Scleroderma 

Updated: Sep 09, 2019
Author: Sergio A Jimenez, MD, MACR, FACP, FRCP(UK Hon); Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

The term scleroderma is derived from the Greek words skleros (hard or indurated) and derma (skin) and it is used to describe a disease characterized by progressive skin hardening and induration. Scleroderma is an aspect of systemic sclerosis, a systemic connective tissue disease that also involves subcutaneous tissue, muscles, and internal organs.

Diagnosis is based on clinical manifestations, but tests and procedures may be used initiallly to exclude alternative diagnoses, and later for assessment of organ involvement and monitoring of disease progression (see Presentation and Workup). Treatment is directed principally toward managing complications and providing symptomatic relief, but disease-modifying agents are under investigation (see Treatment and Medication).

Background

Definition

The term systemic sclerosis is used to describe a systemic autoimmune disease of unknown origin characterized by excessive deposition of collagen and other connective tissue macromolecules in skin and multiple internal organs, prominent and often severe fibroproliferative alterations in the microvasculature, and numerous humoral and cellular immunologic abnormalities. Although systemic sclerosis is not inherited, a genetic predisposition plays an important role in its development.

Systemic sclerosis is a complex and heterogeneous disease with clinical forms ranging from limited skin involvement (limited cutaneous systemic sclerosis) to forms with diffuse skin sclerosis and severe and often progressive internal organ involvement (diffuse cutaneous systemic sclerosis), and occasionally a fulminant course (fulminant systemic sclerosis).

Limited cutaneous systemic sclerosis involves areas distal to the elbows and knees but may involve the face and neck. CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias—although not all are needed for the disorder to be called CREST) is an older term used to describe this subset of limited cutaneous systemic sclerosis.

Diffuse cutaneous systemic sclerosis refers to skin thickening affecting the trunk and the skin of the extremities proximal to the elbows and knees besides involvement of the face. There are rare cases of typical systemic sclerosis internal organ involvement in the absence of clinically apparent cutaneous involvement, a clinical subset known as “scleroderma sine scleroderma”.

Systemic sclerosis involvement is most obvious in the skin; however, the gastrointestinal tract as well as the respiratory, renal, cardiovascular, musculoskeletal, endocrine, and genitourinary systems are frequently involved.

In 2013, a joint committee of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) published a revised classification criteria for systemic sclerosis[1, 2] to improve the sensitivity of the widely used previous classification criteria. The revised criteria for the classification of systemic sclerosis are listed in Table I, below.

Table. (Open Table in a new window)

Table 1: ACR/EULAR Revised Systemic Sclerosis Classification Criteria

Item

Sub-item(s)

Score*

Skin thickening of the fingers of both hands extending proximally to the metacarpophalangeal joints (presence of this criterion is sufficient criterion for SSc classification)

None

9

Skin thickening of the fingers (count the higher score only)

Puffy fingers

2

Sclerodactyly (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints)

4

Fingertip lesions (count the higher score only)

Digital tip ulcers

2

Fingertip pitting scars

3

Telangiectasia

None

2

Abnormal nailfold capillaries

None

2

Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2)

Pulmonary arterial hypertension

2

Interstitial lung disease

2

Raynaud phenomenon

None

3

Systemic sclerosis–related autoantibodies (maximum score is 3)

Anticentromere

3

Anti–topoisomerase I

3

Anti–RNA polymerase III

3

*The total score is determined by adding the maximum score in each category. Patients with a total score equal to or greater than 9 are classified as having definite systemic sclerosis (modified from van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. Nov 2013;65(11):2737-47.[1] )

Historical background

Hippocrates first described this condition as thickened skin.[3] In 1836, Giovambattista Fantonetti used for the first time the term “skleroderma generale” to describe a patient with dark leather-like skin who exhibited a loss of range of joint motion caused by skin tightening.[4] Robert H. Goetz introduced the concept of scleroderma as a systemic disease in 1945 and coined the term progressive systemic sclerosis to emphasize the systemic and often progressive nature of the disease.[5]

The purpose of classification criteria is to enroll a uniform population of patients in research studies and it is based on various parameters that are commonly used for systemic sclerosis diagnosis. It is important to emphasize that these criteria are not diagnostic criteria and are not applicable to patients with scleroderma-like disorders or to patients with skin thickening sparing the fingers.

Pathophysiology

Systemic sclerosis is a systemic disease that besides the skin affects numerous organ systems. The pathogenesis of systemic sclerosis is complex.[6, 7, 8, 9, 10, 11, 12, 13]  Increasing evidence suggests interaction between environmental and genetic factors, with a regulatory epigenetic mechanism involving changes in the expression of DNA and microRNA.[14]

The clinical and pathologic manifestations result from three distinct processes: 1) severe fibroproliferative vascular lesions of small arteries and arterioles, 2) excessive and often progressive deposition of collagen and other extracellular matrix (ECM) macromolecules in skin and various internal organs, and 3) alterations of humoral and cellular immunity. It is not clear which of these processes is of primary importance or how they are temporally related during the development and progression of the disease.

Numerous studies have suggested a sequence of pathogenetic events initiated by unknown etiologic factors in a genetically receptive host, which trigger microvascular injury characterized by structural and functional endothelial cell abnormalities. The endothelial cell abnormalities result in either increased production and release of numerous and potent mediators including cytokines, chemokines, polypeptide growth factors, and various other substances such as prostaglandins, reactive oxygen species (ROS), or in the reduction of important compounds such as prostacyclin and nitric oxide.

The endothelial cell dysfunction allows the chemokine- and cytokine-mediated attraction of inflammatory cells and fibroblast precursors (fibrocytes) from the bloodstream and bone marrow and their transmigration into the surrounding tissues, resulting in the establishment of a chronic inflammatory process with participation of macrophages and T and B lymphocytes, with further production and secretion of cytokines and growth factors from these cells.

The immunological alterations include innate immunity abnormalities, tissue infiltration with macrophages and T and B lymphocytes; production of numerous disease-specific autoantibodies; and dysregulation of cytokine, chemokine, and growth factor production. The released cytokines and growth factors induce the activation and phenotypic conversion of various cellular types, including resident fibroblasts, epithelial cells, endothelial cells, and pericytes into activated myofibroblasts, the cells ultimately responsible for initiation and establishment of the fibrotic process.

This sequence of events (see diagram below) results in the development of a severe and often progressive fibroproliferative vasculopathy, and exaggerated and widespread accumulation of fibrotic tissue, the hallmark of the fibrotic process characteristic of the disease.

Overall scheme illustrating a current understandin Overall scheme illustrating a current understanding of SSc pathogenesis. Hypothetical sequence of events involved in tissue fibrosis and fibroproliferative vasculopathy in SSc. An unknown causative agent induces activation of immune and inflammatory cells in genetically predisposed hosts resulting in chronic inflammation. Activated inflammatory and immune cells secrete cytokines, chemokines, and growth factors which cause fibroblast activation, differentiation of endothelial and epithelial cells into myofibroblasts, and recruitment of fibrocytes from the bone marrow and the peripheral blood circulation. The activated myofibroblasts produce exaggerated amounts of ECM resulting in tissue fibrosis.

The vascular alterations preferentially affect small arteries and arterioles. Vascular dysfunction is one of the earliest alterations of systemic sclerosis. Severe alterations in small blood vessels of skin and internal organs, including endothelial dysfunction, subendothelial fibrosis, and perivascular cellular infiltration with activated T cells and macrophages, are almost universally present in systemic sclerosis affected tissues.[8]

Recent evidence supports the concept that endothelial dysfunction and fibrosis are closely related phenomena and it has been suggested that the vascular alterations, including the phenotypic conversion of endothelial cells into activated mesenchymal myofibroblasts, may be the initiating event and the common pathogenetic alteration leading to the fibrotic and chronic inflammatory involvement of multiple organs.[8, 9]

The activation of endothelial cells induces the expression of chemokines and cell adhesion molecules, causes the attraction, transendothelial migration, and perivascular accumulation of immunologic-inflammatory cells, including T- and B-lymphocytes and macrophages. The inflammatory cells produce and secrete a variety of cytokines and/or growth factors including transforming growth factor beta (TGF-β) and other profibrotic mediators such as endothelin-1, which induce increased proliferation of smooth muscle cells, marked accumulation of subendothelial fibrotic tissue, and initiation of platelet aggregation and intravascular thrombosis, eventually causing microvascular occlusion.

