Scleroderma

Abstract

Scleroderma is a heterogeneous group of chronic inflammatory fibrotic diseases of unknown etiology. Localized scleroderma mainly affects circumscribed skin areas, but depending on the subtype it can also affect structures close to the skin such as fatty tissue, muscles, joints, and bones. In systemic scleroderma/sclerosis, the fibrosis of the skin is accompanied by a very variable involvement of internal organs (gastrointestinal tract, lungs, heart, kidneys), as well as muscles and joints. These are two independent clinical diseases. The broad spectrum of scleroderma-like diseases or pseudoscleroderma must be distinguished.

1 Introduction

Scleroderma comprises chronic diseases of unknown etiology in which an inflammatory phase leads to fibrosis/sclerosis, i.e., a hardening of the connective tissue of circumscribed skin areas or to generalized sclerosis of the skin with the involvement of internal organs. The prognosis of the first mentioned disease is favorable in most cases, but that of the second form is serious. Despite similarities in the histological picture, it is therefore necessary to distinguish between two completely independent diseases owing to their completely different spread, progression, and prognosis:

• Localized scleroderma

• Systemic scleroderma/systemic sclerosis

Skin changes that largely imitate the image of scleroderma, but have a distinct, different etiology, are classified as pseudoscleroderma or scleroderma-like syndromes. Sclerosing skin lesions, which cannot be confused with scleroderma, are referred to as sclerodermiform lesions. An example is the sclerodermiform basal cell carcinoma.

Localized and systemic scleroderma are two independent diseases.

2 Localized Scleroderma

Synonyms

Scleroderma circumscripta ; Localized scleroderma; Morphea

Epidemiology

Scleroderma is relatively rare. The ratio of women to men is 2:1–3:1. Younger adults (20–40 years) are most frequently affected; about 15% of patients are children up to 10 years of age.

Etiopathogenesis

The cause is unknown. In individual cases, traumas have been accused of being triggering factors. Genetic, immunological, hormonal, infectious, toxic, neurogenic, or vascular factors have been discussed but not proven. Also, the suspicion that Borrelia burgdorferi, at least in some cases, acts as an etiological agent (increased antibody titer, detection of Borrelia burgdorferi in diseased skin), has not been confirmed.

2.1 Clinical Variants of Localized Scleroderma

Clinical Features

An incipient lesion begins with a spot-like, moderately inflammatory reddening that expands on all sides. Soon a slowly growing, yellowish-white hard plate forms in the center of the lesion. The result is a disc-like, surface-reflecting, ivory-colored hardening of the skin that is bonded to the base and surrounded by a blue-violet or lilac-colored erythema, the lilac ring (Fig. 1). The hardening is often irreversible. After a longer period, however, atrophy can also develop, with the loss of hair and sebaceous glands, and with pigment changes (hyper- and depigmentation) occurring within the lesion. Laboratory results are usually inconspicuous. Antinuclear antibodies can occur, particularly in linear and disseminated localized scleroderma.

Fig. 1

Localized scleroderma

Changing size and shape of sclerotic connective tissue hardening and changing location of pathological changes in the different levels of the skin allow clinically different forms to be distinguished (Table 1).

Table 1 Classification of circumscribed scleroderma

2.1.1 Morphea, Plaque Type

Here, one or more lesions measuring 1–10 cm are found. Predilection sites are the trunk, the submammary region and the hip/inguinal region. The coexistence of a genital lichen sclerosus (LS) is frequently observed.

2.1.2 Morphea Guttata

Morphea guttata (small-spotted localized scleroderma) is characterized by truncal dissemination of yellowish-white, superficially shiny sclerotic lesions with a fine lilac ring at the edge. Clinical differentiation from lichen sclerosus et atrophicus can be difficult. But follicular hyperkeratosis is always lacking.

2.1.3 Atrophodermia Pasini–Pierini

(Pasini 1923; Pierini and Vivoli 1936)

Synonym

Atrophodermia idiopathica et progressiva

The atrophodermia Pasini–Pierini (erythematous circumscribed scleroderma) form is relatively rare. Usually, a violet erythema develops in several rounded or oval lesions of at least 1–2 cm in size: lilac ring. The predilection site is the trunk. Sclerosing of the lesion is completely absent or is only very slight. Finally, the skin becomes slightly atrophic in the well-defined lesions and sinks like a boat below the skin level. It is a localized scleroderma located superficially in the dermis. It is not uncommon for this form to appear in conjunction with the plaque or generalized form of scleroderma.

2.1.4 Generalized Form of Circumscribed Scleroderma

The generalized form of localized scleroderma (morphea generalisata) occurs when at least three different localizations are affected (Fig. 2). Breath excursions and mobility of the extremities can be significantly restricted. In this form, the coexistence of a genital LS was frequently reported.

Fig. 2

Confluent plaques of a generalized form of circumscribed scleroderma

2.1.5 Disabling Pansclerotic Morphea

(Diaz-Perez et al. 1980)

Disabling pansclerotic morphea is an extremely rare and severe disease caused by a combination of linear and disseminated localized scleroderma. The extensive, progressive skin involvement often leads to severe contractures and poor healing, and sometimes extensive ulcerations. Transformation in ulcerated lesions to squamous cell carcinoma has been observed (Fig. 3).

Fig. 3

Disabling pansclerotic morphea

2.1.6 Linear Circumscribed Scleroderma

Linear circumscribed scleroderma is by far the most common form in childhood and occurs in two variants: scleroderma en coup de sabre and linear circumscribed scleroderma of the extremities.

