmune dis-orders may point to autoimmune polyglandular syndrome (APS). By definition, this is a heterogeneous group of autoimmune disorders characterized by insuf-ficiency of at least two endocrine glands over time (see below) [24]. Viewing the skin as the largest hormone-producing gland of the human body, not only with paracrine but also proven endocrine secretory function, it seems justified to refer to a condition, for example marked by type 1 diabetes mellitus and vitiligo, as APS 4.

The diagnosis of vitiligo is primarily made on clinical grounds. Treatment is complex and, according to the most recent European guidelines, determined by the extent of body surface area (BSA) affected [23]. Depending on the affected site, limited cases (up to 10 % of BSA) may be treated with topical corticosteroids (class II according to German classification) (non-facial lesions) or topical calcineurin inhibitors (off-label use) (facial lesions), both offering the best therapeutic evidence based on controlled randomized trials. UVB therapy (311 nm), possibly combined with systemic antioxidants, represents the method of choice for extensive cases. Should the above-mentioned treatment options fail, targeted light therapy using the excimer laser (308 nm) or excimer lamp (308 nm) may be employed in limited cases. Surgical measures may be considered in stable disease (no changes in depig-mented areas for 1 year). Here, various procedures are available, especially autolo-gous melanocyte transplants. As supportive measures, complete UVA/B protection and, if needed, camouflage should be recommended to every patient [23].

Neuropathy, xeroderma, and drugs all contribute to chronic pruritus in

diabetics.

Apart from antihistamines, pain- modulating agents such as gabapentin,

pregabalin, or antidepressants may be used in diabetic pruritus.

Coexistence of type 1 diabetes mellitus and non-segmental vitiligo should

prompt the consideration of autoimmu-ne polyglandular syndrome.

Topical corticosteroids and calcineu-rin inhibitors as well as UVB therapy

(wavelength 311 nm) offer the best therapeutic evidence in non-segmental

vitiligo.

CME Article


Syndromic skin disorders in diabetes mellitus

Autoimmune polyglandular syndromes

In particular the concomitance of non-segmental vitiligo and diabetes mellitus should prompt the consideration of APS. Especially APS 2 (Addison’s disease and autoimmune thyroiditis or type 1 diabetes mellitus are mandatory for the diag-nosis) and APS 3 patients often exhibit vitiligo or other autoimmune-mediated inflammatory skin disorders, pointing to a common immunopathogenesis [24].

HAIR AN syndrome

Signs of peripheral hyperandrogenism in conjunction with skin manifestations and diabetes mellitus should raise the suspicion for HAIR AN syndrome. This acronym stands for hyperandrogenism, insulin resistance, and acanthosis nigricans. Cha-racteristic cutaneous features of peripheral hyperandrogenism include severe and recalcitrant acne, androgenetic alopecia, seborrhea, and hirsutism. Besides weight optimization, therapeutic options include oral contraceptives, antiandrogens, and in some cases metformin [25].

Therapy-associated skin lesions

Lipodystrophy at insulin infection sites

Adipose tissue atrophy at insulin injection sites may arise months to years af-ter initiation of injections, occasionally even developing at a substantial distan-ce from actual injection sites (Figure 11). The pathogenesis of this therapeutic complication is unclear. The presence of circulating insulin antibodies, IgM and C3 deposits as well as the therapeutic response to topical corticosteroids might suggest an autoimmune pathogenesis [2]. Commonly, lipoatrophy resolves spontaneously after a few years, if injection sites and insulin type have been

Figure 11 Lipoatrophy at insulin injection sites.

APS 2 or 3 patients frequently suffer from diabetes mellitus and

non- segmental vitiligo.

HAIR AN syndrome is characterized by severe acne, androgenetic alopecia,

seborrhea, and hirsutism.

CME Article


changed. For extensive cases, autologous adipose tissue transplantation may be considered.

Rarely, subcutaneous insulin injections may also give rise to adipose tissue hypertrophy, suspected to be caused by stimulation of subcutaneous adipocytes by the injected insulin. Reduction in systemic insulin absorption may impede suf-ficient pharmaceutical control of the diabetic state, which is another reason for regular subcutaneous injection site rotation [2].

