Chapter 157. Scleroderma

Systemic sclerosis (SSc) is a rare, multisystem disease, based on autoimmunological processes, vascular endothelial cell injury and an extensive activation of fibroblasts. It is characterized by a large individual variability in the extent of skin and organ involvement, as well as in disease progression and prognosis. The skin, esophagus, lung, heart and kidneys are the most frequently affected organs.

Women are more frequently affected by SSc, with a female-to-male ratio between 3:1 up to 14:1.1–4 The age of disease onset ranges between 30 and 50 years.4 However, male patients have earlier onset than female patients. Blacks with SSc are frequently younger than whites. Published data about incidence rates increased from 0.6 to 16 patients per million inhabitants, which is also true for the prevalence rates, which rose from 2 to 233 patients per million inhabitants per year,1–3,5 depending on methodological differences in case definition and ascertainment as well as the investigated time period.

SSc has the highest case-specific mortality of any of the autoimmune rheumatic diseases, but it varies individually depending on racial or ethnic differences, presence and severity of organ involvement, SSc subsets, age at diagnosis and gender differences. Although not curable, there have been substantial advances in treatment options for organ-based complications of SSc.

The pathogenesis of this complex disease involves multiple cell types (endothelial cells, epithelial cells, fibroblasts, and lymphocytic cells) interacting through a variety of mechanisms that are dependent on their microenvironment and key mediators.

Major facets of the disease include inflammation, vasculature, and connective tissue-producing cells. The clinical heterogeneity of SSc makes it likely that distinct pathogenetic mechanisms predominate in particular patients or subsets of disease. Similarly, it is likely that the mechanisms are not the same at different stages of SSc. Although a genetic component to etiopathogenesis is likely and evidence supports genetic factors in severity and susceptibility, there is also strong evidence supporting environmental and chemical factors as triggers for the disease.

Genetic Factors

The best evidence for a genetic contribution to SSc comes from studies that report familial clustering and from the limited twin studies that have been undertaken. Although the absolute risk for familial occurring SSc is relative low, the relative risk for first-degree relatives is 13-fold higher compared to the normal population.6 Several studies suggest that a positive family history for SSc is the strongest risk factor, but ethnicity also contributes.6 Assassi et al suggest that members of SSc-affected families tend to show concordant scleroderma-specific autoantibodies.7 Studies of the whole-genome microarray expression studies of skin biopsies and circulating blood cells support the involvement of multiple and complex pathways in the development of SSc.6 Further support is provided from genetic association studies with candidate gene approaches. Most success has been observed in genetic analysis of individual components of the disease such as autoantibody profiles. These appear to have a strong genetic determinant, and this may underlie the apparent mutual exclusivity of the SSc hallmark reactivities. It has been demonstrated that the ability to mount an immune response to a particular SSc-associated antigen is restricted by major histocompatibility complex haplotype. Several studies suggest an association of HLA-DRB1*1302, DQB1*0604/0605 haplotypes with antifibrillarin positive patients,8 while HLA SRB1*0301 occurs in patients with anti-Pm-Scl antibodies.9 Observation from a large number of studies examining genetic markers has identified a number of candidate genes (AIF-1, CD19, CD22, CD86, CTLA-4, CCL-2, CCl-5, CXCL-8, CXCR-2, IL-1α, IL-1β, IL-2, IL-10, IL-13, MIF, PTPN22, TNF-α).6,10 However, as with other complex diseases, in very many instances, it has not always possible to replicate initially promising data. Studies of genetically homogeneous populations have been especially informative, including those of the Choctaw nation of Native Americans. However, it is of interest that some of the associations are very plausible in terms of molecular pathogenesis. It is likely that epistasis and the effect of multiple modifier genes confound simple genetic association studies in SSc, just as in other complex diseases.11

Immune Events

There is substantial evidence of inflammatory changes in the skin and lung of patients with SSc. One example is the presence of highly specific hallmark autoantibodies, which are summarized in Table 157-1. The first inflammatory infiltrates in lesional skin are predominantly cells of the monocyte lineage13 (T cells, macrophages, B cells, and mast cells). Later, T lymphocytes predominate and are detectable in both the circulation and affected organs. These T cells are predominantly CD4+, bear markers of activation, exhibit oligocloncal expansion, suggesting an antigen-driven proliferation, and show a predominant Th2-helper phenotype.14,15 Consequently, increased serum levels of Th2 cell-derived cytokines, i.e., IL-2, IL-4, IL-10, IL-13, and IL-17, have been observed in scleroderma patients.16,17 Besides T cells, B cells are also found in involved skin. Several studies suggest that B cells are able to induce extracellular matrix (ECM) production through secretion of IL-6 and transforming growth factor-β (TGF-β) and are involved in the production of autoantibodies.