Scleroderma en coup de sabre

This not uncommon special form of the band-shaped localized scleroderma often develops paramedian from the eyebrows into the hairy scalp, in which fibrosing alopecia occurs. Sometimes, a channel-shaped atrophy of the underlying bone can be found, so that the overall aspect of a “saber cut” is created (Fig. 4). Double-sidedness is extremely rare. Changes in the central nervous system (as detected by CT, MRI) are often described. Neurological/ophthalmological symptoms are observed. If the lesion is more lateral to the head or chin, an image reminiscent of hemiatrophia faciei progressiva may result.

Fig. 4

Linear circumscribed scleroderma (en coup de sabre)

Coexistence with hemiatrophia has also been described.

Linear Circumscribed Scleroderma of the Extremities

Here, sometimes linear, band-like, or even systematized foci spreading in a longitudinal direction occur. These sclerotic bands can pass over joints and lead to movement restrictions (dermatogenic contractures; Fig. 5). In children, an associated pronounced muscle or bone atrophy can develop in the affected skin areas, and inflammatory joint involvement is also observed in up to 50% of cases.

Fig. 5

Linear localized scleroderma

2.1.7 Progressive Facial Hemiatrophy

(Blaszczyk et al. 2003; Parry 1825; von Romberg 1846)

Synonyms

Hemiatrophia faciei ; Parry–Romberg Syndrome

Progressive facial hemiatrophy is characterized by a primary atrophic transformation of the affected subcutaneous tissue muscle and bone (Fig. 6). Fibrosis is rarely observed. The disease often occurs in adolescence and childhood in the head area and affects cheek muscles, bones, and tongue, resulting in pronounced asymmetry of the face. Participation of the central nervous system is observed, as well as a coincidence with a linear circumscribed scleroderma of the type en coup de sabre.

Fig. 6

Progressive facial hemiatrophy

2.1.8 Nodular Localized Scleroderma

In this rare variant, knotty lesions reminiscent of keloids appear; hence, the designation keloid morphea. Coincidence with typical foci of localized scleroderma occurs and is helpful for diagnosis. Histologically, in contrast to keloid, a normal elastic fiber distribution is found.

2.1.9 Deep Form of Localized Scleroderma (Morphea Profunda) Bielsa and Ariza (2007)

The deep form of circumscribed scleroderma (Morphea profunda) is characterized by the fact that preferably deeper parts of the connective tissue such as the subcutis and fascia are the location of fibrosis. Therefore, the lilac erythema of the lilac ring is missing on the skin surface. Clinically, nodular, strand-like, or keloid-like skin changes are seen that occur symmetrically on the extremities and lead to retractions.

2.1.10 Localized Scleroderma of the Fascia

Circumscribed scleroderma of the fascia (sclerofascia) can be characterized as localized scleroderma with location of disease in the connective tissue of fascia. Preferred localization are the fasciae in the tendon sheaths of the forearm flexures. By shrinking and confining muscles and tendons, this form finally leads to the dermatogenic fixation of the joints. The symptoms of carpal tunnel syndrome can also result.

2.2 Diagnosis and Therapy of Localized Scleroderma

Differential Diagnosis

Other sclerosing skin diseases, such as eosinophilic fasciitis, incipient systemic scleroderma (Sects. 3 and 4), as well as different forms of pseudoscleroderma and lichen sclerosus et atrophicus, should be mentioned here. Overlaps with lichen sclerosus et atrophicus, especially with involvement of the genital mucosa, are more frequently observed.

Histopathology

Early changes are a dense, predominantly lymphocytic, inflammatory infiltrate surrounding the vessels of the superficial and deep plexus, an edematous swelling of the collagen fiber bundles, and often septal panniculitis with lymphocytes, plasma cells, and eosinophils. This inflammatory phase develops into the sclerotic stage, in which the dermal connective tissue spreads at the expense of the subcutaneous fatty tissue. The inflammatory cells disappear, fibroblasts are only sparsely detectable between the homogenized and widened collagen fiber bundles, which are usually arranged parallel to the skin surface. The vessels are narrowed into slits, the adnexa are atrophied. Hair follicles and sebaceous glands disappear almost completely; only the musculi arrectores pilorum remain. Eccrine sweat glands are confined in the hyaline sclerotic corium. The elastic fibers are largely retained. Endothelial thickening and fenestration, as well as thickening of the basement membrane, are observed in the small vessels.

Laboratory

The values are generally within the normal range. Eosinophilia can occur. Increased antinuclear antibody titers without further specificity are described, particularly in linear circumscribed scleroderma.

Course

The intensity of the disease varies and is unpredictable. As a rule, however, it stops spontaneously and the lilac ring, as a sign of inflammatory activity, disappears. Sclerosis can also recede. The mean duration of the disease is 1.5–4 years for plaque-type scleroderma and 5 years for linear circumscribed scleroderma. However, courses of more than 10 years are possible. Skin changes such as secondary hyperpigmentation, calcinosis, contractures or facial hemiatrophy only disappear slowly at best.

The quoad vitam good prognosis is clouded by remaining atrophic foci, possible deformations of the skin, and functional impairments of joint mobility. Sometimes trophic, poorly healing ulcers develop in old scleroderma foci, especially on the lower legs. Coexistence with systemic scleroderma or transitions into this prognostically unfavorable form have only been described in isolated cases. Myositic changes in the diseased area, on the other hand, can be observed more frequently, in the affected extremities.

Therapy

For patients with limited skin involvement, external therapy is usually sufficient. Systemic therapy should be considered for patients with severe skin involvement or extracutaneous involvement (subcutis, fascia, musculature, joints) Kreuter et al. (2016).

Topical

Glucocorticoids can be applied in ointment form, also under occlusive dressing. Intralesional injections of 1:3–1:5 triamcinolone acetonide crystal suspensions diluted with mepivacaine may be considered in the active margin of linear subtypes. Positive results are reported for the use of calcipotriol 0.005% under occlusion or calcineurin inhibitors.

