Systemic Sclerosis

Etiology

The exact etiology of SSc is not completely understood, and both genetic and environmental factors are thought to contribute to the development of SSc.

Genetic Factors

SSc has been associated with familial clustering[9][10], and there is evidence of clusters of multiple other autoimmune diseases occurring in family members of patients with SSc. [11] Genomewide association studies have confirmed the association of major histocompatibility complex genetic region with SSc, similar to other autoimmune disorders such as systemic lupus erythematosus and rheumatoid arthritis. The association of specific human leukocyte antigens (HLA), including HLA DRB1*1104, DQA1*0501, and DQB1*0301, with SSc has been long known.[12] Further, non-HLA loci such as PTPN22, NLRP1, STAT4, and IRF5 have also been implicated in the etiology of SSc.

Environmental Factors

Several environmental triggers have been associated with the subsequent development of SSc. These include infectious agents such as Cytomegalovirus (CMV), Epstein-Barr virus (EBV), and parvovirus B19. Exposure to silica dust has been associated with SSc [13], and exposure to other agents such as organic solvents, toluene, xylene, trichloroethylene, polyvinyl chloride has been occasionally linked. Cigarette smoking has not been proven to be a risk factor. Several scleroderma-like disorders (which can be differentiated from SSc by clinical, histopathologic, and laboratory features) have been associated with environmental exposures (contaminated rapeseed cooking oil with toxic oil syndrome and L-tryptophan with eosinophilia-myalgia syndrome). [14][15][16] Some drugs, such as bleomycin and cocaine, have been associated with the development of SSc-like illness.

Epidemiology

Due to its rarity, epidemiological data for systemic sclerosis are sparse, and the incidence and prevalence reported in various studies are influenced by geography, case definition, and ascertainment methods. The estimated incidence of SSc in the United States was reported to be 19.3 new cases per million adults per year, with a prevalence of 242 cases per million adults in one study conducted in the Detroit area from 1989-1991. [17] In 2003, another study from Quebec reported a prevalence of 443 cases per million adults.[18] The prevalence is greater in the United States and Australia[19] than in Europe[20] and Asia (Japan and Taiwan).[21][22] The highest prevalence of SSc (660 cases per million adults) was noted among the Choctaw Native Americans from Oklahoma, further elicits the geographical difference in the prevalence of SSc.[23]

There is an overall female predominance with a female to male ratio of about 5:1.[24] Females tend to develop SSc at an earlier age compared to males. The peak age of onset is between 45 to 54 in African American females and between 55 to 64 in European American females. The disease is rare in children and teens below 15 years of age.[25] Disease onset between ages 15 and 24 is rare, with an incidence of 21.2 per million in African American females and 11.16 per million in European American females. Patients with African ancestry have a higher risk of developing SSc, develop SSc at an earlier age, and develop more severe disease.[26]

Pathophysiology

The pathophysiology of SSc is complex and not completely understood. The hallmarks of the disease are (1) vascular insult, (2) autoimmunity, and (3) tissue fibrosis. SSc has several clinical phenotypes, which can be attributed to differences in the contribution of these in the pathogenesis of the disease in each patient.

The initial vascular insult in SSc can be triggered by several factors, including viruses, environmental exposures, autoantibodies, proteolytic enzymes, and inflammatory cytokines. This initial vascular insult leads to endothelial cell activation, followed by overexpression of adhesion molecules, leading to the activation of platelets and thrombotic and fibrinolytic cascades. Activated endothelial cells also release ET-1, a potent vasoconstrictor, and promote adhesion of leukocytes, the proliferation of vascular smooth muscle cells, and activation of fibroblasts. Activated endothelial cells transdifferentiate into mesenchymal cells with prominent functional abnormalities such as impaired responsiveness to vasodilators such as nitric oxide and prostacyclins. Activated platelets release thromboxane-A2, PDGF, and TGF-β and activate thrombin, leading to coagulation, thrombosis, vasoconstriction, and fibroblast activation. Thus, this initial vascular insult eventually leads to tissue hypoxia. Patients with SSc have an impaired compensatory vascular repair mechanism along with widespread microangiopathy and a loss of microvasculature in addition to diminished angiogenesis, which leads to chronic tissue hypoxia and oxidative stress.

Immune dysregulation and inflammation play a crucial role in the pathogenesis of SSc, with dysregulation of both innate and humoral immune systems. Activated T-cells are predominant in the tissue as well as peripheral blood in SSc. Patients with SSc have an imbalance of the T-helper 1/T-helper 2 (Th1/Th2) cytokines with a predominant Th2 profile. This Th2 profile skewing leads to more fibrosis by collagen synthesis and myofibroblast transdifferentiation due to more pro-fibrotic cytokines such as TGF-β, IL-4, IL-5, IL-13, and less anti-fibrotic cytokines such as Interferon-γ. Activated macrophages, monocytes, and dendritic cells further promote vascular injury and fibrosis by activating T-cells and B-cells and producing pro-fibrotic and pro-inflammatory cytokines. Humoral autoimmunity and autoantibodies are present in almost all patients with SSc. Activated B-cells produce autoantibodies that are considered directly pathological, in addition to serving as diagnostic markers. Further, autoantibody profiles are specific and are strongly associated with specific disease phenotypes. 