The fibrotic process is characterized by the excessive production and deposition of types I, III, and VI collagens and other ECM and connective tissue macromolecules including COMP, glycosaminoglycans, tenascin, and fibronectin.[10, 11] This crucial component results from the accumulation in skin and other affected tissues of myofibroblasts, cells possessing unique biological functions, including increased production of fibrillar type I and type III collagens, expression of α-smooth muscle actin, and reduction in the expression of genes encoding ECM–degradative enzymes. Thus, the accumulation of myofibroblasts in affected tissues and the uncontrolled persistence of their elevated biosynthetic functions are crucial determinants of the extent and rate of progression of the fibrotic process in systemic sclerosis.

The immunologic alterations include the production of numerous autoantibodies, some with very high specificity for the disease, as well as abnormalities in the innate and acquired cellular immune responses.[12, 13] The exaggerated connective tissue production by systemic sclerosis fibroblasts is induced by cytokines and growth factors released from the tissue-infiltrating inflammatory cells.

One of the growth factors that plays a crucial role in the fibrosis that accompanies systemic sclerosis is TGF-β. One of the most important effects of TGF-β is the stimulation of ECM synthesis by stimulating the production of various collagens and other ECM proteins.[10, 11] Besides its potent ECM stimulatory effects, TGF-β also induces the generation of myofibroblasts and decreases the production of collagen-degrading metalloproteinases. TGF-β also stimulates the production of protease inhibitors, which prevent ECM breakdown.

Etiology

The exact etiology of systemic sclerosis is not known. Systemic sclerosis is not inherited, although a genetic predisposition plays an important role in its development. Environmental factors (eg, triggers or accelerators) may contribute to the development of systemic sclerosis in the proper genetic background.[15, 16, 17, 18, 19] These include the following:

  • Silica exposure

  • Solvent exposure (vinyl chloride, trichloroethylene, epoxy resins, benzene, carbon tetrachloride)

  • Radiation exposure or radiotherapy

Case reports describe the development of scleroderma in patients treated with the immune checkpoint inhibitor pembrolizumab for metastatic melanoma.[20]  

Cytomegalovirus, human herpesvirus 5, and parvovirus B19 have been proposed as viral accelerating factors. However, evidence of their involvement is inconclusive.[21]

Epidemiology

United States statistics

The estimated incidence of systemic sclerosis in the United States is 20 cases per million population, and its prevalence has been estimated at 276 cases per million population, although the reported prevalence varies depending on the methodology used and the targeted population.[22, 23, 24] An increased systemic sclerosis incidence and prevalence has been evident in the last 50 years. Although improved diagnosis and increased survival rate can partially account for this observation, it appears that there has been a real increase in its incidence.

International statistics

Systemic sclerosis occurs worldwide, although its reported prevalence varies significantly in different countries.[23, 24, 25] Obtaining an exact estimate of prevalence is difficult because systemic sclerosis is frequently misdiagnosed. Furthermore, ethnic and geographical clustering may contribute to the variability in terms of frequency. However, it appears that there is higher frequency among black individuals.[26, 27, 28, 29]

Race

Systemic sclerosis affects individuals of all races.[26, 27, 28, 29] However, incidence rates, severity and mortality may vary among ethnic groups.

Recent studies have documented a higher general and age-specific incidence rate in blacks than in whites. It has also been shown that affected African Americans develop more severe disease and have poorer outcomes when compared with other ethnic groups.[26, 27, 28, 29]

The highest prevalence of systemic sclerosis in the US is among the Oklahoma Choctaw Indians. The prevalence in the Choctaws is 469 cases per 100,000 population, which is higher than in non-full blood Choctaw (31 per 100,000) and 20 times higher than the national average.[30]

Sex- and age-related disparities in incidence

The risk of systemic sclerosis is 4-9 times higher in women than in men.[22, 23, 24] However, the mechanisms responsible for the disproportionately higher frequency in females have not been elucidated.

The peak onset occurs in individuals aged 30-50 years. Numerous cases occur in children, however, as well as in very old individuals.

Prognosis

Survival in patients with diffuse cutaneous disease has improved significantly; currently, the 5-year survival is estimated to be about 80%. Five-year survival in patients with limited cutaneous disease is approximately 90%.

Factors associated with a more severe prognosis are as follows:

  • Younger age

  • African descent

  • Rapid progression of skin symptoms

  • Greater extent of skin involvement

  • Anemia

  • Elevated erythrocyte sedimentation rate (ESR)

  • Pulmonary, renal, and cardiac involvement

Complications

Complications of systemic sclerosis include the following:

  • Digital infarctions

  • Pulmonary hypertension

  • Myositis

  • Renal failure

  • Wound infections

Frerix and colleagues have proposed that osteonecrosis of the lunate bone (Kienböck disease), while very rare in the general population, may be a frequent manifestation of systemic sclerosis, and may be linked to vasculopathy from the disorder.[31] Lunate osteonecrosis manifests as pain and stiffness in the affected wrist and decreased grip strength in the hand.

Mortality/morbidity

Systemic sclerosis has the highest case-specific mortality among the systemic autoimmune diseases. Pulmonary hypertension, pulmonary fibrosis (interstitial lung disease), and scleroderma renal crisis are the most frequent causes of mortality.[32, 33, 34, 35, 36, 37, 38, 39]

Survival has improved in recent decades and correlates best with the clinical disease subtype (diffuse cutaneous vs limited cutaneous) and with the extent of organ involvement. Five-year survival among patients with diffuse cutaneous systemic sclerosis has improved significantly, from 69% in the 1990–1993 cohort to 84% in the 2000–2003 cohort. Five-year survival among the patients with limited cutaneous systemic sclerosis remained very high and unchanged for the same periods (93% and 91%, respectively).

Mortality associated with scleroderma renal crisis has declined significantly during the last decades, as use of angiotensin-converting enzyme (ACE) inhibitors. In contrast, pulmonary involvement (interstitial lung disease and/or pulmonary arterial hypertension) has become the most common cause of death in patients with systemic sclerosis.

Patient Education

To minimize the risk of Raynaud phenomenon flare, instruct patients to maintain their core body temperature; strongly encourage smoking cessation in patients who smoke, and advise all patients to avoid exposure to cigarette smoke. Instruct the patient to avoid digital or skin trauma and prolonged cold exposure.

For patient education information, see Scleroderma.

 

Presentation

History

Signs and symptoms of systemic sclerosis may involve the following systems:

  • Skin[40, 41, 42]

  • Vascular[43, 44, 45, 46, 47, 48, 49, 50]

  • Gastrointestinal (GI)[51, 52, 53, 54, 55, 56, 57]

  • Respiratory[58, 59, 60, 61, 62, 63]

  • Musculoskeletal[64, 65, 66, 67, 68, 69]

  • Cardiac[70, 71, 72, 73, 74, 75, 76]

  • Renal[77, 78, 79, 80]

  • Genitourinary[81, 82, 83, 84]

  • Eyes, ears, nose, and throat[85, 86, 87, 88]

  • Endocrine[89, 90] -Hypothyroidism

  • Neurologic/psychiatric[91, 92, 93, 94, 95]

  • Constitutional

Skin manifestations

Skin manifestations of systemic sclerosis are as follows:

  • Progressive skin tightness and induration, often preceded by swelling and puffiness (edematous stage) that does not respond to diuretic therapy

  • Skin induration initially affects the fingers (sclerodactyly) and extends proximally (see image below).

    Tightening of the skin in the face, with a charact Tightening of the skin in the face, with a characteristic beaklike facies and paucity of wrinkles.
  • Tightening of the skin in the face is often noted very early in the course of the disease (see image below)

    Sclerodactyly with digital ulceration, loss of ski Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and sparse hair.
  • Prominent skin pigmentary changes both hyperpigmentation and hypopigmentation (see image below)

    Anterior chest demonstrating salt-and-pepper hypop Anterior chest demonstrating salt-and-pepper hypopigmentation and diffuse hyperpigmentation in a white woman.
  • Diffuse pruritus

Vascular manifestations

Raynaud phenomenon is part of the initial presentation in 70% of patients with systemic sclerosis; 95% eventually develop it during the course of their disease. Raynaud phenomenon may precede obvious systemic sclerosis features by months or even years.

Raynaud phenomenon that is not associated with systemic sclerosis or other autoimmune diseases is known as primary Raynaud phenomenon. It occurs in 5-15% of the general population. The female-to-male ratio is 4:1, with onset occurring usually during adolescence.