Phototherapy

A number of prospective studies support the use of long-wave ultraviolet radiation for the treatment of localized scleroderma. These include in particular bath psoralen ultraviolet light A (PUVA) therapy (bath or cream therapy Kerscher et al. (1996), depending on the affected area 2–4 times per week for 30 irradiations) or UVA-1 therapy (50–80 J/cm²) 3–5 times a week, 30–40 irradiations) Kreuter et al. (2006).

Systemic

In the case of extensive skin involvement or involvement of the subcutaneous fat tissue and musculature, systemic therapy should also be considered in children, especially in the inflammatory stages. Systemic glucocorticoids are used both as monotherapy (prednisolone orally 0.5–1.0 mg/kg bodyweight daily) and in combination with methotrexate (12.5–25 mg/week for adults, 15 mg/m² body surface area, maximum 25 mg/week for children for at least 12 months).

Physiotherapy

In the case of linear forms on the extremities, in addition to pharmacological therapy, measures to maintain joint mobility, such as physical and physiotherapeutic treatments, are indicated. Heat treatment, skin care, and massages can be helpful.

3 Eosinophilic Fasciitis

(Shulman 1974)

Synonyms

Shulman syndrome ; Diffuse fasciitis with eosinophilia

Epidemiology

The disease is rare and probably occurs predominantly in males.

Etiopathogenesis

The cause is unknown; previous local trauma or exaggerated physical exertion is reported.

Clinical Features

The disease can occur at any age, but usually in middle adulthood. Eosinophilic fasciitis is treated separately here, although it is probably not a disease entity, but a variant of the localized scleroderma disease spectrum (Table 1). Without Raynaud’s symptoms, a doughy, sclerodermiform induration, usually of the extremities, develops relatively quickly, less frequently on the trunk. Hands or face are usually not affected. The skin becomes hard, wavy (mattress phenomenon) and is tightly bound to the underlying structures so that contractures can occur within a few weeks (Fig. 7). Symmetrical polyarthritis of the small joints of the hand or an oligoarthritis, for example, of a knee joint, can occur.

Fig. 7

Eosinophilic fasciitis

Differential Diagnosis

Systemic scleroderma, eosinophilia–myalgia syndrome, and pseudoscleroderma diseases such as nephrogenic systemic fibrosis must be distinguished.

Histopathology

In the early phase, dense inflammatory infiltrates of monocytes, eosinophilic granulocytes, and plasma cells are found at the subcutis–fascia junction. In the late phase, cell-poor fibrosis with leading involvement of the fascia is found. Immunoglobulin deposits can often be detected by direct immunofluorescence on basement membranes, blood vessels, or diffusely in connective tissue.

Laboratory

In the early stages, blood eosinophilia (up to 50%), elevated erythrocyte sedimentation rate (ESR), and hypergammaglobulinemia are observed. Antinuclear antibodies are usually not detectable.

Course

It is chronic, but spontaneous remission is possible. The disease usually responds well to glucocorticoid therapy and methotrexate. Cases of association with malignant lymphoma and aplastic anemia have been reported.

Therapy

Glucocorticoids are given at medium doses (around 60 mg prednisone equivalent per day) with very slow reduction, often in combination with methotrexate (Mertens 2017).

4 Systemic Scleroderma

(Crusio 1754; Gintrac 1847; Gabrielli et al. 2009)

Synonyms

Systemic sclerosis ; Sclerodermia diffusa seu progressiva; Progressive systemic scleroderma; Systemic sclerosis

Epidemiology

The disease is rare. In the USA, the morbidity is 105/1 million inhabitants, the number of new cases per year is estimated at 3–12/1 million inhabitants, the mortality at 2–4/1 million inhabitants. Climatic and geographical differences are not pronounced. Depending on the type of disease, associations with a specific HLA locus can be detected. At 3:1–5:1, women contract the disease much more frequently than men. The incidence of the disease in children is very low and increases with age. In over 80% of cases, patients seek medical help between the third and seventh decade of life.

Etiopathogenesis

Although the cause of the disease is still unknown, it is known that three areas are of central importance for the pathogenesis of systemic scleroderma:

• Vascular changes

• Early inflammatory reaction

• Later onset of fibrosis and sclerosis

A genetic disposition is definitely involved. Certain subtypes of systemic scleroderma show a high correlation with defined HLA alleles. In earlier studies, it was attempted to detect chromosomal anomalies in these patients. Also, the persistence of fetal cells in women with systemic scleroderma was held responsible for the induction of a chronic graft-versus-host-like reaction and thus for the triggering of the disease. These studies refer to the great similarity of systemic scleroderma, with changes occurring after bone marrow transplants and a chronic graft-versus-host response.

Potentially important for pathogenesis are environmental factors and chemicals, which can lead to scleroderma-like diseases. Examples include impurities of tryptophan, substances responsible for the toxic oil syndrome in Spain in the 1980s, vinyl chloride, and silicate dust.

The circulating antibodies regularly occurring in systemic scleroderma characterize the phenotype, are genetically determined, point to certain organ involvement in such patients, and therefore have prognostic significance. In recent years, however, it has been pointed out that particular antibodies may have functional significance and can contribute to the pathophysiology of the disease.

Disturbances of the cellular immunity were frequently described. A characteristic finding is the often very pronounced lymphohistiocytic inflammation around blood vessels, which is followed early on by endothelial cell proliferation and vascular occlusion. A large number of cytokines are released and detected. In particular, the family of the transforming-growth factor β and the connective tissue growth factor play a prominent role. These factors seem to induce fibroblast activity and lead to a self-sufficient response that leads to the slowly progressing fibrosis.

