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The main and nearly universal symptom of SSc is skin sclerosis. Still, in some cases patients with characteristic serologic, visceral, and vascular changes lack skin thickening, which are then termed systemic scleroderma sine scleroderma. Several studies have suggested that the extent and progression of skin sclerosis is associated with mortality and internal organ involvement (Clements et al., 2000; Steen and Medsger, 2001).

The most widely used assessment method for skin involvement is the modified Rodnan skin score (Figs. 4 and 5). The initial approach (Rodnan et al., 1979) used a 5-degree scale measured at 20 areas leading to a maximum score of 100. In order to minimize inter-observer variability and increase re-producibility, this system has been subject to constant improvements. Areas that are involved less frequently (e.g. back) are not examined separately. The accuracy and sensitivity to change can be increased, when the investigator follows clear practical guidelines. There has been a recent tendency toward a focus on measuring skin thickness rather than mobility or tethering leading to lower scores, especially in the later stages of the disease, when the skin often becomes very thin and more difficult to lift from the subcutaneous tissue giving a hardened impression. The investigator has to make sure, that this score is not influenced by contributions from edema or inflammation, as they may alter the appearance of the skin without increasing its thickness, which is the crucial parameter to be examined. The body surface is subdivided into 17 areas. It is squeezed between two fingers and the degree of thickness is given scores from 0 (no detectable thickening), 1 (questionable alteration of skin thickness), 2 (clearly detectable skin thickness) to 3 (strong thickening). The total skin score then reflects the sum of all areas. If investigators compare their scoring method regularly at workshops, a variation below 15% can be achieved. When assessing the patient's anatomical areas, the following details should be considered:

In the face the area between the os zygomaticum and lower mandible is to be measured. The forehead should not be evaluated. When checking the fingers, hands, and feet, only the dorsum is

Systemic Sclerosis Mouse Skin Score

Total Score:

17 Regions = face, chest, abdomen, proximal arms, distal arms, hands, fingers, proximal legs, distal legs, feet Score 0 - 3 per region ^ range = 0 - 51 (0 = normal, 1 = weak, 2 = intermediate, 3 = severe skin thickening, sclerosis)

reference: Clements Ph, Lachenbruch P, Siebold J. et al. Inter- and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol 1995; 22: 1281-5

Total Score:

17 Regions = face, chest, abdomen, proximal arms, distal arms, hands, fingers, proximal legs, distal legs, feet Score 0 - 3 per region ^ range = 0 - 51 (0 = normal, 1 = weak, 2 = intermediate, 3 = severe skin thickening, sclerosis)

reference: Clements Ph, Lachenbruch P, Siebold J. et al. Inter- and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol 1995; 22: 1281-5

Figure 4. Skin scoring using the modified Rodnan skin score. The whole body surface is divided into 17 areas. In each area, the skin score ranging from 0 (no thickening) to 3 (very strong sclerosis) is determined. In large areas, the score is averaged to reflect the accurate skin state. The total score ranges from 0 to 51.

T.M. Olski et al. Extend of Skin Sclerosis in ISSc and dSSc limited systemic scleroderma

y U

diffuse systemic scleroderma diffuse systemic scleroderma

Modified Rodnan Skin Score
Figure 5. Differences in extent of skin affection in lSSc and dSSc. In lSSc is limited to the areas distal to the elbows and knees. In diffuse scleroderma (dSSc) no such limitation is observed.

examined. The palmar aspect of the fingers and the skin distal to the distal interphalangeal joint should not be measured. The extremities should be relaxed during examination and an average score is calculated over the whole area. During thorax and abdomen scoring, the patient sits upright (Akesson et al., 2003; Valentini et al., 2001).

It takes less than 10 min to acquire the data for the modified Rodnan skin score. It has been shown to be a reliable, accurate, and reproducible method of assessing the patient's skin and can be used for follow-up tests (Black, 1995; Seibold, 2001; Clements et al., 1995).

Still, clinical experience has shown, that some investigators tend to "maximize" scores. It turns out to be most appropriate to score an average over a certain area, which then reflects the area score most exactly.