The result of vascular injury and inflammation due to autoimmunity leads to tissue fibrosis by mesenchymal cell activation and differentiation, irreversible extra-cellular matrix accumulation, uncontrolled fibroblast activation, persistent myofibroblasts, increase in microvascular pericyte compartment, and pathologic epithelial-mesenchymal transition. 

Histopathology

The hallmark of SSc is non-inflammatory proliferative/obliterative vasculopathy followed by interstitial/vascular fibrosis. Perivascular inflammatory infiltrates of CD4+ T-lymphocytes may be seen early in the disease but are absent in long-standing SSc. 

The vasculopathy of SSc is characterized by bland intimal proliferation along with thickening of the basement membrane, rarefaction of capillaries, loss of vascular endothelial cadherin, platelet aggregation, and microthrombi formation. Vasculitis or immune complex deposition is uncommon. In later stages of SSc, there is extensive perivascular fibrosis, progressive luminal occlusion, and tissue fibrosis. 

Early SSc is associated with dermal edema in the skin, and perivascular inflammatory infiltrate is composed of T-lymphocytes and monocytes. In later stages, dermal fibrosis predominates, and histopathology reveals loss of dermal capillaries and loss of skin appendages, hair follicles, sweat, and sebaceous glands in addition to marked dermal expansion with dense collagen and hyaluronic acid accumulation. There is a loss of dermal lymphatics and the subcutaneous adipose layer. 

Pulmonary involvement is very common in SSc, and similar to skin, pulmonary involvement is associated with inflammatory changes early in the disease with fibrosis and vascular damage later. The early inflammatory changes are seen in the alveolar walls with infiltration with lymphocytes, macrophages, and plasma cells. The pulmonary involvement in SSc is most commonly nonspecific interstitial pneumonitis (NSIP) that shows a fairly uniform distribution of fibrosis in addition to interstitial inflammation and type II pneumocyte hyperplasia. Usual interstitial pneumonia (UIP) showing a patchy distribution of fibrosis with scattered fibroblastic foci can be seen and carries a worse prognosis. Pulmonary artery hypertension occurs due to vasculopathy, as well as a loss of pulmonary microvasculature due to progressive pulmonary fibrosis.

Renal involvement has become less frequent. Chronic ischemic changes are common, but glomerulonephritis is uncommon unless overlap syndrome. Scleroderma renal crisis, a rare but life-threatening manifestation of SSc, is associated with changes seen in thrombotic microangiopathy or malignant hypertension. Onion skinning (intimal proliferation and reduplication of the elastic lamina with luminal narrowing) of the small interlobular and arcuate renal arteries is seen. 

Fibrosis is the predominant pathological finding of SSc and can be seen in other organs, including the gastrointestinal tract (anywhere from the mouth to rectum), thyroid gland, salivary glands, and even penile blood vessels. Inflammatory myositis can also be seen in SSc alone or overlap syndromes. Cardiac involvement can reveal constrictive pericarditis, pericardial fibrosis/effusions, and patchy myocardial fibrosis. 

History and Physical

SSc is a multisystemic disorder, with significant variation in clinical presentation among affected individuals. In general, Diffuse cutaneous SSc (DcSSc) is more severe and has higher mortality than Limited cutaneous SSc (LcSSc), with more common and more severe internal organ involvement. Further, SSc tends to be more severe in males, African-Americans, and with a later age of onset. 

Raynaud Phenomenon

Raynaud phenomenon is an early feature of SSc and is seen in more than 95% of patients with SSc. Vasospasm on exposure to cold leading to triphasic color change can be seen in the digits, more commonly in the upper extremities. These changes can also be seen in the ear, nose, or tongue. Vasospasm leads to initial pallor with well-demarcated white discoloration, followed by ischemic changes with dusky bluish discoloration, followed by reactive hyperemia with red discoloration. Not all patients will report all three colors. Raynaud can precede the visceral involvement by several years, especially in Limited cutaneous SSc (LcSSc), although in Diffuse cutaneous SSc (DcSSc), Raynauds may occur simultaneously or shortly after the skin changes. It must be noted that Raynaud phenomenon occurs in up to 15% of the general population without underlying SSc or connective tissue diseases. This is termed primary Raynaud and is associated with a female predominance (4:1), early age of onset (usually less than 20 years), symmetrical mild clinical features, normal nail fold capillaries, negative ANA, and is benign without ischemic complications. However, secondary Raynaud, as seen in SSc, can be associated with severe complications. In SSc, the vasospastic insult caused by Raynaud is complicated by the underlying nonvasculitic vasculopathy (intimal hyperplasia, fibrosis) and abnormal regulation of local vasomotor control, which leads to loss of vessel flexibility. Digital pitting, digital ulcers, and loss of fingertip tissue are common in SSc and can lead to digital ischemia and dry gangrene, leading to autoamputation. Superimposed infections are common. Raynaud phenomenon in SSc is also associated with an abnormal nail fold capillary exam which reveals capillary dilation, hemorrhages, and drop-out. 

