White : Diseases of the Skin - Collagen Vascular Diseases

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Gary M. White & Neil H. Cox

Diseases of the Skin

13	Collagen Vascular Diseases

SCLERODERMAS

Scleroderma (tight skin) is a term used for a range of disorders in which tight, hard, sclerotic skin is the main feature, but it may also occur in other situations (Table 13.5). Some of these other disorders may be difﬁcult to distinguish from autoimmune collagen vascular type scleroderma at times, especially conditions such as eosinophilic fasculitis. However, Table 13.5 gives some features that help to differentiated these, and they are all discussed elsewhere in the text. This section discusses the collagen vascular sclerodermas which can be classiﬁed as follows.

Morphea (cutaneous scleroderma; Figs 13.37–13.42)

•	plaque,
•	linear,
•	guttate,
•	nodular,
•	profunda (deep morphea),
•	bullous, and
•	generalized (adult) and disabling pansclerotic morphea of childhood.

Systemic scleroderma (Figs 13.43 – 13.54):

•	limited disease (acrosclerosis and CREST), and
•	diffuse disease (systemic sclerosis, SSc, or progressive systemic sclerosis, PSS).

Etiology and pathogenesis

The various forms of scleroderma listed here have different clinical courses, different human leukocyte antigen (HLA) and antibody associations, and probably different pathogenetic mechanisms. For example, ANA is often positive in linear morphea in children but not in other purely cutaneous sclerodermas. However, they all involve different degrees of microvascular obliteration, endothelial damage, and perivascular mononuclear inflammatory response, and increased deposition of collagen and matrix components in the skin.

Occasionally, there may be speciﬁc local factors that influence the development of morphea, such as the type that occurs as a late effect following radiotherapy (postirradiation morphea, see Fig. 13.42). This is typically related to treatment of breast cancer, and is unrelated to silicon breast implants, which have been (controversially) implicated as a cause of systemic sclerosis. Tick bites and Borrelia burgdorferi infection have also been linked with development of morphea, and treatment with penicillin has been advocated. Patients with porphyria cutanea tarda (PCT, see also Ch.17) may also develop sclerotic plaques (Fig.13.43) resembling morphea but usually have other features of PCT as well.

Table 13.5 CAUSES OF SCLERODERMATOUS CHANGES IN THE SKIN

Disorder	Comments
Morphea (cutaneous scleroderma) Systemic scleroderma	May be localized (plaque type), generalized, or speciﬁc variants (linear, en coup de sabre, nodular, guttate, profunda [deep], bullous). May be localized (plaque type), generalized, or speciﬁc variants (linear, en coup de sabre, nodular, guttate, profunda [deep], bullous).
Mixed connective tissue disease (MCTD)	Many collagen vascular diseases may overlap with others; MCTD (see text) overlaps especially with and other collagen vascular overlap CREST. Autoantibodies, other clinical features, and passage of time may all help to achieve a more syndromes precise diagnosis.
Postirradiation morphea	Usually affects the breast (Fig.13.43); may resemble metastatic breast carcinoma, especially if it initially has an inflammatory stage.
Drug and toxin-induced pseudoscleroderma	Causes include bleomycin (usually acral pattern), l-tryptophan, ‘toxic oil syndrome’, polyvinyl chloride, silicosis. Localized scleroderma may be caused by vitamin K injections, silicone, or parafﬁn implants.
Atrophoderma of Pasini and Pierini	Usually affects low back, brownish color, ﬁrm but depressed below skin surface contour.
Graft-versus-host disease (GVHD)	Sclerodermatous change is characteristic of late-stage GVHD (Ch.12), but the diagnosis is generally apparent from the history of marrow transplant.
Porphyria cutanea tarda (PCT)	Sclerodermatous change may occur (Fig. 13.44); the diagnosis is usually apparent from the other features of PCT (Ch. 17).
Dermatomyositis	Sclerodermatous change may occur; it is often patchy and mixed with more classic rash of dermatomyositis.
Eosinophilic fasciitis	Usually affects lower legs, with acute onset and often good response to prednisolone. A sufﬁciently deep biopsy (to include fascia) will usually show tissue eosinophilia. See Chapter 11.
Paraneoplastic fasciitis	May cause acral sclerotic change or tethering similar to that of eosinophilic fasciitis; changes are very resistant to treatment.
Carcinoid syndrome	Scleroderma-like areas may be apparent, and telangiectasia, but there is also flushing and weight loss.
Lipodermatosclerosis	Affects the foot and lower leg, especially above the medial malleolus in patients with chronic venous insufﬁciency (Ch.15).
Diabetic stiff skin and cheirarthropathy	This generally has an acral predominance, without the telangiectasia of CREST; see Chapter 12.

