Chapter 372_ Systemic Sclerosis (Scleroderma) and Related Disorders

NT-proBNP levels correlate with the presence and severity of PAH, as well as survival. It can be useful in screening and monitoring treatment response, but elevated levels are not specific to PAH.

The gastrointestinal (GI) tract is the most common internal organ manifestation of SSc, affecting up to 90% of SSc patients with both limited and diffuse cutaneous disease.

Pathologic findings of GI involvement in SSc include fibrosis, smooth-muscle atrophy, and obliterative small-vessel vasculopathy throughout the length of the GI tract.

Prominent manifestations in the oropharynx include:

1. Diminished oral aperture - Management: Periodontal care
2. Dry mouth - Management: Artificial saliva
3. Periodontitis, gingivitis - Management: Swallowing therapy
4. Swallowing difficulties - Management: Swallowing therapy

Systemic sclerosis (SSc) is an orphan disease characterized by:

• Unknown etiology
• Complex pathogenesis
• Variable clinical presentations
• A chronic and often progressive course
• Associated with significant disability and mortality
• Can affect virtually every organ in the body.

Common complications of systemic sclerosis (SSc) include:

• Gastroesophageal reflux disease (GERD)
• Gastric antral vascular ectasia (GAVE)
• Interstitial lung disease
• Pulmonary artery hypertension
• Scleroderma renal crisis
• Cardiac issues such as pericarditis and arrhythmia
• Skin manifestations like induration and telangiectasia
• Musculoskeletal problems including joint contractures and myositis.

There is marked variability among systemic sclerosis (SSc) patients in:

• Patterns of skin involvement
• Organ complications
• Rates of disease progression
• Response to treatment
• Disease severity
• Survival rates The early stages may show prominent inflammatory features such as edema.

The ACR/EULAR classification criteria for SSc based on skin thickening include:

The clinical features that differentiate dcSSc from IcSSc include:

SSc sine scleroderma is a relatively benign subset of systemic sclerosis where patients may exhibit symptoms such as Raynaud's phenomenon and characteristic clinical and laboratory features of SSc without detectable skin thickening.

Conditions associated with scleroderma-like skin induration include:

Limited Cutaneous SSc has an indolent onset and is limited to the fingers, distal to elbows, and face with slow progression. In contrast, Diffuse Cutaneous SSc has a rapid onset affecting fingers, extremities, face, and trunk with rapid progression.

In Limited Cutaneous SSc, the Raynaud phenomenon antedates skin involvement, sometimes by years, and may be associated with critical ischemia in the digits. In Diffuse Cutaneous SSc, the onset of Raynaud phenomenon coincides with skin involvement, and critical ischemia is less common.

The incidence of SSc in the United States ranges from 9 to 46 cases per million per year, with an estimated 100,000 cases in the U.S., although this number may be higher if including patients not meeting formal classification criteria.

SSc shows a strong female sex bias (4.6:1), particularly pronounced in the childbearing years. Factors contributing to this bias may include sex hormones that have immunostimulatory effects, differences in immune cell composition, and environmental exposures between sexes.

Having an affected first-degree family member with SSc increases the risk of developing the disease by 13-fold.

Limited Cutaneous SSc is associated with anti-centromere autoantibodies, while Diffuse Cutaneous SSc is associated with anti-topoisomerase I (Scl-70) and anti-RNA polymerase III autoantibodies.

The low disease concordance rate of 4.7% in monozygotic twins suggests that genetic factors alone make a relatively modest contribution to the susceptibility of systemic sclerosis (SSc), especially when compared to other autoimmune diseases like rheumatoid arthritis, which has a higher concordance rate of 12.3%.

Genetic factors associated with SSc include:

Environmental factors likely play a major role in SSc susceptibility due to the modest genetic contribution. Potential links include:

• Infectious agents: Viruses such as parvovirus B19, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) have been tentatively linked, though direct evidence is lacking.
• Occupational exposures: Substances like particulate silica, polyvinyl chloride, and organic solvents may contribute to SSc risk.
• Epigenetic modifications: Environmental exposures may lead to heritable changes in gene expression, which could be reversible and represent potential therapeutic targets.

Drugs implicated in SSc-like illnesses include:

1. Bleomycin
2. Pentazocine
3. Cocaine
4. Appetite suppressants linked with pulmonary arterial hypertension (PAH)
5. Immune checkpoint inhibitors (e.g., PD-1 blockers used in cancer therapy)
6. Radiation therapy for cancer, which has been linked to both de novo onset and exacerbation of preexisting SSc.

Genetic studies, including genome-wide association studies (GWAS), help identify genetic susceptibility loci for SSc, focusing on:

• Common variants: These are associated with immune regulation and autoimmunity.
• Candidate gene studies: These explore specific genes related to SSc manifestations.
• Next-generation sequencing: This may uncover rare coding variants that could be causal for SSc, enhancing understanding of the disease's genetic basis.

1. Diffuse microangiopathy
2. Inflammation and autoimmunity
3. Visceral and vascular fibrosis
   These processes contribute to the diverse clinical manifestations and pathologic changes seen in SSc.