Several of these autoantibodies are associated with defined subsets of the disease and are important diagnostic markers (see Table 157-1). The potential role of autoantibodies in pathogenesis is a fascinating and exciting area. The majority of SSc cases have circulating antibodies. These include a number of hallmark reactivities, as well as autoantibodies, that occur in other autoimmune rheumatic diseases (e.g., anticyclic citrullinated peptide, rheumatoid factor) but also antibodies that may have functional significance, since they are directed against cell surface antigens [antiendothelial cell antibodies (AECA), antifibrillin antibodies, anti-PDGF receptor antibodies, etc.]. However, functional impact of these antibodies remains an area of investigation. The best evidence of functional significance is for antiendothelial cell autoantibodies and for antifibroblast-reacting antibodies. Recent reports suggest the presence of antifibrillin autoantibodies and stimulatory autoantibodies reacting with platelet-derived growth factor (PDGF) receptors, although this observation requires further confirmation.

Microchimerism and graft-versus-host disease mechanisms have been suggested in some cases, although the relatively high frequency of microchimerism in healthy individuals or other disease states suggests that this may be contributory rather than causal if it has a role in SSc.

Vasculopathy

Vasculopathy in SSc is based on inappropriate vascular remodeling and repair processes. It involves the microcirculation and arterioles and is very likely a primary event in the pathogenetic processes of the disease and precedes fibrosis. Vascular abnormalities are characterized by vasoconstriction, adventitial and intimal proliferation, inflammation, and thrombosis.18 The earliest signs of vascular dysfunction are represented by enhanced vascular permeability with an imbalance between vasodilatory (NO, prostacyclin, calcitonin gene-related peptide) and vasoconstrictive mediators [endothelin 1 (ET 1), angiotensin II, α2-adrenoreceptors]. Consequently, the impaired blood-flow leads to tissue hypoxia, which induces strong expression of vascular endothelial growth factor (VEGF) and its receptors, associated with a defect of vasculogenesis. However, inflammatory cytokines like TNF-α may stimulate or inhibit angiogenesis depending on the duration of the stimulus.19

In addition to these functional abnormalities, intravascular and structural changes contribute to overt Raynaud phenomenon (RP), and in the course of time to progressive reduction of vessels and blood flow. These vasculopathies clinically manifest in all vessels of virtually all organs. Early lesions in the microcirculation because of structural damage are initially seen in the nail fold capillaries and as vasospastic responses in RP. Furthermore, vascular changes, i.e., overgrowth of the endothelium and deposition of scar tissue produce some of the major complications of SSc, including pulmonary arterial hypertension (PAH), scleroderma renal crisis (SRC), and digital vasculopathy.

Fibrosis

SSc is a multisystem fibrotic disease. The initial inflammation and hypoxia in fibroblasts induces the production of several proteins that are involved in ECM remodeling as, for example, thrombospondin 1, fibronectin 1, lysylhydroxylase-2, TGF-β-induced proteins.20 Deposition of excessive ECM in specialized organs is responsible for much of the morbidity and mortality of the disease. Fibrous connective tissue is deposited by activated fibroblasts and myofibroblasts. From an early stage in the disease, an autonomous population of fibroblasts appears to be established that are responsible for the excessive production and accumulation of ECM. The initiators of this process include a number of key cytokines and growth factors that may represent logical therapeutic targets. The key factor seems to be a disturbed balance between synthetic and degradative mechanisms. Quiescent fibroblasts may be activated by TGF-β, connective tissue growth factor (CTGF), PDGF, or ET-1.21–24 There is increasing evidence that fibroblasts are induced to differentiate into myofibroblasts, which are characterized by a high contractility, ECM production, and cytokine release. Together with altered biophysical properties of the resulting connective tissue this leads to persistent activation of fibroblasts leading to the excessive deposition of ECM components.

A schematic summarizing pathogenetic mechanisms is shown in Fig. 157-1.