Furthermore, some disadvantages have been discussed for the use of the Rodnan skin score (Herrick et al., 2001), as despite very thorough investigations, it may appear difficult to distinguish between inflammatory, edematous, and fibrotic processes. Still, the score was shown to correlate with the weight of biopsy specimen (Furst et al., 1998), indicating, that it reflects the underlying disease process.

Some data suggest a higher variability (Pope et al., 1995) than previously reported (Clements et al., 1993), which has made many scientists look for other more accurate methods.

Various approaches have been proposed, one of them using a skin durometer, which determines hardness and deformability of substances (Romanelli and Falanga, 1993; Aghassi et al., 1995; Seyger et al., 1997). Similar good results were obtained with an elastometer/cutometer (Balbir-Gurman et al., 2002; Enomoto et al., 1996; Ishikawa and Tamura, 1996; Ballou et al., 1990.), which applies a vacuum and measures deformation. Various other devices have been tried. Some measure torsional stiffness (Knight et al.,

2001) or resistance to squeezing with a ''plicome-ter'' (Nives Parodi et al., 1997). Levels of intra- as well as interobserver variability were low enough to call these methods promising for trials to come.

Even more sophisticated devices (Takei et al., 2004) use a tactile skin sensor, which consists of a piezoelectric vibrator with vibration detector. It measures frequency when placed on the skin. All these proposals although appearing as good complements to the classical scoring, still await evaluation.

The use of 22 MHz dermal ultrasound at 17 predefined anatomical locations was proposed (Moore et al., 2003). Previous investigators have reported a correlation between echogenicity and protein composition in the examined areas (Hesselstrand et al.,

2002). The ultrasound approach has been shown to provide reproducible data and appears to suit the prerequisites as a follow-up tool for clinical trials (Akesson et al., 2004).

The investigator should also check for the presence of tendon friction rubs, which appear as a ''leathery crepitus'' while the joint is moved.

As joint contractures may result from sclero-derma, there have been attempts to quantitate the mobility impairment faced by the patient (Sandqvist and Eklund, 2000a and b).

For the correct diagnosis of Raynaud's phenomenon, a detailed history of the patient's symptoms is crucial. The rare occurrence of ''cold fingers'' is not reliable enough to confirm the diagnosis. A discoloration on mental, thermal (cold), or sometimes physical stress has to be observed (Fig. 7). Typically, the patient will tell about pain and a ''whitening'' of his/her distal phalanges immediately after exposure to cold temperatures. For further confirmation, a Raynaud's provocation test, can be performed. The use of thermography has also been described (Schuhfried et al., 2000), in particular, when alternative diagnoses as e.g. scleredema adultorum, scleromyxedema, neph-rogenic fibrosing dermopathy are discussed.

5.1. Histology

A skin biopsy is often recommended and can be helpful in confirming the diagnosis. Compact parallel collagen bundles are visible beneath a thin epidermis. The collagen deposition is not limited to this layer as fiber projections are found in the subcutis and the underlying tissue. Fibrosis can be so extensive that the rete pattern is lost and hair follicles become atrophic. The small blood vessels are typically surrounded by mononuclear cells and the deeper dermal areas show increased numbers of plasma cells, T cells, mast cells, and monocytes.

Histology does not offer specific alterations distinguishing between lSSc or dSSc. However, it allows to detect the presence of inflammatory infiltrates and could therefore be helpful to identify patients, in which anti-inflammatory therapy may be started.

Biopsies over a longer period of time could also be used for a better quantification of the development of fibrosis and are helpful for following diverse cohorts in clinical trials.

6. Differential diagnosis

Diffuse fasciitis with eosinophilia, Shulman's syndrome or eosinophilic fasciitis consist of deeply indurated skin and subcutaneous tissue. It usually appears on the extremities and is associated with initial peripheral eosinophilia, hyper-gammaglobulinemia and elevated sedimentation rate. No Raynaud's phenomenon, autoantibodies or acral scleroderma are detected. Eosinophilic fasciitis lacks all other systemic complications present in SSc (Table 5). It is considered to be a

Table 5

Most important differential diagnoses of SSc and their main characteristics

Disease

Diagnosis

Overlap syndromes MCTD

Graft-versus-host disease

Paraneoplastic scleroderma

Morphea, linear scleroderma, en coup de sabre

Eosinophilic fasciitis

Scleromyxedema

Scleredema (scleredema adultorum Buschke) Eosinophilia-myalgia syndrome (EMS) Other environmentally induced scleroderma (epoxy hydrocarbons, bleomycin, vinyl chloride, etc.) Scleroderma secondary to amyloidosis, diabetes, etc.