Genetic risk factors, particularly HLA and non-HLA genes, interact with environmental exposures (such as drugs, silica, solvents, and viral agents) to induce epigenetic modifications. These modifications alter gene expression, leading to changes in the behavior of multiple cell types, which underlie the pathogenesis of systemic sclerosis.

Autoimmunity and reversible vascular reactivity are early features of systemic sclerosis, while fibrosis and atrophy typically occur later in the disease. The relative severity and contribution of these processes can vary among individual patients and over time.

The three key processes are microvasculopathy, immune dysregulation, and fibrosis.

Vascular injury is an early and possibly primary pathogenic event that triggers a cascade of vascular alterations, leading to manifestations such as telangiectasia, Raynaud's phenomenon, and ischemic digital ulcers.

Animal models help investigate the pathogenetic roles of individual molecules, pathways, and cell types, and are useful for discovering and validating novel therapeutic targets, cell types, and biomarkers.

Manifestations include mucocutaneous telangiectasia, Raynaud's phenomenon, ischemic digital ulcers, acro-osteolysis, scleroderma renal crisis, myocardial involvement, and pulmonary arterial hypertension (PAH).

Fibroblast activation and differentiation lead to sustained and progressive fibrogenesis, resulting in irreversible tissue damage and functional failure of affected organs.

Raynaud's phenomenon is the primary clinical manifestation of SSc, characterized by altered blood-flow response to cold in small digital arteries. Unlike isolated Raynaud's disease, which is generally benign and nonprogressive, SSc-associated Raynaud's often leads to irreversible structural changes in blood vessels, resulting in ischemic digital tip ulcers, necrosis, and potential finger amputation.

Potential triggers of endothelial cell injury in SSc include:

1. Viruses
2. Cytotoxic factors
3. Chemokines
4. Thrombogenic circulating microvesicles
5. Alternate complement pathway activation
6. Neutrophil extracellular trap (NET) formation (NETosis)
7. Autoantibodies targeting endothelial cells, phospholipids, and ẞ2-glycoprotein I (B2GPI)

Endothelial cell damage in SSc disrupts the production of vasodilatory substances (like nitric oxide and prostacyclin) and increases vasoconstricting substances (like endothelin-1). This leads to:

• Enhanced permeability of microvessels
• Increased transendothelial leukocyte diapedesis
• Activation of coagulation cascades
• Formation of neutrophil extracellular traps (NETs)
• Elevated thrombin production and impaired fibrinolysis

Endothelial-mesenchymal transition (EndoMT) is significant in SSc as it leads to the accumulation of smooth-muscle cell-like myointimal cells within the vascular media. This process contributes to:

• Thickening and reduplication of the basement membrane
• Development of perivascular adventitial fibrosis
• Impaired blood flow and tissue ischemia due to progressive luminal occlusion

Recurrent ischemia-reperfusion in SSc generates reactive oxygen species (ROS) that further damage the endothelium through lipid peroxidation. This process:

• Impairs normal revascularization despite elevated angiogenic factors
• Reduces the number and function of bone marrow-derived circulating endothelial progenitor cells
• Contributes to the vicious cycle of fibroproliferative vasculopathy and rarefaction of small blood vessels in late-stage disease

EndoMT (Endothelial-to-Mesenchymal Transition) contributes to SSc vasculopathy by causing endothelial cells to transition into myofibroblasts. This process results in:

• Loss of endothelial cell markers
• Nuclear localization of the transcription factor Snail1
• Accumulation of endothelial cell-derived myofibroblasts in the intima and media of arterioles and small arteries, leading to fibroproliferative vasculopathy and luminal occlusion.
• In capillary vessels, EndoMT leads to destructive vasculopathy characterized by loss of endothelial cells and accumulation of profibrotic interstitial myofibroblasts, resulting in fibrosis and microvessel rarefaction.

The inflammatory and autoimmune response in SSc is characterized by:

• Presence of circulating autoantibodies with defined specificities.
• Clustering of SSc with other autoimmune diseases.
• Activated immune cells, including autoreactive T cells in target organs.
• Prominent type I interferon (IFN) signatures in immune cells.
• Elevated levels of cytokines such as IL-6, TNF-a, IL-4, IL-10, IL-17, and IL-33.
• Genetic associations with variants of MHC and other immune response genes.
• Rapid clinical response to immunomodulatory therapies.

Dendritic cells play a crucial role in the pathogenesis of SSc by:

• Acting as professional antigen-presenting cells that bridge the innate and adaptive immune systems.
• Sensing tissue damage through pattern recognition receptors (e.g., TLRs, NLRs).
• Inducing mediators such as IFN, IL-10, and thymic stromal lymphopoietin (TSLP) upon activation.
• Producing the chemokine CXCL4, which promotes a profibrotic monocyte phenotype and myofibroblast differentiation.

CXCL4 (also known as platelet factor 4) is significant in SSc due to:

• Its role as a potent proinflammatory and antiangiogenic mediator.
• Inducing a profibrotic monocyte phenotype and promoting myofibroblast differentiation from stromal progenitor cells.
• Elevated serum levels of CXCL4 can predict future disease progression in SSc patients.

