Scleroderma

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 1. ACR/EULAR Revised Systemic Sclerosis Classification Criteria (Open Table in a new window)

Historical background

Hippocrates first described this condition as thickened skin.[3, 4] 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.[5] 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.[6]

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.

Systemic sclerosis is a systemic disease that affects numerous organ systems in addition to the skin. The pathogenesis of systemic sclerosis is complex.[7, 8, 9, 10, 11, 12, 13, 14]  Increasing evidence suggests interaction between environmental and genetic factors, with a regulatory epigenetic mechanism involving changes in the expression of DNA and microRNA.[15]

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 those 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 potent mediators—including cytokines, chemokines, polypeptide growth factors, and various other substances such as prostaglandins, and 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 immunologic 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 proposed sequence of events involved in tissue fibrosis and fibroproliferative vasculopathy in systemic sclerosis. 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. The activated myofibroblasts produce exaggerated amounts of extracellular matrix, 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.[9]

Endothelial dysfunction and fibrosis appear to be closely related phenomena. 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.[9, 10]

The activation of endothelial cells induces the expression of chemokines and cell adhesion molecules, and 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. Those 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 cartilage oligomeric matrix protein (COMP), glycosaminoglycans, tenascin, and fibronectin.[11, 12] This crucial component results from the accumulation in skin and other affected tissues of myofibroblasts, which are cells possessing unique biological functions that include 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.[13, 14] 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.[11, 12] 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.

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. In individuals with a genetic predisposition, environmental factors (eg, triggers or accelerators) may contribute to the development of systemic sclerosis.[16, 17, 18, 19, 20] These factors 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.[21]  

Cytomegalovirus, human herpesvirus 5, and parvovirus B19 have been proposed as viral accelerating factors. However, evidence of their involvement is inconclusive.[22]

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.[23, 24, 25] 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; for example, higher prevalence rates are reported in Europe and North and South America than in East Asia.[24, 25, 26, 27] 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.[28, 29, 30, 31]

Race

Systemic sclerosis affects individuals of all races.[28, 29, 30, 31] However, incidence rates, severity and mortality may vary among ethnic groups.

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.[28, 29, 30, 31]

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.[32] Similarly, a prevalence rate of 47 per 100,000 has been found in the indigenous peoples in Canada.[25]

Sex- and age-related disparities

The risk of systemic sclerosis is 4-9 times higher in women than in men.[23, 24, 25] However, the mechanisms responsible for the disproportionately higher frequency in females have not been elucidated.

A multicenter cohort of 2281 patients from the Italian Systemic sclerosis PRogression INvestiGation (SPRING) registry documented an overall female/male ratio of 8.2:1. Males were found to have a shorter time from onset of Raynaud phenomenon to systemic sclerosis diagnosis and an increased prevalence of the diffuse cutaneous subset, renal crisis, and digital ulcers. Women demonstrated a significantly higher percentage of sicca syndrome, serum antinuclear antibodies, antiextractable nuclear antigens, anti-La/SSB, and anticentromere protein.[33]

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

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
• Kidney 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.[34] Lunate osteonecrosis manifests as pain and stiffness in the affected wrist and decreased grip strength in the hand.

A cross-sectional study that included 90 women with systemic sclerosis and 90 healthy controls aged 18–70 years documented a high prevalence of impaired pelvic floor function and sexual function in women with systemic sclerosis. The prevalence of female sexual dysfunction was 73% in systemic sclerosis patients versus 31% in the controls. Impaired sexual function correlated with higher disease activity, the presence of dyspnea and interstitial lung disease, increased systemic inflammation, reduced physical activity, functional disability, more severe depression, more pronounced fatigue, and impaired quality of life.[35]

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 death.[36, 37, 38, 39, 40, 41, 42, 43]

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).