Accompanying symptoms in addition to SSc U1-RNP-antibody

Raynaud's symptom may be present, no anti-topoisomerase or anticentromere autoantibodies, patient's history Typically mainly involving lower extremities

Appearance of plaques, no autoantibodies, localized scleroderma only

Initial eosinophilia, no Raynaud's, no ANA's, typical clinical symptoms

Gylcosamionglycane deposits, affects the face and backside of hands, sometimes light chain gammopathy

Typical clinical symptoms, hands and feet are spared

Initial pruritus, associated with L-tryptophan ingestion, no sclerodactily

Patient's history, typical pattern of affection

Typical pattern of skin affection, biopsy subset of localized scleroderma and can be often treated successfully with systemic corticosteroids. In severe cases, joint contractures and immobilizations have been reported.

The Eosinophilia-myalgia syndrome (EMS) begins with pruritus, cutaneous lesions, scleroderma-like changes, arthralgias and edema. The eosinophilic blood count is elevated. As 96% of all cases have been associated with L-tryptophan consumption, this agent is considered to be the declenching factor. In contrast to SSc, skin sclerosis will not affect digits. The pruritus, the proximal muscle weakness and occasional urticaria are distinguishing features.

Scleromyxedema is a rare disorder characterized by the sclerodermiform and papulous skin changes appearing at the distal extremities, behind the hands and the face. It can be distinguished histo-logically by the presence of glycosamionoglycane deposits found in the specimen. The infiltrate consists mainly of fibroblasts. A monoclonal IgG light chain l gammopathy may also be present.

Sclerodermiform changes have also been described in the course of amyloidoses, mast-ocytoses, Werner's syndrome or diabetes mellitus.

The clinical appearance of graft-versus-host disease especially after bone marrow transplantation can be similar, so that skin stiffening, Raynaud's phenomenon, a characteristic histology, antinuclear antibodies or an elevation of soluble IL-2-receptor can be detected.

Localized forms like linear scleroderma and morphea can usually be distinguished clinically. The most frequent ones are the plaque-type skin changes, which will normally begin with an ery-thematous macule extending excentrically. The center will eventually show depigmentation and become sclerotic. The periphery will still be present with a so-called "lilac ring'', which will give evidence of the ongoing inflammatory process. After variable time spans, the plaque will stabilize or even show remission often leaving some residual atrophy or pigmentation. The number and extent of plaques varies greatly between individuals. In some cases they may extend significantly and lead to mobility impairments, although no organ affection will ever accompany this disorder (Fig. 6).

Scleredema (scleredema adultorum of Buschke) may be associated with the previous streptococcal infections and is usually self-limited, resolving in 6 to 12 months. Histology reveals accumulation of mucopolysaccharides in the dermis and skeletal muscles. Typically, a painless induration occurs in the face, neck, and proximal extremities. Hands and feet are spared.

Scleroderma can occur as a paraneoplastic phenomenon. It may sometimes be hard to distinguish from the ordinary SSc, as Raynaud's phenomenon and autoantibodies have been described. But, a more severe affection of the lower extremities, the sparing of fingers, the patient's history, progression

Linear Scleroderma Hands
Figure 6. Localized scleroderma is a differential diagnosis of SSc. It can appear in a plaque or linear configuration ("en coup de sabre'' as shown). Usually, no autoantibodies are found and it can be distinguished from systemic scleroderma by its typical appearance.

speed, and accompanying symptoms may lead to the suspicion of an underlying tumor.