T cells in SSc exhibit several characteristics:

• Expression of chemokine receptors and a₁ integrin, enhancing their binding to endothelium and fibroblasts.
• Display of TH2-polarized immune response driven by dendritic cells.
• Activation markers such as CD45 and HLA-DR, indicating oligoclonal expansion in response to unknown antigens.
• Enhanced binding to endothelium facilitated by adhesion molecules like ICAM-1.

Neutrophils in SSc can secrete fibrogenic TGF-β and IL-6, release reactive oxygen species (ROS), and are prone to releasing extracellular traps that can trigger thrombotic and immune responses.

Mast cells are attracted into fibrotic skin via plasminogen activator inhibitor (PAI-1) signaling from keratinocytes. They can release fibrogenic mediators such as TGF-β and directly activate fibroblasts via serpine 1.

Circulating antinuclear antibodies (ANAs) can be detected in virtually all patients with SSc, even in early and possibly preclinical stages of the disease, indicating their role in diagnosis and risk stratification.

These autoantibodies are highly specific, mutually exclusive, and have clinical utility for diagnosis and risk stratification.

Functional antibodies identified in SSc patients include those directed against fibrillin-1, matrix metalloproteinases, cell surface markers, and stimulatory antibodies to angiotensin II receptor, endothelin-1 receptor, or the PDGF receptor. Their clinical relevance is still being established.

Fibroblasts are mesenchymal cells responsible for:

• Maintaining the functional and structural integrity of connective tissue.
• They become activated and differentiate into myofibroblasts, which synthesize and deposit extracellular matrix (ECM), leading to tissue fibrosis.

The proposed mechanisms include:

• Proteolytic cleavage of normal proteins
• Increased expression or altered subcellular localization of normal proteins
• Alterations due to mutations in certain tumors, leading to immune recognition as neoepitopes and a break of immune tolerance.

Fibroblast activation involves:

1. Proliferation: Fibroblasts multiply in response to cues.
2. Migration: They move to the site of injury.
3. Secretion: They produce collagens, extracellular matrix molecules, growth factors, chemokines, and cytokines.
4. Transdifferentiation: They can transform into contractile myofibroblasts with stress fibers.

Under normal conditions, these processes are self-limited and promote adaptive tissue repair. However, when sustained, they lead to maladaptive repair and pathologic fibrosis.

TGF-ẞ plays a central role in fibrogenesis in systemic sclerosis (SSc) by mediating fibrosis. It is one of the key stimulatory signals that contribute to the sustained activation of fibroblasts, leading to excessive collagen production and fibrosis.

Soluble mediators involved in fibrogenesis in systemic sclerosis include:

• IL-6
• IL-11
• IL-13
• IL-23
• CXCL4 (chemokine)
• Connective Tissue Growth Factor (CTGF)
• Platelet-Derived Growth Factor (PDGF)
• Lysophosphatidic acid
• Endothelin

These mediators contribute to the activation and proliferation of fibroblasts, leading to fibrosis.

The hallmark pathological finding in systemic sclerosis (SSc) is widespread microangiopathy, characterized by capillary loss and obliteration, combined with fibrosis. This is observed across various organ systems.

In systemic sclerosis, skin fibrosis is characterized by:

• Thickened dermis: Due to accumulation of collagen bundles oriented parallel to the epithelium.
• Atrophy of adnexal glands: Loss of skin appendages.
• Loss of adipose tissue: Replacement of periadnexal and intradermal white adipose tissue with collagen.
• Absence of inflammation: Established skin fibrosis shows no inflammatory infiltrates, although early stages may show perivascular mononuclear cell infiltrates.

Potential sources of pathogenic myofibroblasts in systemic sclerosis include:

• Tissue-resident fibroblasts
• Transformed myofibroblasts
• Bone marrow-derived circulating mesenchymal progenitor cells
• Endothelial cells undergoing EndoMT (endothelial-to-mesenchymal transition)
• Adipocytes undergoing transdifferentiation into myofibroblasts
• Epithelial cells and tissue fibroblasts

These sources contribute to the fibrotic process in SSc.

The most common lung involvement pattern in systemic sclerosis is nonspecific interstitial pneumonia (NSIP), characterized by variable interstitial fibrosis and mild chronic inflammation with T lymphocytes, macrophages, and eosinophils.

Pathological changes in the gastrointestinal tract can include atrophy and fibrosis of the muscularis propria, characteristic vascular lesions in the lower esophagus, and collagenous replacement of intestinal architecture, leading to impaired smooth-muscle contractility and diminished peristaltic activity.

Scleroderma renal crisis is characterized by acute fibrinoid necrosis of afferent arterioles, intimal proliferation (onion-skin pattern), ischemic collapse of glomeruli, and may lead to thrombosis, thrombocytopenia, and intravascular hemolysis, predicting irreversible renal failure.

