Systemic Sclerosis (Scleroderma) and Related Disorders¶
Chapter 372 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 372
Key Clinical Points¶
- Systemic sclerosis (SSc) is an orphan disease characterized by a triad of microangiopathy, inflammation/autoimmunity, and fibrosis.
- Two primary clinical subsets exist: limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc).
- dcSSc features rapid skin progression, higher rates of interstitial lung disease (ILD), and a significant risk of scleroderma renal crisis.
- lcSSc is associated with the CREST syndrome (Calcinosis, Raynaud's, Esophageal dysmotility, Sclerodactyly, Telangiectasia).
- Key autoantibodies include Anti-centromere (lcSSc), Anti-topoisomerase I/Scl-70 (dcSSc), and Anti-RNA polymerase III (dcSSc with high malignancy risk).
- Raynaud's phenomenon is often the earliest clinical sign, potentially preceding skin changes by years.
- Scleroderma renal crisis is a medical emergency involving malignant hypertension and acute renal failure, more common in dcSSc.
- Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are leading causes of mortality.
- Nailfold capillaroscopy is a non-invasive tool to assess microvascular damage progression from normal to late stages.
- Management requires a multidisciplinary approach, especially for ILD and gastrointestinal complications.
DEFINITION & CLASSIFICATION¶
• Definition (Harrison's 22e): Systemic sclerosis (SSc) is an orphan disease of unknown etiology, complex pathogenesis, and variable clinical presentations. • Clinical Course: Chronic and often progressive; involves significant disability and mortality. • Pathological Progression: Early stages feature inflammatory elements (edema); later stages are dominated by structural alterations in vascular beds and visceral organ dysfunction due to fibrosis and atrophy. • SSc sine scleroderma: A subset where Raynaud's phenomenon and SSc features occur without detectable skin thickening.
Subsets of Systemic Sclerosis¶
• Diffuse Cutaneous SSc (dcSSc): ◦ Skin: Rapid onset; extensive induration from fingers to trunk. ◦ Complications: Early ILD, less common acute renal involvement. ◦ Autoantibodies: Anti-topoisomerase I (Scl-70), RNA polymerase III. • Limited Cutaneous SSc (lcSSc): ◦ Skin: Indolent onset; limited to fingers, distal limbs, and face; trunk spared. ◦ Clinical Syndrome: CREST (Calcinosis, Raynaud's, Esophageal dysmotility, Sclerodactyly, Telangiectasia). ◦ Complications: Late-stage pulmonary arterial hypertension (PAH), digital ischemic ulcers. ◦ Autoantibodies: Anti-centromere (ACA).
• Table 3 (372-3) - Comparison of lcSSc vs. dcSSc: ◦ Skin Involvement: lcSSc (Indolent, limited to fingers/face) vs. dcSSc (Rapid, extensive to trunk). ◦ Raynaud's: lcSSc (Antedates skin by years) vs. dcSSc (Concurrent with skin involvement). ◦ Musculoskeletal: lcSSc (Mild arthralgia) vs. dcSSc (Severe arthralgia, carpal tunnel, tendon friction rubs). ◦ ILD: lcSSc (Slowly progressive, mild) vs. dcSSc (Frequent, early, severe). ◦ PAH: lcSSc (Frequent, late, isolated) vs. dcSSc (Often associated with ILD). ◦ Scleroderma Renal Crisis: lcSSc (Very rare) vs. dcSSc (15%; usually <4 years from onset). ◦ Calcinosis Cutis: lcSSc (Frequent, prominent) vs. dcSSc (Less common, mild). ◦ Autoantibodies: lcSSc (Anti-centromere) vs. dcSSc (Scl-70, RNA polymerase III).
Classification Criteria¶
• ACR/EULAR Criteria: Used for clinical research; >90% specific and sensitive. ◦ Requirement: Score of ≥ 9 required for classification. ◦ Components: ◦ Skin thickening (bilateral) proximal to MCP joints: 9 points ◦ Puffy fingers: 2 points ◦ Sclerodactyly: 4 points ◦ Fingertip lesions (ulcer/pitting): 3 points ◦ Abnormal nailfold capillary pattern: 2 points ◦ PAH: 2 points ◦ ILD: 2 points ◦ Raynaud's phenomenon: 3 points ◦ ACA, Scl-70, or RNA polymerase III: 3 points each. • Table 2 (372-1) provides the specific scoring for these criteria.
