image of silk fabric and dry skin


Marcelo Ruiz, MD1; Pilar Valdés, MD1; Kenneth Tomecki, MD2


1Department of Dermatology, Hospital Clínico Universidad de Chile, Santiago, Chile
2Department of Dermatology, Cleveland Clinic, Cleveland, OH, USA

ABSTRACT
The skin is often a window to systemic disease that is available to the trained eye of the dermatologist. Herein, we focus on four dermatoses with associated systemic conditions of interest: scleromyxedema and monoclonal gammopathy, nephrogenic systemic fibrosis in the setting of renal insufficiency, dermatitis herpetiformis and celiac disease, and psoriasis as a risk factor for cardiovascular disease. Dermatologists can play a crucial role in recognizing the cutaneous manifestations linked with these conditions. Identifying the related underlying disorder will contribute to appropriate diagnosis and improved management.

Key Words:
systemic disease, skin signs, cutaneous manifestations, dermatitis herpetiformis, nephrogenic systemic fibrosis, psoriasis, scleromyxedema

Introduction

Dermatologists can play an integral role in the diagnosis and management of an array of systemic diseases that manifest in skin symptoms. Recent advances in elucidating pathogenic mechanisms and described associations hold the potential for early identification and treatment, thereby possibly modifying the disease course. A detailed discussion covering the spectrum of skin conditions with underlying systemic dysfunction is beyond the scope of this review, instead a look at the hematologic, renal, gastrointestinal, and cardiovascular systems is undertaken, with a focus on four skin disorders with systemic involvement.

Scleromyxedema and Monoclonal Gammopathy

Scleromyxedema (SM), also known as generalized lichen myxedematosus (LM), is a cutaneous mucinosis. Although LM is considered a chronic nonlethal disease, its generalized form (SM) is associated most frequently with monoclonal gammopathy and other systemic disorders that may result in death.1,2 By contrast, the more localized forms of LM are not associated with paraproteinemia and usually have no systemic manifestations. SM is a rare disease of unknown etiology that usually affects middleaged adults between 30 and 80 years of age.3 It is characterized by a generalized papular and sclerodermoid eruption, mucin deposition, increased fibroblast proliferation, fibrosis, and monoclonal gammopathy, in the absence of thyroid disease. An increased production of hyaluronic acid by fibroblasts occurs, possibly due to paraprotein stimulation.2,3

Clinically, SM appears as a generalized eruption of 2 mm to 3 mm waxy lichenoid (flattopped) papules, often in a linear arrangement; lesions are most common on the hands, elbows, forearms, upper trunk, face, and neck. These lichenoid lesions coalesce, leading to induration of the underlying tissue that resembles scleroderma. Typical involvement of the glabella with deep longitudinal furrows can be reminiscent of leonine facies1,4 and a characteristic elevated rim with central depression can be seen on the proximal interphalangeal joints (“doughnut sign”). Histologic examination of involved skin demonstrates fibroblast proliferation, fibrosis, and dermal deposition of mucin.4 Systemic manifestations of SM are serious and have been fatal in some cases, secondary to mucin deposition in various organs. It may involve the cardiovascular, gastrointestinal, pulmonary, rheumatologic, and central nervous systems. Dysphagia is the most common extracutaneous manifestation of SM.2,3 Up to 83% of cases have an associated paraproteinemia, predominantly an immunoglobulin G (IgG) lambda subtype, and a minority of these patients develop a plasma cell dyscrasia or multiple myeloma (10%).1,2 Other associated diseases include Waldenstrom’s macroglobulinemia as well as Hodgkin’s and non-Hodgkin’s lymphomas.1,2

Work-up, including serum protein electrophoresis, immunofixation electrophoresis, and measurement of immunoglobulin levels, is critical in all patients with suspected SM. Follow-up should be done at least every 6 months.4 SM is characteristically quite resistant to therapy, although anecdotal reports attest to the efficacy of melphalan, thalidomide, and intravenous immunoglobulins (IVIG).2,3 Autologous stem cell transplantation could be beneficial in some cases.4,5

Nephrogenic Systemic Fibrosis in Renal Insufficiency

Nephrogenic systemic fibrosis (NSF), or formerly known as nephrogenic fibrosing dermopathy, is a scleroderma-like fibrosing disorder that develops in the setting of renal insufficiency. It occurs predominately in patients with end-stage renal disease on dialysis (80%) and occasionally in patients with acute renal failure or after kidney transplantation.6 The cause remains unclear, but most cases are related to the use of gadolinium-based contrast agents (GBCA) in magnetic resonance imaging (MRI), such as gadodiamide and gadopentetate. These gadolinium (Gd) chelates tend to easily release free Gd into the surrounding tissue.7 In patients with renal insufficiency, increased retention of GBCA leads to increased free Gd that could ultimately trigger NSF.6 A concomitant proinflammatory event (e.g., infection and major surgery) can confer additional risk.8