Common cardiac pathologies in systemic sclerosis include concentric intimal hypertrophy, luminal narrowing of arterioles, patchy contraction band necrosis, loss of cardiac myocytes, myocardial fibrosis, and fibrosis of the conduction system, particularly at the sinoatrial node.

The frequency of epicardial atherosclerotic coronary artery disease may be increased in SSc compared to the general population, similar to other systemic inflammatory diseases.

Common pathological findings in the hands of patients with SSc include synovitis, which progresses to fibrotic synovium. Unlike rheumatoid disease, pannus formation or bone resorption is uncommon. Fibrosis of tendon sheaths and fascia may occur, sometimes accompanied by calcifications, leading to palpable tendon friction rubs.

Placental findings in SSc pregnancies show decidual vasculopathy, which is associated with poor perinatal outcomes and fetal death.

In systemic sclerosis (SSc), inflammation, atrophy, and fibrosis of skeletal muscles are common findings, which are similar to those observed in polymyositis.

The dichotomous stratification of SSc patients into diffuse and limited cutaneous subsets is useful in clinical practice, but SSc is more complex with multiple distinct clusters or endophenotypes associated with characteristic manifestations and outcomes.

Skin involvement occurs in 90% of patients with limited cutaneous SSc and in 100% of patients with diffuse cutaneous SSc.

In dcSSc, the interval between Raynaud's phenomenon and other manifestations is brief, with early signs including soft tissue swelling and puffy fingers. In contrast, IcSSc has a more indolent course, with a longer interval before disease manifestations appear, such as gastroesophageal reflux disease and cutaneous telangiectasia.

Common features during the early inflammatory phase of dcSSc include:

1. Soft tissue swelling
2. Puffy fingers
3. Pruritus
4. Diffuse hyperpigmentation of the skin
5. Carpal tunnel syndrome
6. Arthralgias
7. Muscle weakness
8. Fatigue
9. Decreased joint mobility

The early stage known as VEDOSS is characterized by puffy fingers, Raynaud's phenomenon, and SSc-specific autoantibodies. Patients in this stage generally show progression to frank disease, highlighting the importance of early recognition and intervention.

Raynaud's phenomenon, also known as secondary Raynaud's, is characterized by episodic vasoconstriction in the fingers and toes, sometimes affecting the nose and earlobes. It typically starts with pallor, followed by cyanosis, and can lead to hyperemia upon rewarming. The phenomenon can be triggered by cold temperatures, emotional stress, and vibration.

Primary Raynaud's disease is characterized by:

1. Absence of an underlying cause
2. Family history of Raynaud's phenomenon
3. Absence of digital tissue necrosis or ulceration
4. Negative ANA test

In contrast, secondary Raynaud's phenomenon tends to occur at an older age, is more severe, and is frequently complicated by ischemic digital ulcers and loss of digits.

Nailfold capillaroscopy allows visualization of nailbed capillaries. In primary Raynaud's disease, the capillaries appear as evenly spaced parallel vascular loops. In secondary Raynaud's phenomenon, the capillaries are distorted with widened and irregular loops, dilated lumen, microhemorrhages, and areas of vascular dropout, aiding in the differentiation and early diagnosis of SSc.

Recent GWAS revealed a robust link of Raynaud's phenomenon with the ADRA2A gene, suggesting that deregulated alpha-adrenergic signaling may play a role in its pathogenesis.

Secondary Raynaud's phenomenon can lead to complications such as:

• Ischemic digital ulcers
• Loss of digits
• Increased severity of episodes (more frequent, prolonged, and painful)
• Complications from treatments with beta blockers and anticancer drugs like cisplatin and bleomycin.

Bilateral symmetrical skin thickening is the hallmark feature that distinguishes SSc from other connective tissue diseases.

Skin involvement in systemic sclerosis starts in the fingers and characteristically advances from distal to proximal extremities in an ascending fashion.

Some patients may note diffuse tanning in the absence of sun exposure as a very early manifestation of systemic sclerosis.

In dark-skinned individuals, vitiligo-like hypopigmentation may occur, leading to a 'salt-and-pepper' appearance of the skin, especially on the scalp, upper back, and chest.

Dermal sclerosis can obliterate hair follicles, sweat glands, and eccrine and sebaceous glands, leading to hair loss, decreased sweating, xerosis, and itching in affected areas of the skin.

In patients with systemic sclerosis, transverse creases on the dorsum of the fingers disappear, and fixed flexion contractures of the fingers can lead to reduced hand mobility and muscle atrophy.

Sclerodactyly is characterized by puffy and indurated fingers and fixed flexion contractures of proximal interphalangeal joints in patients with limited cutaneous systemic sclerosis.

Patients with established SSc may exhibit a characteristic 'mauskopf' facial appearance, which includes:

• Taut and shiny skin
• Expressionless facies due to reduced mobility of eyelids, cheeks, and mouth
• Thinning of the lips with accentuation of central incisor teeth
• Prominent perioral radial furrowing (rhytides)
• Reduced oral aperture (microstomia) affecting eating and oral hygiene
• Pinched, beak-like appearance of the nose

Telangiectasias, which are dilated skin capillaries measuring 2-20 mm in diameter, are frequently observed on the face, hands, lips, and oral mucosa in patients with systemic sclerosis. The number of telangiectasias correlates with the severity of microvascular disease, including pulmonary arterial hypertension (PAH).

