Skin and systemic diseases
Dermatology is most interesting where it overlaps with general internal medicine. Skin lesions may be part of a systemic disease (e.g. in sarcoidosis or systemic lupus erythematosus), or they may be a manifestation of an underlying disease or process as in the case of acanthosis nigricans, which can be associated with either an underlying adenocarcinoma in older patients, or with insulin resistance and sometimes overt diabetes mellitus in younger obese patients.
Sarcoid can affect the skin in numerous ways, including erythema nodosum, nodular sarcoid lesions, multiple papules, and larger plaques, particularly on the nose, a site at which the skin changes are frequently perniotic in appearance (lupus pernio, scar sarcoidosis, and rarely angiolupoid sarcoid).
Diabetes mellitus can also affect the skin in a myriad of ways, with more common forms including granuloma annulare, necrobiosis lipoidica, diabetic dermopathy, cutaneous infections, and the consequences of neuropathy.
Liver disease may affect the skin by causing pruritus, pigmentation (grey or jaundice), vascular changes (spider naevi), porphyria cutanea tarda, dryness, and hair/nail alterations. Renal disease may affect the skin by causing pruritus, pigmentary changes, dryness, and calciphylaxis, and use of immunosuppression can lead to an increase in malignancy in some cases.
Common associations of pyoderma gangrenosum include inflammatory bowel diseases (ulcerative colitis and Crohn’s disease), rheumatoid arthritis and other rheumatological disease, haematological malignancies, and monoclonal gammopathies.
The noninfectious granulomatous disorders of the skin include sarcoidosis, granuloma annulare, and necrobiosis lipoidica. Granulomatous diseases caused by bacterial infections (e.g. tuberculosis and leprosy) and fungal infections are discussed in Chapter 23.9 and Section 7.
Sarcoidosis and the skin (Chapter 18.12)
Sarcoidosis has been defined as ‘a disease characterized by the formation in all or several affected organs or tissues of epithelial cell tubercles, without caseation, although fibrinoid necrosis may be present at the centre of a few, proceeding either to resolution or to the conversion of the epithelial cell tubercles into hyaline fibrous tissue’. Other changes present to a varying degree include partial or complete suppression of tuberculin and other intradermal cell-mediated immune responses, and an elevated serum calcium level. The Kveim test, which was positive in most active cases, is no longer available.
Many infectious agents have been put forward as the potential cause of sarcoidosis, but cultures have been negative and responses to anti-infective treatments have been disappointing. A polymerase chain reaction (PCR) study revealed the presence of various subtypes of mycobacterial DNA in 16 of 20 cases of cutaneous sarcoidosis, but the significance of these and other findings are unclear. Genetic factors may be important, HLA type, for example, seeming to influence the pattern of the disease rather than determining its occurrence.
The prevalence of sarcoidosis in developed countries is greater than 10 per 100 000 population, but an apparent increased incidence in the last 50 years is probably due to improved methods of detection.
Skin lesions occur in about 30% of patients with systemic sarcoidosis, but cutaneous sarcoidosis can occur without systemic disease. Significant pulmonary disease may be asymptomatic and the extent of skin involvement does not correlate with the extent of systemic disease.
The specific skin lesions of sarcoidosis arise from a dense accumulation of epithelioid granulomas in the dermis or subcutis and can be of variable morphology. Erythema nodosum (Fig. 23.15.1) is a nonspecific clinical feature of early or acute sarcoidosis without the characteristic sarcoidal granulomas (see Chapter 23.7). Nodular sarcoid lesions are often annular and reddish-brown or violaceous in colour. There may be multiple papules and larger plaques, particularly on the nose, a site at which the skin changes are frequently perniotic in appearance (lupus pernio) (Fig. 23.15.2). Skin lesions can affect pre-existing scars (the Koebner or isomorphic phenomenon), sometimes referred to as scar sarcoidosis. A rare but characteristic telangiectatic form of sarcoidosis, angiolupoid sarcoid, affects women, almost always on the sides of the nasal bridge, on the adjacent cheek or below the eyebrows. Sometimes the nodular lesions are solely subcutaneous, and erythrodermic and lichenoid sarcoidosis are unusual morphological forms.