Cutaneous Manifestations

Skin involvement is the most overt feature of SSc and is present in almost all patients with SSc with varying degrees and severity. The classification of SSc into LcSSc and DcSSc is based on the extent of cutaneous involvement. Skin involvement distal to elbows and knees with sparing of the trunk is classified as LcSSc, while skin involvement proximal to elbows or knees and/or trunk involvement is classified as DsSSc. The face may be involved in both LcSSc and DcSSc. 

The initial "puffy finger phase" is associated with inflammation and non-pitting edema of hands and may last several months. Pruritis, burning pain, and erythema are common. The edema can lead to compression of underlying structures, and compression neuropathies such as carpal tunnel syndrome are common. Loss of skin appendages causes dry, uncomfortable skin. Skin thickening and fibrosis begin to develop during this initial phase, which is then followed by the fibrotic phase.

During this second prolonged fibrotic phase, skin fibrosis and thickening begins distal to the metacarpophalangeal joints (sclerodactyly) and progresses proximally. The thick leather-like skin and fibrosis of deeper subcutaneous structures lead to permanent contractures and decreased mobility of the peripheral joints. There is further loss of skin appendages and subcutaneous adipose tissue (lipodystrophy). Facial involvement causes small oral aperture (fish-mouth or masked facies). Skin ulcers may develop at sites of trauma such as extensor surfaces of metacarpophalangeal, interphalangeal, or elbow joints. A salt-and-pepper-like appearance due to areas of depigmentation among normally pigmented skin can be seen. 

The final skin-softening phase may be occasionally seen and usually occurs many years after the initial presentation. During this phase, the skin, especially on the trunk and upper arms, may begin to soften and return to clinically normal skin, although the underlying subcutaneous tissue is still fibrotic.

Telangiectasias can be seen in SSc due to dilatation of capillaries, and are common on the hands, face, mucosal surfaces, and sometimes on the trunk. Telangiectasias blanch on applying pressure. They can increase over time and are considered to be associated with an increased risk of pulmonary hypertension. 

Subcutaneous calcinosis can be seen in both DcSSc and LcSSc, although it is more common in LcSSc and patients with a positive anti-centromere antibody. Calcinosis is due to clusters of subcutaneous deposition of calcium hydroxyapatite and is most frequently seen over areas of trauma such as finger pads and extensor surfaces of elbows. Calcinosis can lead to skin ulceration and secondary infection.

Musculoskeletal Manifestations

Musculoskeletal symptoms are seen in almost all patients with SSc. Arthralgia and myalgia are commonly present. True synovitis and inflammatory arthritis can also be seen and can have a rheumatoid arthritis-like pattern with the involvement of metacarpophalangeal, proximal interphalangeal, wrist, and ankle joints. Erosions are, however, rare but can be seen in association with periarticular calcinosis. Large joint involvement is rare but can be seen in DcSSc. Overlap of SSc with RA can be seen in up to 5% of cases.[27][28] Distal bone resorption and osteolysis can be seen in the late stages of DcSSc. Joint contractures involving the hands are common, and large joint contractures can be rarely seen in DcSSc. Tendon friction rubs due to inflammation, edema, and fibrosis of tendon sheath can be seen in up to 30% of cases, especially in DcSSc. These are associated with a poor overall prognosis. 

Muscle involvement or myopathy in SSc can be multifactorial. An inflammatory myopathy or myositis similar to polymyositis can be seen in up to 10% of patients with SSc and is associated with rapidly progressive proximal muscle weakness, elevated muscle enzymes, and biopsy with inflammatory myositis. Further, patients with SSc can experience decreased muscle strength due to malnutrition or due to deconditioning due to joint disease and skin fibrosis. A fibrosing myopathy can also be seen due to direct muscle involvement in SSc, leading to muscle fibrosis and atrophy. These patients may have mildly elevated muscle enzymes, and biopsy shows fibrosis and atrophy with little or no inflammation. They usually do not respond to anti-inflammatory agents, which are usually effective in inflammatory myopathies. Myopathy in SSc is also associated with a poor overall prognosis.

Gastrointestinal Manifestations

Gastrointestinal involvement is also almost universal in SSc, both DcSSc and LcSSc. Symptoms may be mild to severe, and any segment gastrointestinal tract can be involved. Oropharyngeal involvement includes perioral skin tightening and decreased oral aperture, periodontitis, and gingivitis. Dry mouth can be seen due to salivary gland fibrosis due to SSc or due to inflammatory infiltrate due to secondary Sjögren syndrome. Esophageal dysmotility due to esophageal fibrosis, especially involving the distal two-thirds of the esophagus leading to dysphagia and heartburn, is seen in up to 90% of patients with SSc. The lower esophageal sphincter becomes hypotonic, which worsens reflux symptoms. Complications of esophageal dysmotility can include esophagitis, esophageal strictures, Barrett’s esophagus, and even bleeding. Gastric involvement can include delayed gastric emptying (gastroparesis) that can lead to early satiety, bloating, nausea, emesis, and anorexia, which can cause malnutrition and weight loss. Gastric antral vascular ectasia (GAVE), also known as "watermelon stomach," is the result of gastric telangiectasias and can lead to occult or large amounts of gastrointestinal bleeding. Intestinal dysmotility can cause diarrhea, constipation, and intestinal bacterial overgrowth. Mucosal telangiectasias can cause occult gastrointestinal bleeding. Intestinal dysmotility can lead to pseudo-obstruction that can be serious. Wide-mouthed diverticula due to intestinal mucosal muscular atrophy are unique to SSc. Reduced anal sphincter tone can lead to rectal prolapse and incontinence. Hepatic involvement is not seen in SSc, although SSc has been associated with primary biliary cirrhosis.[29]