Chronic ulcerations in systemic sclerosis can lead to several complications, including:

• Painful ulcers that heal slowly
• Secondary infections resulting in osteomyelitis
• Characteristic fixed digital 'pits' after healing of ischemic fingertip ulcerations
• Resorption of the terminal phalanges (acro-osteolysis) due to loss of soft tissue at the fingertips

Acro-osteolysis refers to the dissolution of distal terminal phalanges, which is associated with digital ischemia. It is commonly seen in patients with long-standing limited cutaneous systemic sclerosis (IcSSc) and Raynaud's phenomenon.

Dystrophic calcifications (calcinosis cutis) occur in the skin and subcutaneous tissues in the presence of normal serum calcium and phosphate levels. They are found in up to 40% of patients, most commonly in those with long-standing anti-centromere antibody-positive IcSSc. These calcific deposits can vary in size and are composed of calcium hydroxyapatite crystals.

Large calcific deposits can lead to:

1. Pain
2. Nerve compression
3. Ulceration through the overlying skin, which may result in drainage of chalky white material and secondary infections.
4. Neurologic complications may occur due to paraspinal sheet calcifications.

Calcinosis cutis is characterized by calcific deposits that can break through the skin. In patients with limited cutaneous systemic sclerosis (lcSSc), these deposits can be seen as white, circular formations on the skin, particularly near joints, as illustrated in clinical observations.

Dual-energy computed tomography is used to visualize calcific deposits in systemic sclerosis. It reveals the presence of calcific deposits at the proximal interphalangeal joints, providing a detailed view of the deposits associated with the condition.

The two principal forms of lung involvement in SSc are Interstitial Lung Disease (ILD) and pulmonary vascular disease.

Less common pulmonary complications of SSc include:

1. Aspiration pneumonitis associated with chronic gastroesophageal reflux
2. Pulmonary hemorrhage due to endobronchial telangiectasia
3. Obliterative bronchiolitis
4. Pleural reactions
5. Restrictive physiology due to chest wall fibrosis
6. Spontaneous pneumothorax
7. Drug-induced lung toxicity
8. Increased incidence of lung cancer.

Risk factors for significant ILD in SSc patients include:

• Male sex
• African-American race
• Diffuse skin involvement
• Severe gastroesophageal reflux
• Presence of topoisomerase I autoantibodies
• Low forced vital capacity (FVC) or single-breath diffusing capacity (DLCO) at initial presentation.

The most common presenting respiratory symptoms of ILD in SSc include:

• Exertional dyspnea
• Fatigue
• Reduced exercise tolerance
• A chronic dry cough may also be present.

In patients with established SSc-ILD, pulmonary function testing (PFT) typically shows a restrictive ventilatory defect, characterized by:

• FVC <70% predicted
• FEV1/FVC ratio >0.8
• Reduced total lung capacity (TLC)
• Reduced DLCO.

A significant reduction in DLCO compared to lung volumes may indicate pulmonary vascular disease.

Characteristic imaging findings of ILD in SSc on HRCT include:

• Bilateral lower lobe subpleural reticular linear opacities
• Ground-glass opacifications with an apicobasal gradient
• Mediastinal lymphadenopathy
• Pulmonary nodules
• Traction bronchiectasis
• Honeycomb changes (uncommon).

The extent of interstitial changes on HRCT at baseline is a predictor of ILD progression and mortality.

The histologic pattern on lung biopsy in SSc may predict the risk of progression of ILD, with the Nonspecific Interstitial Pneumonia (NSIP) pattern having a better prognosis than the Usual Interstitial Pneumonia (UIP) pattern.

PAH is defined as a mean pulmonary artery pressure (mPAP) >20 mmHg with a pulmonary capillary wedge pressure ≤15 mmHg and pulmonary vascular resistance >2.0 Wood units.

Common symptoms include exertional dyspnea, reduced exercise capacity, angina, near-syncope, and signs of right-sided heart failure such as tachypnea, elevated jugular venous pressure, and dependent edema.

Risk factors include limited cutaneous disease, older age at disease onset, high numbers of cutaneous telangiectasia, and antibodies to centromere, U3-RNP (fibrillarin), and B23.

Diagnosis is confirmed through cardiac catheterization, which assesses the severity of PAH, rules out other causes of pulmonary hypertension, and provides prognostic parameters. Doppler echocardiography is used for initial screening.

The 3-year survival of SSc patients with untreated PAH is less than 50%, indicating a poor prognosis.

Principal manifestations in the esophagus include:

1. Reflux - Management: Lifestyle modifications, prokinetic drugs
2. Dysphagia - Management: Prokinetic drugs
3. Strictures - Management: Proton pump inhibitors
4. Barrett's metaplasia - Management: Endoscopic procedures

Upper GI tract involvement in SSc leads to:

• Decreased oral aperture, which interferes with regular dental hygiene.
• Loss of periodontal ligament, causing teeth loosening.
• Symptoms of GERD such as heartburn, regurgitation, and dysphagia due to reduced lower esophageal sphincter pressure and impaired esophageal clearance.