Sarcoidosis is more common in black skin and in African-Americans; typical lesions include annular lesions on the nose (Fig. 23.15.3), hypopigmented macules and papules, keloid-like lesions, ulcerative, verrucous, and large nodular forms. Erythema nodosum is uncommon in black skin. In white skin the colour of the lesions ranges from yellowish to the livid violaceous colour which is most marked in lupus pernio. The epidermis is rarely affected and scarring is unusual except in the papular and annular forms.
The differential diagnosis includes lupus vulgaris, a cutaneous form of tuberculosis, syphilis, and tuberculoid leprosy (see Chapters 23.10, 7.6.25, 7.5.27, and 7.6.36). These can usually be distinguished on histology. Other common disorders with granulomatous histology include granuloma annulare, rosacea, and Crohn’s disease. Sarcoid-like reactions in a scar should be distinguished from a foreign body reaction. A granulomatous sarcoidal reaction to any pigment of a tattoo may occur, either alone or accompanied by other signs of sarcoidosis.
A skin biopsy is usually required to show the characteristic granulomatous histology. However, a patient with erythema nodosum and bilateral hilar lymphadenopathy may not require histological confirmation of the erythema nodosum (a form of panniculitis) for the diagnosis of acute sarcoidosis to be acceptable.
A chest X-ray (radiograph) should be performed in all cases. Angiotensin-converting enzyme (ACE) is produced by sarcoidal granulomas and serum ACE is raised in about 60% of patients with systemic sarcoidosis. However, serum ACE may be elevated in diabetes mellitus and alcoholic liver disease, and is often normal in localized sarcoidosis of the skin. Serum calcium should be checked, as an increased level may lead to renal failure. Less specifically, the erythrocyte sedimentation rate (ESR) is usually raised, with a slight anaemia, neutropenia or lymphopenia, and hypergammaglobulinaemia in over 50% of patients. An ECG is required to exclude cardiac involvement.
Pulmonary function tests may be indicated and computed tomography of the chest is helpful to define lung involvement. Hand radiographs may show cystic changes in chronic disease, usually when there are clinical abnormalities in the fingers.
The most specific investigation was the Kveim test, in which sarcoidal tissue from the spleen of an affected individual was injected intradermally to produce an epithelioid cell granulomatous reaction. A positive response was the development of a reddish papule at 2 to 3 weeks. Excision at 6 weeks showed the confirmatory histology. However, this test is no longer used because of the infective risk of injecting human tissue. See Chapter 18.12 for further details of investigation of the patient with suspected sarcoidosis.
Limited cutaneous sarcoidosis can resolve spontaneously, so a conservative approach to treatment is often adopted. Papular and subcutaneous skin lesions may settle spontaneously but lupus pernio tends to persist.
Superpotent topical corticosteroids are usually tried and can be helpful. Intralesional triamcinolone is often effective, care being taken to inject deeply to avoid atrophy of the skin. In some types of cutaneous sarcoid, e.g. lupus pernio, cosmetic camouflage advice is useful.
Other local therapies reported to be beneficial have included cryotherapy, radiotherapy, PUVA (psoralen ultraviolet A) in hypopigmented and erythrodermic sarcoidosis, pulsed dye laser in lupus pernio, and topical tacrolimus.
Commonly used systemic therapies include oral corticosteroids, pulsed intravenous corticosteroids, methotrexate, and azathioprine. The most frequent indications for systemic treatment include symptomatic pulmonary disease, ocular disease not responding to local corticosteroids, disfiguring skin disease or lymphadenopathy, hypercalcaemia, liver disease with significant dysfunction or hepatomegaly, other organ involvement such as myocardial disease, nervous system disease or renal disease, myopathy or myositis, and thrombocytopenia. See Chapter 18.12 for further details of treatment of the patient with sarcoidosis.
Prednisolone is usually prescribed at 30 to 40 mg mane and reduced over about 2 months to a maintenance dose of prednisolone 15 mg on alternate mornings. Treatment may be necessary for about 6 months, and azathioprine is often introduced for its immunosuppressive and steroid-sparing effects. Intravenous pulsed methylprednisolone, e.g. 1 g/week for 2 months, has been effective in patients with severe systemic disease.
Methotrexate is often an effective systemic agent, usually prescribed as a weekly oral dose (e.g. 7.5–25 mg weekly), with careful monitoring. The response of sarcoidosis to other drugs has been variable, including ciclosporin, chlorambucil, allopurinol, isotretinoin, thalidomide, and minocycline.
