Prevalenceepidemiology

Systemic scleroderma appears worldwide and affects all races. Women overall are affected approximately three times as often as men and even more often during the late childbearing and early menopausal years. Although, no strong racial predilection has been reported, certain incidence data suggest, that blacks have a higher risk of developing the disease than whites. The annual incidence has been estimated to be between 0.6 and 19 cases

Disease activity score from EUSTAR

Parameter Scorea Evaluation

Modified Rodnan skin

1

Evaluation of skin thickness on a scale from 0 (normal) to 3 (very strong) in 17

score>14

anatomical areas resulting in overall scores between 0 and 51

Scleredema

0.5

Swelling and increase in connective tissue with loss of wrinkles and rete patterns

Skin

2

On being asked, whether the skin manifestations have changed during the last month,

the patient confirms a worsening

Digital ulcers

0.5

Active digital ulcers are present

Vascular

0.5

The patient declares, that his/her perfusion problems have worsened during the last

month

Arthritisb

0.5

Symmetric swelling and hyperesthesia of peripheral joints

DLCOc

0.5

DLCO <80% of the predicted value

Heart/lungs

2

The patient confirms, that his heart-/lung problems have worsened during the last

month

ESR>30

1.5

Westergren-method

Hypocomplementemia

1

Either low C3 or C4 according to any quantitation method

Note: Various parameters are determined including skin score, digital ulcers and parameters reflecting systemic affection. The disease is considered to be active, if the score equals or exceeds 3.

a The disease is considered to be active, if the total score equals or exceeds 3. b Excluding articular or periarticular inflammation caused by subcutaneous crystals. c CO2-diffusion capacity.

Note: Various parameters are determined including skin score, digital ulcers and parameters reflecting systemic affection. The disease is considered to be active, if the score equals or exceeds 3.

a The disease is considered to be active, if the total score equals or exceeds 3. b Excluding articular or periarticular inflammation caused by subcutaneous crystals. c CO2-diffusion capacity.

Table 2

ACR criteria for systemic scleroderma

Table 2

ACR criteria for systemic scleroderma

Major criterion

Minor criteria

Proximal scleroderma

Sclerodactyly

Digital pitting scars

Bibasilar pulmonary fibrosis

Note: Either one major or two minor criteria have to be fulfilled.

Note: Either one major or two minor criteria have to be fulfilled.

per million population. The reported prevalence of SSc is between 19 and 75 per 100,000 persons. The real numbers are probably underestimated, as many patients are diagnosed at very late stages of the disease. The incidence increases with age, peaking in the principal manifestation age, which is between 45 and 55 years (Ioannidis et al., 2005; Mayes et al., 2003; Medsger et al., 1971).

Although SSc is not considered to be an inheritable disorder, an exceptionally high prevalence of SSc (472 per 100,000 persons) has been noted in the Choctaw Native Americans in Oklahoma. An individual also appears to have a higher risk of developing SSc, if it has occurred in a first-degree relative. Attempts to prove associations between certain human leukocyte antigens and the susceptibility to SSc have not lead to strong correlations. Still, the occurrence of anticentromere antibodies has been shown to be associated with HLA-DRp1*0101 and HLA- DQp1*0501. Similar associations have been suggested for the other autoantibodies and antigens, as well.

It has long been discussed that infectious agents may play a role in SSc.

The environment could also have an effect, as gold miners have a higher incidence for SSc, suggesting that silica dust may be a predisposing factor. Other environmental agents involved may include polyvinylchloride, epoxy resins and aromatic hydrocarbons, such as benzine, toluene, and trichloroethylene. Pentazocine and bleomycin have also been considered as putative causes for SSc.