Patients with insulin-dependent diabetes mell-itus may develop digital sclerosis and contractures (prayer hand deformity). Primary amyloidosis and amyloidosis associated with multiple myeloma may involve the skin of the extremities and face diffusely to give the appearance of scleroderma. Biopsy will clearly differentiate these entities. Chemically induced forms have to be considered as well. Vinyl chloride, pentazocine, bleomycin, and epoxy carbons may cause similar changes. The aberrant pattern of skin affection, serology will help finding the cause, in addition to the crucial history taking of the patient.

In patients with acute or chronic renal failure, the acute onset of induration involving the upper and lower limbs may herald a nephrogenic fibro-sing dermopathy (Swartz et al., 2003). No effective treatment has been found, yet. No histocompati-bility antigens or laboratory abnormalities were shown to be consistently associated with this condition. Histology detected the presence of smooth muscle actin-positive myofibroblasts.

7. Treatment

It appears almost impossible to cure the underlying disease process of SSc, however considerable progress has been made to provide symptomatic organ specific therapy (Genth, 2001).

As patients show major differences in the course of the disease, it appears extremely difficult to evaluate the effectiveness of pharmaceutical interventions in SSc. Although, various treatments have been tried in the treatment of scleroderma, none of them has shown proven clinical benefit. D-penicillamine has been, initially, observed to have a positive effect on skin thickness in uncontrolled studies. But the results of a double-blind randomized trial (Clements et al., 2004), which compared high-dose D-penicillamine (750 to 1000mg/day) with low-dose D-penicillamine (125 mg/day) in patients with early diffuse SSc, have shown no significant difference for skin thickening, the occurrence of organ involvement or mortality between the two dosages. Patients in the early rapidly progressive inflammatory stage are still treated by a significant number of physicians with certain immunosuppressants like azathioprin (Dheda et al., 2004), methotrexate (Pope et al., 2001; van den Hoogen et al., 1996), cyclosporine A (Basso et al., 2001; Roch et al, 2004), cyclophosph-amide (Airo et al., 2004) or others, although no controlled studies exist proving their effectiveness. Colchicine, ^-aminobenzoic acid, vitamin E and human relaxin belong to the drugs, which despite initial optimism still lack the proof of their effectiveness. Prednisone has been used for reduction of edema appearing in the early phase. Otherwise, glucocorticoids are not indicated in the long-term treatment even less as high dose glucocorticoid application has been suggested to play a role in precipitating renal crisis (Steen and Medgser, 1998; Pai et al., 1995; Sharada et al., 1994).

Promising new treatments like interferon or ex-tracorporeal photochemotherapy have been used for some patients. So far, no therapy has shown a clear suppression or even reversal of the disease process in a controlled, prospective study.

High-dose immunosuppression followed by au-tologous stem cell transplantation is an innovative approach currently under examination in a Europe-wide trial, which aims mainly at patients with a rapid onset of cutaneous disease and show internal organ involvement very early (Binks et al., 2001).

To improve mobility and comfort in daily life, various physical therapies have been proven to be effective. Regular physical exercise training should focus on improving joint extension to prevent contractures. The positive influence of specific physical exercise has been shown even for individual joints resulting in gain of function and improved life-quality (Pizzo et al., 2003). Specialized massages improving lymph drainage can be helpful as well. Hand exercise against a resistant substance using a warm paraffin bath helps in increasing joint motility as well as peripheral blood flow. Clinical trial data supports its effectiveness (Sandqvist et al., 2004). Innovative approaches enlarge the spectrum of physical therapy by co-applying vibration (Klyscz et al., 1999).

Among the first and most effective measures to be taken are skin care as dryness of the skin should be reduced by avoiding detergent soaps and by application of bath oils. Fingertip ulcerations may heal faster with the use of hydrocolloid membranes. They should be kept clean, which may require intermittent debridement.

Besides all medical or physical approaches, it is indispensable, that the patient him/herself avoids harmful environmental influences. Cold places should be avoided and nicotine consumption is known to worsen digital perfusion even leading to digital ulcers in patients, who without smoking would have been spared from this complication.

The frequently used calcium channel blockers nifedipine and amlodipine have been proven very effective in alleviating Raynaud's symptoms but show side effects like light-headedness and palpitations. ACE inhibitors as well as angiotensin receptor blockers have been shown to be effective.