For patients with scleroderma renal crisis, 1-year mortality is 20-30% and 5-year mortality is 30-50%; for normotensive scleroderma renal crisis, which accounts for about 10% of all cases, 1-year mortality is 60%.[44] Half of patients with scleroderma require hemodialysis, and kidney function recovers spontaneously in only one quarter of those. Predictors of worse outcome in patients with scleroderma renal crisis include the following[45] :

• Older age
• Male gender
• Serum creatinine > 3 mg/dL at presentation
• Incomplete blood pressure control within the first 3 days of the crisis
• Normal blood pressure
• Use of an angiotensin-converting enzyme (ACE) inhibitor prior to scleroderma renal crisis is also an independent predictor of poor outcome, possibly because by keeping the blood pressure under control, the medication blunts recognition of the unfolding renal crisis.

Mortality associated with scleroderma renal crisis has declined significantly in recent decades. 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.

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.

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

• Skin ^{[46, 47, 48]}
• Vascular ^{[49, 50, 51, 52, 53, 54, 55]}
• Gastrointestinal (GI) ^{[56, 57, 58, 59, 60, 61]}
• Respiratory ^{[62, 63, 64]}
• Musculoskeletal ^{[65, 66, 67, 68, 69]}
• Cardiac ^{[70, 71, 72, 73, 74, 75]}
• Renal ^{[76, 77, 78, 79]}
• Genitourinary ^{[80, 81, 82, 83]}
• Eyes, ears, nose, and throat ^{[84, 85, 86, 87]}
• Endocrine ^{[88, 89]} - Hypothyroidism
• Neurologic/psychiatric ^{[90, 91, 92, 93, 94]}
• 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).

  Scleroderma: Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and sparse hair.

• Tightening of the skin in the face is often noted very early in the course of the disease (see image below)

  Scleroderma: Tightening of the skin in the face, with a characteristic beaklike facies and paucity of wrinkles.

• Prominent skin pigmentary changes—both hyperpigmentation and hypopigmentation (see image below)

  Scleroderma: 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
• Gastric angioectasias

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 (due to abnormal gut peristalsis)
• Constipation alternating with diarrhea from bacterial overgrowth (may lead to malabsorption)
• Fecal incontinence
• Malnutrition from inadequate caloric intake
• Occult gastrointestinal blood loss (usually due to gastric antral vascular angioectasias (GAVE), sometimes termed "watermelon stomach")

Respiratory manifestations

Respiratory complaints 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
• Other manifestations 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
• Oliguric acute kidney injury (a result of "renal crisis")
• Chronic kidney insufficiency

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

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.

Scleroderma: Tightening of the skin in the face, with a characteristic beaklike facies and paucity of wrinkles.

Scleroderma: 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)

  Scleroderma: 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, 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.[95]

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—pallor, cyanosis, and then erythema (white, blue, red)—in the fingers, toes and other acral body parts, 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 on 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.

  Scleroderma: 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.

• The murmur of tricuspic regurgitation (a high-pitched holosystolic murmur heard best at the left lower sternal border with radiation to the right sternal border) may be heard and is usually a result of the late stages 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.

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).

Scleroderma: 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
• Mucosal telangiectasia
• Anal sphincter incompetence

Renal system

Renal crisis presents as the following:

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

Cardiac system

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

Cor pulmonale manifests on physical exam with progressive lower extremity edema, jugular vascular distension, and the murmur of tricuspid regurgitation.

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

Cardiac system

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

Gastrointestinal system

Gastric antral vascular ectasias (GAVE, sometimes termed "watermelon stomach") may lead to rapid or chronic, progressive iron deficiency anemia due to blood loss.

Complications of disrupted lower esophogeal sphincter tone may lead to aspiration events.

Renal system

Scleroderma renal crisis occurs most often in patients with early, rapidly progressing, diffuse skin involvement. This manifestation occurs in approximately 10% of cases.  However, in 20% of cases these patients have no skin disease, and renal crisis is their first manifestation of scleroderma.[45]

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.