Clinical Features

Systemic scleroderma is a heterogenous disease (Varga et al. 2017). Within the diverse clinical picture, two disease types can be distinguished (Table 2; Figs. 8, 9, and 10).

Table 2 Classification of systemic scleroderma. (From: LeRoy et al. 1988)

Fig. 8

Systemic scleroderma with trunk involvement, typical nipple recess

Fig. 9

Systemic scleroderma of the acral type with typical facial abnormality

Fig. 10

Sclerotic stage of scleroderma of the acral type

Limited Form of Systemic Scleroderma (Limited Cutaneous Systemic Scleroderma )

Acroscleroderma (limited systemic scleroderma [lcSSc]) is characterized by an increasing fibrosis of the acral regions with centripetal spread to below the elbows and knee joints (Fig. 11a). The facial skin can also be affected. In this disease variant, the onset of skin fibrosis is usually preceded for many years by Raynaud’s phenomenon and the detection of antinuclear antibodies. Characteristic is the detection of anticentromere antibodies in about 50% of these patients. Organ manifestations occur later. Important for the prognosis quoad vitam is the occurrence of pulmonary arterial hypertension. There are two particular subtypes of systemic scleroderma (SSc), which are meanwhile assigned to the limited form. This includes on the one hand the CREST syndrome (calcinosis, Raynaud’s disease, esophageal involvement, sclerodactyly, telangiectasias), which is usually associated with centromere antibodies, and the rare subtype of systemic scleroderma sine scleroderma. Although these patients do not have scleroderma, they suffer from Raynaud’s phenomenon, pulmonary arterial hypertension or characteristic gastrointestinal changes, in addition to the detection of anticentromere antibodies.

Fig. 11

a, b Regions affected by fibrosis: a in the limited cutaneous form, b in the diffuse cutaneous form of systemic scleroderma

Diffuse Form of Systemic Scleroderma (Diffuse Cutaneous Systemic Scleroderma, dcSSc)

Diffuse systemic scleroderma (dcSSc) is the faster developing and more severe variant and is often characterized by a centrifugal spread of the skin sclerosis (Fig. 11b). The skin hardening goes beyond the elbows and can also occur in the sequence trunk, face, extremities, usually in the first 1–2 years after the onset of Raynaud’s phenomenon. This often leads to organ involvement of different types (gastrointestinal tract, lung, heart, kidney) at an early stage. Topoisomerase (Scl-70) autoantibodies can be detected in more than half of the patients. Other antibodies, such as those against RNA polymerase III, are associated with an increased risk of kidney involvement or are indicative of paraneoplasia (Hunzelmann et al. 2008a).

A further group of patients can be assigned to the scleroderma overlap syndrome. These patients show major symptoms of systemic scleroderma, such as acrosclerosis, bilateral basal pulmonary fibrosis in combination with symptoms of another non-organ-specific autoimmune disease or a major symptom of such a disease (such as myositis, Sjögren’s syndrome or lupus erythematosus). Antibodies against anti-uriclin 1- ribonucleoprotein (U1-RNP) or polymyositis - scleroderma (PM-Scl) are frequently detected in these patients.

Patients nowadays often present relatively early in the course of the disease without having developed characteristic signs of SSc. Here, it has proven to be useful to describe these patients as having undifferentiated systemic scleroderma. They are characterized by the appearance of Raynaud’s phenomenon, capillary microscopic changes typical of scleroderma, edematous swelling of fingers and hands, and/or SSc-associated antibodies.

Raynaud’s Syndrome

The appearance of Raynaud’s phenomenon is a characteristic early symptom of the disease, which occurs in more than 90% of affected patients and precedes further organ manifestations. It is a vascular spasm caused by cold or emotional stress, especially on the hands, with the typical sequence of the three stages of painful ischemia (white), local cyanosis (blue), and arterial hyperemia (red; tricolor- phenomenon). Raynaud’s phenomenon can be very painful. Cold provocation can be helpful for the reliable detection of Raynaud’s phenomenon. Differentiation from the much more frequent primary Raynaud’s phenomenon without underlying disease allows the detection of antinuclear antibodies and clinically with asymmetric involvement of individual fingers. The capillary microscopic examination of the nail fold is an essential examination in all patients with Raynaud’s phenomenon or suspected SSc. Early changes are the formation of ectasias and megacapillaries with microbleeding as an indication of disease activity. In later stages, a rarefication of the capillaries (avascular areas) can be observed, partly with signs of neovascularization.

Skin Involvement

Skin involvement as the most common manifestation begins at the extremities or in the fingers. Even before the doughy, edematous, slightly red swelling of the fingers, hands (“puffy hands”), and forearms (stadium edematous), Raynaud’s syndrome occurs. Fist closure is increasingly restricted. Involvement of the feet is rare. In the further course, the skin becomes extremely tight, taut, wax-like, and can no longer be lifted into wrinkles (stadium sclerosum). For the determination of the course of the disease the modified Rodnan Skin Score (mRSS) is the best validated parameter to date. It shows a relatively good correlation with organ involvement, especially of the lungs (Fig. 12). The sclerotic shrinkage of the skin limits the mobility of hands and feet: dermatogenic contracture. The fingers become bent into claw-like bending contractures, finally becoming completely immovable. At the fingertips and above the joints, small necroses (digital ulcerations, rat bite necroses [a better expression not used today]), or pits are often found (Fig. 13). Soft tissues and bones are subject to pressure atrophy. In severe cases, the distal phalanges appear pointed (Madonna finger) or mutilated. The nails are remodeled by transverse bulges and transverse stripes.