Diabetes mellitus and the skin (Chapter 13.11.1)
Skin disorders in individuals with diabetes mellitus include diabetic dermopathy, the most common skin disorder associated with diabetes, cutaneous infections, the consequences of diabetic neuropathy, acanthosis nigricans (related to insulin resistance), and, as discussed above, necrobiosis lipoidica and probably generalized granuloma annulare. Anogenital pruritus in diabetes mellitus may be caused by candidiasis or streptococcal infection, but diabetes is not a proven cause of generalized pruritus. See Chapter 13.11.1 for further discussion of diabetes.
Diabetic dermopathy (diabetic shin spots)
This occurs in about half of the patients with diabetes, men being more commonly affected than women. Diabetic dermopathy is thought to be due to microangiopathy and possible neuropathy. Reddish oval macules and slightly scaly plaques are seen on the shins, forearms, thighs, and over bony prominences, later evolving into brownish atrophic scars, the brown pigment being due to haemosiderin deposition. The presence of these lesions has been suggested to correlate with other internal complications of diabetes including retinopathy, nephropathy, and neuropathy.
Granuloma annulare (GA) is a reaction pattern in the skin with a well-established morphology and natural history, although the aetiology and pathogenesis are unclear. A number of potential antigenic trigger factors have been suggested. There is an association between GA and diabetes mellitus but this is seen uncommonly. Granuloma annulare can occur at any age but most patients are under 30 years old, women being affected more frequently than men.
Localized GA is the most common form and presents as reddish collections of papules which form annular lesions, with palpable edges, often over the knuckles (Fig. 23.15.4) and on the elbows. Other areas of the skin may be involved and a diffuse or generalized pattern occurs uncommonly. In the generalized pattern, there are numerous skin-coloured or erythematous, slightly palpable coalescing papules, arranged symmetrically on the trunk and limbs. Annular lesions may be violaceous in colour and itching is often a feature of the generalized form. Perforating (referring to extrusion of material through the epidermis) and subcutaneous GA are uncommon patterns, the latter sometimes being difficult to distinguish from rheumatoid nodules.
It is reasonable to exclude diabetes mellitus in patients with GA, but this probably occurs in only about 5% cases of localized GA, rising to about 20% in the generalized form. The association of GA with diabetes mellitus is debatable, however, and some relatively small studies have not shown a definite association. The distinction from necrobiosis lipoidica, more strongly associated with diabetes mellitus, is usually made histologically but GA and necrobiosis lipoidica can occur in the same patient.
The sporadic occurrence of GA and its tendency to remit spontaneously makes it difficult to assess the efficacy of treatment and in many cases no treatment is needed. Spontaneous remission would occur in about 50% of patients within 2 years but recurrence, usually at the same sites, occurs in 40%.
Potent topical corticosteroids may hasten resolution of localized GA and intralesional triamcinolone can be effective if treatment is required. Cryotherapy has also been used. PUVA seems to be effective for generalized GA. Other treatments reported to be of benefit include retinoids, ciclosporin, local injections of low-dose recombinant interferon-γ, and topical imiquimod or tacrolimus. However, better clinical studies are required in what is a sporadic disorder. In one clinical trial of generalized GA treated with oral potassium iodide, the active drug had no advantage over placebo.
The precise pathogenesis of necrobiosis lipoidica is unknown, but impaired vascularity of the microcirculation is considered to play a role. The occurrence of diabetes mellitus in up to 60% patients who have necrobiosis lipoidica was probably overestimated previously in tertiary referral populations. Necrobiosis lipoidica may precede the development of diabetes in about one in 10 individuals. However, it does not occur exclusively in diabetes, and the term necrobiosis lipoidica diabeticorum is no longer used. It can occur at any age but usually develops in young adults and in early middle age. There is a female to male ratio of 3:1. Only about 0.3% patients with diabetes mellitus will have necrobiosis lipoidica.
Necrobiosis lipoidica occurs as reddish-yellow shiny plaques on the shins, with atrophy and telangiectasia (Fig. 23.15.5), but early lesions are less obvious. Lesions may ulcerate and a chronic course is usual. In most cases, lesions are bilateral, and they are similar in appearance whether occurring in diabetic or nondiabetic patients.
The differential diagnosis includes granuloma annulare, in which there is less necrobiosis on histology. The yellowish appearance may resemble xanthomatous lesions but this will be distinguished on histology. Necrobiotic xanthogranuloma is a rare disease in which red-orange or yellowish indurated plaques occur on the trunk and periorbital regions, associated with systemic lesions and a monoclonal gammopathy.