Cutaneous lesions of NSF usually develop over a variable period of time (few days to several months) and subsequently assume a chronic, unremitting course. Approximately 5% of patients experience NSF that is rapidly progressive (fulminant).6 The primary skin lesions are usually papules or nodules that are erythematous and coalesce to form indurated irregular plaques. These areas may appear slightly edematous with peau d’orange and erythematous surface features, and can be easily confused with cellulitis, lymphangitis or chronic lymphedema.6 They are often symmetrical, commonly involving the lower extremities up to the knees and the upper extremities up to the elbows. The face is usually spared. Over time, the skin tends to develop a “cobblestone” appearance and browny hyperpigmentation. Affected areas and subcutaneous tissues are extremely hard (“woody”), warm, and tender, as well as often accompanied by pruritus and burning sensation. Yellow scleral plaques are found in some cases.6,9-11 Differential diagnosis is made with several other fibrosing processes, including scleroderma and scleromyxedema.11 The clinical distribution of lesions in NFS, which favors the extremities and spars the face, is opposite to that seen in scleromyxedema, and paraproteins are not detected in the serum of NFS patients.6 Histopathology of NFS is very similar to scleromyxedema, including their immunohistochemical staining profiles. A scoring system, based on clinical and histopathological criteria, has been recently proposed to aid diagnosis.11

Major organ or systemic involvement can include muscles, joints (contractures), and viscera, such as the pulmonary, cardiovascular, gastrointestinal and renal systems.6 The chronology of the visceral involvement is not clear, but is more common in patients exhibiting extensive skin symptoms. The severity and rapidity of progression of the cutaneous lesions correlate with poor prognosis and death.12

Therapeutic modalities include oral and topical steroids, pentoxifylline, photopheresis, plasmapheresis, psoralen plus ultraviolet light, IVIG, sodium thiosulfate, and physical therapy, however, all with little benefit. Improvement of renal function can terminate the progression of NSF, so renal transplantation is the best option for these patients. Implementation of preventive strategies, including the use of alternatives to Gd-enhanced MRI, has been shown to reduce the risk of NSF.6,8-10

Dermatitis Herpetiformis and Celiac Disease

Dermatitis herpetiformis (DH) is a chronic, intensely pruritic blistering disease characterized by symmetric grouped vesicles, papules, and wheals on the elbows, knees, scalp, and buttocks. It has a clear relationship to celiac disease (CD) and is considered the cutaneous manifestation of gluten sensitivity.13 Despite this, the majority of DH patients have silent or mild gastrointestinal CD. Pathophysiologies of both disorders are closely related, involving genes and the environment. Human leukocyte antigens (HLA) DQ2 and DQ8 have been identified as predisposing factors.13,14 Tissue transglutaminase (tTG or TG2) and epidermal transglutaminase (eTG or TG3) are thought to be the main autoantigens in CD and DH, respectively. tTG, an ubiquitous enzyme, plays a role in gluten intolerance by modifying gliadin (fraction of gluten) into an efficient autoantigen and forming tTG-gliadin immunogenic complexes. eTG is homologous to tTG, localized in the epidermis to maintain the cornified envelope integrity.13,14

Clinically, the primary lesions of DH (papules and vesicles) are often absent, replaced by erosions and excoriations, sometimes leading to lichenification. Purpura on the fingers and toes is an interesting clinical finding but not always present. It rarely has mucosal involvement.13,14 Evolution with symptom-free months during summer occurs in some patients due to a beneficial sun exposure effect.14

Biopsy reveals a subepidermal cleft with neutrophils and a few eosinophils at the tips of dermal papillae, and direct immunofluorescence is confirmatory, by demonstrating pathognomonic granular deposition of IgA at the dermalepidermal junction.13 Serologic tests are useful to aid diagnosis and monitor disease activity, looking for IgA-TG or antiendomysial antibodies. In DH, IgA antibodies can be specific for eTG, making the detection of specific IgA-eTG antibodies a promising tool that needs further validation.13,14 Genetic testing for HLA DQ2 and DQ8 can be useful in some cases to rule out DH. Differential diagnosis includes linear IgA dermatosis, bullous pemphigoid, scabies, contact dermatitis, and bullous lupus erythematosus.13