Other vascular manifestations of systemic sclerosis include the following:

  • Healed pitting ulcers in fingertips

  • Large fingertip ulcers may lead to finger amputation

  • Cutaneous and mucosal telangiectasias

  • Evidence of macrovascular involvement including non-atherosclerotic myocardial infarction

Gastrointestinal manifestations

GI findings in systemic sclerosis include the following:

  • Gastroesophageal reflux caused by lower esophageal sphincter (LES) incompetence and decreased or absent peristalsis in the lower two thirds of the esophagus (may lead to hoarseness, dysphagia and aspiration pneumonia)

  • Dyspepsia, bloating, and early satiety

  • Intestinal pseudo-obstruction

  • Constipation alternating with diarrhea from bacterial overgrowth (may lead to malabsorption)

  • Fecal incontinence

  • Malnutrition from inadequate caloric intake

  • Chronic iron deficiency anemia from occult blood loss

Respiratory manifestations

Respiratory compaints in systemic sclerosis include the following:

  • Progressive dyspnea

  • Chest pain (precordial) due to pulmonary artery hypertension

  • Dry persistent cough due to restrictive lung disease

Musculoskeletal manifestations

Musculoskeletal complaints in systemic sclerosis include the following:

  • Arthralgia

  • Myalgia

  • Loss in joint range of motion and joint flexion contractures

  • Tendon friction rubs

  • Symptoms of carpal tunnel syndrome

  • Muscle weakness

Cardiac manifestations

Cardiac signs and symptoms in systemic sclerosis include the following:

  • Dyspnea due to congestive heart failure or myocardial fibrosis

  • Palpitations, irregular heart beats, and syncope due to arrhythmias or conduction abnormalities

  • Symptoms of congestive heart failure or right sided heart failure

  • Systemic sclerosis is an independent risk factor for acute myocardial infarction

Renal manifestations

Renal signs and symptoms in systemic sclerosis include the following:

  • Hypertension

  • Renal crisis

  • Chronic renal insufficiency

  • History of high dose corticosteroid use.

Genitourinary manifestations

Patients with systemic sclerosis may present with the following:

  • Erectile dysfunction

  • Bladder fibrosis

  • Dyspareunia (if introitus is affected)

  • Vaginal narrowing, dryness and pain caused by vaginal fibrosis

Eyes, ears, nose, and throat manifestations

Patients may present with the following:

  • Sicca syndrome

  • Poor dentition secondary to sicca syndrome

  • Loosening of dentition caused by alterations in the tooth suspensory ligament and thickening of the periodontal membrane

  • Hoarseness due to acid reflux with vocal cord inflammation or fibrosis

  • Increased risk for tongue cancer

  • Decreased oral aperture

  • Blindness caused by retinal artery occlusion

Neurologic/psychiatric manifestations

Patients may present with the following:

  • Facial pain and decreased sensation due to trigeminal neuralgia

  • Hand paresthesias and weakness due to carpal tunnel peripheral entrapment neuropathy

  • Headache and stroke during hypertensive renal crisis

  • Depression and anxiety

Constitutional manifestations

Constitutional complaints in systemic sclerosis include the following:

  • Fatigue

  • Weight loss

  • Loss of appetite

Physical Examination

Skin

The skin of the hands may be edematous or swollen early in systemic sclerosis and the patient may initially report these changes as puffiness. This edematous stage precedes the indurated sclerotic stage. Slow progression of the sclerotic phase is associated with a better prognosis, whereas a rapid progression of cutaneous sclerosis indicates a worse prognosis and more extensive and severe visceral organ involvement with an increased risk of renal crisis or interstitial lung disease and higher mortality.

In the sclerotic phase, the skin appears tight and shiny (see image below), with a characteristic loss of hair, decreased sweating, and loss of the ability to make a skin fold. This process of skin thickening usually begins distally on the fingers (sclerodactyly; see image below) and progresses proximally in a continuous symmetrical fashion.

Tightening of the skin in the face, with a charact Tightening of the skin in the face, with a characteristic beaklike facies and paucity of wrinkles.
Sclerodactyly with digital ulceration, loss of ski Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and sparse hair.

Other skin findings are as follows:

  • · Reduced oral aperture (microstomia) caused by perioral fibrosis (assessed by measurements of the incisor-to-incisor distance)

  • Skin pigmentary changes include a salt-and-pepper appearance, with areas of hyperpigmentation and hypopigmentation, or an overall appearance of darkened skin not related to sun exposure (see image below)

    Anterior chest demonstrating salt-and-pepper hypop Anterior chest demonstrating salt-and-pepper hypopigmentation and diffuse hyperpigmentation in a white woman.
  • Telangiectasias are dilated vessels located just beneath the dermis on any skin area, but they are most obvious in the face, hands, and anterior chest; occasionally, telangiectasias may occur in mucosal surfaces and cause either obvious or occult bleeding

  • Calcinosis may develop in the fingers and extremities (see image below), most commonly in the finger tips, the extensor surface of the forearms and in the prepatellar regions; however, any area of the body can be affected. Occasionally, large calcium deposits with the appearance of tumoral calcinosis may occur

    A radiograph of the distal digits demonstrating ca A radiograph of the distal digits demonstrating calcinosis and distal phalanx reabsorption (acral osteolysis).

Eyes, ears, nose, and throat

Salivary production may be decreased and spontaneous sublingual pooling of saliva may be absent.

Xerostomia and xerophthalmia may be part of the examination findings. A confirmatory minor salivary gland biopsy may show fibrosis without the pronounced lymphocytic aggregates that would be expected with primary Sjögren syndrome. Furthermore, patients with systemic sclerosis typically do not harbor anti-Ro and anti-La antibodies.

Funduscopic examination during the hypertensive episodes of scleroderma renal crisis may reveal exudates and vascular alterations. Retinal artery occlusion causing acute loss of vision has been described in rare instances.

Vascular changes

Raynaud phenomenon results in characteristic color changes of pallor, cyanosis, and then erythema (white, blue, red) in the fingers, toes and other acral body parts, and is usually accompanied by numbness, tingling, or pain. These events are triggered by cold exposure, smoking, or emotional stress. Subintimal hyperplasia, typically present in systemic sclerosis vessels, can cause a severe reduction of their luminal diameter, limiting blood flow. The baseline reduction in vessel lumen coupled to an exaggerated response to vasoconstricting stimuli accounts for the severity of Raynaud phenomenon in systemic sclerosis.

Other manifestations of vascular involvement are as follows:

  • Infarction and dry gangrene of the fingers and toes may be caused by severe vasospasm superimposed to structural fibrotic and fibroproliferative vascular narrowing

  • Some studies suggest that patients with systemic sclerosis have an increased risk of coronary atherosclerosis, peripheral vascular disease, and cerebrovascular calcification compared with healthy individuals, and may develop non-atherosclerotic myocardial infarction

  • Nail-fold capillary microscopy demonstrates fewer capillaries than normal (ie, capillary loop drop; see image below) and numerous dilated and tortuous capillary loops

    Fingernail capillary bed demonstrating capillary d Fingernail capillary bed demonstrating capillary dropout with large dilated vessels.

Musculoskeletal system

Patients may present with generalized arthralgia and morning stiffness that may mimic other systemic autoimmune diseases. However, clinically apparent synovitis is uncommon.

Hand and joint function usually decline over time because of skin tightening rather than arthropathy. Flexion contractures of affected joints is common.

Tendon friction rubs are found almost exclusively in diffuse systemic sclerosis and may be detected as the tendon is moved actively or passively. The following are common sites where palpable tendon friction rubs may be found:

  • Shoulders - Scapula

  • Elbows - Olecranon

  • Knees - Patella

  • Wrists - Flexor or extensor

  • Fingers - Flexor or extensor (rare)

  • Ankles - Anterior tibia, posterior tibia, peroneal, Achilles tendon

Myositis may cause weakness and muscle wasting. Acroosteolysis (ie, resorption or lysis of the distal end of the phalanx) may occur.

Respiratory system

Respiratory findings are as follows:

  • Dry rales may be the only physical examination finding that suggests pulmonary involvement in systemic sclerosis

  • Patients may present with findings of aspiration pneumonia caused by aspiration of gastric contents due to lower esophageal sphincter incompetence

  • An accentuated pulmonic second heart sound (P2) or a right ventricular heave may indicate the presence of pulmonary artery hypertension

  • Blacks have a higher risk of developing pulmonary involvement and when it occurs it is of greater severity than in whites

    Lung biopsy demonstrating severe interstitial fibr Lung biopsy demonstrating severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of a pulmonary arteriole compatible with pulmonary hypertension.
    Lung biopsy demonstrating expansion of the interst Lung biopsy demonstrating expansion of the interstitium of the lung by fibrous tissue along with chronic inflammatory cells.

Gastrointestinal system

Atrophy of smooth muscle and submucosal fibrotic changes leading to decreased peristalsis throughout the gastrointestinal (GI) tract cause gastroesophageal reflux disease [GERD], gastroparesis, severe constipation, and pseudo-obstruction (see image below).

Barium swallow demonstrating reflux into the dista Barium swallow demonstrating reflux into the distal esophagus, as well as an accordion appearance in the duodenum.