Common extraesophageal manifestations of GERD in SSc include:

• Hoarseness
• Cough
• Chronic or recurrent microaspiration, which can aggravate underlying interstitial lung disease (ILD).

Complications of chronic GERD in SSc patients include:

• Esophageal strictures
• Barrett's esophagus, which is associated with an increased risk of adenocarcinoma, necessitating regular surveillance endoscopy with biopsy.

Gastric antral vascular ectasia (GAVE), also known as 'watermelon stomach', is characterized by subepithelial lesions in the gastric antrum that reflect the small-vessel vasculopathy of SSc. It may present with acute life-threatening or recurrent episodes of gastrointestinal bleeding, leading to chronic unexplained iron-deficiency anemia.

Gastrointestinal complications of SSc related to the lower GI tract include:

• Weight loss and malnutrition due to impaired intestinal motility and malabsorption.
• Chronic diarrhea secondary to bacterial overgrowth.
• Fat and protein malabsorption, along with vitamin B12 and D deficiencies.
• Intestinal pseudo-obstruction presenting with acute abdominal pain, nausea, and vomiting.
• Constipation and potential complications like sigmoid volvulus.
• Anorectal dysfunction, including fecal incontinence and GI bleeding from telangiectasia or rectal prolapse.

Scleroderma renal crisis is characterized by:

• Accelerated hypertension and acute kidney injury.
• Occurs in less than 15% of SSc patients, typically within 4 years of disease onset.
• Can be the presenting manifestation of SSc.
• Pathogenesis involves obliterative vasculopathy of renal arteries leading to intravascular hemolysis and a vicious cycle of renal vasoconstriction.
• Risk factors include African-American race, male sex, and diffuse skin involvement.
• High-risk patients should monitor blood pressure daily, and glucocorticoid use should be minimized due to its association with the crisis.

Pathologic findings in scleroderma renal crisis include:

• Intimal proliferation and myxoid changes in medium-sized renal arteries.
• Fragmentation of circulating red blood cells due to intravascular hemolysis, indicating significant vascular damage.

Patients with scleroderma renal crisis typically present with:

• Accelerated hypertension (generally >150/90 mmHg)
• Progressive oliguric renal insufficiency
• Approximately 10% may present with normal blood pressure, which is associated with a poor outcome.

Accompanying symptoms may include:

• Headache
• Blurred vision
• Congestive heart failure
• Pulmonary edema

Laboratory findings often show:

• Moderate thrombocytopenia
• Microangiopathic hemolysis with fragmented red blood cells
• Urinalysis typically reveals mild proteinuria, granular casts, and microscopic hematuria.

Cardiac involvement in systemic sclerosis is significant because:

• It is detected in 10–50% of SSc patients using sensitive diagnostic tools.
• Clinical cardiac involvement is more frequent in diffuse cutaneous SSc (dcSSc) than in limited cutaneous SSc (lcSSc).
• It can be primary or secondary to pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), or renal involvement.
• Cardiac involvement is associated with poor outcomes, including heart failure.

Common manifestations include:

• Pericarditis, pericardial effusions, constrictive pericarditis, and arrhythmias.
• Microvascular involvement and ischemia-reperfusion injury contribute to myocardial fibrosis and dysfunction.

Common musculoskeletal complications in systemic sclerosis include:

• Carpal tunnel syndrome as a presenting manifestation.
• Generalized arthralgia and stiffness, particularly in early disease.
• Progressive impairment of mobility in small and large joints, leading to fixed contractures.
• Tendon friction rubs, which are associated with increased risk for renal and cardiac complications.
• Muscle weakness due to factors like deconditioning, disuse atrophy, malnutrition, inflammation, and fibrosis.
• Chronic noninflammatory myopathy characterized by atrophy and fibrosis in late-stage SSc.
• Bone resorption leading to acro-osteolysis and difficulties in biting due to mandibular condyle resorption.

Dry eyes and dry mouth, known as sicca complex, are common in SSc. A biopsy of the minor salivary glands typically shows fibrosis rather than the focal lymphocytic infiltration seen in primary Sjögren's syndrome.

Patients with SSc have an increased cancer risk, particularly for lung cancer and esophageal adenocarcinoma, often linked to long-standing interstitial lung disease (ILD) or gastroesophageal reflux disease (GERD). Breast, lung, ovarian carcinomas, and lymphomas may occur close to the onset of SSc, especially in patients with autoantibodies to RNA polymerase III, suggesting SSc may represent a paraneoplastic syndrome triggered by the antitumor immune response.