Fig. 12

Modified Rodnan Skin Score in 17 regions: face, front chest, abdomen, upper arms, forearms, hands, fingers, thighs, lower legs, feet/score 0–3 per region; range 0–51 (0 = normal, 1 = weak, 2 = moderate, 3 = severe skin thickening, sclerosis) (Clements et al. 1995)

Fig. 13

Digital ulcerations, pits

A second major manifestation site of skin involvement for this disease form is the face. It loses its range of expression: sclerodermic amimia. By tightening and sclerosing of the skin, the face is reduced in size. The nose is pointed and covered with a tense reflective skin. The cheeks are wrinkleless, the lips narrow. The mouth has become a reduced rounded opening, opening is more difficult: microstomy (Fig. 14). The mobility of the eyelids is also limited. The forehead is no longer wrinkly, the lips can no longer be pursed for whistling. On palpation, the facial skin is firm and hard, its color is whitish-yellowish pale. Not infrequently, a slowly increasing occurrence of telangiectasias is observed.

Fig. 14

Restricted mouth opening, narrowing of lip redness, telangiectasia, and shortened frenulum of tongue

In diffuse systemic scleroderma, sclerotic hardening of the skin can increasingly spread to the neck, trunk, and proximal limbs. Mobility is increasingly restricted, even breath excursions are limited. The abdominal wall appears stretched, drum-like. Dermatogenic stretch contractures develop on the legs. Finally, the patient is confined in the sclerotic skin as if in a suit of armor.

Further Skin Changes

Atrophy, telangiectasias, spot-shaped to striped hypopigmentation, and/or generalized hyperpigmentation can thus produce the picture of poikiloderma. In the extremities, after small injuries, torpid ulcerations may develop. The skin appendages go into atrophy, involvement of the capillitium leads to sclerodermatous alopecia. In up to 25% of the patients, circumscribed calcium deposits (calcinosis cutis) are observed.

Calcinosis

Subcutaneous, interstitial calcium deposits are not uncommon in SSc. They occur particularly in women (compared with men, at 10:1, they are more frequently affected) at the pointed fingertips, where crumbly chalk masses can empty to the outside. Less frequent are coarse calcium deposits on the hips, above the spine, on elbows, knees, and the insteps. A variant of systemic scleroderma with pronounced calcinosis was described as Thibièrge–Weissenbach Syndrome (1911) (probably the first description (Weber 1878)) the combination of calcinosis, Raynaud’s syndrome with finger ulcerations, sclerodactyly, and telangiectasias (Figs. 15 and 16), also called CRST (calcinosis, Raynaud’s phenomenon, sclerodactyly, and telangiectasia) or with additional esophageal involvement, called CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia; Winterbauer 1964).

Fig. 15

Telangiectasias

Fig. 16

Telangiectasias of the palm of the hand

Mucosal Involvement

Small or large sclerosis and atrophy can be detected on the mucous membrane of the mouth. Often there is sicca syndrome. Perioral fibrosis results in a microstomy. The surface of the tongue becomes atrophic and smooth, the mobility of the tongue is restricted by the sclerotic, shortened tongue frenulum (frenulum sclerosis). Even the genital mucous membrane is not spared.

Further Findings

The heterogeneous clinical pictures and variable disease courses of systemic scleroderma result from the varying degree of involvement of internal organs, which finally determine the prognosis of the individual patient. The most common is esophageal involvement in up to 80% of patients, followed by musculoskeletal involvement and pulmonary fibrosis in about 50% of patients, and cardiac involvement and pulmonary arterial hypertension in 15–20%. A milder impairment of renal function is observed in about 15% of patients. The renal crisis is only detectable in about 2% of patients.

Teeth

Sclerosis and gingival atrophy of the periodontium can have an effect on bones (X-ray) and, due to sicca symptoms, on teeth (caries, tooth loss). Dental treatment can be very difficult because of microstomy.

Digestive Tract

In up to 90% of patients with systemic scleroderma, the digestive tract is also affected. The esophagus is most frequently affected. Symptoms are reflux and dysphagia. Radiological findings are atonic dilatation, loss of peristalsis, mucous membrane atrophy, ulcerations, sometimes sclerotic stenosis in the lower third of the esophagus. Manometrically, a lack of slackening during the swallowing act and cinematographic emptying can be proven. In the stomach, sclerosing can lead to anacidity, smooth mucosal relief with ulcerations, and prepyloric spasms. Also, in the small and large intestine, atonic extensions, constrictions, and dyskinesias can be found to varying extents. Symptoms can range from diarrhea (small intestine bacterial overgrowth) and constipation to paralytic ileus.

Lungs

The extent of pulmonary fibrosis (interstitial lung disease) is of major prognostic importance. Radiological changes consist of ground glass opacification, fibrosis or cyst formation (honeycomb lung) and are found in about 40% of patients, pathological lung function tests in about 70% of patients, and often before the radiologically detectable changes. In autopsies, a higher proportion of pathological changes can still be detected. Symptoms such as dyspnea, cough, and cyanosis often occur only in the advanced stages. The tendency toward bronchopneumonia is then high, especially after food consumption. Pulmonary arterial hypertension is a serious late complication, especially in patients with lcSSc. Typical early signs are increasing exertional dyspnea and symptoms of incipient right heart compensation, such as syncope or peripheral edema.

Heart

Diffuse interstitial myocardial fibrosis develops. The individual muscle fibers are constricted by fibrosis, which prevents diastolic slackening and thus also weakens the contractile force. Heart involvement may also be secondary to pulmonary fibrosis (cor pulmonale), vascular changes, high pressure or a combination of different pathomechanisms. Pericarditis also occurs. ECG changes are found in over 50% of patients. Cardiac arrhythmia such as paroxysmal tachycardia, partial or complete heart block, atrial fibrillation, and finally heart failure are possible clinical symptoms.