Other GI findings are as follows:

  • Abdominal distention

  • Malabsorption

  • Mucosal telangiectasia

  • Anal sphincter incompetence

  • Anemia caused by blood loss from either mucosal telangiectasias or gastric antral vascular ectasia (GAVE), also known as “watermelon stomach

Renal system

Renal crisis presents as the following:

  • Accelerated hypertension (absent in approximately 10% of cases)

  • Oliguria

  • Headache

  • Dyspnea

  • Edema

  • Rapidly rising serum creatinine levels

Cardiac system

Cardiac involvement indicates a worse prognosis. Cardiac arrhythmias and conduction abnormalities, including complete A-V block, may be revealed during physical exam but must be confirmed by routine electrocardiography or, more accurately, with 24-hour Holter monitor or echocardiography.

Pericardial effusion may develop in up to one third of patients with systemic sclerosis but is usually asymptomatic. Clinically significant pericarditis is rare.

Other cardiac findings in systemic sclerosis are as follows:

  • Cor pulmonale may develop secondary to pulmonary fibrosis and/or pulmonary artery hypertension

  • Infiltrative cardiomyopathy with replacement of cardiac muscle by fibrous tissue can lead to arrhythmias, heart failure, or both

  • Contraction band necrosis results from global ischemia and reperfusion; patients may have recurrent episodes of vasospasm that are caused by the same mechanism involved in Raynaud phenomenon; this process can lead to cardiomyopathy and heart failure

  • Non-atherosclerotic myocardial infarction may result from inflammation and fibrotic narrowing of coronary vessels

Neurologic system

Neurologic involvement is rare. Trigeminal neuralgia (uncommon) and carpal tunnel symptoms may result from peripheral entrapment neuropathies. Although rare, sensory neuropathies unrelated to entrapment may be present.

Genitourinary system

Findings may include the following:

  • Women may present with vaginal dryness and vaginal mucosal inflammation; vaginal narrowing from vaginal fibrosis has been described

  • Erectile dysfunction is common in men, and may be the presenting symptom in some cases

  • Urinary bladder fibrotic infiltration may cause micro-hematuria

 

DDx

Diagnostic Considerations

The following disorders may present clinical similarities with systemic sclerosis (“scleroderma mimics”) and need to be included in the differential diagnosis:[96, 97, 98, 99]

  • Nephrogenic Systemic Fibrosis

  • Eosinophilic Fasciitis

  • Eosinophilia-Myalgia Syndrome

  • Graft Versus Host Disease

  • Reflex Sympathetic Dystrophy

  • Generalized morphea

  • Diabetic cheiroarthropathy

  • Porphyria cutanea tarda

  • Morphea

  • Linear scleroderma

  • Radiation exposure

  • Scleromyxedema (generalized lichen myxedematosus)

  • Scleredema adultorum of Buschke

  • Scleredema diabeticorum

Gadolinium-based contrast agents, bleomycin, pentazocine, and several other drugs and chemicals have been shown to cause disorders resembling systemic sclerosis. These must be considered in the differential diagnosis.

 

Workup

Approach Considerations

The diagnosis of systemic sclerosis is based on the clinical manifestations. Nevertheless, a number of tests and procedures may be used in the initial diagnosis (eg, to exclude alternative diagnoses), the assessment of organ involvement, and monitoring of disease progression.

Laboratory testing may include the following:

  • Complete blood cell count (CBC)

  • Serum muscle enzyme levels

  • Erythrocyte sedimentation rate

  • Serum CXCL4 level

  • N-terminal pro-brain natriuretic peptide

  • Autoantibody assays

Assessment of gastrointestinal involvement

Conventional radiography is the principal imaging study for assessment of gastrointestinal involvement in systemic sclerosis. Plain abdominal radiographs may reveal pseudointestinal obstruction, or rarely pneumatosis cystoides intestinalis. For more information, see Gastrointestinal Scleroderma Imaging.

Esophagogastroduodenoscopy with appropriate biopsies, esophageal manometry assessment, and pH monitoring studies should be performed to survey and evaluate the upper gastrointestinal system, including documentation of esophageal dysmotility and an incompetent lower esophageal sphincter.[100] A gastric emptying study should be performed to document delayed gastric emptying. Colonoscopy can identify wide-mouth colonic diverticula, which are uniquely characteristic for systemic sclerosis.

Assessment of pulmonary involvement

Chest radiography is an insensitive imaging procedure that typically shows only late findings of pulmonary fibrosis, such as increased interstitial markings.[101] High-resolution computerized tomography (HRCT) is highly sensitive for revealing pulmonary involvement. HRCT scanning should be performed every 6 months if active alveolitis or interstitial pulmonary fibrosis is present and every year if these abnormalities are not present. For more information, see Thoracic Scleroderma Imaging.

Pulmonary function testing is important in all patients with systemic sclerosis, although lung volumes may correlate poorly with the extent of interstitial lung disease. Results of pulmonary function testing are ultimately abnormal in 80% of the patients. Pulmonary function tests should be performed every 6 to 12 months to detect early abnormalities indicative of development and/or progression of pulmonary hypertension or pulmonary fibrosis.

Bronchoscopy with bronchoalveolar lavage is used to differentiate active infections from progressive interstitial lung disease.[102, 103]

Assessment of cardiovascular involvement

Elevated CXCL4 serum levels correlate with the severity of pulmonary fibrosis and progression of pulmonary hypertension.[104] Elevated serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) may correlate with early pulmonary hypertension.[105, 106, 107]

Hughes et al propose using cardiac troponins as a screening tool to detect asymptomatic cardiac involvement, with measurement of cardiac troponin T followed by confirmatory cardiac troponin I. Cardiac involvement is unlikely if levels of both troponins are normal and is probable if levels of both are high. Low-titer troponin T levels may reflect skeletal muscle involvement, but cardiac assessment is nevertheless warranted.[108]

Electrocardiograms (ECGs) should be performed routinely to identify arrhythmias and conduction defects. ECGs can identify early changes of right ventricular strain caused by pulmonary hypertension, and in advanced states, right atrial hypertrophy. Perform 24-hour ambulatory Holter monitoring to evaluate arrhythmias and serious conduction defects.

Transthoracic echocardiography is a noninvasive study for assessing pulmonary artery pressure. Conduct this test to evaluate the patient's pulmonary artery pressure at initial evaluation and during serial follow ups and to assess septal fibrosis or pericardial effusions.

Right-heart catheterization is the standard criterion and only definitive test for diagnosing pulmonary hypertension. It is usually performed after an elevated pulmonary artery pressure is found on echocardiographic screening.[109, 110]

Other studies

The workup may also include the following:

  • Extremity radiography should be performed to reveal calcinosis, resorption of the distal tufts of the digits, and to exclude osteomyelitis secondary to infected digital ulcers[111, 112]

  • Mandibular radiographs may reveal resorption of the ramus and the angle of the mandible

  • Nail-fold capillary microscopy is a noninvasive procedure of substantial value for the assessment of microvascular alterations in systemic sclerosis[113, 114, 115, 116]

Laboratory Studies

Findings on laboratory studies may include the following:

  • A rapid increase in serum creatinine levels is typical of scleroderma renal crisis

  • A microangiopathic hematologic picture and thrombocytopenia may precede renal crisis

  • Serum levels of muscle enzymes (creatine kinase, aldolase) are elevated in patients with inflammatory myopathy

  • CXCL4 is a very potent anti-antiangiogesis cytokine produced by plasmocytoid dendritic cells. Elevated CXCL4 serum levels have been found in a large proportion of systemic sclerosis patients and higher levels correlated with the severity of pulmonary fibrosis and progression of pulmonary hypertension[104]

  • Elevated serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) may correlate with early pulmonary hypertension[105, 106, 107]

  • The erythrocyte sedimentation rate (ESR) is almost always normal; however, an elevated ESR is associated with a poor outcome

  • Anemia (microcytic) resulting from chronic blood loss is frequent and is often associated with iron deficiency

Autoantibodies

Owing to the almost universal involvement of the immune system, most patients have specific humoral and cell-mediated immunity abnormalities.[117, 118, 119, 120, 121] The value of serology testing is for initial diagnosis and assessment of associated conditions; it is of little use for monitoring disease activity.

Antinuclear antibodies are present in about 90%-95% of affected patients, usually with a speckled or centromere pattern. A nucleolar pattern, although less common, is more specific for systemic sclerosis.

Topoisomerase I antibodies (also known as Scl-70) are present in approximately 30% of patients with diffuse disease (absent in limited disease). Patients harboring Scl-70 antibodies are at higher risk of developing pulmonary parenchymal involvement, in contrast to patients harboring anti-centromere antibodies.

Anticentromere antibodies are present in about 45%-50% of patients with limited disease. They are rare in patients with diffuse disease.