Drug reactions to insulin or oral antidiabetic agents

Local allergic reactions to insulin or other components of the injection solution (for example preservatives) have been described at subcutaneous injection sites [1]. In rare cases, there may be life-threatening IgE-mediated anaphylactic reactions to insulin. Moreover, administration of oral antidiabetics may cause drug eruptions, urticaria, erythema exsudativum multiforme, pruritus, and erythema nodosum [1]. Phototoxic and photoallergic reactions have also been reported. Structurally rela-ted to sulfonamides, especially first-generation sulfonylureas most frequently cause skin eruptions.

References1 Behm B, Schreml S, Landthaler M, Babilas P. Skin signs in diabetes mellitus. J Eur Acad

Dermatol Venereol 2012; 26: 1203–11.2 Ahmed I, Goldstein B. Diabetes mellitus. Clin Dermatol 2006; 24: 237–46.3 American Diabetes Association. Diagnosis and classification of diabetes mellitus.

Diabetes Care 2014; 37 Suppl 1: S81–90.4 Köster I, Huppertz E, Hauner H, Schubert I. Direct costs of diabetes mellitus in

Germany – CoDiM 2000–2007. Exp Clin Endocrinol Diabetes 2011; 119: 377–85.5 Blakytny R, Jude EB. Altered molecular mechanisms of diabetic foot ulcers. Int J Low

Extrem Wounds 2009; 8: 95–104.6 Gkogkolou P, Böhm M. Advanced glycation end products: Key players in skin aging?

Dermatoendocrinol 2012; 4: 259–70.7 Karrer S. Diabetic foot syndrome. Hautarzt 2011; 62: 493–503.8 Lobmann R. Das diabetische Fußsyndrom. Internist 2011; 52: 539–48.9 Prompers L, Huijberts M, Schaper N et al. Resource utilisation and costs associated

with the treatment of diabetic foot ulcers. Prospective data from the Eurodiale Study. Diabetologia 2008; 51: 1826–34.

10 O’Loughlin A, McIntosh C, Dinneen SF, O’Brien T. Review paper: basic concepts to novel therapies: a review of the diabetic foot. Int J Low Extrem Wounds 2010; 9: 90–102.

11 Rogers LC, Frykberg RG, Armstrong DG et al. The Charcot foot in diabetes. Diabetes Care 2011; 34: 2123–9.

12 Suaya JA, Eisenberg DF, Fang C, Miller LG. Skin and soft tissue infections and associ-ated complications among commercially insured patients aged 0–64 years with and without diabetes in the U.S. PLoS One 2013; 8: e60057.

13 Oumeish OY. Skin disorders in patients with diabetes. Clin Dermatol 2008; 26: 235–42.14 Morgan AJ, Schwartz RA. Diabetic dermopathy: A subtle sign with grave implications.

J Am Acad Dermatol 2008; 58: 447–51.15 Reid SD, Ladizinski B, Lee K et al. Update on necrobiosis lipoidica: A review of etiology,

diagnosis, and treatment options. J Am Acad Dermatol 2013; 69: 783–91.16 Kreuter A, Knierim C, Stücker et al. Fumaric acid esters in necrobiosis lipoidica: results

of a prospective noncontrolled study. Br J Dermatol. 2005; 153: 802–7.17 Kowalzick L. Granuloma annulare. Hautarzt 2005; 56: 1071–81.18 Meguerditchian C, Jacquet P, Béliard S et al. Scleredema adultorum of Buschke:

an under recognized skin complication of diabetes. Diabetes Metab 2006; 32: 481–4.19 Cherqaoui R, McKenzie S, Nunlee-Bland G. Diabetic cheiroarthropathy: a case report

and review of the literature. Case Rep Endocrinol 2013; 1–3.

In rare cases, subcutaneously injected insulin may lead to severe IgE-mediated

anaphylactic reactions.

Among all antidiabetic agents, sulfo-nylureas most frequently cause skin

eruptions in diabetics.