Pulmonary Manifestations

Pulmonary disease is the leading cause of mortality in patients with SSc. The characteristic pulmonary involvement includes interstitial lung disease (ILD) and/or pulmonary hypertension (PAH). Less common pulmonary manifestations include pleuritis, obstructive airway disease, aspiration pneumonia, pulmonary hemorrhage, and cryptogenic organizing pneumonia. Pulmonary disease in SSc can range from clinically asymptomatic disease to progressive respiratory failure with severe morbidity.

ILD is seen as bibasilar pulmonary fibrosis and is more common and more severe in DcSSc, African-Americans, males, and in those with anti–topoisomerase I antibody. Clinically significant ILD can be seen in 50% of SSc, although it can be asymptomatic, and postmortem examinations revealed ILD in 80% of patients with SSc.[30] ILD typically develops within the first 4 to 5 years of SSc diagnosis. NSIP is more common than UIP, although a mixed pattern can be seen as well. Symptoms of ILD include dyspnea, fatigue, and later a non-productive cough. Pulmonary function test (PFT) reveals a restrictive pattern with a decrease in lung volumes and decreased FEV1/FVC ratio. Diffusion capacity (DLCO) may be reduced, although it may partly also be due to the underlying pulmonary vascular disease. High-resolution CT (HRCT) of the chest is very sensitive, and early in the disease, it reveals increased subpleural lung attenuations in the bilateral posterior basal areas. Ground-glass opacities can be seen, which suggest alveolitis. Other findings include honeycombing, traction bronchiectasis, and thickening of the interlobular septa.

PAH is the other common pulmonary manifestation and can range from asymptomatic disease to severe PAH with right heart failure. PAH usually occurs late in the disease, usually more than 10 years after SSc diagnosis. PAH can be seen in SSc is between 30% and 50%, more commonly in LcSSc. PAH risk is higher with the late age of diagnosis of SSc, multiple telangiectasias, and presence of anti-U3-RNP antibody. Symptoms include dyspnea initially, and chest pain, lower extremity swelling, lightheadedness, and syncope later in the disease. Accentuated P component of the second heart sound (S2) can be present. PFT show isolated reduction in diffusion capacity (DLCO). NT-proBNP blood levels may be increased. An echocardiogram can show elevated peak right ventricular systolic pressure (RVSP). When suspected, a right heart catheterization shall be performed to confirm the diagnosis of PAH and to rule out other etiologies. Elevation in mean pulmonary arterial pressure to 25mmHg or more, with a normal pulmonary capillary wedge pressure, is considered diagnostic of PAH.

Cardiac Manifestations

Cardiac manifestations include pericarditis, pericardial effusion, dilated cardiomyopathy, and arrhythmias. Left ventricular diastolic dysfunction can occur secondary to PAH. Cardiac involvement is associated with a poor prognosis. Pericardial effusions are usually small, exudative and tamponade is uncommon. Pericardial effusions are more common in DcSSc and are predictive for scleroderma renal crisis. Dilated cardiomyopathy occurs due to patchy myocardial fibrosis. Conduction pathway fibrosis can lead to arrhythmias, with the most common finding being premature ventricular contractions, although heart block, intraventricular conduction delays, and supraventricular tachycardia have been reported.

Renal Manifestations

Scleroderma renal crisis (SRC) was almost always fatal and was the leading cause of mortality in SSc before the discovery of the angiotensin-converting enzyme (ACE) inhibitors. SRC is seen in about 10% of patients with SSc, almost exclusively in DcSSc, and is usually seen within 3 years of diagnosis. Risk factors for SRC development include African-American race, pericardial effusion, tendon friction rubs, new-onset anemia, DcSSc, anti–RNA polymerase III antibody, and use of high dose (or even chronic low-dose) corticosteroids. Indicators for poor outcomes in SRC include male sex, older age of onset, and serum creatinine of more than 3 mg/dL. The pathology of SRC is that of vasculopathy as seen in other vessels in SSc and not glomerulonephritis. Clinical features include new-onset hypertension or malignant hypertension, along with renal insufficiency. Due to the associated microangiopathy, hemolytic anemia and thrombocytopenia are frequently seen. Proteinuria, if seen, is usually mild. Microscopic hematuria is frequently present.