Anti-RNA polymerase I and III antibodies are present in 15%-20% of patients with diffuse disease and correlate with rapid cutaneous involvement and high frequency of renal crisis. Anti-ThRNP is present mostly in limited disease and is associated with more extensive visceral disease. Anti-PM-Scl is present in patients with overlap connective tissue disease or with mixed connective tissue disease (MCTD) and is associated with myositis and renal involvement.

Fibrillarin antibodies and antibodies to ribonucleoprotein (RNP) may be present. Anti-RNP is present mostly in patients with diffuse disease with overlap syndromes and in patients with MCTD. These antibodies are more common in patients with skeletal muscle involvement and pulmonary disease.

Computed Tomography

High-resolution computerized tomography (HRCT) scans are required to evaluate pulmonary involvement.[117, 122] HRCT is highly sensitive for revealing pulmonary involvement. Patients with normal initial HRCT findings have a good long-term prognosis.

On HRCT, the first abnormality observed during the development of lung fibrosis is a ground-glass appearance, which occurs in areas of active alveolitis or septal fibrosis. As interstitial fibrosis becomes established, the ground-glass appearance is subsequently replaced by honeycombing and traction bronchiectasis or bronchiolectasis.

HRCT scanning should be performed every 6 months if active alveolitis or interstitial pulmonary fibrosis is present and every year if these abnormalities are not present.

For more information, see Thoracic Scleroderma Imaging.

Pulmonary Function Studies

Pulmonary function testing is important in all patients with systemic sclerosis,[123, 124, 125, 126] although lung volumes may correlate poorly with the extent of interstitial lung disease. Pulmonary function tests should be performed every 6 to 12 months to detect early abnormalities indicative of development and/or progression of pulmonary hypertension or pulmonary fibrosis. Results of pulmonary function testing are ultimately abnormal in 80% of the patients.

Carbon monoxide diffusion capacity (DLCO) is very sensitive and helps establish lung involvement at an earlier stage. Pulmonary function tests may demonstrate a restrictive pattern with decreased forced vital capacity and total lung capacity and a low DLCO. These changes reflect fibrotic infiltration in the lung (see images below). An isolated or disproportionate reduction of DLCO with a ratio of forced vital capacity (FVC) or total lung capacity (TLC) to DLCO of greater than 1.6 indicates pulmonary vascular obliteration associated with pulmonary hypertension.

Transthoracic Echocardiography

Transthoracic echocardiography is a noninvasive study for assessing pulmonary artery pressure.[23, 127] Conduct this test to evaluate the patient's pulmonary artery pressure at initial evaluation and during serial follow ups and to assess septal fibrosis or pericardial effusions. Roughly 30% of patients have asymptomatic pericardial effusions.

A systolic pulmonary artery pressure of greater than 35 mm Hg is considered to represent pulmonary arterial hypertension. However, right-sided heart catheterization is required to obtain an accurate evaluation of pulmonary artery pressure.

Electrocardiography and Holter Monitoring

Electrocardiograms should be performed routinely to identify arrhythmias and conduction defects.[128, 129] Electrocardiography can identify early changes of right ventricular strain caused by pulmonary hypertension, and in advanced states, right atrial hypertrophy. Perform 24-hour ambulatory Holter monitoring to evaluate arrhythmias and serious conduction defects.

Gastrointestinal Endoscopy

Esophagogastroduodenoscopy with appropriate biopsies, esophageal manometry assessment, and pH monitoring studies should be performed to survey and evaluate the upper gastrointestinal system.[130, 131] The following alterations can be evaluated:

  • Reflux due to decreased lower esophageal sphincter pressure

  • Severe esophagitis

  • Candida esophagitis

  • Esophageal strictures

  • Barrett metaplasia

  • Esophageal cancer

  • Gastric vascular antral ectasia (GAVE; dilated submucosal capillaries), with an endoscopic appearance that has been described as “watermelon stomach”

Nail-fold Capillary Microscopy

Nail-fold capillary microscopy is a non-invasive procedure of substantial value for the assessment of microvascular alterations in systemic sclerosis.[113, 114, 115, 116] The typical findings demonstrate fewer capillaries than normal (ie, capillary loop drop; see image below) and numerous dilated, and irregular and tortuous capillary loops. Recent evidence indicates a predictive value of nailfold capillaroscopy for future severe organ involvement.

Fingernail capillary bed demonstrating capillary d Fingernail capillary bed demonstrating capillary dropout with large dilated vessels.

Histologic Findings

Skin biopsies and lung biopsies provide conclusive diagnosis of systemic sclerosis, however, these are not routinely used for diagnostic purposes as the diagnosis of systemic sclerosis is based on the clinical manifestations. However, biopsy specimens are obtained to exclude systemic sclerosis mimics as listed in Diagnostic Considerations.

The pathologic changes in systemic sclerosis encompass a spectrum reflecting variable stages of development and progression of the three major processes occurring in the affected tissues, as follows:

  • Severe tissue fibrosis with exaggerated deposition of collagen and other connective tissue components in the extracellular matrix

  • Chronic inflammation, occurring predominantly in the early stages of disease and characterized by infiltration with mononuclear cells, mostly of the macrophage and T-cell lineages

  • Microvascular disease, characterized by intimal proliferation, concentric subendothelial deposition of collagen and mucinous material, and narrowing and thrombosis of the vessel lumen

The histopathological findings in the skin include marked thickening of the dermis with massive accumulation of dense collagen causing epidermal atrophy, flattening of the rete pegs, and replacement of sebaceous and sweat glands, as well as hair follicles (see image below). A prominent inflammatory infiltrate is often present at the dermal-adipose tissue interphase, especially in early lesions. The small vessels of the lower dermis show fibrous thickening but evidence of vasculitis is absent.

Skin biopsy showing extensive fibrosis. The biopsy Skin biopsy showing extensive fibrosis. The biopsy has a square morphology, which reflects the rigidity of the tissue biopsy specimen due to striking pan-dermal sclerosis. In addition, the fibrosing reaction extends into the panniculus. The number of adnexal structures is reduced, another characteristic feature of scleroderma. A significant inflammatory cell infiltrate is not observed. This is in contradistinction to morphea, in which a prominent inflammatory cell infiltrate is present.
Skin biopsy showing severe fibrosis. The fibrosis Skin biopsy showing severe fibrosis. The fibrosis reflects a widening of collagen bundles in concert with an increase in the number of collagen fibers. Note the superimposed deposition of the newly synthesized delicate collagen bundles interposed between the preexisting collagen bundles, the latter appearing wide and manifesting a hyalinized morphology.

In the lungs, fibrosis of the alveolo-capillary membrane and the parenchymal interstitium accompanied by severe mononuclear cell infiltration is present frequently, resulting in marked disruption of their architecture. Prominent vascular abnormalities with intimal proliferation causing narrowing or complete obliteration of small vessels are frequent (see image below).

Lung biopsy demonstrating severe interstitial fibr Lung biopsy demonstrating severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of a pulmonary arteriole compatible with pulmonary hypertension.
Lung biopsy demonstrating expansion of the interst Lung biopsy demonstrating expansion of the interstitium of the lung by fibrous tissue along with chronic inflammatory cells.

The renal lesions display severe narrowing and obliteration of the medium-size arterioles due to sub-intimal accumulation of loose connective tissue and intimal and perivascular fibrosis. The glomeruli frequently appear ischemic and there is no evidence of glomerulitis. Severe interstitial, perivascular, and periglomerular fibrosis may be present in cases of long duration.

Other affected organs display variable degrees of fibrosis, mononuclear cell infiltration and microvascular obliteration and fibrosis.

 

Treatment

Approach Considerations

Current treatment of systemic sclerosis is directed toward managing complications and providing symptomatic relief. In addition, a range of disease-modifying treatments have been investigated.