Laboratory findings in SSc may include:

1. Mild microcytic anemia indicating recurrent GI bleeding or chronic esophagitis.
2. Macrocytic anemia due to folate and vitamin B12 deficiency or drugs like methotrexate.
3. Microangiopathic hemolytic anemia during scleroderma renal crisis.
4. Elevated C-reactive protein (CRP) indicating higher risk of progressive fibrosis and mortality.
5. Elevated IL-6 levels associated with worse outcomes.
6. Normal erythrocyte sedimentation rate (ESR), with elevation signaling coexisting myositis or malignancy.

The main autoantibodies associated with SSc include:

The primary clinical features that help establish the diagnosis of lcSSc include:

1. Raynaud's phenomenon
2. Gastroesophageal reflux disease (GERD) symptoms
3. Sclerodactyly
4. Nailfold capillary changes
5. Cutaneous telangiectasia
6. Calcinosis cutis

Diagnosing early-stage dcSSc can be challenging due to:

• Initial symptoms being often nonspecific.
• Absence of Raynaud's phenomenon.
• Physical examination may only show upper extremity edema and puffy fingers.
• Potential misdiagnosis as arthritis, systemic lupus erythematosus (SLE), myositis, or undifferentiated connective tissue disease, leading to delays in diagnosis.

Nailfold microscopy is helpful in differentiating primary Raynaud's disease from early or limited SSc because:

• In primary Raynaud's disease, nailfold capillaries appear normal.
• In SSc, nailfold capillary changes are typically present, aiding in the diagnosis.

Key indicators suggesting a diagnosis of systemic sclerosis sine scleroderma include:

• Raynaud's phenomenon with fingertip ulcerations or evidence of digital ischemia.
• Telangiectasia.
• Distal esophageal dysmotility.
• Unexplained interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH).
• Accelerated hypertension with renal failure in the absence of clinically evident skin induration.

Screening for interstitial lung disease (ILD) in patients with a new diagnosis of systemic sclerosis (SSc) is important because:

• It allows for early detection of potential lung complications.
• Regular pulmonary monitoring is necessary for several years to manage and mitigate risks associated with ILD.

A 'precision medicine' approach is significant because it tailors treatment specifically to each individual patient's unique needs, considering the marked heterogeneity in disease manifestations, course, and outcomes. This approach aims to optimize care and improve patient outcomes by addressing the specific characteristics and requirements of each patient.

While few therapies significantly alter the natural history of SSc, a variety of interventions have been effective in alleviating symptoms, slowing progression of cumulative organ damage, and reducing disability, which collectively contribute to a significant decrease in disease-related mortality.

Patient education plays a crucial role by empowering patients to understand potential complications, encouraging them to engage actively in their care, and fostering a long-term relationship with their physician that includes ongoing counseling and dialogue.

Glucocorticoids alleviate stiffness and aching in early inflammatory-stage dcSSc but do not influence the progression of skin or internal organ involvement. Their use is associated with an increased risk of scleroderma renal crisis, so they should be given only when absolutely necessary, at the lowest dose possible, and for brief periods only.

Both oral and intravenous cyclophosphamide have been shown to reduce the progression of SSc-associated ILD, with stabilization and, less commonly, modest improvement of pulmonary function, HRCT findings, respiratory symptoms, and skin induration. However, its potential toxicity must be considered.

Mycophenolate mofetil has been shown to improve both skin induration and interstitial lung disease (ILD) in patients treated with it, and the drug was well tolerated in clinical trials.

Tocilizumab, a monoclonal antibody that blocks IL-6 receptor signaling, has shown some benefit on both skin and lung involvement in randomized SSc trials and is well tolerated, particularly in the treatment of SSc-associated ILD in relatively early disease.

Intensive immune ablation using high-dose chemotherapy followed by HSCT has been associated with durable remission and improved long-term survival in multiple randomized clinical trials. HSCT is indicated for selected patients with severe SSc but carries risks of treatment-related morbidity and mortality.

Antifibrotic therapy aims to interfere with the fibrotic process that underlies organ damage in SSc. Drugs like nintedanib have shown benefits in slowing lung function decline in patients with SSc-associated ILD, although they may not significantly benefit skin involvement.

The goal of Raynaud's therapy is to control episodes, prevent and enhance the healing of ischemic complications, and slow the progression of the disease.

Patients should dress warmly, minimize cold exposure, and avoid drugs that precipitate or exacerbate vasospastic episodes.

Extended-release dihydropyridine calcium channel blockers like amlodipine and diltiazem can ameliorate Raynaud's phenomenon but are often limited by side effects such as palpitations, dependent edema, and worsening gastroesophageal reflux.

Options include:

1. α₁-adrenergic receptor blockers (e.g., prazosin)
2. 5-phosphodiesterase inhibitors (e.g., sildenafil)
3. Topical nitroglycerine
4. Intermittent IV infusions of prostaglandins
5. Low-dose aspirin and dipyridamole for platelet aggregation prevention
6. Endothelin-1 receptor antagonist bosentan for ischemic digital tip ulcerations
7. Digital sympathectomy and intradigital injections of botulinum type A (Botox) for severe ischemia.

Risk factors for ILD progression include:

• Male sex
• Older age at initial presentation
• Anti-topoisomerase I positivity
• Progressive skin involvement
• Myocardial disease.