CREST: calcinosis, Raynaud phenomenon, esophagus, sclerodactyly, telangiectasia.

Clinical aspects, diagnosis, and investigations

Some identiﬁable subsets of the sclerodermatous disorders are discussed individually. Morphea is considered here, although it is not associated with Raynaud phenomenon, and does not have the same implications for general health as the other sclerodermatous disorders. For most variants in the scleroderma spectrum, the diagnosis is primarily clinical, with support from autoantibody tests and investigations to determine internal organ involvement, as appropriate. Skin biopsies can conﬁrm skin thickening and sclerosis, but this is somewhat subjective and varies according to the body site; it can be useful to exclude deposition disorders such as scleredema (Ch. 11).

A clinically similar condition known as eosinophilic fasciitis is discussed in Chapter 11; it usually affects the lower legs.

A malignancy-associated fasciitis syndrome has also been described.

Morphea

This is a disorder of localized scleroderma (Figs 13.37–13.42), which usually occurs as one or a few lesions, usually of several centimeters in diameter. The characteristic appearance is of a shiny ivory-white sclerotic area with surrounding purplish inflammatory erythema, which gradually fades with time (Fig. 13.37). The skin is palpably hard, a feature that may not be apparent with visual inspection alone. The lesions may soften or become more brown over a long period, and generally the only problems are itch in early lesions and the cosmetic aspects.

One or more localized plaques of morphea are by far the commonest pattern, but several variants occur, as listed earlier. Linear and en coup de sabre types are discussed in more detail below. Guttate morphea is a pattern in which there are multiple tiny spots; it may be difﬁcult to diagnose with conﬁdence. Subcutaneous deep morphea (morphea profunda) is uncommon but also poses particular diagnostic difﬁculties, as does nodular morphea, in which lesions resemble keloids. Bullous morphea is rare.

Generalized or diffuse morphea is rare and may be confused with systemic sclerosis; it involves a large proportion of the body surface area (often sparing around the nipples), and causes some skin tightness, but without the internal involvement or relentless constriction of systemic sclerosis (Fig. 13.38). Disabling pansclerotic morphea of childhood is a similar process but has implications that do not apply in adults; sclerosis of the skin when growth is still occurring may lead to joint contractures and muscular atrophy.

Large studies suggest that about 5% of patients with morphea may develop systemic sclerosis, but some of these may actually have had localized skin lesions of systemic sclerosis from the outset, or may have had generalized morphea rather than systemic sclerosis. About 30% of patients with linear morphea have positive ANA, and morphea-like plaques occur in a similar proportion of patients with eosinophilic fasciitis. Antihistone antibodies are common in extensive morphea, but other antibodies (to topoisomerase I, centromere, SSA, SSB, or dsDNA) are not found.

Fig. 13.37 A typical lesion of early morphea. The center is ivory-colored and shiny, with loss of follicles, and there is a violaceous inflammatory border. This type of lesion may improve using strong topical steroids, although the white color usually persists.

Fig. 13.38 A more diffuse pattern of morphea, which might resemble the sclerodermatous skin of systemic sclerosis. However, diffuse morphea often has a brownish color, does not particularly affect the upper trunk (a common distribution for systemic sclerosis), and characteristically spares the periareolar region.