Disease-modifying treatment aims at inhibiting tissue fibrosis and vascular and immune system alterations, which are the three crucial components of disease pathogenesis.[132, 133, 134, 135, 136, 137] Therapies targeting cytokine signalling, including interleukin-6 (IL-6), and other immune-inflammatory therapies, have produced promising results.[138]

To date, the US Food and Drug Administration (FDA) has not approved any disease-modifying therapies for systemic sclerosis. In June 2015, however, the FDA granted breakthrough therapy designation to the IL-6 receptor antagonist tocilizumab, to expedite its development as a treatment for systemic sclerosis.[139]  A phase 3 trial of tocilizumab in systemic sclerosis has been completed, but results have not yet been published.[140]

No placebo-controlled studies have demonstrated clear superiority for any drug except for a modest benefit from use of methotrexate.[141, 142] Numerous uncontrolled prospective and retrospective trials along with post-hoc analysis have suggested a beneficial effect from mycophenolate mofetil.[143, 144, 145] Retrospective uncontrolled studies also supported a beneficial role for D-penicillamine,[146] but a large high-dose versus low-dose controlled trial failed to demonstrate benefits of the higher dose versus the lower dose.[147]

Other agents are currently being studied for skin and lung involvement. For example, trials of rituximab have yielded promising results, with improvement of skin fibrosis and prevention of worsening lung fibrosis.[148, 149, 150, 151]

Phototherapy using longer-wavelength ultraviolet A (UVA) light (ie, UVA1, 340-400 nm) has proved beneficial for cutaneous lesions in scleroderma. UVA1 inhibits the inflammatory process and can soften former sclerotic skin lesions. However, data on this technique remain limited, and the most effective dose has yet to be determined.[152]

No serious systemic effects of UVA1 phototherapy have been reported. Skin pigmentation or tanning, which can persist for months, is the most common acute adverse effect; uncommon acute adverse effects include reactivation of herpes simplex, cholinergic urticaria, and transient and reversible changes in the appearance of moles. The risk of long-term adverse effects, particularly skin cancer, has not been determined.[152]

Transplantation

Hematopoietic stem cell transplantation (HSCT) has been shown to be effective. However, it is associated with a high rate of procedure-related complications.[153, 154, 155, 156]  

In the prospective Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3 comparison of autologous  HSCT with 12 successive monthly intravenous pulses of cyclophosphamide in 156 patients with early diffuse cutaneous systemic sclerosis, HCST was associated with higher treatment-related mortality than in the first year after treatment. However, HCST conferred a significant long-term survival benefit.[157]

In ASTIS during the first year, 13 events, including 8 treatment-related deaths, occurred in the HSCT group and 8 events with no treatment-related deaths occurred in the control group (16.5% vs. 10.4%, respectively). At 4 years, however, 15 events had occurred cumulatively in the HSCT group compared with 20 events in the control group (19% vs. 26%, respectively).[157]

In the Scleroderma: Cyclophosphamide Or Transplantation (SCOT) trial, a randomized, open-label, phase 2 trial in 75 patients with  severe scleroderma, autologous HSCT improved event-free and overall survival, at a cost of increased expected toxicity, compared with 12 monthly infusions of cyclophosphamide. Rates of treatment-related death and post-transplantation use of disease-modifying antirheumatic drugs (DMARDs) were lower than those in previous reports of nonmyeloablative transplantation.[158]

In SCOT participants who received a transplant or completed 9 or more doses of cyclophosphamide, event-free survival was 79% in the transplantation group and 50% in the cyclophosphamide group (P = 0.02) at 54 months and 74% vs 47%, respectively, at 72 months (P = 0.03), By 54 months, 9% of the participants in the transplantation group had initiated DMARDs, as compared with 44% of those in the cyclophosphamide group (P = 0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months; no treatment-related deaths occurred in the cyclophosphamide group.[158]  

A review by Sullivan et al of HSCT for patients with scleroderma and pulmonary involvement suggested that indications for referral for HSCT in this population may include the following[159] :

  • Diffuse cutaneous systemic sclerosis with internal organ involvement
  • Age < 65 years
  • Disease duration < 5 years
  • Modified Rodnan skin thickness score (MRSS) >15
  • Early pulmonary involvementj, documented on High-resolution computed tomography (HRCT) and pulmonary function tests (PFTs)

These authors recommended the following as PFT criteria for pulmonary involvement[159] :

  • Forced vital capacity (FVC) or hemoglobin‐adjusted diffusing capacity of the lungs for carbon monoxide (DLCO) between 80% and 45% predicted
  • A decline in FVC of >10% or DLCO of >15% on serial testing
  • Failure to respond to initial therapy on serial PFT monitoring

Recommended exclusion criteria for HSCT include the following[159] :

  • FVC or hemoglobin‐adjusted DLCO of < 45% predicted
  • Pulmonary arterial hypertension
  • Cardiac insufficiency or involvement with systemic sclerosis
  • Renal insufficiency
  • Prior cyclophosphamide treatment of >6 months’ duration

Current studies of autologous stem cell transplantation, including a large randomized control study, the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, are ongoing.

Skin Fibrosis

Numerous experimental drugs or interventions have been investigated for treatment of skin induration and fibrosis in systemic sclerosis. Interventions that have demonstrated benefit include the following:

  • D-penicillamine[146, 147]

  • Bovine collagen[160] - Possible benefit in late-phase disease

  • Methotrexate[141, 142]

  • Mycophenolate mofetil[143, 144, 145]

  • Allogeneic bone marrow transplantation[148, 149, 150, 151, 153, 154, 155]

Interventions that have failed to demonstrate significant benefit for treatment of skin induration and fibrosis in systemic sclerosis include the following:

  • Human relaxin[161]

  • Interferon-alpha[162]

  • Anti–transforming growth factor beta antibodies[163]

Pruritus

Treatment measures for pruritus include the following[164] :

  • Moisturizers
  • Histamine 1 (H1) and histamine 2 (H2) blockers
  • Tricyclic antidepressants
  • Trazodone

Raynaud Phenomenon

Raynaud phenomenon can be treated with the following agents[45, 46, 165] :

  • Calcium channel blockers (increasing the dose to tolerance)
  • Prazosin
  • Prostaglandin derivatives (eg, prostaglandin E1)
  • Dipyridamole
  • Aspirin
  • Topical nitrates

Sildenafil, an inhibitor of phosphodiesterase 5 (PDE-5), has been approved for treatment of pulmonary hypertension. In addition, it has been shown to be effective and well tolerated in patients with Raynaud phenomenon.[166, 167, 168]

In the event of thrombosis and vascular flow compromise, a tissue plasminogen activator, heparin, and urokinase may be necessary.[169] In very severe cases, patients may benefit from intravenous iloprost or related prostanoids. Some patients may require pharmacologic cervical sympathectomy or surgical digital sympathectomy.[170, 171, 172]

Digital ulcers

Repeated episodes of Raynaud phenomenon in individuals with systemic sclerosis may result in digital ulcers. Bosentan, a dual endothelin receptor antagonist approved for treatment of systemic sclerosis–associated pulmonary hypertension, may curtail the formation of new digital ulcers.[173, 174] Combination therapy with iloprost and bosentan has also shown benefit in reducing new digital ulcers.[175] Ambrisentan and other endothelin receptor antagonists have also shown beneficial effects in preliminary or open label studies.[176, 177]

Gastrointestinal Involvement

Treatments for gastrointestinal symptoms of systemic sclerosis include the following[51, 178, 179] :

  • Antacids
  • Histamine 2 (H2) blockers
  • Reflux and aspiration precautions
  • Proton pump inhibitors
  • Prokinetic agents
  • Octreotide
  • Stool softeners
  • Laxatives

Pulmonary Fibrosis/Alveolitis

Although there is some controversy regarding the beneficial effects of immunosuppressive therapy in idiopathic pulmonary fibrosis, numerous studies support the use of these agents in systemic sclerosis–associated interstitial lung disease.[180, 181] Pulmonary fibrosis in systemic sclerosis has been successfully treated with cyclophosphamide, either orally or in intravenous pulses.[182, 183, 184] Several nonrandomized studies have also shown benefit from mycophenolate mofetil.[143, 144, 145, 185, 186]

Nintedanib was approved by the FDA in September 2019 to slow the rate of decline in pulmonary function in patients who have interstitial lung disease associated with scleroderma. Nintedanib is a tyrosine kinase inhibitor that targets growth factors (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGFR] 1-3, colony-stimulating factor 1 receptor [CSFIR]) that are implicated in the pathogenesis of interstitial lung diseases.

Approval of nintedanib was based on results from the phase 3 SENSCIS trial (n=576). Results showed that nintedanib slowed the loss of pulmonary function by 41 mL/year in patients with systemic sclerosis–related interstitial lung disease relative to placebo, as measured by forced vital capacity (FVC) over a 52- week period.[203]

Pulmonary Hypertension

Numerous newer agents have been approved by the FDA for the treatment of pulmonary arterial hypertension (PAH). These include the following:

  • Prostaglandin derivatives such as epoprostenol, treprostinil, beraprost, and iloprost
  • Phosphodiesterase type 5 (PDE-5) inhibitors such as sildenafil and tadalafil
  • Endothelin receptor antagonists such as bosentan, ambrisentan and macitentan

The combination of ambrisentan and tadalafil was approved by the FDA in October 2015 as up-front therapy for PAH to reduce the risk of worsening disease and improve exercise ability.[187] In a prospective multicenter open-label trial by Hassoun et al, this combination significantly improved hemodynamics, right ventricular structure and function, and functional status in treatment-naïve systemic sclerosis patients with PAH.[188]

One study reported that warfarin provided no significant benefit in either systemic sclerosis–associated or idiopathic pulmonary arterial hypertension.[189]

Scleroderma Renal Crisis

Patients with diffuse, rapidly progressive skin involvement have the highest risk of developing scleroderma renal crisis. Renal crisis occurs in about 10% of all patients with systemic sclerosis.