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
• C-reactive protein
• Creatinine
• 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 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 annually to identify arrhythmias and conduction defects. Consider performing baseline ECGs in all new patients with sclerderma. ECGs can identify early changes of right ventricular strain caused by pulmonary hypertension, and in advanced states, right atrial hypertrophy. 24-hour ambulatory Holter monitoring may be performed 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. Especially in patients with diffuse disease and in those with decreases in diffusing capacity for carbon monoxide (DLCO), this test should be performed annually to screen for pulmonary artery hypertension.

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 may be performed as indicated to reveal calcinosis, resorption of the distal tufts of the digits, and to exclude osteomyelitis secondary to infected digital ulcers (see the image below).[111, 112]

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

• 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]

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; this finding should prompt consideration of gastric antral vascular ectasias (GAVE), which can be confirmed via an upper endoscopy.

Owing to the almost universal involvement of the immune system, most patients have specific humoral and cell-mediated immunity abnormalities.[117, 118, 119, 120] 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-Th/To  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.

Antibodies to ribonucleoprotein (U1-RNP) may be present. Anti-U1RNP 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.

Fibrillarin antibodies (anti-U3RNP) is another specific antibody for scleroderma. It generally suggests diffuse systemic sclerosis and is also associated with cardiac fibrosis as a manifestation. Patients with anti-U3RNP are also at increased risk for progressive pulmonary manifestations.

High-resolution computerized tomography (HRCT) scans are required to evaluate pulmonary involvement.[117, 121] 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. This pattern of lung involvement is often termed nonspecific interstitial pneumonia (NSIP), but cases of usual interstitial pneumonia (UIP) pattern have also been known to occur. 

HRCT scanning should be performed every 6 months if active alveolitis or interstitial pulmonary fibrosis is present.

For more information, see Thoracic Scleroderma Imaging.

Pulmonary function testing is important in all patients with systemic sclerosis,[122, 123, 124, 125] 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.

Diffusing capacity for carbon monoxide (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 (FVC) and total lung capacity (TLC) and a low DLCO. These changes reflect fibrotic infiltration in the lung. An isolated or disproportionate reduction of DLCO with an FVC/DLCO or TLC/DLCO ratio of greater than 1.6 indicates pulmonary vascular obliteration associated with pulmonary hypertension.

Transthoracic echocardiography is a noninvasive study for assessing pulmonary artery pressure.[24, 126] 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.

Electrocardiograms should be performed annually to identify arrhythmias and conduction defects.[127, 128] 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.

Esophagogastroduodenoscopy with appropriate biopsies, esophageal manometry assessment, and pH monitoring studies should be performed to survey and evaluate the upper gastrointestinal system.[129, 130] The following disorders 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 is a non-invasive procedure of substantial value for the assessment of microvascular alterations in systemic sclerosis.[113, 114, 115, 116] Typical findings in systemic sclerosis are fewer capillaries than normal (ie, capillary loop drop; see image below) and numerous dilated, irregular, tortuous capillary loops. Severe findings on nail-fold capillaroscopy appear to predict future severe organ involvement.[116]

Scleroderma: Fingernail capillary bed demonstrating capillary dropout with large dilated vessels.

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 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 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 the images below).

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 interstitium of the lung by fibrous tissue along with chronic inflammatory cells.

Kidney 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.

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.[131, 132, 133, 134, 135] Therapies targeting cytokine signalling, including interleukin-6 (IL-6), and other immune-inflammatory therapies, have produced promising results.[136]

To date, the US Food and Drug Administration (FDA) has approved nintedanib and as well as tocilizumab for refractory, progressive intersitial lung disease due to systemic sclerosis.