Other Manifestations

Hypothyroidism is seen in up to 15% of patients with SSc (especially LcSSc) and can be due to fibrosis of the thyroid gland. Further, autoimmune thyroid diseases (Hashimoto thyroiditis and Graves disease) are more common in patients with SSc. Patients with SSc are at increased risk for other autoimmune diseases such as primary biliary cirrhosis and secondary Sjögren syndrome. Overlap syndromes are common and can include an overlap of SSc with rheumatoid arthritis and polymyositis. Patients with SSc are also at increased risk of psychological disorders such as depression which is seen in up to 50% of patients with SSc. Systemic sclerosis sine scleroderma is a variant of SSc characterized by several internal organ manifestations of SSc (especially pulmonary and gastrointestinal) without skin thickening. These patients almost always have Raynaud phenomenon with an abnormal nail fold capillary exam and a positive ANA. 

Classification Criteria

In 2013, the American College of Rheumatology published the updated classification criteria for systemic sclerosis [31], which are more sensitive and specific than the older 1980 classification criteria. While the criteria are aimed at the inclusion of eligible patients in clinical studies, they can be used in clinical practice with caution. These criteria are score-based, and a score of 9 or more can be classified as SSc.

1. Bilateral skin thickening proximal to metacarpophalangeal joints: 9
2. Skin thickening of fingers (count only higher score)
   1. Between distal and proximal interphalangeal joints: 4
   2. Puffy fingers: 2
3. Fingertip lesions (count only higher score)
   1. Fingertip pitting scars: 3
   2. Digital tip ulcers: 2
4. Telangiectasia: 2
5. Abnormal nail fold capillaries: 2
6. Raynaud phenomenon: 3
7. Lung disease (maximum score of 2)
   1. ILD: 2
   2. PAH: 2
8. Positive SSc-specific antibodies (anticentromere, anti–Scl-70, Anti–RNA polymerase III): 3

Evaluation

The diagnosis of Systemic sclerosis is a clinical diagnosis. Early detection of the disease and the extent of involvement and continuing surveillance for internal organ involvement is crucial in the management of patients with SSc. 

Clinical Evaluation

Skin thickness shall be evaluated by the modified Rodnan skin score, which gives scores 0 to 3, 0 for uninvolved areas, and 3 for severe skin thickening. The score should be followed up as the skin thickness progression rate carries prognostic value. Nail fold capillary exam shall be performed in all patients with Raynaud phenomena with suspicion for SSc. The multisystemic physical exam shall be performed at each visit to evaluate for underlying organ involvement. Close monitoring of blood pressure in the clinic as well as at home is strongly recommended, especially in patients with a recent diagnosis of DcSSc has new-onset hypertension, or significant worsening of baseline hypertension can be an indicator for scleroderma renal crisis.

Autoantibody Tests

Autoantibodies not only serve as an important diagnostic tool, but they also carry prognostic value and can predict disease phenotype and disease outcome. Anti-Nuclear Antibody (ANA), when measures by direct immunofluorescence, is positive in more than 90% of the cases of SSc. In patients who are negative for the ANA, other differential diagnoses shall be ruled out before confirming the diagnosis of SSc. Other more specific autoantibodies are positive in 60 to 70% of cases of SSc. These more specific autoantibodies are mutually exclusive and can be present several months to years before the clinical diagnosis of SSc.

Anti-centromere antibody: Anti-centromere antibodies target 4 centromere antigens (CENP -B, -A, -C, D) and are seen in LcSSc, although it may rarely be seen in DcSSc as well. They can also be seen in Sjögren syndrome and systemic lupus erythematosus. Anti-centromere antibodies are associated with an increased risk of pulmonary arterial hypertension. They are also associated with limited cutaneous involvement, lower risk of interstitial lung disease, and overall better survival compared to the other autoantibodies.

Anti-topoisomerase I (Scl-70) antibody: Anti-SCL-70 antibodies target the catalytic region of DNA helicase topoisomerase I. Anti-SCL-70 antibodies are seen in DcSSc, and rarely in LcSSc. Anti-SCL-70 antibodies are associated with an increased risk of diffuse cutaneous involvement, interstitial lung disease, and cardiac involvement.

Anti-RNA polymerase III antibody: Anti-RNA polymerase III antibodies target the eukaryotic RNA polymerase III. These are more specific for DcSSc and are associated with rapidly progressing and aggressive diffuse skin involvement, poor cutaneous outcomes, and scleroderma renal crisis. Anti-RNA polymerase III antibodies are also associated with a lower risk of interstitial lung disease and pulmonary hypertension. Some studies have indicated an association of malignancies in patients with SSc positive for Anti-RNA polymerase III antibodies.

Anti-U3-RNP (fibrillarin) Antibody: Anti-U3-RNP antibodies are present more in African Americans and associated with overall poor prognosis, more internal organ involvement, diffuse cutaneous involvement, interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, myositis/myopathy, and cardiac involvement.