EPIDEMIOLOGY¶
• General: Acquired sporadic disease; worldwide distribution; rising incidence. ◦ US Incidence: 9–46 cases per million per year. ◦ Prevalence: Estimated 100,000 U.S. cases (potentially higher). • Demographics: ◦ Sex: Strong female bias (4.6:1). ◦ Age: Peak onset in women is 65–74 years; earlier in Black patients. ◦ Ethnicity: Black patients have higher incidence, more dcSSc, more ILD, and worse prognosis. • Genetics: ◦ Risk Factors: HLA class II haplotypes (HLA-DRB111:04, DQA105:01, DQB103:01); non-HLA genes (NOTCH4, PSORSC1). ◦ Immune Pathways: Variants in BANK1, BLK, CD247, IL2RA, CCR6, IDO1, TNFSF4/OX40L, PTPN22, TNIP1; STAT4 and IRF5 (Type I IFN production). ◦ Specific Associations: ◦ ILD: CTGF, CD226 ◦ PAH: TNIP1 ◦ Scleroderma Renal Crisis: HLA-DRB1 ◦ Anti-centromere: HLA-DPB1*05:01
ETIOLOGY & PATHOPHYSIOLOGY¶
• Etiology: Unknown; likely driven by environmental triggers in genetically predisposed individuals. ◦ Environmental Factors: Silica, solvents, drugs (bleomycin), viral agents (EBV, CMV, Parvovirus B19). ◦ Epigenetics: Potential for reversible modifications (DNA methylation, histone modification) as therapeutic targets. • Pathogenesis Triad: ◦ 1. Microangiopathy ◦ 2. Inflammation/Autoimmunity ◦ 3. Fibrosis → Illustrated in Figure 1 (372-3) and Figure 2 (372-4). • Microangiopathy: ◦ Raynaud's: Early sign; involves altered blood flow, impaired neuropeptide production, and heightened α-adrenergic sensitivity. ◦ Endothelial Damage: Leads to reduced nitric oxide/prostacylin, increased endothelin-1, and activation of coagulation cascades. ◦ Fibroproliferative Vasculopathy: Endothelial-mesenchymal transition (EndoMT) → myointimal cells; basement membrane thickening; perivascular fibrosis → vessel rarefaction. • Inflammation & Autoimmunity: ◦ Immune Markers: Type I IFN signatures, elevated IL-6, TNF-α, IL-10, IL-17, IL-33, and chemokines (CCL2, CCL9, CXCL4). ◦ Dendritic Cells: Sense tissue damage via TLRs; produce CXCL4 (Platelet Factor 4). ◦ CXCL4 Pathogenicity: Binds to self-nucleic acids → activates endosomal TLRs → promotes monocyte differentiation and myofibroblast activation. ◦ T-cells: Th2-polarized response (IL-4, IL-13, IL-33, TSLP) drives fibrosis; Th1 (IFN-γ) is anti-fibrotic. ◦ B-cells: Elevated CD19, CD80, CD86; produce IL-6 and TGF-β. ◦ Neutrophils: Release TGF-β, IL-6, and NETs (triggering thrombosis). • Fibrosis: ◦ Driven by TGF-β and other cytokines. ◦ Result: Deposition of collagen types, elastin loss, and architectural distortion of organs.
Autoantibody Profiles¶
• Table 4 (372-4) - Major SSc-Specific Autoantibodies: ◦ Topoisomerase I (Scl-70): Speckled pattern; dcSSc; associated with tendon friction rubs, digital ulcers, early ILD, and renal crisis. ◦ RNA polymerase III: Speckled pattern; dcSSc; rapid progression, joint contractures, GAVE, and concurrent cancers. ◦ Th/To: Nucleolar pattern; lcSSc; associated with ILD and PAH. ◦ Ro52/TRIM21: Overlap; older-age onset, ILD. ◦ U1-RNP: Speckled pattern; MCTD (PAH, inflammatory arthritis, myositis).