Treatment with a superpotent topical corticosteroid under polythene occlusion is effective in settling the active inflammatory process of necrobiosis lipoidica, but the chronic atrophic changes are not reversible and the lesions persist. Early treatment is therefore recommended. Intralesional triamcinolone has been used with good effect, and some dermatologists use perilesional triamcinolone to prevent extension of the process centrifugally. Short courses of prednisolone have been reported to arrest the process but are usually not required.
Psoralen and ultraviolet A (PUVA) using a topical psoralen has been beneficial, as has excision and grafting in severe cases. Other treatments which have been tried in the past with limited success include nicotinamide, clofazimine, pentoxifylline, ciclosporin, mycophenolate mofetil and, more recently, infliximab.
Cutaneous infections in diabetes mellitus
Skin infections due to Staphylococcus aureus and group A Streptococcus haemolyticus are common in diabetes mellitus. Infections with boils (furuncles), carbuncles (with multiple sinuses), and styes were more common before insulin and antibiotics became available, and good skin care, especially of the feet and lower legs, is essential to help prevent cellulitis. Uncommonly, diabetics are prone to soft tissue infections with a mixture of organisms, sometimes referred to as nonclostridial gas gangrene or bacterial synergistic cellulitis/gangrene, probably a form of necrotizing fasciitis. Well demarcated red areas on the legs and feet of older diabetics do not necessarily indicate cellulitis or erysipelas, and this is sometimes referred to as erysipelas-like erythema.
Candida albicans infections of the mouth, nail folds, genitals, and intertriginous zones (skinfolds) are common in diabetes. A high glucose level in the saliva seems to be related to the increased prevalence of oral candidiasis. Recurring candidal infection is thought to be the cause of an increased prevalence of phimosis in diabetic men.
Older patients with diabetes mellitus are at risk of developing a peripheral neuropathy with mixed sensory and motor nerve involvement. Good foot care is essential to prevent the formation of indolent painless perforating ulcers, particularly at pressure points (e.g. from footwear or the bed). The ulcer is usually punched out and often occurs on the sole of the foot in the middle of a callosity. Diabetic ulcers are usually due to a combination of factors including microangiopathy, neuropathy, and an increased tendency to infection.
Acanthosis nigricans and insulin resistance
Acanthosis nigricans, in which there is hyperpigmentation and hyperkeratosis of the flexures (e.g. a velvety appearance in the axillae), exists in two forms. In the absence of obesity, acanthosis nigricans (Fig. 23.15.6) may be an important clinical sign of an underlying adenocarcinoma, e.g. carcinoma of the stomach. The changes of acanthosis nigricans in younger obese patients, in which the nape of the neck and antecubital fossae are often involved, are associated with insulin resistance (hyperinsulinaemia) and sometimes overt diabetes mellitus. There are considered to be two syndromes of insulin resistance, type A occurring in hyperandrogenic women due to a genetic defect affecting insulin receptor function, and type B in older women with signs of immunological dysfunction.
Other skin disorders associated with diabetes mellitus
Various forms of diabetic blisters occur, presenting as apparently spontaneous lesions mostly on the feet and hands. A typical subepidermal blister occurs on a noninflamed base and heals without scarring in a few weeks.
Skin reactions to insulin
Insulin may cause immediate or, more commonly, delayed reactions in the skin. A delayed reaction usually begins after 2 weeks as an itchy nodule at the site of the injection. It lasts for days before healing, with hyperpigmentation and sometimes scarring.
Insulin lipodystrophy is rare. Atrophic lesions at the sites of insulin injections reflect localized fat atrophy which usually persists.
Vitiligo occurs more frequently in patients with diabetes mellitus, a prevalence of about 5% being reported in late-onset diabetes.
Liver disease and the skin (Section 14)
Numerous systemic diseases may affect the liver and some of these will have cutaneous features (e.g. as occurs in sarcoidosis). The predominant dermatological features and dermatoses associated with liver diseases are discussed here. For a full discussion of liver disease, see Section 14.
Pruritus in liver disease
Generalized pruritus is the most common symptom associated with liver disease. It may precede the onset of jaundice and may be a feature of hepatitis. Itching is most prominent in primary biliary cirrhosis, sclerosing cholangitis, and other forms of biliary tract obstruction, being less of a problem in alcoholic cirrhosis, autoimmune chronic active hepatitis, and haemochromatosis. Improvement in hepatic itching by drugs which block the action of opiates suggests that endogenous opiates may be important in the mechanism of itching.