Kidneys

Changes are detected by autopsy much more frequently than clinically and consist of fibrosis of the interlobular arteries and arterioles, microinfarctions, atrophy of the tubules, and development of a shrunken kidney. The first clinical sign of kidney involvement is usually proteinuria, followed by creatinine clearance disorders. A serious complication is the renal crisis. Severe malignant hypertension develops acutely, accompanied by increasing kidney failure, which often results in loss of kidney function.

Skeleton

Resorptive osteolysis, osteoporosis, and cystic brightening can be detected radiologically, especially on the distal phalanges of the finger and toe. Arthralgia is not uncommon (25–50%). Radiologically detectable arthritis is observed in about 5% of patients. Tendovaginitis (about 25%) is associated with a severe course and can be detected as palpable tendon friction during movement.

Musculature

Myalgia and muscle weakness, as well as histologically, serologically, and electromyographically detectable myositis, also occur frequently. In these cases, a differential diagnosis of dermatomyositis or SSc overlap syndrome should be considered. Secondarily, pronounced muscular atrophy may develop.

Differential Diagnosis

In pronounced cases, the clinical picture is clear. Diagnostic procedures should strive to determine the extent of the skin disease and to clarify the various organ involvements. In acute onset, dermatomyositis or systemic lupus erythematosus should be considered, as well as overlapping syndromes. The disseminated circumscribed scleroderma must also be distinguished. Exclusion of pseudoscleroderma is important.

Diagnostic Procedure

The following information is recommended for reliable diagnosis and initial work-up: (Hunzelmann et al. 2008b)

• Raynaud’s symptoms

• Capillary microscopy

• ESR/C-reactive protein (CRP), blood count, clinical chemistry

• The clinical picture with distribution of fibrotic changes (extremities, face) including mRSS

• The antinuclear antibodies including SSc-specific autoantibodies

• the various organ-related procedures (high-resolution computed tomography of the chest, lung function test including forced vital capacity (FVC) and diffusing capacity of carbon monoxide for a single breath (DLCOc/SB), electrocardiography (ECG), echocardiography, and upper gastrointestinal endoscopy, as well as basic examinations of renal function)

Annual follow-up examinations

Apart from the patient group with a rapidly progressive course of the disease, which requires a more frequent follow-up, the following annual examinations are recommended for patients with a slower, insidious course, including a thorough history and clinical examination:

ECG, echocardiography to control for pulmonary arterial pressure, lung function to determine FVC/FEV1, including DLCOc/SB, CRP, CBC, clinical chemistry, and protein excretion. Weekly blood pressure self-monitoring in RNA-Pol-positive patients is recommended.

Histopathology

The histological substrate of skin lesions in systemic scleroderma corresponds to that described in circumscribed scleroderma. The sclerosing changes often originate from the connective tissue septum in the subcutaneous fatty tissue.

Laboratory

Apart from the detection of disease-specific and associated circulating antibodies, the laboratory values are not specific and depend on the acuity of the inflammation and the extent of organ involvement:

Signs of Inflammation

Signs of inflammation are detectable during inflammatory relapses: increase in ESR, CRP, dysproteinemia, with hypoalbuminemia, and a relative increase in γ globulins.

Markers of Organ Involvement

An increase in creatine kinase in serum indicates muscle involvement associated with clinical symptoms. Proteinuria is associated with a worse prognosis. Retention of urinary substances is found in the late stage of manifest renal insufficiency. Anemia (25%) often occurs as a result of chronic inflammation, malabsorption, or gastrointestinal bleeding.

Depending on the course of the disease, the internal organs affected by systemic scleroderma should be examined at least once a year.

Immunopathology

Antinuclear autoantibodies (ANAs) are detectable in over 90% of patients with SSc (Table 3). However, the titers show no correlation with clinical activity. Anti-centromere autoantibodies are typical for lcSSc and anti-topoisomerase antibodies for the diffuse form. Recently, several antigens have been precisely identified, and by assigning the corresponding clinical symptoms, circulating antibodies can be used to identify subtypes of systemic scleroderma (Table 3).

Table 3 Frequent antibodies in patients with systemic scleroderma (SSc)

In up to a quarter of patients, antibodies such as Anti-Ro (SSA) and/or Anti-La (SSB) that are not specific for scleroderma are also detected. The detection of rheumatoid factors or cyclic citrullinated peptide antibodies indicates rheumatoid arthritis; anti-mitochondrial antibodies (M coexisting) indicate associated primary biliary cirrhosis.

Course

The course of the disease cannot be assessed with certainty in individual cases, but can be assessed much more favorably with limited scleroderma than with diffuse scleroderma. Overall, the prognosis of the disease has improved significantly. In large studies, a 10-year survival rate of over 80% is reported. Fulminant, strongly inflammatory courses of the diffuse form can, however, end lethally in a few years and are less favorable for men than for women. Often the disease protracts unrelentlessly for 5, 10, 20 or more years without a self-healing tendency. Causes of death are bronchopneumonia, heart, lung or kidney failure, sometimes with malignant hypertension. The disease rarely stops spontaneously. Further annual follow-up examinations are strongly recommended.

Therapy

The oligosymptomatic onset of the disease, the large number of affected organ systems, and the chronic and often severe course of the disease are a particular challenge for the attending physician. Highly qualified specialist care is only possible through the cooperation of experienced specialists, mostly in dermatology and rheumatology, in cooperation with a number of specialist disciplines such as gastroenterology, pulmonary diseases, cardiology, and nephrology. An effective causal therapy is not yet known. For the symptomatic therapy of the different organ participations partly effective therapeutics are available in the meantime (Knobler et al. 2017).