Renal crisis is observed within 4 years of diagnosis in about 75% of patients but may develop as late as 20 years after diagnosis. Renal crises are slightly more common in blacks than in whites, and men have a greater risk than women. The presence of RNA polymerase III antibodies increases the risk for renal crisis.

Scleroderma renal crisis that is not treated promptly and aggressively invariably leads to renal failure requiring dialysis or renal transplantation, or even death. Consequently, it is critical to check blood pressure, monitor serum creatinine, and start angiotensin-converting enzyme (ACE) inhibitors at the earliest signs of hypertension in at-risk patients.

High doses of corticosteroids should be avoided in patients with systemic sclerosis owing to an increased risk of developing renal crisis.

Musculoskeletal Symptoms

Carpal tunnel entrapment symptoms may require local corticosteroid injections although frequently these symptoms resolve spontaneously.

Myositis may be treated cautiously with steroids (first choice), or with methotrexate or azathioprine in corticosteroid-resistant cases or when there are contraindications to corticosteroid use. Doses of prednisone greater than 40 mg/d are associated with a higher incidence of scleroderma renal crisis.

Arthralgias can be treated with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs).

Pregnancy

Pregnancy in women with systemic sclerosis is considered a high risk because of a higher risk of pregnancy loss and higher complication rates, but a diagnosis of systemic sclerosis without pulmonary hypertension is not an absolute contraindication for pregnancy. However, there is an increased risk of maternal mortality during pregnancy in patients with pulmonary hypertension and some consider that pulmonary hypertension is a contraindication for pregnancy.[190] A study of 50 patients (67 pregnancies) showed that 18% miscarried, 26% delivered preterm, and 55% delivered at full term.

Pregnancy risk is greatest in those who have had the disease for less than 4 years and who also have diffuse cutaneous involvement.

Some systemic sclerosis symptoms may increase during pregnancy (eg, edema, arthralgias, gastroesophageal reflux disease [GERD]). Skin manifestations are not reported to worsen. Raynaud symptoms may improve during pregnancy, only to worsen after delivery.

Certain medications, such as D-penicillamine, mycophenolate mofetil, cytotoxic agents, and angiotensin-converting enzyme (ACE) inhibitors, should be discontinued prior to pregnancy

Surgical Care

Digital sympathectomy and botulinum toxin injections may be used in patients with severe Raynaud phenomenon who have an unrelenting acute attack and who are threatened by digital loss. Many ulcers require management by a wound care specialist. Debridement or amputation may be required in severe ischemic or infected digital lesions. Digital sympathectomy may be indicated in severe cases.

Hand surgery may be performed to correct severe flexion contractures.

Removal of severely painful, draining or infected calcinotic deposits is occasionally required.

Surgical fundoplication may be required to treat severe esophageal reflux with complicating aspiration pneumonitis. Laser ablation or even gastric antrectomy may be required to control persistent bleeding caused by gastric antral vascular ectasia (GAVE).

Episodes of acute abdominal pain need to be evaluated with extreme care to avoid the misdiagnosis of an acute abdomen since occasionally patients with systemic sclerosis present with symptoms of acute abdomen that resolve with proper medical treatment and do not require surgical intervention (pseudo acute abdomen).

Diet

There are no specific dietary recommendations in patients with systemic sclerosis. Appropriate caloric intake should be encouraged. The following points may be considered:

  • Patients with esophageal involvement should avoid hard solid foods

  • Patients with intestinal hypomotility may benefit from high-fiber diets

  • Vitamin deficiencies and malabsorption should be addressed in patients with frequent or severe bacterial overgrowth

  • Large doses of vitamin C (>1000 mg/d) should be avoided because this stimulates collagen formation and may enhance fibrotic tissue deposition

A study of 51 Romanian patients with systemic sclerosis that 25hydroxy-hydroxyvitamin D serum levels were insufficient in approximately two thirds of cases, and inadequate in almost one quarter. Vitamin D levels did not correlate with extent of skin involvement, but low levels did seem to be related to more aggressive disease with multivisceral and severe organ involvement, especially pulmonary and cardiac.[191]

Activity

Recommendations regarding activity include the following:

  • Ensure that the patient maintains a core body temperature to try to minimize the occurrence of Raynaud phenomenon episodes.

  • Assist the patient in avoiding contamination of any skin wound caused by ischemic lesions or calcinosis.

  • Digital ulcers must be kept clean and dry.

  • Instruct the patient to perform continuous physical and occupational therapy to maintain joint range of motion and to minimize or delay joint contractures.

  • Encourage patients with pulmonary fibrosis to receive pulmonary rehabilitation treatment.

Consultations

All patients with systemic sclerosis should be treated in conjunction with an experienced rheumatologist who has a full understanding of the disease, the complications of the therapies, and the frequently serious adverse effects. Consultation with an experienced practitioner can help avoid potentially fatal pulmonary, vascular, or renal complications.

Patients with systemic sclerosis may need to be treated by other subspecialists, depending on the involvement of specific organ systems (eg, cardiologist, pulmonologist, gastroenterologist, nephrologist, endocrinologist, vascular surgeon, wound care specialist, hand surgeon).

Renal and lung transplantation are performed in specialized centers for patients with end-stage renal or lung involvement.

Long-term Monitoring

Evaluate the patient every 3-6 months, depending on the disease activity and progression. Serial skin scoring (also known as the modified Rodnan skin score) is useful for monitoring skin changes over time. New techniques are currently being studied. For example, durometry, a technique for objectively measuring skin involvement, uses digital, hand-held, spring-loaded devices that measure hardness by applying an indentation load.[192] Follow up for other complications, as well.

 

Medication

Medication Summary

Pharmacologic therapy consists principally of treatment directed toward complications of the disease and providing symptomatic relief. Nintedanib is the first treatment approved by the FDA to slow the rate of decline in pulmonary function in adults with interstitial lung disease associated with scleroderma.

Corticosteroids

Class Summary

These agents are used to treat inflammatory complications (eg, myositis, pneumonitis).

Prednisone (Deltasone, Rayos, Prednisone Intensol, Sterapred, Sterapred DS)

Prednisone is an immunosuppresant used for treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing inflammatory cell activity. Prednisone is inactive and must be metabolized to prednisolone. Metabolism may be impaired in patients with liver disease.

Immunosuppressive agents

Class Summary

These agents inhibit key steps in immune reactions.

Azathioprine (Azasan, Imuran)

Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA and RNA. It may decrease proliferation of immune cells, which results in lower autoimmune activity.

Methotrexate (Trexall, Rheumatrex, Otrexup, Rasuvo)

Methotrexate is an antimetabolite that inhibits DNA synthesis and cell division in malignant cells. It may suppress the immune system. Satisfactory response is observed in 3-6 wk following administration

Cyclophosphamide (Cytoxan)

Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth and proliferation of normal and neoplastic cells.

Mycophenolate (CellCept, Myfortic, MMF)

Mycophenolate is a potent selective, noncompetitive, and reversible inhibitor of purine synthesis. It has cytostatic effects on lymphocytes. It may suppress the immune system.

Rituximab (Rituxan)

Rituximab is a potent immunosuppressive drug that acts by causing a selective depletion of B lymphocytes. Rituximab was initially approved for treatment of certain hematologic malignancies. However, owing to its potent immunosuppressive effects, its use in the therapy of autoimmune diseases, including systemic sclerosis, is expanding rapidly.

Pulmonary, Tyrosine Kinase Inhibitors

Class Summary

Nintedanib is a tyrosine kinase inhibitor that targets growth factors (eg, vascular endothelial growth factor receptor [VEGFR], fibroblast growth factor receptor [FGFR], platelet-derived growth factor receptor [PDGFR] 1-3, colony-stimulating factor 1 receptor [CSFIR]) that are implicated in the pathogenesis of interstitial lung diseases.

Nintedanib (Ofev)

Indicated to slow the rate of decline in pulmonary function in patients who have interstitial lung disease associated with scleroderma.

Endothelin receptor antagonist

Class Summary

These agents bind to endothelin receptors present in endothelium and vascular smooth muscle cells. The effect can result in vasodilation.