Correspondence to

Prof. Dr. med. Markus BöhmKlinik für HautkrankheitenUniversitätsklinikum Münster

Von-Esmarch-Straße 5848149 MünsterGermany

E-mail: [email protected]

CME Article


20 Higgins SP, Freemark M, Prose NS. Acanthosis nigricans: a practical approach to evaluation and management. Dermatol Online J 2008; 14: 2.

21 Ständer S, Darsow U, Mettang T et al. S2k guideline. Chronic Pruritus. J Dtsch Dermatol Ges 2012; 10 Suppl 4: S1–27.

22 Stumpf A, Ständer S. Neuropathic itch: diagnosis and management. Dermatol Ther 2013; 26: 104–9.

23 Taieb A, Alomar A, Böhm M et al. Vitiligo European Task Force (VETF); European Academy of Dermatology and Venereology (EADV); Union Européenne des Médecins Spécialistes (UEMS). Guidelines for the management of vitiligo: the European Dermatology Forum consensus. Br J Dermatol 2013; 168: 5–19.

24 Amerio P, Tracanna M, De Remigis P et al. Vitiligo associated with other autoimmune diseases: polyglandular autoimmune syndrome types 3B+C and 4. Clin Exp Dermatol 2006; 31: 746–9.

25 Rager KM, Omar HA. Androgen excess disorders in women: the severe insulin- resistant hyperandrogenic syndrome, HAIR-AN. ScientificWorldJournal 2006; 6: 116–21.

CME Article


1. Welche Aussage ist falsch?a) Circa 30 % der Diabetiker haben

im Laufe ihres Lebens assoziierte Hauterscheinungen.

b) Die Prävalenz von Diabetes mellitus weltweit im Jahr 2010 war 6,4%.

c) Das Granuloma anulare dissemina-tum ist mit einer erhöhten Mortalität verbunden.

d) Einige der Hauterscheinungen bei Diabetes mellitus können vor der Manifestation der Erkrankung auftreten.

e) Bestimmte diabetische Hautmani-festationen sind mit extrakutanen diabetischen Komplikationen wie Neuropathie und Angiopathie korreliert.

2. Welche Aussage trifft nicht zu?

Die Necrobiosis lipoidica …a) betrifft meistens die Streckseiten der

unteren Extremitäten.b) führt bei circa 30 % der Patienten zu

schmerzhaften Ulzera.c) wird aufgrund der klinisch

sichtbaren Gelbfärbung der Haut den eosinophilen Dermatosen zugerechnet.

d) kann mit topischen Steroiden und PUVA behandelt werden.

e) zeigt typische histologische Veränderungen in der gesamten Dermis.

3. Welche Aussage zum diabetischen

Fußsyndrom trifft nicht zu?a) Circa 15–25 % der Diabetiker werden

in ihrem Leben ein diabetisches Ulkus haben.

b) Die Amputationsrate liegt bei 25 %.c) Die Morbidität beträgt 5 %.d) In der Pathogenese spielen Neuro-

pathie, Angiopathie, das beeinträch-tigte Immunsystem und Deformitä-ten des Fußskeletts wichtige Rollen.

e) Meist geht dem diabetischen Fuß-syndrom ein Bagatelltrauma voraus.

4. Welche Angabe zum Prozedere

bei der Diagnostik und Therapie des

diabetischen Fußsyndroms ist

falsch?a) Die Klassifikation erfolgt laut einer

DDG-Leitlinie nach Wagner und Armstrong.

b) Eine angiologische Diagnose gehört nicht zur Beurteilung des diabeti-schen Fußsyndroms, da Revaskula-risierungsmaßnahmen laut Studien keinen Effekt auf das Risiko einer Amputation haben.

c) Anpassung von orthopädischen Schuhen zur Entlastung von druck-belasteten Stellen und regelmäßige podologische Pflege gehören zu den unterstützenden Maßnahmen beim diabetischen Fußsyndrom.

d) MRT ist der Goldstandard zur Diagnostik einer Osteomyelitis.

e) Bei fehlenden operativen Revasku-larisierungsmöglichkeiten können Infusionen mit Alprostadil oder Iloprost die akrale Durchblutung fördern.