The treatment options are directed against the three essential factors for pathophysiology: vascular involvement, inflammation and fibrosis, as well as symptomatic organ-specific therapy. Recently, the recommendations of the European League Against Rheumatism were published (Kowal-Bielecka et al. 2017).

Systemic Therapy

Systemic therapy includes anti-inflammatory, antifibrotic, and organ-specific approaches.

Anti-inflammatory

The use of glucocorticoids should be restricted, not least because of the association with the occurrence of sclerodermal renal crisis at doses above 15 mg of a prednisolone equivalent. In acute inflammatory changes of the lung, muscle or joint involvement, however, the use of glucocorticoids is often unavoidable. Most immunosuppressants that have been used in the treatment of systemic scleroderma lack good prospective, controlled studies. The best data are available for the use of cyclophosphamide and mycophenolate mofetil, which appear to have a particular effect on lung and skin involvement. Initial data are available on the superiority of stem cell transplantation in patients with a rapidly progressing disease (Sullivan et al. 2018).

Anti-fibrotic

A variety of systemic drugs have been investigated for the treatment of fibrosis. Methotrexate is recommended for milder courses. The best data for rapidly progressive fibrosis with trunk involvement are available for cyclophosphamide and mycophenolate mofetil. A number of observations also support the efficacy of UVA-1 or PUVA therapy in the treatment of early fibrotic changes.

Organ-Specific Therapy

Depending on the organ concerned, various options are available.

With skin involvement protection against cold, injuries, skin care, as well as lymph drainage and physiotherapy, are recommended. Ectopic calcification or calcinosis can be treated surgically or with a CO₂ laser. The partially pronounced telangiectasias, especially in the facial area, are easily accessible for laser treatment.

In the case of digital vasculopathy there is the best evidence for the administration of calcium antagonists in the treatment of Raynaud’s phenomenon. The efficacy of phosphodiesterase 5 inhibitors has also been demonstrated and in severe forms of Raynaud’s phenomenon by intravenous administration of prostacyclin. Intravenous administration of prostacyclin analogs is recommended for the treatment of acute digital ulcerations. If multiple digital ulcerations occur, prophylaxis with the endothelin antagonist bosentan is recommended. A renunciation of nicotine is indispensable.

With gastrointestinal involvement proton pump inhibitors or H2 blockers should be used at an early stage to treat complaints resulting from reflux esophagitis. In this context, appropriate supporting measures such as increasing the headboard height, smoking bans, and smaller meals should also be pointed out.

Lung involvement such as inflammatory alveolitis or active interstitial fibrosis should be treated immunosuppressively, especially with cyclophosphamide or mycophenolate mofetil, in close consultation with the pneumologist. For the treatment of pulmonary arterial hypertension, approved drugs from the group of endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostacyclin analogs or guanylyl cyclase inducers are available.

Within the framework of kidney involvement the renal crisis is feared. It is a medical emergency early use of angiotensin-converting-enzyme inhibitors or sartans represents a decisive therapeutic advance. In cooperation with nephrologists, the use of further vasodilator substances should be considered at an early stage, depending on the clinical course.

5 Pseudoscleroderma

(Jablonska 1975; Fabri and Hunzelmann 2007)

Pseudoscleroderma is a disease that is clinically reminiscent of scleroderma, but which can be classified differently both etiologically and pathogenetically. The most important diseases are listed in Table 4 and described in the respective chapters.

Table 4 Differential diagnosis of scleroderma: pseudoscleroderma

5.1 Nephrogenic Systemic Fibrosis

(Cowper et al. 2000; Girardi et al. 2011)

Synonym

Nephrogenic fibrosing dermopathy

Epidemiology

This disease was first observed in 1997. Further cases were then reported worldwide; after clarification of the mechanism and appropriate precautions, the frequency decreases remarkably.

Etiopathogenesis

The pathogenesis of nephrogenic fibrosing dermopathy is essentially due to a pre-existing, limited renal function in combination with the administration of a gadolinium derivative, in particular gadodiamide. In the patients, there is also histologically verifiable increased storage of gadolinium in the skin, which may have a direct activating function on macrophages or fibroblasts.

Clinical Features

The disease begins with swelling of the extremities, usually leaving out the hands and feet, which turns into fibrosis. Affected skin areas are often characterized by livid areas lying above them. Relatively quickly, within a few months, pronounced contractures of the large joints such as elbows and knees can develop. The face is omitted. Frequently, pronounced itching occurs. During the course of the disease, an involvement of the internal organs is observed. Pulmonary fibrosis and involvement of the diaphragmatic muscles and pulmonary arterioles are typical.

Histology

Nephrogenic systemic fibrosis is a cell-rich fibrosis with a largely absent inflammatory infiltrate. The fibroblastic, partly spindle-like cells, which can also spread to the fascia in strands, are positive for smooth muscle actin and CD34.

Differential Diagnosis

The distinction from systemic scleroderma is simple because of the absence of Raynaud’s phenomenon and autoimmune phenomena. The characteristic histology allows differentiation from scleromyxedema or eosinophilic fasciitis.

Therapy

An effective therapy is not yet known. Positive reports are available on the use of kidney transplantation or tyrosine kinase inhibitors.

5.2 Eosinophilia–Myalgia Syndrome

(Eidson et al. 1990)

A disease clinically very similar to eosinophilic fasciitis, but with pronounced internal manifestations, was identified after the ingestion of L-tryptophan-containing drugs. This leads to systemic fasciitis rich in eosinophils with clear involvement of the skin, muscles, and joints, but also to pneumonia, myocarditis, and encephalopathy. The disease appears to be induced by an as yet unknown contamination of the drug, but even after discontinuation, it regresses only very slowly. The exclusion of eosinophilic myositis, eosinophilic fasciitis, trichinosis, and polyarteritis nodosa is important for differential diagnosis.