Cyclophosphamide (IV or oral for 6-12 months) and mycophenolate mofetil are preferred, with mycophenolate mofetil generally favored due to fewer side effects. If ILD progresses despite immunotherapy, nintedanib may be added.

Management strategies include:

• Regular dental care
• Elevating the head of the bed
• Eating frequent small meals
• Avoiding alcohol, caffeine, and known reflux exacerbants
• Proton pump inhibitors for acid reflux
• Prokinetic agents (e.g., erythromycin, prucalopride)
• Botulinum toxin injections for gastric emptying issues
• Endoscopic treatments for gastric bleeding
• Antibiotics for small intestinal bacterial overgrowth.

PAH carries an extremely poor prognosis and accounts for 30% of deaths in patients with systemic sclerosis. It is often asymptomatic until advanced stages, necessitating regular screening.

First-line treatments include oral endothelin-1 receptor antagonists (e.g., bosentan) and phosphodiesterase-5 inhibitors (e.g., sildenafil). Other options include riociguat and selexipag, which improve symptoms and survival.

Treatment options for PAH in SSc patients include:

1. Prostacyclin analogues (e.g., epoprostenol, treprostinil) given by:

   • Continuous IV infusion
   • SC infusion
   • Intermittent nebulized inhalations

2. Combination therapy with different classes of agents acting additively or synergistically.

3. Lung transplantation for selected patients who fail medical therapy, with 2-year survival rates comparable to idiopathic ILD or PAH.

Early recognition and treatment of scleroderma renal crisis are crucial because:

• The outcome is largely determined by the extent of renal damage at the time aggressive therapy is initiated.
• High-risk SSc patients should monitor blood pressure daily and report significant changes.
• Prompt treatment with short-acting ACE inhibitors can lead to rapid normalization of blood pressure, potentially preventing severe renal damage.

Recommended treatments for skin involvement in systemic sclerosis include:

1. Antihistamines and low-dose glucocorticoids for inflammatory symptoms.
2. Cyclophosphamide and methotrexate for skin induration.
3. Hydrophilic ointments and bath oils to manage skin dryness.
4. Regular skin massage to improve skin condition.
5. Pulsed dye laser for cosmetic treatment of telangiectasia.
6. Occlusive dressings for ischemic digital ulcerations to promote healing.
7. Topical antibiotics and surgical debridement for infected skin ulcers.

Musculoskeletal complications in systemic sclerosis manifest as:

• Arthralgia (joint pain)
• Joint stiffness

Treatment options include:

1. Nonsteroidal anti-inflammatory agents for pain relief.
2. Methotrexate and hydroxychloroquine for symptom alleviation.
3. Low-dose glucocorticoids for inflammation control.
4. Physical and occupational therapy to prevent loss of musculoskeletal function and joint contractures.

The natural history of systemic sclerosis (SSc) is variable:

• Diffuse cutaneous SSc (dcSSc) tends to have a more rapidly progressive course and worse prognosis.
• Limited cutaneous SSc (lcSSc) follows a markedly different clinical course.

Key points include:

• Inflammatory symptoms in early dcSSc subside within 2-4 years, but visceral organ involvement may develop.
• Scleroderma renal crisis typically occurs within the first 4 years.
• In late-stage disease, skin is usually soft and atrophic, with regression occurring in a specific order.
• Raynaud's phenomenon often precedes other manifestations by years in lcSSc.

The median survival for patients with systemic sclerosis (SSc) is 11 years.

The major causes of death in patients with systemic sclerosis include pulmonary arterial hypertension (PAH), pulmonary fibrosis, gastrointestinal involvement, and cardiac disease.

The prognosis in systemic sclerosis correlates with the extent of skin involvement, which serves as a surrogate for visceral organ involvement.

Laboratory predictors of increased mortality at initial evaluation include an elevated ESR, anemia, proteinuria, and anti-topoisomerase I antibodies.

The advent of ACE inhibitors for scleroderma renal crisis dramatically improved survival, increasing from less than 10% at 1 year in the pre-ACE inhibitor era to over 70% at 3 years currently.

The long-term prognosis for patients with mixed connective tissue disease (MCTD) is generally better than that of systemic sclerosis (SSc).

Eosinophilic fasciitis is characterized by abrupt skin induration, a coarse cobblestone 'peau d'orange' appearance, and absence of Raynaud's phenomenon and internal organ involvement.

The study compares the effectiveness of mycophenolate mofetil versus oral cyclophosphamide in treating scleroderma-related interstitial lung disease through a randomised controlled, double-blind, parallel group trial.

The research highlights the association of scleroderma, an autoimmune disease, with an immunologic response to cancer, suggesting potential links between autoimmune conditions and cancer immunology.

The study investigates the similarities and differences between interstitial lung disease associated with systemic sclerosis and idiopathic pulmonary fibrosis, focusing on their clinical and pathological features.

The authors discuss molecular stratification and precision medicine in systemic sclerosis, utilizing genomic and proteomic data to improve understanding and treatment of the disease.