Treatment is directed at the underlying cause, e.g. drug withdrawal in drug-induced cholestasis, surgery for mechanical biliary obstruction. Antihistamines are usually ineffective. Other approaches have included colestyramine, rifampicin, and various forms of phototherapy.
Pigmentary changes in liver disease
Jaundice is first seen in the sclerae before it becomes generalized. Carotenaemia and drugs, including mepacrine, can also cause yellowing of the skin.
A grey hyperpigmentation may occur in chronic liver disease of any cause. There may be a yellowish tinge due to associated jaundice. The pigmentation is usually more prominent on sun-exposed sites, including the face with perioral and periorbital accentuation. Pigmentation sometimes localizes to the palmar creases, and men sometimes have increased pigmentation of the areola in association with gynaecomastia.
Vascular changes in liver disease
Some of the recognized vascular changes in liver disease are nonspecific, including spider naevi (spider telangiectases/spider angiomas) and palmar erythema. Finger clubbing, thought to be due to increased digital pulp blood flow and dilation of arteriovenous anastomoses, occurs in about 15% of patients with cirrhosis.
Hair, nail, and collagen changes in liver disease
The body hair is often thinned and men tend to develop a female pubic hair pattern, due to increased production and decreased metabolism of oestrogens, associated with decreased production and increased metabolism of testosterone. Extensive loss of scalp hair may be due to zinc deficiency.
Nail colour changes include diffuse white colour, proximal white colour, and distal reddish-pink colour, and white bands. Nail plate changes include clubbing (see above), and flattened nails or koilonychia, associated with poor nutrition or altered iron metabolism. Striae occur in both sexes, especially on the lower abdomen, thighs, and buttocks.
Porphyria cutanea tarda
Porphyria cutanea tarda (PCT) is associated with chronic liver disease. In this form of porphyria, there is photosensitivity with blisters, scarring, milia (small epidermal cysts), and hyperpigmentation on sun-exposed areas (e.g. dorsa of hands and forearms) with hypertrichosis of the face (e.g. the temples). See Chapters 11.5 and 23.9.
The cause of most cases of lichen planus is unknown but lichen planus has been reported in primary biliary cirrhosis, usually following treatment with penicillamine, and in chronic active hepatitis. Hepatitis C virus has also been associated with lichen planus. See Chapter 23.5.
Renal disease and the skin
The skin and renal system may be affected by the same disease process. This occurs in various forms of collagen diseases and vasculitis (see Chapter 23.7), in hereditary syndromes such as Fabry’s disease (angioma corporis diffusum) and nail-patella syndrome, and in metabolic diseases, including calcific arteriolopathy (calciphylaxis) and primary systemic amyloidosis. Here we concentrate on the cutaneous signs of chronic renal failure, with discussion of recent findings in calcific arteriolopathy and nephrogenic fibrosing dermopathy.
Generalized severe pruritus occurs in about one-third of patients with renal failure, with many more patients experiencing less troublesome pruritus. In one study, up to 85% of patients on haemodialysis suffered from pruritus, the haemodialysis seeming to provoke the itching in two-thirds of them. There seems to be a correlation between pruritus and predialysis plasma urea levels, but a less obvious relationship between itching and dry skin (xerosis) and secondary hyperparathyroidism. The mechanism of pruritus is complicated, since a reduction in uraemia often does not improve the itching, and pruritus is unusual in acute renal failure. Uraemic neuropathy affects about 60% of patients with renal failure or on long-term haemodialysis and may play a role in uraemic pruritus.
The incidence of uraemic pruritus has been reported to be decreasing, which in part may be due to the use of more sophisticated techniques and equipment for dialysis. In dialysis, lowering the magnesium concentration of the dialysate has been reported to be helpful. In intractable itching, emollients and ultraviolet B (UVB) radiation are reported to be the most effective therapy. Other treatments have included UVA (without psoralen), colestyramine, activated charcoal, and erythropoietin therapy.
Pigmentary changes in chronic renal failure
Anaemia presenting as pallor is an early and common sign of chronic renal failure, resulting from reduced haemopoiesis and increased haemolysis. A greyish-brown discolouration develops in many cases, due to deposition of melanin. Increased nail pigmentation, usually confined to the distal nail, occurs in a proportion of patients. This distal brown or reddish colour, combined with a proximal white appearance gives rise to the term ‘half and half’ nails, a distinctive pattern seen in about 10% of patients with renal failure.