3. Etiology/pathogenesis of skin fibrosis

The etiology of SSc still remains obscure. Certain features like lymphocytic infiltration in the skin, antinuclear antibodies, and the occurrence of overlap syndromes with lupus erythematodes, der-matomyositis or Sjogren's syndrome point toward an autoimmune pathogenesis. Several disease models hypothesize, that genetically predisposed

Table 3

Characteristics of the dSSc lSSc subtypes of systemic scler-oderma

Diffuse cutaneous SSc (dSSc)

Onset of Raynaud's syndrome less than one year before skin changes

Skin changes also affecting trunk and proximal extremities

Tendon friction rubs

Increased incidence of organ damages:

Interstitial pulmonary

Renal insufficiency

Diffuse gastro-intestinal affection

Myocardial complications

No anti-centromeric antibodies Scl-70-autoantibodies

Capillaroscopy: dilatation and destruction of capillaries

Limited cutaneous SSc (lSSc)

Long history (10-15 years) of Raynaud's syndrome

Skin affection distal to elbows and knees only

Risk of pulmonary arterial hypertension and

Trigeminal neuralgias

Subcutaneous calcifications

Teleangiectasias

Often associated with anti-centromere antibodies Capillaroscopy: dilated capillaries

individuals (with certain HLA characteristics) may develop an immune response on contact to external triggers like infectious agents, certain autoantigens, or cell components previously unen-countered by the immune system.

The outstanding feature of SSc is overproduction and accumulation of collagen and other extracellular matrix proteins, including fibronectin, tenascin, and glycosaminoglycans, in skin and other organs. The disease process involves immu-nologic mechanisms, vascular endothelial cell activation and/or injury, and activation of fibroblasts resulting in production of excessive collagen.

Raynaud's phenomenon results from an abnormal regulation of blood flow. It can lead to and accompany vascular injury to endothelial cells and basal lamina involving small arteries, arterioles, and capillaries appearing early in SSc, which precedes fibrosis. Subsequently, the intima thickens, narrowing the lumen, and finally leading to the obliteration of blood vessels.

T cells play a role by secreting granzyme 1, which may stimulate an immune response to the basal lamina. Furthermore, autoantibodies against endothelial cells, AECA, are found to be elevated in a significant number of SSc-patients. They mediate cytotoxic reactions and apoptosis in endo-thelial cells. AECA also stimulates the expression of VCAM-1, ICAM-1, E- and P-selectin, and elevates IL-1 and IL-8 levels, which are all involved in cell adhesion or chemoattraction. They may facilitate the adhesion and diapedesis of mon-ocytes, T- and B cells into the interstitium with consequences for the inflammatory process.

The damage to the vascular endothelium results in lower levels of prostacyclin. Vasoconstriction and platelet aggregation results in the release of PDGF. This in turn acts as a chemotactic factor and mitogen for fibroblasts and smooth-muscle cells. Transforming growth factor (TGF) leads to an elevation of collagen synthesis and acts together with the other cytokines in further promoting in-timal fibrosis.

The vasodilator nitric oxide is diminished in some patients with SSc, suggesting an impairment of its synthesis on endothelial damage. The initial damages caused by tissue hypoxia can be aggravated by reperfusion, which can declench the release of oxygen free radicals. Laminin and type IV collagen have been proposed as possible targets for cell-mediated immunity in the early stages of SSc. The tissue surrounding small blood vessels in the dermis shows high contents of mononuclear and activated helper-inducer T cells.

Another factor possibly involved in the development of skin sclerosis is the vasoconstrictor ET-1. It is a potent pro-fibrotic signalling molecule, which stimulates the synthesis of extracellular matrix. It inhibits the production of matrix-degrading enzymes. ETA- and ETB-receptors transduce these signals. In vitro, ET-1 makes myoblasts differentiate and leads to production of intercellular adhesion molecule-1 by fibroblasts. ET-1 is a promising target for clinical trials as in addition to these biochemical properties its inhibition has been shown to be beneficial for exercise capacity in pulmonary arterial hypertension resulting from

SSc as well as beneficial for the treatment of scleroderma digital ulcers.

Following inflammation with an activation of T cells a number of different factors lead to the induction of fibroblasts in scleroderma. It is assumed that significant numbers of fibroblasts are permanently activated, due in part to autocrine and par-acrine stimulation by TGF-p and connective tissue growth factor (CTGF) and these cells overproduce collagens I and III (Kawakami et al., 1998).