Environmental Factors

Scleroderma-like syndromes have been reported in association with numerous environmental toxins and drugs. These agents include solvents (vinyl chloride, benzene, toluene, epoxy resins), drugs (bleomycin, cardiopa, pentazocine, cocaine, docetaxel, metaphenylenediamine), and miscellaneous substances.25

SSc was reported to occur in underground coal and gold miners. In male patients with silicosis who were older than 40 years of age, the likelihood of developing SSc was approximately 190 times greater than in males not exposed to silica, and 50 times greater than in males without silicosis but exposed to silica dust.26 The role of silicone gel implants and other silicone products in the development of scleroderma has been questioned.27 However, most epidemiologic studies have failed to show a significant association. An unusual form of scleroderma characterized by RP, morphea-like skin changes, capillary abnormalities of the nail fold (similar to those in SSc), osteolysis of the distal phalanges, and hepatic and pulmonary fibrosis (PF) may occur in workers exposed to polyvinyl chloride. Bleomycin also produces PF, RP, and cutaneous changes indistinguishable from those of SSc.27 The development of these changes appears to be dose-dependent and is reversible on discontinuation of the drug. Collectively, chemical exposures account for a small fraction of scleroderma-like diseases. Large epidemiologic studies have not yet revealed a significant role for toxins and drugs in scleroderma.

The clinical manifestations of SSc depend to a large extent on the subset and stage of disease. The clinical features of established SSc are diverse, include severe fibrosis of the skin with all additional cutaneous manifestations and reflect the multiple patterns of internal organ involvement and the consequences of progression of the underlying pathologic processes of vasculopathy, inflammation, and fibrosis. Particular consideration must be given to the hallmark complications of hypertensive SRC, PAH, PF, and gastrointestinal (GI) dysmotility.

Classification and Definition of Different SSC Subsets

The heterogeneity of SSc arises from the range of disease manifestations that vary in extent and severity of organ involvement between patients. However, some clinical features that are almost always present are RP and skin sclerosis. The extent of skin sclerosis defines each major disease subset. Each subset has particular features, although there are common features to each.

The American College of Rheumatology (ACR) published in 1980 preliminary classification criteria for SSc to classify patients with established disease,28 showing 97% sensitivity and 98% specificity for SSc. The diagnosis is proven, if either one major criterion or at least two or more minor criteria are found. As major criterion are chosen scleroderma proximal to the metacarpophalangeal or metatarsophalangeal joints, and the minor criteria included sclerodactyly, digital ulcerations and/or pitting digital scars, and bibasilar PF.

Furthermore, in 1988 a descriptive subclassification of limited versus diffuse SSc by LeRoy,29 which was primarily associated with the extent of cutaneous involvement, has been widely accepted and used in clinical practice. In 2001, LeRoy and Medsger30 published amended criteria, with the additional presence of autoantibodies and nail fold capillaroscopic alterations. Furthermore, these criteria include a separate group of patients with early onset of SSc, with minimal skin thickening. It was mandatory that patients with early (limited) SSc have evidence of RP plus scleroderma-specific autoantibodies and/or nail fold capillaroscopic manifestations.31,32 However, there are several other classifications published, for example, by Nadashkevich O et al, Maricq and Valter, etc.32,33

Diffuse cutaneous SSc (dcSSc) is defined as a progressive form with an early onset of RP, usually within 1 year of onset of skin thickening. This subset is characterized by rapid skin involvement of trunk, face, upper arms, and thighs, showing very frequently, anti-Scl 70 (antitopoisomerase-I) or anti-RNAPIII antibodies.29 Furthermore, there is a higher propensity to develop PF, cardiac involvement, and SRC.

Limited cutaneous SSc is characterized by a long preexisting history of RP and skin changes of the extremities distal to the knee and elbow joints, including facial skin.29 This variant of SSc-subset often (50%–70%) presents with anticentromere-antibodies (ACA) and is frequently associated with isolated PAH. The traditional acronym CREST (calcinosis, RP, esophageal dysmotility, sclerodactyly, and telangiectasias) is nowadays obsolete and assigned to the limited form of SSc.