A phase 3 trial of tocilizumab in systemic sclerosis failed to meet its primary endpoint of improvement in modified Rodnan skin score; however, tocilizumab therapy did result in preservation of lung function. After 48 weeks, decline in lung function from baseline, as defined by changes in predicted forced vital capacity (FVC), had occurred 50.5% of patients in the tocilizumab arm, versus 70.3% of those in the placebo arm (P = 0.015). In patients with systemic sclerosis–related interstitial lung disease, a clinically meaningful decline of 10% or more in lung function was seen in 24.5% of placebo recipients, compared with 8.6% of tocilizumab recipients. Supporting the FVC results, high-resolution computed tomography showed less progression of lung fibrosis with tocilizumab than with placebo.[137, 138, 139]

No placebo-controlled studies have demonstrated clear superiority for any drug except for a modest benefit from use of methotrexate[140, 141] and improvement in scleroderma-related interstitial lung disease with cyclophosphamide.[142, 143] Numerous uncontrolled prospective and retrospective trials along with post-hoc analysis have suggested a beneficial effect from mycophenolate mofetil.[144, 145, 146] Retrospective uncontrolled studies also supported a beneficial role for D-penicillamine,[147] but a large high-dose versus low-dose controlled trial failed to demonstrate benefits of the higher dose versus the lower dose.[148]

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.[149, 150, 151, 152] The tyrosine kinase inhibitor nintedanib is approved for slowing the rate of decline in pulmonary function in adults with systemic sclerosis–related interstitial lung disease.

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.[153]

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.[153]

Transplantation

Hematopoietic stem cell transplantation (HSCT) has been shown to be effective. However, it is associated with a high rate of procedure-related complications.[154, 155, 156, 157]  

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.[158]

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).[158]

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.[159]

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.[159]  

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[160] :

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

These authors recommended the following as PFT criteria for pulmonary involvement[160] :

• 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[160] :

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

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 ^{[147, 148]}
• Bovine collagen ^[161] - Possible benefit in late-phase disease
• Methotrexate ^{[140, 141]}
• Mycophenolate mofetil ^{[144, 145, 146]}
• Allogeneic bone marrow transplantation ^{[149, 150, 151, 152, 154, 155, 156]}

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

• Human relaxin ^[162]
• Interferon-alpha ^[163]
• Anti–transforming growth factor beta antibodies ^[164]

Treatment measures for pruritus include the following[165] :

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

Raynaud phenomenon can be treated with the following agents[50, 51, 166] :

• 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.[167, 168, 169]

In the event of thrombosis and vascular flow compromise, a tissue plasminogen activator, heparin, and urokinase may be necessary.[170] In very severe cases, patients may benefit from intravenous iloprost or related prostanoids. Some patients may require pharmacologic cervical sympathectomy or surgical digital sympathectomy.[171, 172, 173]

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.[174, 175] Combination therapy with iloprost and bosentan has also shown benefit in reducing new digital ulcers.[176] Ambrisentan and other endothelin receptor antagonists have also shown beneficial effects in preliminary or open-label studies.[177, 178]

Treatments for gastrointestinal symptoms of systemic sclerosis are listed below.[56, 179, 180]

Gastroesophageal reflux disease:

• Antacids
• Histamine 2 (H2) blockers
• Reflux and aspiration precautions
• Proton pump inhibitors

Gastroparesis:

• Prokinetic agents
• Octreotide

Colonic / anorectal dysmotility:

• Stool softeners
• Laxatives

Some patients with scleroderma may also develop small intestinal bacterial overgrowth (SIBO). This manifestation generally improves with the addiition of rifaximin.[181]

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.[182, 183] Pulmonary fibrosis in systemic sclerosis has been successfully treated with cyclophosphamide, either orally or in intravenous pulses.[184, 142, 143] Several nonrandomized studies showed benefit from mycophenolate mofetil.[144, 145, 146, 185, 186] The Scleroderma Lung Study II (SLS-II), a double-blind, parallel group, randomized controlled trial, found that a 2-year course of mycophenolate mofetil was better tolerated and associated with less toxicity than 12 months of oral cyclophosphamide, and yielded comparable significant improvements in lung function, dyspnea, lung imaging, and skin disease.[187]

Nintedanib was approved by the FDA in 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.[188]