CLINICAL FEATURES¶
• Skin Involvement: ◦ Sclerodactyly: Thickened skin distal to MCP joints; puffy/indurated fingers. ◦ Calcinosis Cutis: Calcium deposits in skin/subcutaneous tissue (Fig. 9). ◦ Telangiectasia: Dilated vessels on face/nose (common in lcSSc). • Musculoskeletal: ◦ Arthralgia, carpal tunnel syndrome, tendon friction rubs. • Pulmonary: ◦ Interstitial Lung Disease (ILD): Common in dcSSc; leads to fibrosis. ◦ Pulmonary Arterial Hypertension (PAH): Often associated with ILD in dcSSc; can be isolated in lcSSc. • Renal: ◦ Scleroderma Renal Crisis: Medical emergency; malignant hypertension and acute renal failure; more common in dcSSc (10-15%) than lcSSc (2%). • Gastrointestinal: ◦ GAVE (Gastric Antral Vascular Ectasia): "Watermelon stomach" appearance. ◦ Dysmotility: Reflux, dysphagia, gastroparesis. ◦ Table 6 (372-6) - Gastrointestinal Management: ◦ Oropharynx: Periodontal care, artificial saliva, swallowing therapy. ◦ Stomach: Prokinetic agents; endoscopic laser cryotherapy for GAVE. ◦ Anorectum: Biofeedback, sacral nerve stimulation, surgery for sphincter incompetence.
DIFFERENTIAL DIAGNOSIS¶
• Scleroderma-like Skin Induration: ◦ Table 1 (372-2) - Conditions with similar features: ◦ Localized scleroderma, Morphea (Guttate, Diffuse, Linear). ◦ Mixed connective tissue disease (MCTD), SSc/polymyositis. ◦ Scleromyxedema, Scleroderma of Buschke. ◦ Chronic graft-versus-host disease. ◦ Eosinophilic fasciitis (Shulman's disease). /// Other conditions: ◦ Stiff skin syndrome, Pachydermatoperiostosis. ◦ Drug/Chemical: Vinyl chloride, Nephrogenic systemic fibrosis (gadolinium), Eosinophilia-myalgia syndrome.
DIAGNOSTIC APPROACH¶
- Initial Clinical Assessment: • Identify hallmark features: Raynaud's, sclerodactyly, telangiectasia.
- Serologic Testing (Autoantibodies): • Determine subset and risk profile: ◦ Anti-centromere → lcSSc. ◦ Scl-70 → dcSSc + ILD/Renal Risk. ◦ RNA Polymerase III → dcSSc + Rapid progression/Cancer risk.
- Microvascular Evaluation: • Nailfold Capillaroscopy (Fig. 4): ◦ Normal: Uniform "hairpin" loops. ◦ Early: Dilated capillaries. ◦ Active: Giant capillaries + microhemorrhages. ◦ Late: Dropout, fibrosis, neoangiogenesis.
- Imaging and Functional Studies: • HRCT (Fig. 8): Monitor ILD progression. ◦ Early → Ground-glass opacities/subpleural reticulations. ◦ Late → Honeycombing, traction bronchiectasis. • PFTs: Assess FVC and other parameters for lung function.
MANAGEMENT & TREATMENT¶
- Interstitial Lung Disease (ILD) Management: • Monitoring: Regular screening via HRCT, PFT, and FVC. • Pharmacotherapy: ◦ Mycophenolate mofetil (MMF) → primary for ILD progression. ◦ Cyclophosphamide → used to reduce progression; monitor for bone marrow suppression, infection, hemorrhagic cystitis. • Glucocorticoids: Use only for stiffness/inflammation; must be at lowest dose possible and for brief periods only (due to renal crisis risk). • Escalation: If standard therapy fails → "Rescue therapy" (HSCT, lung Tx, or Palliative care).
- Scleroderma Renal Crisis (SRC) Management: • Emergency Protocol: Treat as medical emergency for malignant hypertension and acute renal failure.
- Gastrointestinal Management: • Oropharynx: Periodontal care, artificial saliva, swallowing therapy. • Stomachs: Prokinetic agents; endoscopic laser cryotherapy for GAVE. • Anorectum: Biofeedback, sacral nerve stimulation, surgery.
- General Principles (Table 7): • Early/accurate diagnosis → identify organ involvement → define stage/activity → tailored therapy → monitor response.