Other autoantibodies: Anti-Th/To antibodies are associated with limited skin disease. Anti-PM/Scl antibodies are associated with limited skin disease and overlap syndrome with a higher risk of inflammatory myositis and interstitial lung disease. Anti-U1-RNP antibodies are more common in African Americans and are associated with overlap syndrome and mixed connective tissue disease with limited cutaneous involvement and more risk of inflammatory arthritis, myositis, lupus-skin rashes, and lupus nephritis. Anti-Ku antibodies are also associated with overlap syndrome in SSc with more inflammatory arthritis and myositis.

Laboratory Evaluation

Complete blood counts to check for anemia which may be multifactorial, shall be done. The renal function along with 24-hour urine protein or urine protein/creatinine ratio shall be closely monitored. Inflammatory markers usually do not add significant significance although, a significant elevation in these markers can be seen in patients with active inflammatory myopathy or inflammatory arthritis. Muscle enzymes, including creatine kinase and aldolase, may be elevated especially when inflammatory myopathy is present.

Ancillary and Radiographic Evaluation

X-rays of the extremities can reveal calcinosis and loss of distal phalanx. Periarticular erosions are rare and uncommon, although periarticular osteopenia can be seen. Musculoskeletal ultrasound can show features of tenosynovitis. When muscle involvement is suspected, the electromyogram/nerve conduction velocity test is the initial test of choice and, if abnormal, shall be followed by a muscle biopsy. The imaging modality of choice for evaluation of interstitial lung disease is a high-resolution CT scan, as chest x-ray may not show subtle findings. Pulmonary function tests, including spirometry, lung volumes, and diffusion capacity, can detect a restrictive pattern in interstitial lung disease very early in the disease. A lung biopsy is of very limited value and shall be avoided unless other diagnostic concerns. Transthoracic echocardiography is usually initially done when pulmonary arterial hypertension is suspected, although right heart catheterization shall be followed to confirm the diagnosis and to rule out other etiologies. Electrocardiography and Holter monitor can be useful in detecting arrhythmias. Pericardial effusions can be well visualized on transthoracic echocardiography. Cardiac MRI may be needed in patients where myocardial involvement is suspected. Upper GI endoscopy, esophageal manometry, barium swallow studies, and 24-hour pH probe can be used when esophageal involvement and upper GI involvement are suspected. Esophageal dysmotility leading to a dilated esophagus with imaging finding of excessive air in the esophagus is a characteristic finding that can be seen on a CT scan.

Treatment / Management

There is no definitive treatment or universally accepted disease-modifying agent that can alter the natural course of the disease. However, the management of the affected system or systems has proven effective. Early diagnosis is a key strategy to achieving improved outcomes.[32][8][33] Clinical evaluation and identification of affected organ and disease progression are critical to treatment efficacy. Furthermore, it is important that treatment goals be holistic and tailored towards optimizing the quality of life for the affected patients, in addition to preventing further organ damage. Patient Education about the disease and encouragement to be involved in regular exercises, healthy diet, and lifestyle along with emotional support shall be considered in every individual with Ssc.

Several agents have been studied for various manifestations of SSc, although there is a generalized lack of large randomized controlled trials confirming the efficacy of any of these agents. Cyclophosphamide (lung disease, skin disease), mycophenolate mofetil (lung disease, skin disease), methotrexate (skin disease, inflammatory arthritis, myositis), azathioprine (skin disease, lung disease, myositis), and hydroxychloroquine (skin disease) are some of the most commonly used immunosuppressive agents. Cyclosporine (skin disease), infliximab (inflammatory arthritis), and rituximab (skin disease, lung disease) have limited data on them. Corticosteroids shall be generally avoided in SSc. High-dose corticosteroids and even long-term use of low to moderate dose corticosteroids have been associated with precipitation of scleroderma renal crisis. The shall be used in the lowest possible dose for the lowest possible time only if absolutely needed, such as inflammatory myositis, inflammatory arthritis that is refractory, and/or active inflammatory alveolitis.

Specific Therapies in Scleroderma

Raynaud Phenomenon

The goal of treatment in Raynaud is to prevent digital ischemia and ulcers. These ischemic ulcers are much easier to prevent than to treat. Conservative management for Raynaud phenomenon is still the cornerstone of management, and patients shall be avoided to keep the extremities and body warm, avoid smoking, stress and eliminate sympathomimetic medications when possible. In patients on beta-blockers, an attempt must be made to switch to another agent if possible, as beta-blockers can worsen Raynaud. Vasodilator therapy has been proven to be effective in Raynaud syndrome. The first-line agents are the dihydropyridine calcium channel blockers such as nifedipine or amlodipine. Other vasodilators such as pentoxifylline, nitroglycerin, phosphodiesterase inhibitors (sildenafil) can also be considered. Prostacyclin analogs (iloprost) and endothelin receptor antagonists (bosentan) can be used for refractory cases with digital ischemic ulcers. Proximal/distal sympathectomy can be considered in refractory cases. Botulinum toxin injections have been shown to be effective in some small studies, although efficacy is still limited. Vasodilator pumps can be used in patients unable to tolerate vasodilator therapies. Appropriate wound care is crucial in the management of patients with digital ulcers.