Purpura due to mild thrombocytopenia or more marked platelet dysfunction is common and may be partly corrected by dialysis. Urea frosting, in which crystalline urea is deposited on the skin, is now exceedingly rare.
Renal transplantation and the incidence of skin cancer
The incidence of skin cancers in patients who have received a renal transplant is above that of the general population, and patients often have numerous viral and dysplastic lesions on their skin, some of which will become malignant. The incidence of basal cell carcinomas (BCCs) rises in a linear fashion from the date of transplantation, but the increase in the incidence of squamous carcinomas (SCCs) rises in an exponential fashion. Sun exposure does play a major aetiological role in these immunosuppressed patients, as in the nontransplanted population. There is a high incidence in Australia with a mean nonmelanoma skin cancer (NMSC) incidence of 28.1%, with a maximum incidence of 47.1% in patients immunosuppressed for more than 20 years. The same group from Queensland noted that white patients at highest risk for developing NMSC have blue or hazel eyes, have spent a longer time living in a hot climate, and are more likely to have a pretreatment SCC. See Chapter 23.14.
Sun avoidance advice is important in all potential renal transplant patients and should be encouraged among the general population.
Calcific arteriolopathy (calciphylaxis)
Calcific arteriolopathy (calciphylaxis, calcific uraemic arteriolopathy, CUA)) is a disorder in which patients, usually with renal failure, develop large painful areas of ulceration. These can be distal involving the limbs, or can be proximal causing large areas of ulceration on the breasts, abdomen, and buttocks.
Recent studies have shown that the calcification is not the same as that seen in patients with skin necrosis, and the term calciphylaxis is considered inaccurate. CUA indicates the site of the calcification and the usual clinical state of the patients. However, CUA has been reported in patients with minimal or no renal failure, hence the author’s preferred use of the term calcific arteriolopathy.
In addition to renal failure, the other major risk factors include female gender, white race, diabetes mellitus, obesity, and warfarin and the clotting disorders such as protein C and protein S deficiency. It has also been shown that the use of calcium salts and vitamin D in chronic renal failure is a risk factor. A direct role of hyperparathyroidism in the development of calcific arteriolopathy is not proven, the disease having been described in the presence of a normal parathormone level.
The usual presentation of calcific arteriolopathy is of areas of ulceration on the legs, buttocks, abdomen, or breasts which are painful and may be extensive. Livedo reticularis around the ulcers may be present. Acral ulceration can also occur, causing autoamputation. The differential diagnosis is any cause of ulceration, especially vasculitis, in which livedo reticularis may also be present. Increasing awareness of the condition is allowing the diagnosis of calcific arteriolopathy at an earlier nonulcerative stage, before the subcutaneous indurated plaques develop into ulcers.
The diagnosis of calcific arteriolopathy is usually by biopsy, the histology showing calcification of the media of small arterioles in the skin. This is associated with a brisk intimal proliferation, sometimes with fibrin thrombi visible in the lumen. Other types of vascular calcification are seen in chronic renal failure. The calcification seen in calcific arteriolopathy is no longer thought to be a passive process. The calcium deposited is hydroxyapatite, which is the same as seen in bone. This is different from the compounds found in other types of calcification.
If calcific arteriolopathy is diagnosed at the nonulcerative stage there is some evidence for the use of oral prednisolone at a dose of 30 to 50 mg mane for up to 8 weeks. If ulceration is already present, debridement of the necrotic tissue is sometimes recommended and use of antibiotics to prevent overwhelming sepsis is important. Adequate pain control is another important management measure.
The outcome is poor, with a mortality of about 60% for proximal disease and about 20% for distal disease, usually from overwhelming sepsis. Since there is such a high mortality, the approach should be to aim for prevention. The control of the hyperphosphataemia is thought to be fundamental to this. Phosphate binders are used, with some evidence showing that the non-calcium-containing binders are better. Parathyroidectomy has been found to be useful in the control of calcific arteriolopathy in some series but not in others.
Nephrogenic fibrosing dermopathy
Nephrogenic fibrosing dermopathy (NFD) is a recently reported fibrotic disease occurring in patients with renal disease. NFD was initially reported in patients with established renal failure, either on dialysis or having had a transplant, but it has since been reported in patients with chronic renal insufficiency not requiring renal replacement therapy. An association with the intravenous injection of gadolinium-based radiocontrast media has been suggested.