Tocilizumab, an anti-IL-6 inhibitor has also shown promise for the treatment of interstitial lung disease due to scleroderma. In the focuSSed trial with open-label extension, the decline in FVC over 48 months was 14 mL in the tocilizumab group compared with 255 mL in the placebo group.[189]

Numerous 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 2015 as up-front therapy for PAH to reduce the risk of worsening disease and improve exercise ability.[190] 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.[191]

One study reported that warfarin provided no significant benefit in either systemic sclerosis–associated or idiopathic pulmonary arterial hypertension.[192]

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.[45]

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 kidney failure requiring dialysis or kidney 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. The preferred ACE inhibitor of choice is captopril, owing to its short half-life and ease to titrate quickly, which aid in managing the hypertensive urgency that is common in patients presenting with scleroderma renal crisis. 

High doses of corticosteroids (> 20 mg) should be avoided in patients with systemic sclerosis owing to an increased risk of developing renal crisis.

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

Myositis may be treated cautiously with corticosteroids (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. Use of methotrexate should be guarded if there is severe or active baseline pulmonary interstitial disease.

Arthralgias can be treated with acetaminophen. In cases of more severe arthritis or inflammatory arthritis, low-dose prednisone (10 mg) may be considered for the short term. Hydroxychloroquine is generally the preferred first-line therapy for long-term treatment. Methotrexate, biologics (such as tocilizumab or abatacept), and Janus kinase inhibitors (such as tofacitinib) may also be considered in refractory cases. 

Physical therapy has been shown to be beneficial in improving hand function in patients with scleroderma.[193, 194, 195] In a randomized controlled trial in 24 patients with systemic sclerosis, Maitland's joint mobilization and therapeutic exercises, twice weekly for 12 weeks, improved hand functionality, reduced pain in the hands and wrists, increased range of motion, and improved quality of life.[193] In another study, a 4-week complex, supervised rehabilitation protocol in 27 patients improved hand and overall function for up to 6 months, compared with a control group of 24 patients prescribed a home exercise program alone. However, the improvement was not sustained after 6 months, suggesting that the rehabilitation program should be repeated every 3-6 months.[195]

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, maternal mortality during pregnancy is increased in patients with pulmonary hypertension and some consider pulmonary hypertension to be a contraindication for pregnancy.[196] 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

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).

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 found 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.[197]

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.

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).

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

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. Patients with scleroderma need annual ECGs (to screen for cardiac arrhythmias) and serial pulmonary function tests (PFTs) to screen for interstitital lung disease/pulmonary hypertension. Annual transthoracic echocardiograms may also be considered for screening. Durometry, a technique for objectively measuring skin involvement, uses digital, hand-held, spring-loaded devices that measure hardness by applying an indentation load.[198]  

Pharmacologic therapy consists principally of treatment directed toward complications of the disease and providing symptomatic relief. Nintedanib and tocilizumab are approved by the US Food and Drug Administration to slow the rate of decline in pulmonary function in adults with interstitial lung disease associated with scleroderma.

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. High dose corticosteroids (e.g.- prednisone >20mg) should be avoided in systemic sclerosis because it increases the risk of renal crisis.

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. Methotrexate use in systemic sclerosis should be avoided in severe or active interstitial lung disease.

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.

Tocilizumab (Actemra)

Tocilizumab is indicated for treatment of interstitial lung disease in systemic sclerosis that is refractory or highly progressive.

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.

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.

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.

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.

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).

Kidney and lung transplantation are performed in specialized centers for patients with end-stage kidney 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.

Patients should be counseled to keep regular follow up appointments with their rheumatologist. Patients should be vigilant to look for decreases in their exercise tolerance as cardiopulmonary disease is the largest cause of mortality in scleroderma. Patients should also be vigilant to watch their Raynaud's phenomenon closely, avoid cigarette smoke, conservatively warm their hands in cool weather/environments, and look for any developing digital tip ulcerations. Consider providing patients with diffuse systemic sclerosis a blood pressure cuff so they can monitor their blood pressure weekly (to screen for scleroderma renal crisis).