Patients with features of scleroderma together with those of another autoimmune rheumatic disease are combined; are designated overlap syndromes. This is defined as a disease occurring with clinical aspects of SSc (according to the ACR-criteria) or main symptoms of SSc simultaneously with those of other connective tissue diseases or other autoimmune diseases such as dermatomyositis, Sjögren's syndrome, systemic lupus erythematosus, vasculitis, or polyarthritis. These patients present mostly high titers of anti-U1-RNP-, anti-nRNP-, antifibrillarin-, or anti-PmScl-antibodies.34

Patients suffering from early SSc, also known as undifferentiated SSc, are defined by positive RP and at least one further feature of SSc (positive nail fold capillary alterations, puffy fingers, pulmonary hypertension) and/or detectable scleroderma-associated autoantibodies without fulfilling the ACR-criteria.35

A very small proportion of cases (1.5%) develop vascular (RP and/or PAH), immunologic (most commonly anti-centromere antibodies), and organ-based fibrotic features of SSc but do not show skin sclerosis.36 Patients suffering from this subset are classified as SSc sine scleroderma.

In addition, the frequency and timing of different visceral manifestations of SSc differs between major subsets. However, there is some overlap between subsets in terms of organ-based disease and the extent and severity of skin sclerosis. In all patients, the extent and severity of skin sclerosis can be assessed by the modified Rodnan skin score (mRSS). Skin score at baseline correlates with disease severity and outcome in dcSSc. Thickening and fibrosis of the skin as one of the first recognized phenomenon in SSc still forms the basis of most classification criteria and proposed subsets of the disease.

Autoantibody-based classification of SSc has been proposed, and there is evidence from association studies that this may be clinically meaningful, as indicated in Table 157-1. Moreover, genetic association analysis using a candidate gene approach has demonstrated an association between serologically based subsets of SSc that are stronger than with SSc overall. The significance of this is uncertain, and it should be noted that a genetic basis for autoantibody reactivity has been well described, leading to the suggestion that the serologic subsets may be more genetically homogeneous than unselected SSc cases or clinically defined subsets of SSc.

Organ Manifestation

Vasculopathy

Distinctive for this disease is the initial onset of RP, which appears in more than 90% of SSc-patients. It is defined by recurrent attacks of vasospasm of small digital arterioles/arteries at fingers and toes, usually caused by cold and/or other stimuli, for example, emotional stress. RP clinically appears suddenly and is clearly restricted and is accompanied by painful pallor/ischemia of single or several digits/toes, followed by reactive hyperemia after reheating at the end of a RP attack, in severe cases cyanosis (tricolore phenomenon) also ensues (see Fig. 157-2).

Patients presenting only with RP should be studied for capillary alterations as well as autoantibody-status. To identify and visualize vascular-cutaneous alterations due to SSc, nail fold capillaroscopy is a noninvasive, simple, and one of the most useful diagnostic and prognostic methods (see Table 157-2). Furthermore, it is a useful tool to categorize capillary changes into early, active, and late patterns. Furthermore, laser Doppler perfusion imaging (LDPI) is also a noninvasive microvascular imaging technique able to provide maps of the cutaneous blood flow.37

Skin Involvement

Skin involvement is a cardinal feature of SSc and usually appears first in the fingers and hands. Within time, patients develop nonpitting oedema of the fingers (puffy fingers) (see Fig. 157-2), hands, and extremities, whereupon an increasing induration and skin thickening appear (sclerodactyly). Depending on the localization of skin thickening, restricted mobility of joints (dermatogenous contractures), and/or restricted breath-excursion may be present. Typical facial features include telangiectasias, a beak-shaped nose as well as reduced mouth-aperture (microstomy). The typical physiognomy of FSSc patients is characterized by a radial furrowing around the mouth, no expression, a stiff and mask-like facial appearance, and sclerosis of the frenulum. Besides cosmetic/aesthetic problems, skin sclerosis causes considerable difficulties regarding eating and oral hygiene (summarized in Fig. 157-3).

The abnormal deposition of cutaneous and/or subcutaneous calcium (calcinosis cutis), usually occurs over pressure points (acral, joints) (see Fig. 157-4). Calcinosis cutis next to joints is designated as Thieberge–Weissenbach syndrome. Further skin manifestations include hypo- and hyperpigmented skin (salt and pepper) (see Fig. 157-3), loss of hair follicles and sweat glands (hypo-/anhydrosis).