5. Welche Aussage zu infektiösen

Erkrankungen bei Diabetes mellitus ist

falsch?a) Sie sind mit einem fünffachen

Komplikationsrisiko und einem vierfachen Hospitalisierungsrisiko assoziiert.

b) Eine unbehandelte Interdigitalmy-kose dient oft als Eintrittspforte für Weichteilinfektionen wie Zellulitis und Erysipel.

c) Meistens sind gramnegative Keime die Ursache einer nekrotisierenden Fasziitis.

d) Die maligne externe Otitis wird durch Pseudomonas aeruginosa verursacht. Als Komplikation kann eine Meningitis auftreten.

e) Rezidivierende bakterielle und mykotische Infekte der Haut sollten an einen Diabetes mellitus denken lassen.

6. Welche Aussage zum diabetischen

Pruritus trifft nicht zu?a) Lokalisierter Pruritus im Genito-

analbereich kommt sehr oft durch Candida-Spezies zustande.

b) Die diabetische Neuropathie spielt eine wichtige pathogenetische Rolle.

c) Gabapentin ist beim diabetischen Pruritus wirkungslos.

d) Eine verminderte Nervenfaserdichte ist in Hautbiopsien von Patienten mit Diabetes beschrieben worden.

e) Glimepirid und Metformin können Auslöser von Pruritus bei diabeti-schen Patienten sein.

7. Welche Aussage zur Therapie-

assoziierten Hauterscheinungen bei

Diabetes ist zutreffend?a) Eine Lipohypertrophie an Insulin-

Injektionsstellen hat keinen Einfluss auf die systemische Resorption von Insulin.

b) Die IgE-vermittelte Hypersensiti-vität gegen Insulin ist eine seltene aber potenziell lebensbedrohliche Reaktion.

c) Phototoxische und photoallergische Reaktionen sind am häufigsten mit Metformin beschrieben worden.

d) Lokale Reaktionen an Injektionsstellen sind immer auf eine Insulinunverträglichkeit zurückzu-führen.

e) Fettgewebeatrophien sind eine Frühkomplikation der antidiabeti-schen Therapie.

8. Welche Aussage zum Charcot-Fuß

trifft nicht zu? Die wichtigsten

Differenzialdiagnosen sind …a) Erysipel.b) tiefe Beinvenenthrombose.c) Gichtanfall.d) akute Ischämie.e) Zellulitis.

Fragen zur Zertifizierung durch die DDG

CME Article


Liebe Leserinnen und Leser,der Einsendeschluss an die DDA für diese Ausgabe ist der 17. Oktober 2014. Die richtige Lösung zum Thema „Kutane Lymphome“ in Heft 1 (Januar 2014) ist: (1c, 2c, 3c, 4b, 5c, 6c, 7b, 8d, 9b, 10c).

Bitte verwenden Sie für Ihre Einsen-dung das aktuelle Formblatt auf der folgenden Seite oder aber geben Sie Ihre Lösung online unter http://jddg.akademie-dda.de ein.

9. Welche Angabe zur diabetischen

Cheiroarthropathie ist nicht richtig?a) Sie sollte von einer Dupuytren-

schen Kontraktur und systemischen Sklerodermie abgegrenzt werden.

b) Betroffene Patienten weisen kein erhöhtes Risiko für eine diabetische Neuropathie und Angiopathie auf.

c) Histologisch zeigen sich verdickte Kollagenfasern und Muzinablage-rungen.

d) Mittels Sonographie oder MRT kann eine Verdickung der periartikulären Weichteilstrukturen festgestellt werden.

e) Akkumulation von AGEs und Akti-vierung profibrotischer Signalwege scheinen eine pathogenetische Rolle zu spielen.

10. Welche Aussage zum Scleroedema

adultorum trifft nicht zu? Die Erkran-

kung kommt außer bei Diabetes melli-

tus noch gehäuft vor bei …a) Paraproteinämien.b) bakteriellen Infekten durch Strepto-

kokken.c) rheumatoider Arthritis.d) viralen Infekten.e) multiplem Myelom.

Documents

Skin disorders in diabetes mellitus