Fig. 13.39 Morphea en coup de sabre (a). Involvement of the scalp, producing linear alopecia. This pattern generally extends on to the forehead and distorts the forehead crease lines when frowning. The scalp defect can sometimes be excised if necessary. (b) Less commonly, there are two (as shown here) or even three bands.

Fig. 13.40 Parry�Romberg syndrome (progressive facial hemiatrophy) may occur in isolation or with lesions of morphea at other sites. Some authors view morphea en coup de sabre as an abortive form of this condition.

Fig. 13.41 Rare types of morphea: linear and deep patterns. Linear morphea (a) is uncommon, and most frequently affects a single limb, although other body sites can be affected. On the leg, in particular, there is a risk of altered bone growth and flexion contractures. Some patients have a positive antinuclear antibody test. (b) Deep morphea extends into the fat but may have minor skin surface changes; it may present due to the hardness of the skin or the functional impairment. This patient responded to oral ciclosporin after periods using other topical and oral agents, but some cases may spontaneously resolve.

Fig. 13.42 Postirradiation morphea is probably an underestimated condition. Its importance, apart from the cosmetic aspects, is the potential difficulty in excluding a sclerotic cancer recurrence on the breast, especially in early cases, when there may be inflammation resembling carcinoma erysipeloides.

Fig. 13.43 Sclerotic plaques due to porphyria cutanea tarda may resemble lesions of morphea, but affected patients may also have photosensitivity, blistering of exposed skin, and facial hypertrichosis. (Courtesy of Michael O. Murphy, M.D.)

Fig. 13.44 Scleroderma of the face, causing prominent mat telangiectases of the lips and cheeks. This pattern may be confused with hereditary hemorrhagic telangiectasia.

Fig. 13.45 CREST syndrome with telangiectasia of the hands (a) and face (b), a common feature of this condition.

Fig. 13.46 Mat telangiectasia of the hand in CREST syndrome. In some patients, this may precede other changes by several years.

Fig. 13.47 Scleroderma demonstrating a �salt and pepper� pattern of brown spots on a white background. The brown areas may represent initial follicular sparing.

Fig. 13.48 Calcinosis is one of the typical features of CREST syndrome. Occasionally, calcified material may be transepidermally eliminated from dystrophic fingertip skin, as shown in this case.

Fig. 13.49 Scleroderma of the fingers, showing telangiectases and a dusky swollen finger (note that the changes of mixed connective tissue disease, Fig. 13.56a, may be identical).

Fig. 13.50 (a,b) Digital ulceration may occur in CREST or systemic sclerosis, may affect either the skin over joints or the finger pulps, and often leads to further tightness and pigment change if it heals (a). In this case, ulceration has occurred over the bony prominence of the proximal interphalangeal joint due to the flexion contracture and tight skin on the fingers in a patient with advanced and disabling contractures, causing a �claw hand�.

Fig. 13.51 Pulp atrophy of digits, seen at an early stage in Figs 13.48 and 13.54, may progress with underlying bone resorption, leading to a shortened digit with a small fingernail, as shown here.

Fig. 13.52 Perioral changes are common in CREST, and include telangiectasia (Fig. 13.44) and changes due to constriction of the lips (radial furrows and restricted mouth opening). Patients who wear dentures may find it difficult to insert these if mouth opening is impaired.

Fig. 13.53 Treatment with anthralin (dithranol): residual brown staining after treatment. This lasts only a week or so after lesional clearance, but some patients may not wish to use it on exposed sites such as the hands.

Fig. 13.54 Treatment with anthralin (dithranol): residual brown staining after treatment. This lasts only a week or so after lesional clearance, but some patients may not wish to use it on exposed sites such as the hands.

Linear morphea

This uncommon variant of morphea is of importance due to involvement of underlying structures (Fig. 13.41). It usually affects a single limb, and may be associated with morphea plaques elsewhere. Deep ﬁbrosis may affect fat and muscle, with melorrheostosis of the underlying bone, and joint contractures are common if the process extends across joints. Impaired bone growth may occur.