Skin Disease

Several immunosuppressive agents have been used in sclerodactyly, including methotrexate, hydroxychloroquine, mycophenolate mofetil, and cyclophosphamide. While there is a lack of robust data, mycophenolate mofetil is the preferred agent by most rheumatologists in moderate to severe skin thickening. Antihistamines and topical moisturizing agents can help the pruritus. Telangiectasias usually do not require any treatment, although laser therapy can be considered for cosmetic purposes. No medical treatment has been proven to be effective in calcinosis, and surgical debulking may provide some relief in severe cases.

Musculoskeletal Involvement

Most patients have mild arthralgias that do not require treatment by themselves or respond well to nonsteroidal anti-inflammatory drugs. Inflammatory arthritis can be managed by disease-modifying antirheumatic drugs such as hydroxychloroquine, methotrexate. Anti-TNF agents can be used in refractory severe inflammatory arthritis.[34] Physical and occupational therapy is crucial in preventing contractures. Inflammatory myositis management is similar to that in polymyositis, although high-dose corticosteroids shall be avoided. Immunosuppressive agents such as methotrexate and azathioprine are efficacious in the management of inflammatory myositis in SSc. The management of noninflammatory myopathy in SSc is difficult, and physical therapy and exercises are more beneficial than immunosuppressive agents.(B3)

Pulmonary Involvement

Pulmonary involvement in SSc is now the leading cause of mortality. Management requires interprofessional involvement, including rheumatologists, pulmonologists, and cardiologists.

Interstitial lung disease: Early detection and management may be key, and management of interstitial lung disease in SSc. Cyclophosphamide has been studied and did show benefit for up to 18 months, but the benefit was lost at 24 months.[35] There have been small studies demonstrating the efficacy of cyclophosphamide followed by azathioprine for maintenance. Mycophenolate mofetil has also been shown to be beneficial. Lung transplantation may be needed in carefully selected individuals. Nintedanib, a tyrosine kinase inhibitor, was approved by the FDA for the management of interstitial lung disease in systemic sclerosis in 2019, as clinical trials on it showed a slowing of the decline of pulmonary function test in patients with SSc with interstitial lung disease. Other investigational modalities include stem cell transplants and anti-fibrotic agents.(A1)

Pulmonary arterial hypertension: In addition to patient education, healthy lifestyle, and exercise as tolerated, supplemental oxygen, diuretics, and anticoagulation are recommended when no contraindication. Calcium channel blockers are usually not effective. Vasodilator therapy is recommended and can include phosphodiesterase - 5 inhibitors (tadalafil, sildenafil), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan, macitentan), and/or prostacyclin analogs (epoprostenol, treprostinil, beraprost, iloprost). Prostacyclin therapy is considered to be most effective, although all these agents improve hemodynamics and quality of life. Combination therapy can be considered in patients who fail to improve on monotherapy or have severe pulmonary arterial hypertension.

Cardiac Involvement

Management of arrhythmias includes antiarrhythmic agents and, sometimes, pacemaker placement. So far, there is no evidence of any efficacy of immunosuppressive agents or vasodilators therapy in scleroderma-related cardiac involvement.

Gastrointestinal Involvement

Exercises can help with decreased oral aperture, and good dental hygiene is required to prevent caries and cavities due to sicca symptoms. Sugar-free lozenges and secretagogues such as pilocarpine or cevimeline can also be used to help the dry mouth. In patients with heartburn and gastroesophageal reflux, lifestyle and dietary modifications such as elevating the head of the bed, avoiding late and large meals, and avoiding spicy foods, consuming small frequent meals are recommended. NSAIDs shall be avoided. Proton pump inhibitors are recommended over H2 blockers, and high doses of proton pump inhibitors may be used, especially in patients with erosive esophagitis. In severe cases, a combination of proton pump inhibitors with H2 blockers can be considered. Patients with gastroparesis may benefit from motility agents such as metoclopramide in addition to proton pump inhibitors. Laser coagulation shall be considered in patients with bleeding secondary to gastric antral vascular ectasia. Patients with small bowel bacterial overgrowth syndrome may need rotational antibiotics.

Scleroderma Renal Crisis

Angiotensin-converting enzyme (ACE) inhibitors are the only effective treatment for scleroderma renal crisis. They shall be initiated at the earliest signs of SRC, and a maximum tolerated dose shall be used. Captopril, a shorter-acting ACE-inhibitor, is preferred due to the flexibility with its dosing, although any ACE-inhibitor can be used. There is no data on the efficacy of angiotensin receptor blockers and renin inhibitors in scleroderma renal crisis. Renal function may continue to decline initially; however, the ACE-inhibitor shall be continued. When appropriately managed, renal function can improve considerably, although it may take several months to years, allowing for discontinuation of dialysis. Notably, prophylactic use of ACE inhibitors does not prevent scleroderma renal crisis and is not recommended and has been shown to be associated with increased morbidity and mortality.[36][37](B2)

Differential Diagnosis

Systemic sclerosis is a clinical diagnosis. Several diseases can mimic SSc and shall be considered in the differential diagnosis.