5.3 Toxic Oil Syndrome

(Tabuenca 1981)

Toxic oil syndrome, which occurred epidemically in Spain in 1981 and is very similar to SSc, was also characterized by severe myalgia, intensive blood eosinophilia, extensive skin sclerosis, contractures, lung and liver involvement, and encephalopathy. It was induced by toxic chemicals contained in edible oil, probably acetanilide.

6 Lichen Sclerosus et Atrophicus

(Hallopeau 1887; Darier 1892)

Synonyms

Lichen sclerosus ; Lichen albus (Johnston and Sherwell 1903)

Epidemiology

This relatively rare disease has two epidemiological peaks in the female sex: predominantly women in their fifth to sixth decade of life suffer from the disease; more rarely, female infants or children before puberty. The vulva, perineum, and anus are often affected. In adult men, the glans and prepuce are the most common sites of disease. The disease was only exceptionally observed in dark-skinned people. Family occurrences were described sporadically. Transitions or coincidence (also of genital form) with the occurrence of circumscribed scleroderma are increasingly reported.

Etiopathogenesis

The cause of the disease is unknown. It rarely occurs with lichen ruber, vitiligo, lupus erythematosus, or in chronic graft-versus-host reactions, which suggests an autoimmune pathogenesis. Observations that the disease spontaneously improves or heals in girls at puberty suggest hormonal influences.

Clinical Features (Powell 1999)

The lesions can be disseminated or circumscribed. Predilection sites are the sides of the neck, the clavicular region, the area between and below the breasts, the flexor sides of the forearms, the shoulders, and the genitals, especially the vulva, prepuce, and glans penis. Perianal and anal changes are also not uncommon. If disease is suspected, all predilection sites must therefore be examined (Figs. 17, 18, and 19).

Fig. 17

Initial lichen sclerosus et atrophicus

Fig. 18

Lichen sclerosus et atrophicus

Fig. 19

Lichen sclerosus et atrophicus, partially bullous and hemorrhagic

Initial changes in the form of single erythematous papules are observed only in exceptional cases. Typical findings are small, measuring up to about 0.5 cm, porcelain or more bluish white, round or oval atrophic lesions, which remain flat at the skin level and can coalesce to irregularly configured, larger areas (Figs. 17 and 18). Occasionally, they have a pinkish-violet rim. Older lesions show a fine parchment-like pleating of the surface and characteristic comedo-like follicular hyperkeratoses. The epidermis sometimes becomes detached with hemorrhagic blisters (Fig. 19). Stronger induration, itching, or other subjective complaints are usually lacking.

Changes in the mucous membranes are rare and manifest as whitish foci on the cheek or palate mucosa.

The genital changes in the vulva, prepuce, and glans penis similarly consist of whitish atrophic lesions with often marked scarring shrinkage (secondary phimosis, frenulum sclerosis, or synechia). Hemorrhagic blisters that heal with scarring are not uncommon. Clinically, the symptoms correspond to kraurosis vulvae or kraurosis penis.

Balanitis xerotica obliterans has been described as an independent clinical picture with scarring shrinkage of the prepuce, frenulum, glans, and urethral opening, and is associated with lichen sclerosus et atrophicus. If the glans in the vicinity of the urethral orifice is involved, it can lead to stenosis with chronic urinary retention (balloon bladder) (chapter “Diseases of the Male Genitalia”). In girls and women, genital changes can cause severe itching (chapter “Diseases of the Female Genitalia”).

Differential Diagnosis

Disseminated small-spotted circumscribed scleroderma (histologically preserved elastic fibers); furthermore, small-spotted atrophic lichen planus, which should also be distinguished histologically.

Histopathology

Initial thickening and then atrophy of the epidermis with follicular hyperkeratosis develops. Directly below the basement membrane lies a zone with loss of elastic fibers and edematous hyalinized connective tissue. Below this area, a band-like or more perivascular lymphocytic infiltrate can be observed. Massive edema sometimes leads to subepidermal continuity disorder with capillary corrosion and blood leakage (hemorrhagic blistering). Sometimes the lymphatic vessels are dilated. IgG, IgM, IgA, complement factors, and fibrin can accumulate in diseased skin.

Course

The course is chronic, with sometimes intermittent phases of activity. Spontaneous remission is possible at any time, especially in children during puberty. Atrophy usually does not regress. In the case of coincidence with leukoplakia at the vulva or at the penis, the development of a spinocellular carcinoma is possible. Annual follow-up checks are therefore recommended.

Therapy (Kirtschig et al. 2015)

Topical

External application of class III–IV glucocorticoids in the form of creams or ointments is recommended. Glucocorticoids can also be applied under occlusive dressing, condoms or as an injection of crystal suspension (diluted 1:3–1:5 with mepivacaine) intralesionally. In the case of lichen sclerosus of the vulva, estrogen ointments may also be considered. A number of open studies support the use of calcineurin inhibitors (pimecrolimus, tacrolimus). Because of the high relapse rate (80%), a vulvectomy is not indicated.

Systemic

Glucocorticoid therapy, possibly in combination with methotrexate, is rarely indicated, especially as its efficacy is uncertain. Retinoids (acitretin or isotretinoin) may be tried, but require careful consideration of risk and benefit.

Operative

In men with genital involvement, circumcision is recommended in the early stages where there is resistance to therapy. For smaller areas, the use of CO₂ laser ablation may be considered. If the development of a spinocellular carcinoma of the vulva or penis is suspected, a biopsy should be performed.