Management Flowchart: ILD¶
- Initial Assessment: Evaluate SSc-associated ILD via HRCT, PFT, and FVC.
- Proactive Management: Early intervention → Multidisciplinary team approach.
- Glucocorticoid Pathway: If used for stiffness/inflammation → must be at lowest dose possible and for brief periods only (to mitigate renal crisis risk).
- Cyclophosphamide Pathway: Used to reduce progression of SSc-associated ILD → balance against bone marrow suppression, infections, and hemorrhagic cystitis.
- Escalation/Rescue Path: If standard therapies are insufficient or disease progresses → move toward "Rescue therapy" (HSCT, lung Tx, Palliative care).
COMPLICATIONS & PROGNOSIS¶
• Mortality: Primarily driven by ILD and PAH. • Renal Crisis: Occurs in 10-15% of dcSSc; usually early (<4 years from onset). • Digital Damage: Ischemic ulcers, necrosis, and acro-osteolysis (Fig. 7) due to microangiopathy. • Gastrointestinal: GAVE, gastroparesis, and motility issues. • Cancer Risk: Increased in patients with RNA polymerase III antibodies.
SPECIAL POPULATIONS¶
• Pregnancy: (Not detailed in source text). • Elderly: Peak age of onset for both lcSSc and dcSSc is 65–74 years. • Black Patients: Earlier age of onset; higher likelihood of dcSSc, ILD, and mortality.
KEY PEARLS & HIGH-YIELD POINTS¶
• The SSc Triad: Vasculopathy + Immune Activation + Fibrosis. • Rapid Rule: ◦ Anti-centromere → lcSSc. ◦ Scl-70 → dcSSc (High ILD/Renal risk). ◦ RNA Pol III → dcSSc (High Cancer risk). • Renal Crisis: A medical emergency; avoid prolonged steroids to prevent progression. • Nailfold Capillaroscopy: Essential for monitoring microvascular damage and predicting ILD risk. • GAVE: Recognized as "watermelon stomach" on imaging; managed with laser cryotherapy.
Reference Tables¶
TABLE 372-2 Conditions Associated with Scleroderma-Like Skin Induration Systemic sclerosis (SSc)¶
Harrison's 22e, p.2860
- Systemic sclerosis (SSc)
Limited cutaneous SSc
Diffuse cutaneous SSc
Localized scleroderma
Guttate (plaque) morphea, diffuse (pansclerotic) morphea, bullous morphea
Linear scleroderma, coup de sabre, hemifacial atrophy
Pansclerotic morphea
Overlap syndromes
Mixed connective tissue disease
SSc/polymyositis
Diabetic scleredema and scleredema of Buschke
Scleromyxedema (papular mucinosis)
Chronic graft-versus-host disease
Diffuse fasciitis with eosinophilia (Shulman’s disease, eosinophilic fasciitis)
Stiff skin syndrome
Pachydermatoperiostosis (primary hypertrophic osteoarthropathy)
Chemically induced and drug-associated scleroderma-like conditions
Vinyl chloride–induced disease
Eosinophilia-myalgia syndrome (associated with l-tryptophan contaminant
exposure)
Nephrogenic systemic fibrosis (associated with gadolinium exposure)
Paraneoplastic syndrome
TABLE 372-1 ACR/EULAR Classification Criteria for Diagnosis of Systemic Sclerosis (SSc) ITEM Skin thickening…¶
Harrison's 22e, p.2860
| ITEM | SUBITEM | WEIGHT/SCORE |
|---|---|---|
| Skin thickening (bilateral)— fingers extending proximal to MCP joints |
9 | |
| Puffy fingers Sclerodactyly (skin thickened distal to MCP joints) |
||
| Fingertip lesions | Digital tip ulcer or pitting scar | 2 3 |
| Abnormal nailfold capillary pattern |
2 | |
| PAH Interstitial lung disease |
||
| Raynaud’s phenomenon | 3 | |
| ACA Scl-70 RNA polymerase III |
TABLE 372-3 Subsets of Systemic Sclerosis (SSc): Features of Limited Cutaneous Versus Diffuse Cutaneous Disease¶