A wide range of autoimmune disorders are associated with DH, such as diabetes type I or hypothyroidism, the latter being the most common. Screening for common autoimmune disorders is generally indicated. Clinical examination of the skin may reveal a concurrent autoimmune disease, such as vitiligo, primary biliary cirrhosis (jaundice), pernicious anemia, alopecia areata or lupus erythematosus.14 Clinical signs of malabsorption may also be present, such as anemia due to iron, folate, or B12 deficiency, and caries or diffuse alopecia due to zinc deficiency. DH patients may also have a higher risk of developing non-Hodgkin lymphoma, particularly enteropathy-associated T-cell lymphoma. This is an important comorbidity to rule out, especially in longstanding, untreated DH or CD.14,15

Therapy is always based on a gluten-free diet. Skin lesions and pruritus of DH are rapidly responsive to oral dapsone. Other treatments include sulfasalazine and sulfamethoxypyridazine.15

Psoriasis and Cardiovascular Disease

Psoriasis is a chronic relapsing inflammatory disease of the skin that affects 1-3% of the population.16,17 Dermatologists are well familiarized with the clinical presentation, subtypes, and histologic features of psoriasis, but there is still much to learn about disease physiopathology, systemic consequences, and how these factors influence therapy. At present, there is great interest in elucidating the potential link between psoriasis and significant comorbidities, such as an increased risk for metabolic dysfunction and cardiovascular disease (CVD), which could be explained by a systemic inflammatory process. As we know, a complex interplay between environmental and genetic factors sets the scene for psoriasis-initiating events, allowing activation of the immune system and generation of effector T cells that reside in the skin and interact with keratinocytes. Chronic inflammation is maintained through the action of key cytokines (e.g., tumor necrosis factor-alfa).18 Systemic inflammation could be responsible for subsequent insulin resistance, endothelial cell dysfunction, and atherosclerosis.17,19-21

Different population-based cohort studies indicate that there is a higher risk for myocardial infarction (MI) in psoriasis patients,22-27 with increased risk of cardiovascular death and all-cause mortality.28,29 These findings are independent to the presence of other major cardiac risk factors and comparable to them in the magnitude of risk, similar to diabetes mellitus. However, there is also controversial evidence against these results.30-32 According to most of the studies that found an increased risk, clinical characteristics of psoriasis patients that are related to a higher risk are young age (<50 years), severe skin affection (defined by Psoriasis Area and Severity Index or the need of systemic therapy) and psoriatic arthritis (PsA). The incidence of cerebrovascular and peripheral vascular disease could also be higher among psoriasis patients compared to the general population.23,33,34

In light of this evidence, it is critical to know whether systemic therapies do have a cardioprotective effect and a preventive role in the development of CVD in severe psoriasis patients, as this answer could change current paradigms of treatment. There are already some published studies addressing this issue. By measurements of biomarkers of cardiovascular risk (e.g., C-reactive protein, homocysteine, and lipid profile), direct evaluation of atherosclerotic progression (e.g., carotid ultrasonography), and assessment of MI risk, promising results have been reported showing beneficial effects of different systemic agents when compared to patients using only topical therapy.35-39 However, a recent study that compared MI risk in psoriasis patients after being treated with phototherapy, traditional systemic agents, or different biologics, found no overall relevant changes in MI risk.35 At the moment, there is still a lack of evidence supporting the use of systemic therapies for the prevention of CVD in psoriasis patients. Therefore, larger multicenter studies are needed to confirm this data and the longterm safety profiles of biologic drugs.

Regular screening for CVD risk factors is recommended in psoriasis,40,41 especially for patients with severe disease and PsA, but the fact that other cardiac risk factors (e.g., obesity or metabolic syndrome) are more common in psoriasis42-44 points out that this practice could be beneficial for all psoriatics, allowing early implementation of preventive measures.45 A detailed history inquiring about diabetes, dyslipidemia or hypertension should be performed, together with the evaluation of blood pressure, body mass index and waist circumference at least every 2 years. Fasting serum lipoproteins, blood glucose and glycosylated hemoglobin should be determined at least every 5 years, or every 2 years if other risk factors are present. Another recommended approach is to undertake these assessments every 6 months in patients receiving systemic therapy and yearly in those undergoing topical treatment.40,41,45

Conclusion

Scleromyxedema, nephrogenic systemic fibrosis, dermatitis herpetiformis, and psoriasis are skin diseases associated with well-recognized systemic disorders that may result in significant morbidity and mortality. Although important progress has been made in understanding the physiopathology of these conditions, precise disease mechanisms remain unknown and treatment challenges persist. To improve therapeutic outcomes, dermatologists should be aware of these associations and pathogenic cofactors, in order to ensure that both skin and systemic abnormalities are properly addressed.45

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