En coup de sabre morphea

This is a site-speciﬁc variant of linear morphea that affects the face, usually affecting the paracentral forehead and frontal scalp (Fig.13.39). There is usually a single band, but may be more. It may be a variant of facial hemiatrophy (Parry–Romberg syndrome, Fig. 13.40).

Limited systemic sclerosis (CREST syndrome)

This variant of systemic sclerosis affects the hands, forearms, feet, face, and esophagus (Figs 13.44–13.46). The features that make up the acronym CREST are calcinosis, Raynaud phenomenon, esophageal involvement, sclerodactyly, and telangiectasia. Most patients have had Raynaud phenomenon for many years prior to any other symptomatic disease, although telangiectasia of the lips and ﬁngers is prominent at an early stage in some individuals (and is morphologically similar to that of hereditary hemorrhagic telangiectasia). Nail fold telangiectasia (giant capillary loops) is usually prominent. Sclerosis around the mouth causes deep skin creases (radial furrows), and on the digits causes tight, shiny, bound-down skin with loss of hair, pigmentary variation, and is associated with loss of ﬁngertip tissue and pulp infarcts. Esophageal involvement is usually manifest as reflux symptoms due to disordered motility causing abnormal peristalsis. Other gastrointestinal involvement, such as malabsorption due to small bowel involvement, is a late feature. Pulmonary hypertension is also a late feature.

The diagnosis is largely clinical. Serologic tests are useful, as most patients have a positive anticentromere antibody test; this test is less commonly positive in diffuse systemic sclerosis and uncommonly in primary Raynaud disease. Esophageal motility studies should be performed.

PRACTICE POINTS

•	Palpation of the skin to assess ﬁrmness and texture is an integral part of the examination. Failure to do this will result in incorrect diagnosis and inappropriate treatment in patients with morphea.

Diffuse systemic sclerosis

Diffuse systemic sclerosis is manifest dermatologically by a more generalized sclerodermatous process, which particularly affects the upper trunk and distal limbs (Figs 13.47 – 13.54). There may be preceding Raynaud phenomenon, although in some patients the onset is abrupt and very rapidly progressive (the only subgroup in whom systemic steroids appear to be useful, probably because there is cutaneous inflammation and edema at this stage prior to ﬁbrosis).

In the initial stages of disease, for the ﬁrst few years, there may be non-speciﬁc features of malaise and tiredness, with internal organ involvement in several systems.

•	Musculoskeletal—arthritis, myositis, and tendinitis.
•	Pulmonary—basal ﬁbrosis with restrictive defect, causing cough and exertional dyspnea.
•	Gastrointestinal—esophageal symptoms as in CREST, reduced small intestinal motility (causing malabsorption), dilatation, and sacculation of the colon.
•	Cardiac—pericarditis and myocardial ﬁbrosis.
•	Renal—severe hypertension and renal failure.

Investigations for internal disease are important and may need to be repeated at intervals, depending on symptoms. ANAs are positive in 95% of patients. Scl-70 (antibody to topoisomerase, producing a diffuse speckled nuclear fluorescence) is positive in 25–30%, and is associated with proximal sclerosis and lung disease; anticentromere antibody is positive in a smaller proportion and is associated with acral and less severe disease.

Mixed connective tissue disease and overlap syndromes

Mixed connective tissue disease does not neatly ﬁt as any of the classic collagen vascular diseases, but has features that clearly belong within this overall category. Although some such patients may eventually fulﬁll criteria for systemic sclerosis or SLE, some patients have mixed features for prolonged periods. The most frequent features are Raynaud phenomenon, swollen hands with restricted movement of digits, sclerodactyly, arthralgia, and esophageal disease, but there may also be myositis, heliotrope rash, calcinosis, and other non-speciﬁc signs (Figs 13.55–13.57). A speckled pattern of ANA due to anti-U1RNP is typical but non-speciﬁc, and there should be negative tests to other more speciﬁc antibodies such as dsDNA, histones, Sm, Scl-70, SSA, and SSB. Pleurisy and pulmonary hypertension may occur, but severe renal or central nervous system disease is uncommon.