Skin involvement/scleroderma should be evaluated using mRSS. Usually, 17 sites are assessed and skin thickness is categorized to grade 1, 2, or 3, corresponding to mild, medium, and severe, according to palpation of the skin by a trained examiner (see Fig. 157-5). Furthermore, new techniques for calculating skin thickening have been evaluated. Besides mRSS38 also 20-MHz ultrasound,39 MRI,40 and Plicometer41 are useful methods to assess skin thickening (recommended diagnostic procedures are listed in Table 157-2). Further physical procedures to monitor skin fibrosis are Durometer,42 Cutometer,43 and Elastometer.44 Besides all these noninvasive methods, a further appropriate but invasive method includes skin biopsy with histological evaluation of the dermal skin thickness. This also allows the characterization of the inflammatory infiltrates.

Approximately 50% of patients with SSc are affected by digital ulceration associated with vasculopathy at some point in their disease. This is the major external feature of structural vessel disease, probably due to thickened intima and lumen-occluded vessels. Tender and painful pitting scars are very frequent and, on occasion, progress to ulcers. These occur on the finger- or toe-tips, over the extensor surfaces of the joints due to microtrauma or in association with the above-mentioned calcinosis cutis. Digital ulcers are associated with strong, local pain and a major impact on quality of life regarding all-day functions, i.e., dressing, eating, etc. Other complications include critical digital ischaemia, paronychia, infections, gangrene, osteomyelitis, and finger pulp loss or amputation.

Cardiopulmonary Manifestations

There are different ways that the cardiopulmonary system may be involved, most often appearing as fibrosis and PAH. The differentiation between these manifestations is often clinically difficult because of similar, overlapping clinical features, such as dyspnea, nonproductive cough, disturbed diffusion-capacity, and cyanoses. PAH is currently the most common cause of disease-related death in SSc. It occurs in both limited and diffuse cutaneous subsets, although the most typical cases are those of limited SSc (lSSc) associated with isolated PAH. This condition has substantial similarities to idiopathic PAH. Thus, two patterns of disease occur in SSc. Most cases have PAH, but there are some patients with late-stage extensive interstitial lung fibrosis in SSc that develop a true secondary PH. Besides the right-heart worsening due to PAH, the heart could also be involved because of diffuse interstitial myocardio-fibrosis. This could lead to a diastolic dysfunction as well as a restricted contractibility of the myocardium. These patients clinically present cardiac arrhythmia, paroxysmal tachycardia, incomplete or complete right-heart blocks, and heart insufficiency.

Individuals with SSc should be followed up at least annually using pulmonary function tests, echocardiography, a 6-minutes walk test, and high-resolution computer tomography (HRCT). Pulmonary function tests are the most important techniques to determine possible cardiopulmonary involvement, because of impaired diffusion capacity (DLCO ≤75%) being an early marker of both lung fibrosis and PAH.

To determine the presence of interstitial lung involvement, i.e., subpleural localized line opacities, ground-glass opacities, and subpleural cysts with honeycomb formations, HRCT and/or thoracic X-ray should be used.

Follow-up should also include transthoracal-executed Doppler echocardiography, a noninvasive procedure, which can indicate a hypertrophy with or without enlargement of the right ventricle, paradoxical motion of the interventricular septum, tricuspid valve insufficiency, and pericardial effusion. Right-heart catheterization is indeed the gold standard, but an invasive diagnostic procedure for certain determination of PAH. Pulmonary arterial hypertension (PAH) is defined as a mean pulmonary pressure (mPAP) of >25 mm Hg at rest together with a pulmonary capillary wedge pressure of <15 mm Hg as determined by right-heart catheterization.45,46

Cardiac magnetic resonance imaging is also a further potential strategy for assessing myocardiac involvement in SSc. Besides imaging procedures, there is also some promise for the use of N-terminal brain natriuretic peptide (NTproBNP) to detect right ventricular impairment (see Table 157-2).

Gastrointestinal Involvement

GI involvement is the most common internal organ involvement in patients suffering from both, limited and diffuse SSc (>60%).4 Many parts of the GI-tract may be impaired, affecting motility, digestion, absorption, and excretion.47

Esophageal involvement includes symptoms like dysphagia, heartburn due to reflux, nausea, and/or vomiting. A weakened lower esophageal sphincter and impaired peristalsis increase the risk for esophagitis. If untreated, this could lead to peptic esophagitis, gastric/esophageal ulcerations, peptic stricture formations, and fistulae. Chronic gastroesophageal reflux can be complicated after a time by a higher risk of Barrett's esophagus, which may progress into an adenocarcinoma.

Possible gastric manifestations include atrophy of the mucous membrane associated with anacidity, ulcerations, and delayed gastric emptying.