Eosinophilic Fasciitis (EF)

EF is characterized by eosinophilic inflammation of the deep fascia that leads to thickening and a woody induration of the upper and lower extremities sparing the hands and feet. Raynaud phenomenon is not associated with EF, and the nail fold capillary exam is usually normal. ANA and more specific autoantibodies are negative. Patients may develop contractures similar to SSc. It may be associated with underlying malignancies. Skin biopsy usually reveals eosinophilic infiltrate in the deep fascia.

Scleromyxedema

Scleromyxedema is usually seen in patients with monoclonal gammopathy or multiple myeloma and is characterized by papular waxy lesions on the face, neck, extremities, and fingers. Patients may have associated seizures and dementia. Raynaud phenomenon is not associated with scleromyxedema, and the nail fold capillary exam is usually normal. ANA and more specific autoantibodies are negative. Skin biopsy usually reveals dermal fibrosis with perivascular inflammation along with deposition of mucin and fibrocytes, which are not usually seen in SSc.

Scleredema

Scleredema can be associated with diabetes mellitus, monoclonal, fatigue, infections, and malignancies and is characterized by the doughy, indurated appearance of the skin on the neck, back, and face. Digits are usually spared. Raynaud phenomenon is not associated with scleredema, and the nail fold capillary exam is usually normal. ANA and more specific autoantibodies are negative. Skin biopsy usually reveals dermal fibrosis without perivascular inflammation along with the deposition of mucin.

Nephrogenic Systemic Fibrosis (NSF)

This is a rare phenomenon seen in patients with end-stage renal disease on exposure to gadolinium contrast. It is characterized by cobblestone-like nodular plaques on the extremities, trunk, hands, and feet with sparing of the face. Raynaud phenomenon is not associated with NSF, and the nail fold capillary exam is usually normal. ANA and more specific autoantibodies are negative. Skin biopsy usually reveals dermal and epidermal fibrosis without perivascular inflammation along with the deposition of mucin and fibrocytes.

Eosinophilia Myalgia Syndrome

This syndrome was an epidemic associated with the use of L-Tryptophan, leading to severe myalgias, visceral involvement, and elevated CK.

Toxic Oil Syndrome

This syndrome was also an epidemic in Spain associated with the intake of adulterated rapeseed oil, leading to livedo reticularis, pulmonary infiltrates, and elevated CK.

Prognosis

SSc is associates with high mortality, and of all the collagen vascular disorders, systemic sclerosis has the highest case-specific mortality. The most common cause of mortality was the scleroderma renal crisis prior to the advent of ACE inhibitors. The use of ACE inhibitors and more awareness has decreased SRC-related mortality, and the most common cause of mortality now is pulmonary disease.[38] Overall, the prognosis in SSc has improved over the past 30 years. 5-year survival rates are up to 80%. However, patients with advanced pulmonary arterial hypertension have less than a 50% 2-year survival rate. Further, patients with SSc-related pulmonary arterial hypertension have a poor prognosis compared to those with idiopathic pulmonary arterial hypertension. Before the discovery of ACE inhibitors, the 1-year survival rate for patients with scleroderma renal crisis was less than 15%, but with more awareness and use of Ace inhibitors, the 1-year survival rate in scleroderma renal crisis is more than 85% now. Patients with SSc are also at a high risk of malignancies, especially lung cancer. The risk of esophageal adenocarcinoma may be increased in SSc associated with chronic gastroesophageal reflux leading to Barrett esophagus.[32][39][40]

Prognostic Factors and Associations in SSc

• African American race: Develop disease early, develop more severe disease, interstitial lung disease, scleroderma renal crisis
• Late age of diagnosis: Pulmonary arterial hypertension, poor outcomes after scleroderma renal crisis
• DcSSc: Diffuse skin disease, large joint inflammatory arthritis, tendon friction rubs, joint contractures, distal bone osteolysis, scleroderma renal crisis, interstitial lung disease, pericardial effusion 
• LcSSc: Limited skin disease, calcinosis, pulmonary arterial hypertension, hypothyroidism
• Multiple telangiectasias: Pulmonary arterial hypertension
• Pericardial effusion: Scleroderma renal crisis
• Tendon friction rubs: Scleroderma renal crisis, poor overall prognosis
• New-onset anemia: Scleroderma renal crisis
• Corticosteroid use: Scleroderma renal crisis
• Anti-centromere antibody: LcSSc, pulmonary arterial hypertension. Lower risk of interstitial lung disease.
• Anti-SCL-70 antibody: DcSSc, interstitial lung disease, cardiac involvement
• Anti-RNA polymerase III antibody: Rapidly progressing and aggressive diffuse skin involvement, poor cutaneous outcomes, scleroderma renal crisis, malignancies. Lower risk of interstitial lung disease and pulmonary hypertension

Complications

SSc is associated with several complications, mostly secondary to end-organ damage caused by fibrosis. Digital ischemia can lead to gangrene needing amputation. Gastrointestinal involvement can lead to malnutrition. Pulmonary involvement is the leading cause of morbidity in patients with SSc, leading to permanent pulmonary fibrosis. Patients with scleroderma renal crisis can have permanent renal damage, although, with ACE inhibitors, renal function recovers in most of these patients.