Raynauds Ulcers
Figure 7. Severe Raynaud's symptoms and chronic digital ischemia can lead to the development of ulcerations. The use of vasodilators has been very effective in treatment of these complications.

The frequency and severity of Raynaud's attacks can be significantly reduced and the healing of digital ulcers is increased by using the prostacyclin analogue iloprost intravenously (Bettoni et al., 2002). A double-blind study on the use of the end-othelin receptor antagonist bosentan is under way.

Any diagnosis of severe Raynaud's phenomenon should explicitly include the possibility of a primary vascular occlusion, which after having been revealed by angiography should be treated by rev-ascularization or digital sympathectomy by vascular surgeons. Digital ulcers may become more and more severe, leading to gangrene and requiring surgical amputation (Fig. 7).

Surgical correction of contractures can bring substantial improvement in the ability to perform everyday tasks (Bogoch and Gross, 2005). Still, there is the risk of developing postoperative digital ulcers secondary to vascular changes and surgical wounds. Correction of severe microsurgical revascularization of the hand and digital arterial reconstruction may improve digital vascular perfusion, heal digital ulcers, and relieve pain. Peripheral sympathectomy may alleviate severe ischemic pain. Subcutaneous calcifications can be removed with a carbon dioxide laser or a highspeed burr (Chamberlain and Walker, 2003).

Teleangiectasias can be treated with different (585 nm, KTP) lasers (Ciatti et al., 1996), as well.

UV therapy is becoming more and more important, when dealing with skin fibrosis.

UVA irradiation can increase the expression, synthesis and activation of metalloproteinases enhancing turnover of the extracellular matrix.

It can be applied in different dosages ranging from 20 (300J/cm2 cumulative dose) up to 130 J/ cm2 (up to 1800 J/cm2 cumulative dose).

The first hints for the benefit of UV therapy came from the treatment of localized scleroderma (Hunzelmann et al., 1998; Kerscher et al., 1994; El-Mofty et al., 2004).

In an uncontrolled study, low-dose UVA1 phototherapy has been reported to have a benefit in acrosclerosis (von Kobyletzki et al., 2000). The dosage used was 30 J/cm2 UVA1 for a total of 50 sessions resulting in a cumulative dose of 1500 J/ cm2. Other studies were able to confirm a positive effect (Morita et al., 2000; El-Mofty et al., 2004).

As mentioned above, considerable progress has been made to improve organ specific therapy. This includes the management of pulmonary arterial hypertension, lung fibrosis, and renal crisis.

Organ specific therapy, however, also requires a continuous follow-up of the patient and an early diagnosis of organ involvment. The methods required for such early diagnostic procedures have been continuously improved and allow for a much better management of the disease (Sule and Wigley, 2003; Wigley and Sule, 2001).

Key points

• Systemic scleroderma (SSc) manifests clinically by initial edematous skin changes and Raynaud's phenomenon followed by a sclerotic or indurative phase and an atrophic phase. Further complications may include the appearance of digital ulcers, hyperpigmentation, microstomia, joint contractures, teleangiectasias, the development of calcific deposits intra- and subcutaneously and the affection of internal organs.

• Two subtypes of the disease are usually distinguished (LeRoy et al., 1988). In patients suffering from limited cutaneous scleroderma, skin thickening is limited to distal extremities and the face. In diffuse cutaneous scleroderma, the patient rapidly develops a symmetric skin thickening of extremities, the face and trunk.

• Several disorders have to be distinguished from systemic scleroderma as they may cause similar skin changes, like eosinophilic fasciitis, localized scleroderma, scleromyxedema, amyloidoses, mastocytoses, Werner's syndrome or diabetes mellitus, graft-versus-host disease, scleredema or forms chemically induced by vinyl chloride, pentazocine, bleomycin or epoxy carbons.

• The most widely used assessment method for skin involvement is the modified Rodnan skin score, but there have been attempts to obtain more reproducible measures using technical devices like skin durometers or 22 MHz dermal ultrasound.

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Handbook of Systemic Autoimmune Diseases, Volume 5 The Skin in Systemic Autoimmune Diseases

Piercarlo Sarzi-Puttini, Andrea Doria, Giampiero Girolomoni and Annegret Kuhn, editors

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