SSc can also affect the intestine, and includes atonic dilatation, constrictions, malabsorption, pseudoobstructions, diarrhea, fecal incontinence, and severe malnutrition.

The presence of esophagitis can be determined by upper GI endoscopy with histological evaluations. Impaired motility of the esophagus can usually be diagnosed by scintigraphic evaluation following a radiolabeled meal or 24 hours ph-manometry (see Table 157-2).

Kidney Involvement

SRC appears in 5%–10% of SSc patients, and may cause an abrupt onset of significant systemic hypertension (>150/85 mm Hg), proteinuria (>200 mg/g urine-creatinine), followed by an acute renal failure (≥30% reduction in estimated glomerular filtration rate). Studies suggest that a chronic vasculopathy with reduced glomerular filtration rate is frequent. In addition, there is evidence of an increase in fibrillar collagen deposition within the renal interstitium in SSc. Many cases occur within the first 12 months of disease, and in up to one-fourth of patients with SRC the diagnosis of SSc is made at the time of the renal presentation. End-organ damage can result in encephalopathy with generalized seizures or flash pulmonary edema. Microangiopathic anemia is common, and sometimes disseminated, intravascular coagulation develops. Nephrotoxic drugs and high-dose prednisolone (>7.5 mg/day) should be avoided in patients suffering from SSc. Early diagnosis is the key role in improving the outcome of SRC using regular blood pressure monitoring, urine-analyses microelectrophoresis, and determination of creatinine clearance (see Table 157-2).

The histopathology of SSc shows fibrosis of the lower two-thirds of the dermis and the subcutaneous fibrous trabeculae, because of excessive deposition of ECM proteins, most notably collagen type I and III (Fig. 157-6).

Panniculitis and mucoid edema may also be prominent features in the early stages, whereby subcutaneous fat is replaced by a fibrous connective tissue. It is possible to differentiate histologically an early cellular stage on the one hand and a later fibrotic stage on the other hand. In the early stages, the dermis presents pathologically collagen bundles within the reticular dermis, and appear pale, homogenous, running parallel to the skin surface, and swollen, and there is often a perivascular lymphocytic infiltrate. These inflammatory cell infiltrates are localized between the collagen bundles but mainly around the vessels, and can also spread into subcutaneous fat tissue. The infiltrate can also entrap sweat glands. The epidermis often becomes atrophic in the overlying areas. Vessels of all sizes may be involved in SSc. In the early stages, there may only be dilatation of capillaries, then endothelial proliferation and complete occlusion of vessels occur. With the progression of scleroderma, the involved skin becomes more avascular and inflammation decreases. In later stages, pilosebaceous units and eccrine glands disappear, collagen bundles appear to be packed closely, and there may be an effacement of the rete ridges.

The diagnosis of SSc is clinical. Although there are classification criteria that were developed to facilitate the distinction of SSc from other connective tissue diseases, no formal diagnostic criteria have been developed. The main differential diagnosis is with other conditions within the scleroderma spectrum and with the scleroderma overlap syndromes. There are several differential diagnoses, which imitate scleroderma, i.e., circumscript (localized) scleroderma, eosinophilic fasciitis, sclerodermiform genodermatoses, acrodermatitis chronica atrophicans, scleroderma-like syndromes induced by environmental factors, scleroderma adultorum Buschke, scleroderma diabeticorum, scleromyxoedema, nephrogenic fibrosing dermopathy, porphyria cutanea tarda, graft-versus-host disease, and scleroderma-like lesions in malignancies. More details are summarized in Table 157-3).

Three facets of SSc are potentially amenable to therapeutic modulation, and this raises the possibility of true disease-modifying treatment. At present, vascular therapies and immunomodulation have the widest range of candidate therapies. These approaches are summarized in Tables 157-4 and 157-5. Antifibrotic treatment remains much more of a challenge. Some encouragement is provided by recent clinical trials of idiopathic PF. However, at present there is no proven antifibrotic agent. Further details about possible treatment approaches are provided in Table 157-6. A simplified schematic for integrating putative disease-modifying therapy with programs of screening and surveillance that permit timely intervention in SSc is shown in Figure 157-7 with organ-based strategies that currently form the basis of the majority of SSc therapeutics. Possibilities for targeted disease modifying therapy depend on the availability of therapeutic agents and a clear understanding of their role in pathogenesis.