The clinical presentation of this rare disorder is of plaques of indurated skin on the extensor surfaces of the limbs, and scleral involvement has been described. The limbs are affected in a symmetrical manner with skin-coloured papules coalescing to form brawny plaques with a ‘peau d’orange’ appearance, occasionally with swelling of the hands and feet. Patients may complain of pain, pruritus, and causalgia. Most patients do not have systemic involvement, but when this is present the disease may be rapidly fatal.
The histology shows an increase in dermal collagen with a paucity of inflammatory cells. There is mucin deposition with abundant eosinophilic spindle cells in the upper dermis that stain for CD34. The disease that NFD is most similar to is scleromyxedema, but the relative sparing of the face in NFD and the lack of a paraprotein allows the diseases to be separated on clinical grounds.
The mainstay of treatment is improvement of the renal function but transplantation is not guaranteed to cure the disease. Treatments such as plasmapheresis, topical calcipotriol under occlusion, PUVA, and oral steroids have been tried, but the results are difficult to assess, since an improvement in renal function is itself an effective form of therapy.
Other systemic diseases and the skin
Pyoderma gangrenosum (PG) is an uncommon, noninfectious neutrophilic dermatosis commonly associated with underlying systemic disease. Several clinical variants of PG have been described, including ulcerative, pustular, bullous, and vegetative forms.
An immune-mediated process is thought to play an important pathogenetic role, with about 50% of patients having an associated systemic disease. Common associations include inflammatory bowel diseases (ulcerative colitis and Crohn’s disease), rheumatoid arthritis and other rheumatological disease, haematological malignancies, and monoclonal gammopathies.
A characteristic presentation of PG begins with small tender papules or pustules that evolve into painful ulceration with typical undermined violaceous edges (Fig. 23.15.7). Lesions may be solitary or multiple. Healing usually occurs with an atrophic cribriform scar (i.e. having a number of small holes within it). Associated symptoms include fever, malaise, myalgia, and arthralgia. Bullous PG is often associated with myeloproliferative disorders. Vegetative or superficial granulomatous PG may have superficial and deep components and is not usually associated with any systemic disease.
The diagnosis of PG is made by recognizing the characteristic clinical features and by excluding other causes of ulceration. A biopsy across the edge of a lesion, depending on the type of PG, will show a neutrophilic infiltrate, but at best the histology is ‘consistent with’ as opposed to ‘diagnostic of’ PG.
Many effective treatments for PG have been reported, the precise choice depending on disease severity as well as on the presence of an underlying systemic disease. For early or mild PG, topical therapy with a superpotent corticosteroid or tacrolimus, along with good wound care, may be sufficient. Intralesional triamcinolone may also be effective.
For more severe cases or PG resistant to topical therapy, oral prednisolone has been the mainstay of treatment. Other treatments include pulsed intravenous corticosteroids, minocycline, dapsone, and immunosuppressants such as azathioprine or ciclosporin. Ciclosporin is usually effective at a dose of less than 5 mg/kg per day. Methotrexate has been used for patients with underlying inflammatory bowel disease and, more recently, infliximab and other biological agents have been effective. Less commonly used treatments include plasmapheresis, intravenous immunoglobulin, and thalidomide.
Behçet’s disease (Chapter 19.11.5)
Behçet’s disease is a multisytem disease that is defined by the presence of oral aphthosis with at least two of the following: genital aphthae, synovitis, posterior uveitis, cutaneous pustular vasculitis, or meningoencephalitis, in the absence of inflammatory bowel disease or autoimmune diseases. It typically affects young adults and is uncommon in northern Europe and the United States of America, but common in Middle Eastern and Japanese populations. Here we focus on cutaneous manifestations, but see Chapter 19.11.5 for a full discussion of Behçet’s disease.
Behçet’s disease was named after the Turkish dermatologist who described the multisystem disease. The pathogenesis is unclear, but there may be a genetically determined response to an infectious agent. Biopsies of early aphthae or of lesions of pustular vasculitis show a leukocytoclastic vasculitis, although late lesions are lymphocytic.