There is also increasing evidence for posttrans-lational modification of the deposited collagen indicating the development of "bone-type" collagen crosslinks in the fibrotic skin of scleroderma (Brinckmann et al., 2001; van der Slot et al., 2003). There, it has been hypothesized that altered collagen crosslinks may result in reduced susceptibility to proteolytic degradation.

TGF-p is considered to be the major factor in the induction of fibrosis (Denton and Abraham, 2001). Its intracellular signalling cascade involving different smad proteins has been elucidated in detail. The TGF-p, receptor and the regulation of smad proteins appear to be interesting target structures for developing novel therapeutic approaches (Simms and Korn, 2002).

4. Clinical manifestations

The first symptoms of SSc are usually puffy fingers and Raynaud's phenomenon, which can be detected in 95% of patients. It appears as recurrent vasoconstriction of small arteries at fingers and toes, sometimes also affecting the tip of the nose (Table 4).

Patients may experience Raynaud's phenomenon for months or even years before they develop skin sclerosis. It is estimated that 10 to 15% of patients experiencing isolated Raynaud's phenomenon will develop a connective tissue disorder, subsequently.

The intermittent hypoperfusion can aggravate and finally lead to the development of digital ulcers. In very severe cases, subsequent gangrene may necessitate amputation. The risk for the development of digital ulcers is especially high during the winter months.

Swelling of fingers and hands appearing early during the disease usually begins distally in the extremities and advances proximally extending to the forearms, feet, lower legs, and face usually not affecting the lower extremities. The edematous stage can last for months or even years. The edema may be accompanied by erythema. After these initial changes, the skin thickens and will show more induration. The speed of disease progression varies greatly between patients.

As mentioned above, two main subsets of clinical manifestations can be distinguished (Sub-commitee for scleroderma criteria of the American Rheumatism Association). In limited SSc, skin sclerosis affects the extremities up to knees or elbows (Fig. 5). In diffuse cutaneous SSc, skin changes are more generalized, also involving proximal extremities, followed by the face and trunk. This process can take months up to years. A

Table 4

The main skin manifestations, how they are detected/quantitated and how they are treated

Symptom Diagnosis Treatment

Skin sclerosis

Raynaud's phenomenon, digital ischemia, digital ulcerations

Teleangiectasias

Calcinoses

Contractures

Modified Rodnan skin score (mRSS) durometer, elastometer 22 MHz dermal ultrasound

Anamnesis, capillaroscopy, angiography, thermoimaging, thermoprovocation

Anamnesis, physical exam, X-ray Mobility testing

UV-therapy, physical exercise, antifibrotic, and immunosuppressive drugs

Warm environment, vasodilators, Ca-inhibitiors, ACE inhibitors, prostaglandin derivatives (iloprost), ET-1-antagonists, vardenafil/sildenafil, paraffin bath exercise Laser

Surgery, CO2- laser

Physical exercise, lymph drainage, paraffin bath exercise, surgery rapid progression of these changes in less than 3 to 4 years poses a greater risk of developing visceral involvement, which can affect the lungs, heart, or kidneys. Interestingly, in diffuse cutaneous SSc, the skin fibrosis can improve after 3 to 5 years of progression, particularly affecting the trunk and proximal extremities. Patients with lSSc usually show a slower progression of skin induration (Fig. 1). Independent of the subset of SSc, distal extremities are affected more severely, in general. In later stages of the disease, the skin may become atrophic. Especially in the extremities, the tethered skin leads to impairment of extension and flexion, resulting in contractures (Fig. 2). A typical complication is ulcer of the fingertips, and the proximal inter-phalangeal joints, eventually with secondary infection. The affected skin may show hyper-pigmentation, which may also occur over superficial blood vessels and tendons. Interspersed maculae of hypo-pigmented skin may become visible in a vitiligo-like appearance predominantly at the scalp and around the hair follicles resulting in a typical "salt-and-pepper" appearance.

The involvement of the face leads to a mask like appearance with loss of wrinkles, microstomia, diminished facial expression and perioral wrinkles perpendicular to the thinned lips.