There has been much more success in the field of organ-based therapeutics in SSc.

Digital Vasculopathy and Its Complications

Simple but important recommendations include the reduction of vasoconstriction by avoiding precipitating factors like nicotine, sympathomimetics, emotional stress and coldness, and instead to pay attention to have a heated home, thick and airtight clothes, heatable gloves, soles, or infrared hyperthermy, regular paraffin bath treatments, and minimal trauma.

Current local management of digital ulcers includes a combination of nonpharmacological care, antibiotics (in case of infection), analgesia, and individually applied wound dressings, if necessary.

Potential pharmacological treatment requires optimal therapy for RP, including agents that may have the potential for vascular remodeling and/or dilatation, such as calcium channel blockers, i.e., nifedipine, that should be considered as first-line therapy, while experience with other treatment options such as diltiazem, ACE-inhibitors, etc, have given contractory results.64,65,66,67,77

Parenteral prostacyclin derivatives, in particular iloprost, are widely used, and help to heal digital ulcers and may prevent recurrent lesions. Prostacyclin derivatives by intravenous infusion are the mainstay of therapy for critical digital ischaemia.71,72 Antiplatelet agents such as aspirin or clopidogrel are used especially in critical digital ischaemia.

More recently, there has been enthusiasm about therapies that are effective for PAH in digital vasculopathy. Thus, Bosentan, an oral dual specificity endothelin receptor antagonist, has been demonstrated in two large controlled trials to significantly reduce the number of new digital ulcers, compared with placebo.78 No positive effect on healing of established ulcers has been demonstrated. Other agents, such as phosphodiesterase type 5 inhibitors sildenafil and tadalafil, have also been used for treatment of RP and digital ulcers, but prospective clinical trial data are not available.76 Surgical treatments include digital microarteriolysis, which can benefit single fingers with refractory ulcers. Whenever possible, surgical amputation of digits is avoided, and prolonged treatment with parenteral prostacyclin and potent analgesia may help with this. Lumbar sympathectomy may be helpful for lower limb RP or ulceration. Generally, a temporary procedure is performed initially to determine the likely benefit from a definitive sympathectomy. In cases of critical digital ischemia, antiplatelet therapies are often given, with anecdotal reports of the benefit of clopidogrel in preventing digital infarction (see Table 157-5 and 157-6).

Skin Involvement

A key element in the management of skin manifestations of SSc physical therapy and regular exercise to maintain circulation, joint mobility, and muscle strength to improve the quality of life of SSc patients. Skin affected by scleroderma tends to be very dry, taut, and susceptible for trauma.

Skin hardening may be improved by physical therapy and exercise, lymphatic drainage, topical treatment with steroids, calcineurin inhibitors, and moisturizing crèmes. Systemic therapies include immunosuppressive drugs, systemic steroids (for just a short time), and phototherapy (UVA1 or PUVA). UVA1-irradiation appears to inhibit fibrotic and inflammatory processes and reduce the amount of sclerotic skin.

Dry and itching skin should be treated topically with steroids, cannabinoid agonists, capsaicin, emollients, and phototherapy (see above). Local steroid injections and laser or surgical therapies could also be tried for the treatment of calcinosis cutis.

Laser therapies or noninvasive methods like camouflage have been used for telangiectases. Bleaching agents, salicylic acids, and chemical peels as well as camouflage, retinoids, or corticosteroids may have the potential to improve hyper- or hypopigmentations79 (see Table 157-7).

Two randomized clinical trials have shown that methotrexate improves the skin score in early diffuse SSc, while positive effects on other organ manifestations have not been established.51–53 On the other hand, cyclophosphamide has been shown to improve skin sclerosis in two randomized clinical trial.54,55 All other systemic treatment options have not demonstrated success (see Table 157-4). Protein kinase-inhibitors (e.g., imatinib) have recently been used but controlled clinical trials have not yet been reported.

Cardiopulmonary Manifestations

It is increasingly appreciated that a group of patients with some lung fibrosis have predominantly PAH and that this group may respond to standard PAH therapies. There have been substantial advances in the treatment of PAH over the past decade. Most cases are treated with oral agents: either an endothelin receptor antagonists (e.g., bosentan, ambrisentan) or a phosphodiesterase 5 inhibitor (e.g., sildenafil, tadalafil) once they are significantly functionally limited (New York Heart Association class III). Later, if progression takes place, combination of oral treatment or introduction of parenteral prostacyclin is used, by either the intravenous or subcutaneous route. Inhaled delivery systems for iloprost are available.