Overlap syndromes are those in which there appears to be a true association of different diseases, with sufﬁcient features of each to have a ﬁrm diagnosis. Sjögren disease, in particular, may be associated with other disorders such as SLE, scleroderma, or rheumatoid arthritis. Some patients with childhood dermatomyositis may subsequently develop features of LE, and myositis may occur in LE.

Differential diagnosis

Plaque-type morphea is usually characteristic but, especially if not palpated, the inflammatory stage may be confused by the less experienced practitioner with tinea or other annular lesions (see Table 1.2). Older lesions may be referred non-speciﬁcally as ‘pigmentary disturbance’.

The guttate pattern of morphea may be difﬁcult to distinguish from the similar-sized variant of lichen sclerosus. Morphea profunda clinically resembles deep variants of disorders such as sarcoidosis, granuloma annulare, and interstitial granulomatous dermatitis (see later in this chapter). The rare nodular variant resembles spontaneous keloids.

The pufﬁness and limited mobility of the hands in CREST should be differentiated from MCTD, from other causes and differential diagnoses of Raynaud phenomenon (Table 13.1), and from diabetic cheirarthropathy (see Fig. 12.17). Telangiectasia in CREST may be difﬁcult to distinguish from that of hereditary hemorrhagic telangiectasia, although the latter is usually manifest at a young age.

Generalized morphea and systemic sclerosis need to be distinguished because of the prognostic differences, and from the sclerotic disorders listed in Table 13.5 (which also provides some features that may help to make the diagnosis). Most disorders that may have scleroderma-like features usually have other features that readily distinguish them from scleroderma (such as blisters in PCT and flushing in carcinoid syndrome), but some may be similar to primary scleroderma processes (such as MCTD, eosinophilic fasciitis, and overlap syndromes). Other diffuse skin inﬁltrates, such as scleredema or scleromyxedema, may cause diagnostic problems, but both are rare, and biopsy will show mucin in these latter disorders.

Rare pediatric conditions such as stiff skin syndrome and congenital fascial dystrophy are unlikely to be confused with autoimmune sclerodermas.

Fig. 13.55 Telangiectasia on the lips in a patient with mixed connective tissue disease, a similar pattern to that seen in CREST.

Fig. 13.56 Mixed connective tissue disease, (a) presenting as a dusky blue discoloration of the hands, with cold skin and Raynaud phenomenon, and (b) showing marked radiologic evidence of calcification.

Fig. 13.57 Mixed connective tissue disease, demonstrating the prayer sign (see also Fig. 12.17). The tight, puffy skin of the fingers prevents the hands from being pressed flat together when the wrists are extended to 908.

Treatment

Many patients with localized lesions of morphea do not require any speciﬁc therapy other than explanation and reassurance; indeed, therapy is often not effective in established lesions. In the inflammatory stage, topical corticosteroids may have a role; these must be sufﬁciently potent to achieve penetration into the sclerotic skin. For more widespread cutaneous involvement, PUVA and UVA1 (a high-intensity long-wavelength UV treatment) can be effective, but the latter is not widely available.

Treatment of systemic sclerosis is complex, due to the multiple organs involved. Treatment of Raynaud phenomenon has already been discussed but, in addition, ﬁngertip ulceration may require treatments such as mupirocin for secondary infection, and locally applied vasodilators such as glyceryl trinitrate.

Physiotherapy is important for skin and joint disease, with non-steroidal antiinflammatory drugs (NSAIDs). Immunosuppressive drugs (steroids if very acute, methotrexate, and cyclophosphamide) and antiﬁbrotic drugs such as penicillamine have been recommended, with varying beneﬁt. Colchicine, interferon, isotretinoin, and sulphasalazine have all been used with occasional apparent responses. Angiotensin-converting enzyme inhibitors are usually used for treatment of hypertension, in view of the associated renal arteriolar disease. Symptomatic treatment of reflux symptoms includes antacids, H2 antagonists, and proton pump inhibitors. Malabsorption may, in part, be due to bacterial overgrowth and respond to appropriate antibiotics.