The clinical course of Behçet’s disease is variable, although patients typically have oral aphthae with any combination of genital aphthae, cutaneous pustular vasculitis, ocular lesions, or arthritis. Only pustular vasculitis and erythema nodosum-like nodules should be used to satisfy diagnostic criteria, although a wide range of skin findings (e.g. pyoderma gangrenosum-like lesions) may be present in patients with Behçet’s disease. Posterior uveitis is the only ocular criterion for the diagnosis of Behçet’s disease, but there are other ophthalmological manifestations. The posterior uveitis in Behçet’s disease is due retinal vasculitis and may result in blindness. The musculoskeletal involvement in Behçet’s disease is an asymmetrical, migratory, nonerosive oligoarthritis, mimicking rheumatoid arthritis. Many neurological manifestations may occur, but only meningoencephalitis is considered to be a diagnostic criterion. Vascular involvement in Behçet’s disease may affect arteries and veins, leading to aneurysms or occlusions that are sometimes fatal.
The diagnosis of Behçet’s disease should be suspected in any patient with recurrent and extensive oral aphthosis. Other causes of aphthosis such as inflammatory bowel disease, as well as lesions that mimic aphthae such as herpes simplex virus infection, must be excluded. The diagnosis should also be considered in young patients with deep venous thrombosis, particularly in the absence of other risk factors or thrombophilia.
A positive pathergy provocation test, read at 24 to 48 h, may further support the diagnosis.
Aphthae may be treated with topical or intralesional corticosteroids, topical tacrolimus, or with viscous lidocaine (lignocaine). Oral colchicine may also be used to treat mucocutaneous manifestations, although this option might be limited by gastrointestinal intolerance and requires monitoring for neutropenia. Dapsone in combination with colchicine has also been used successfully. Thalidomide may be effective in this situation but is becoming increasingly difficult to prescribe for women because of the risks to the foetus.
Behçet’s disease with manifestations other than mucocutaneous involvement may be treated with systemic corticosteroids, although this may not control severe ocular, neurological, or nonvasculitic vascular disease. Immunosuppressive agents such as ciclosporin, azathioprine, and methotrexate have been used for patients with severe Behçet’s disease.
There are different forms of xanthoma. Eruptive xanthomas of the skin, often on the buttocks and limbs, may develop in patients with hyperlipoproteinaemia in association with diabetes mellitus. Control of the hyperlipoproteinaemia and diabetes usually leads to resolution of the yellowish papules. See Chapter 11.6 for more detailed discussion.
Crohn’s disease and the skin
Periorificial granulomatous lesions sometimes occur in Crohn’s disease. Perianal abscesses and multiple fissures with fistulae occur in about a quarter of patients. Anal tags which are oedematous or have granulomatous histology are common. Oral Crohn’s disease presents as a thickened corrugated appearance of the oral mucosa and lips. Granulomatous cheilitis may precede other features of Crohn’s disease.
Cutaneous Crohn’s disease may also affect sites not in continuity with the bowel, and reactive dermatoses associated with Crohn’s disease include oral aphthae, erythema nodosum (see Chapter 23.7), and pyoderma gangrenosum (see below), a neutrophilic dermatosis. Other skin diseases are rarely associated with Crohn’s disease, and it can be difficult to distinguish perianal Crohn’s disease from hidradenitis suppurativa.
Thyroid disease and the skin
Thyroid disease is discussed in detail in Chapter 13.4. However, there are a number of cutaneous manifestations of both hypothyroidism and hyperthyroidism. Skin features associated with hypothyroidism include pale and cold extremities, absence of sweating, puffy oedema of hands and face, eczema craquele and pruritus, xanthomatosis (secondary to hyperlipidaemia), coarse sparse hair, brittle/striated nails, purpura/ecchymoses, punctuate telangiectasia on arms and fingertips, and delayed wound healing. Features associated with hyperthyroidism include soft and dry skin, palmar erythema, flushing, increased sweating, fast nail growth, pruritus and urticaria, pretibial myxoedema, acropachy, and diffuse addisonian hyperpigmentation.
Pruritus without a rash
Pruritus associated with systemic disease has been dealt with elsewhere within this chapter, but individuals presenting with itch in the absence of skin disease, should be carefully assessed. It can sometimes be difficult to distinguish secondary changes associated with excoriation from primary skin disease. However, detailed history (including drug history) and thorough systemic examination are crucial. Routine initial investigations might include renal function, full blood count with differential and haematinics, thyroid function, and liver function, with consideration of other investigations dependent on the clinical findings, such as chest radiograph, HIV testing, and screening for malignancy.
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