Although PAH is probably responsible for more deaths than lung fibrosis in SSc, lung fibrosis remains an important complication. Treatment of SSc-PF remains challenging.80 Adding to a substantial body of uncontrolled or retrospective data suggesting benefit for cyclophosphamide in SSc-PF, the results of two randomized double-blind placebo-controlled trials have recently been reported. Both show a modest placebo-subtracted benefit for cyclophosphamide.56,81,82 For change in forced vital capacity (percent predicted), this was statistically significant for the Scleroderma Lung Study comparing oral cyclophosphamide with placebo, showing a strong trend (p = 0.06) in the trial of intravenous cyclophosphamide followed by oral azathioprine. At present, most centers use cyclophosphamide as treatment for severe or progressive SSc-PF, defining the extent and severity by pulmonary function tests and HRCT. The extent of disease by HRCT and a history of progressive restrictive abnormality on pulmonary function tests is the best predictor of future decline in lung function and is generally used to make decisions about therapy. Other therapies that are in use include carbocysteine and low-dose corticosteroids. The place of other immunosuppressive strategies remains uncertain and requires evaluation in prospective multicenter clinical trials. It is noteworthy that despite strong theoretic rationale as a treatment for lung fibrosis, the endothelin receptor antagonist bosentan was not superior to placebo in a recent large multicenter study of SSc-PF cases.

Cardiac involvement from SSc is also an important contributor to mortality but remains one of the least well understood and poorly recognized of the internal organ complications of SSc. A large number of studies confirm that radionuclide imaging, electrophysiologic, and functional abnormalities are frequent in SSc, but the significance of these findings is uncertain. Hemodynamically significant cardiac involvement occurs in up to 10% of cases of dcSSc. An inflammatory component of myocarditis may respond to immunosuppression, and so an operational approach to management of cardiac scleroderma is indicated in Fig. 157-7. This is not based on data but could form the basis for prospective evaluation of the significance of impaired left ventricular ejection fraction and elevated circulating troponin levels in SSc.

There have been many advances in SSc, including a better appreciation of the diversity of the condition, improved understanding of the underlying pathologic mechanisms, and major progress in treating organ-based complications. This includes the accumulation of robust clinical trial data that demonstrate effectiveness or lack of benefit of individual therapies and in validation of measures of disease assessment.83

Gastrointestinal Involvement

Involvement of the GI tract is very frequent in SSc. Esophageal symptoms can respond very well to proton pump inhibitors and agents that increase lower esophageal sphincter tone such as domperidone. Midgut involvement takes many forms. Pseudo-obstruction requires conservative management initially but may require parenteral nutritional supplementation. Small intestinal bacterial overgrowth can be treated using broad-spectrum antibiotics, and pancreatic insufficiency may require enzyme supplements. Large bowel involvement is a major challenge. Anorectal incontinence sometimes responds well to an implanted sacral nerve stimulator or to less elaborate approaches such as bioplastic injection to increase the internal anal sphincter bulk. Associated rectal prolapse may require additional surgical intervention. Chronic constipation, sometimes with overflow diarrhea, is a common problem. An adjustment to diet and judicious use of stimulating, softening, or bulking aperients is recommended, but an individualized approach with substantial patient involvement is generally the most successful approach. On occasion, defunctioning colostomy is needed, but this is only appropriate in a very limited number of cases.

Scleroderma Renal Crisis

Overall, approximately two-thirds of cases of SRC presenting to a specialist center require renal replacement therapy. Of these, approximately one-half of cases eventually recover sufficiently to discontinue dialysis. This can occur over 24 months after the crisis, and so decisions about renal transplantation should be postponed until that time. The possibility of late recovery distinguishes SRC from other causes of end-stage renal failure. These outcomes are possible through the use of angiotensin-converting enzyme inhibition as routine therapy for SRC. Before their availability, the mortality from established SRC was more than 90% at 12 months. The most critical aspect of management of SRC is prompt identification and treatment of significant hypertension in the context of scleroderma, with initiation of ACEi. This is a medical emergency and any features of renal impairment or end-organ damage should prompt hospitalization.

The frequency of organ involvement in two networks for SSc (Germany and United Kingdom) are seen in Table 157-8.