Increased fibrosis of the skin resulting in itching and eczema may result in a loss of hair follicles and sweat, and sebaceous glands leading to dryness.

1 6 10 years

Figure 1. Approximate course of skin thickening in patients having diffuse cutaneous (dSSc) or limited cutaneous scleroderma (lSSc). During the initial 3 to 5 years in dSSc, skin sclerosis progresses most rapidly. Organ manifestations may develop. In later stages, many investigators report no further progression of skin thickness or even a decrease. Patients with lSSc show a much slower progression and a lower risk for developing systemic affections. Still, pulmonary arterial hypertension may develop in later stages.

1 6 10 years

Figure 1. Approximate course of skin thickening in patients having diffuse cutaneous (dSSc) or limited cutaneous scleroderma (lSSc). During the initial 3 to 5 years in dSSc, skin sclerosis progresses most rapidly. Organ manifestations may develop. In later stages, many investigators report no further progression of skin thickness or even a decrease. Patients with lSSc show a much slower progression and a lower risk for developing systemic affections. Still, pulmonary arterial hypertension may develop in later stages.

Joint Contractures And Scleroderma
Figure 2. Skin sclerosis in the distal upper extremities. The fibrosis can result in joint contractures. Chronic digital ulcerations may necessitate amputations.

Especially patients with the limited cutaneous form of the disease can develop calcific deposits intra- and subcutaneously. They may appear as nodules of considerable size even with pseudotu-morous appearance. They are tightly bound to the skin surface but mobile above the deeper dermal layers. These are present mainly at finger pads, and extensor surfaces of elbows and knees. They can cause complications, reveal their presence by causing local painful inflammations or resolve by drainage of the calcific material after skin damage.

Teleangiectasias, which are usually round-shaped, are frequently encountered over fingers, lips, face, and oral mucosa. Although, patients with limited cutaneous SSc may show these vascular changes more frequently, they can also be observed in diffuse cutaneous SSc-patients (Fig. 3).

Capillaroscopy shows typical changes. Capillaries are enlarged and dilated. Areas of complete loss of capillaries can be found (Cutolo et al., 2004). Patients suffering from Raynaud's phenomenon will not show these changes except for a slightly increased capillary diameter. If the patient complains of dry eyes or dry oral mucosa, this may be due to either periglandular fibrosis or due to an overlap with Sjogren's syndrome. In these Sjogren-patients, SS-A (Ro) or SS-B (La) autoantibodies are found.

The progression of the disease is highly variable and very difficult to predict. If the patient suffers from diffuse cutaneous disease, the first 1 to 3 years will belong to the inflammatory stage. Usually, this is the period, when the skin sclerosis progresses the most. In general, the time following this phase is characterized by a stabilization of the sclerosis or even subjective improvements, as physical therapy and regular exercise will help the patient to maintain or even regain motility. These first 3 years are the most critical for the development of visceral complications.

If in patients with limited SSc skin sclerosis only affects fingers and does not appear proximal to the elbows or knees (except for the face), then progression, most often, is much slower, resulting in a much better prognosis and patients will not experience any significant progression, once a certain level is reached. The probability of developing internal organ complications is by far lower than in dSSc.

Photos Narines Bouchee
Figure 3. Teleangiectasias developing in the course of the disease are most often associated with lSSc.

Prognosis depends on the extent and progression of skin sclerosis. A recent study in the US estimated the average 5-year survival rate at 77%. The appearance of pulmonary, renal, or cardiac complications has a significant impact on both short-term (<5 years) and long-term (>10 years) survival (Mayes et al., 2003). The combination of several risk factors (high skin score, pulmonary affection, inflammatory symptoms, and anaemia) results in higher mortality, which ranges from 2% (no risk factors), 26% (2 risk factors) up to 75% (4 risk factors). If no organ involvement has appeared during the first 6 years after initial symptoms, the patient can be reassured, that the probability of still developing visceral complication is very low, as only 10% of all patients will show a worsening after this time point (Silman, 1991; Mayes, 2003).

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