Bosentan (Tracleer)

Bosentan is a dual endothelin A and B receptor antagonist for treatment of pulmonary arterial hypertension. It decreases both pulmonary and systemic vascular resistance and increases cardiac output without increasing heart rate

Ambrisentan (Letairis)

Ambrisentan is an endothelin receptor antagonist indicated for pulmonary arterial hypertension in patients with World Health Organization (WHO) class II or III symptoms. It improves exercise ability and decreases progression of clinical symptoms. Ambrisentan inhibits vessel constriction and elevation of blood pressure by competitively binding to endothelin-1 receptors ETA and ETB in endothelium and vascular smooth muscle. This leads to significant increase in cardiac index associated with significant reduction in pulmonary artery pressure, pulmonary vascular resistance, and mean right atrial pressure.

Because of the risks of hepatic injury and teratogenic potential, this agent is available only through the Letairis Education and Access Program (LEAP). Prescribers and pharmacies must register with LEAP in order to prescribe and dispense. For more information, see http://www.letairis.com or call (866) 664-LEAP (5327).

Macitentan (Opsumit)

Macitentan is a novel agent acting as dual endothelin receptor-1(ETA and ETB) antagonist with sustained receptor-binding properties. It has been approved by the FDA for the treatment of pulmonary hypertension. Studies assessing its efficacy and safety in ischemic digital ulcers secondary to Raynaud phenomenon is systemic sclerosis are under way.

PAH, PDE-5 Inhibitors

Class Summary

These agents may increase vasodilation in the pulmonary vascular bed.

Tadalafil (Adcirca)

Tadalafil is aphosphodiesterase type-5 inhibitor indicated for improving and increasing exercise capacity in patients with World Health Organization (WHO) class I pulmonary arterial hypertension. It increases cyclic guanosine monophosphate (cGMP), which is the final mediator in the nitric-oxide pathway. Tadalafil has been shown to improve systemic sclerosis associated pulmonary hypertension and Raynaud phenomenon. Tadalafil has an extended half-life and therefore can be administered once daily without compromising its effectiveness.

Sildenafil (Revatio)

Sildenafil promotes selective smooth muscle relaxation in lung vasculature, possibly by inhibiting phosphodiesterase type 5. This effect results in subsequent reduction of pulmonary artery pressure and increase in cardiac output.

Sildenafil has been shown to be effective in reducing pulmonary artery pressure in systemic sclerosis associated pulmonary hypertension. Because of its potent peripheral vasculature vasodilatory effects it has also been used for treatment of severe Raynaud phenomenon with digital ulcers. However, owing to the short duration of its vasodilatory effects, sildenafil has to be administered several times per day.

Chelating agents

Class Summary

These agents may improve the fibrotic aspects of systemic sclerosis.

Penicillamine (Cuprimine, Depen)

Penicillamine inhibits the formation of mature collagen crosslinks, rendering un-crosslinked molecules more susceptible to proteolytic degradation. The inhibition of collagen crosslink formation very likely causes a marked decrease in tissue stiffness, an important profibrotic mechanism.

 

Follow-up

Further Outpatient Care

Evaluate the patient every 3-6 months, depending on the disease activity and progression. Serial skin scoring (also known as the modified Rodnan skin score) is useful for monitoring skin changes over time. New techniques are currently being studied. For example, durometry, a technique for objectively measuring skin involvement, uses digital, hand-held, spring-loaded devices that measure hardness by applying an indentation load.[192] Follow up for other complications, as well.

Further Inpatient Care

Patients with systemic sclerosis may need to be treated by other subspecialists, depending on the involvement of specific organ systems (eg, cardiologist, pulmonologist, gastroenterologist, nephrologist, endocrinologist, vascular surgeon, wound care specialist, hand surgeon).

Renal and lung transplantation are performed in specialized centers for patients with end-stage renal or lung involvement.

Current studies of autologous stem cell transplantation, including a large randomized control study (SCOT trial), are ongoing. Several uncontrolled studies have indicated that this procedure may lead to disease remission.

 

Questions & Answers

Overview

What is scleroderma?

What is systemic sclerosis?

What are the types of systemic sclerosis?

What are the ACR/EULAR Revised Systemic Sclerosis Classification Criteria?

What is the pathophysiology of scleroderma?

What is the role of vascular alterations in the pathogenesis of scleroderma?

What causes scleroderma?

What is the prevalence of scleroderma in the US?

What is the global prevalence of scleroderma?

What are the racial predilections of scleroderma?

What are the sexual predilections of scleroderma?

Which age groups have the highest prevalence of scleroderma?

What is the prognosis of scleroderma?

What are the possible complications of scleroderma?

What are the mortality rates of scleroderma?

What is included in patient education about scleroderma?

Presentation

Which organ systems are affected by scleroderma?

What are the dermatologic signs and symptoms of scleroderma?

What are the signs and symptoms of vascular involvement in scleroderma?

What are the GI signs and symptoms of scleroderma?

What are the respiratory signs and symptoms of scleroderma?

What are the musculoskeletal signs and symptoms of scleroderma?

What are the cardiac signs and symptoms of scleroderma?

What are the renal signs and symptoms of scleroderma?

What are the genitourinary signs and symptoms of scleroderma?

What are the ocular and ENT signs and symptoms of scleroderma?

What are the neurologic and psychiatric signs and symptoms of scleroderma?

What are the constitutional signs and symptoms of scleroderma?

Which dermatologic findings are characteristic of scleroderma?

Which ENT findings are characteristic of scleroderma?

Which ocular findings are characteristic of scleroderma?

Which physical findings are characteristic of Raynaud phenomenon in scleroderma?

Which physical findings are characteristic of vascular involvement in scleroderma?

Which musculoskeletal findings are characteristic of scleroderma?

Which respiratory findings are characteristic of scleroderma?

Which GI findings are characteristic of scleroderma?

Which renal findings are characteristic of scleroderma?

Which cardiac findings are characteristic of scleroderma?

Which neurologic findings are characteristic of scleroderma?

Which genitourinary findings are characteristic of scleroderma?

DDX

Which conditions are included in the differential diagnoses of scleroderma?

Workup

How is scleroderma diagnosed?

Which lab tests are performed in the workup of scleroderma?

How is GI involvement assessed in scleroderma?

How is pulmonary involvement assessed in scleroderma?

How is cardiovascular involvement assessed in scleroderma?

What is the role of radiography in the workup of scleroderma?

How are microvascular alterations assessed in scleroderma?

What is the role of lab tests in the workup of scleroderma?

What is the role of autoantibody testing in the workup of scleroderma?

What is the role of CT scanning in the workup of scleroderma?

What is the role of pulmonary function tests in the workup of scleroderma?

What is the role of transthoracic echocardiography in the workup of scleroderma?

What is the role of ECG in the workup of scleroderma?

What is the role of endoscopy in the workup of scleroderma?

What is the role of nail-fold capillary microscopy in the workup of scleroderma?

What is the role of biopsy in the diagnosis of scleroderma?

Which pathologic changes are characteristic of scleroderma?

Which histologic findings are characteristic of scleroderma?

Treatment

How is scleroderma treated?

What is the role of HSCT in the treatment of scleroderma?

When is HSCT indicated for the treatment of scleroderma with pulmonary involvement?

What are pulmonary function test (PFT) criteria for pulmonary involvement in scleroderma?

What are the exclusion criteria for HSCT for the treatment of scleroderma with pulmonary involvement?

How is skin fibrosis in scleroderma treated?

How is pruritus treated in scleroderma?

How is Raynaud phenomenon treated in scleroderma?

How are digital ulcers treated in scleroderma?

How are the GI symptoms of scleroderma treated?

How is scleroderma pulmonary fibrosis treated?

How is pulmonary arterial hypertension (PAH) in scleroderma treated?

How is a scleroderma renal crisis treated?

How are the musculoskeletal symptoms of scleroderma treated?

How is scleroderma treated during pregnancy?

What is the role of surgery in the treatment of scleroderma?

Which dietary modifications are used in the treatment of scleroderma?

Which activity modifications are used in the treatment of scleroderma?

Which specialist consultations are beneficial to patients with scleroderma?

What is included in the long-term monitoring of scleroderma?

Medications

What is the role of medications in the treatment of scleroderma?

Which medications in the drug class PAH, PDE-5 Inhibitors are used in the treatment of Scleroderma?

Which medications in the drug class Endothelin receptor antagonist are used in the treatment of Scleroderma?

Which medications in the drug class Pulmonary, Tyrosine Kinase Inhibitors are used in the treatment of Scleroderma?

Which medications in the drug class Immunosuppressive agents are used in the treatment of Scleroderma?

Which medications in the drug class Corticosteroids are used in the treatment of Scleroderma?

Which medications in the drug class Chelating agents are used in the treatment of Scleroderma?

Follow-up

What continued outpatient care is indicated in the treatment of scleroderma?

When is inpatient care indicated in the treatment of scleroderma?