Harrison's 22e, p.2861
| CHARACTERISTIC FEATURE |
LIMITED CUTANEOUS SSc | DIFFUSE CUTANEOUS SSc |
|---|---|---|
| Skin involvement | Indolent onset. Limited to fingers, distal to elbows, face; slow progression |
Rapid onset. Diffuse: fingers, extremities, face, trunk; rapid progression |
| Antedates skin involvement, sometimes by years; may be associated with critical ischemia in the digits |
||
| Musculoskeletal | Mild arthralgia | Severe arthralgia, carpal tunnel syndrome, tendon friction rubs |
| Slowly progressive, generally mild |
||
| Pulmonary arterial hypertension |
Frequent, late, may occur as an isolated complication |
Often occurs in association with interstitial lung disease |
| Very rare | ||
| Calcinosis cutis | Frequent, prominent | Less common, mild |
| Anti-centromere |
TABLE 372-4 Major Systemic Sclerosis (SSc)-Specific Autoantibodies and Principal Associated Features¶
Harrison's 22e, p.2864
| TARGET ANTIGEN; CHARACTERISTIC IMMUNOFLUORESCENCE PATTERN |
— | SSc SUBSET |
PROMINENT CHARACTERISTIC CLINICAL ASSOCIATION |
|---|---|---|---|
| Topoisomerase I (Scl-70) Speckled pattern |
— | dcSSc | Tendon friction rubs, digital ischemic ulcers, extensive skin involvement, early-onset ILD, cardiac involvement, scleroderma renal crisis |
| — | lcSSc | ||
| RNA polymerase III Speckled pattern |
— | dcSSc | Rapidly progressive skin involvement, tendon friction rubs, joint contractures, GAVE, renal crisis, contemporaneous cancers; digital ulcers rare |
| — | dc/lcSSc | ||
| Th/T 0 Nucleolar pattern |
— | lcSSc | ILD, PAH |
| — | lcSSc | ||
| Ro52/TRIM21 | — | Overlap | Older-age onset, ILD |
| — | Overlap | ||
| U1-RNP Speckled pattern |
— | MCTD | PAH, inflammatory arthritis, myositis overlap |
| — | dc/lcSSc |
TABLE 372-5 Frequency of Clinical Organ Involvement in Limited Cutaneous and Diffuse Cutaneous Systemic Sclerosis (SSc)¶
Harrison's 22e, p.2866
| CLINICAL FEATURES | LIMITED CUTANEOUS SSc (%) |
DIFFUSE CUTANEOUS SSc (%) |
|---|---|---|
| Skin involvement | 90a | 100 |
| 99 | ||
| Ischemic digital ulcers | 50 | 25 |
| 90 | ||
| Interstitial lung disease | 35 | 65 |
| 15 | ||
| Myopathy | 11 | 23 |
| 9 | ||
| Scleroderma renal crisis | 2 | 10-15 |
| 30 |
TABLE 372-6 Prominent Gastrointestinal Manifestations of Systemic Sclerosis (SSc) and Their Management¶
Harrison's 22e, p.2870
| SITE IN GASTROINTESTINAL TRACT |
PRINCIPAL MANIFESTATION | MANAGEMENT |
|---|---|---|
| Oropharynx | Diminished oral aperture Dry mouth Periodontitis, gingivitis Swallowing |
Periodontal care Artificial saliva Swallowing therapy |
| Reflux Dysphagia Strictures Barrett’s metaplasia |
||
| Stomach | Gastroparesis Gastric antral vascular ectasia (GAVE; watermelon stomach) |
Prokinetic agents Endoscopic laser cryotherapy |
| Bacterial overgrowth (small intestinal bacterial overgrowth) Diarrhea/constipation Pseudo-obstruction Pneumatosis intestinalis Malabsorption Colonic pseudo-diverticula |
||
| Anorectum | Sphincter incompetence | Biofeedback, sacral nerve stimulation, surgery |
TABLE 372-7 Key Principles in Management • Establish early and accurate diagnosis. • Detect and evaluate internal organ…¶
Harrison's 22e, p.2873
- • Establish early and accurate diagnosis.
• Detect and evaluate internal organ involvement.
• Define clinical disease stage and activity.
• Tailor individualized therapy to each patient’s unique needs.
• Assess treatment response, and adjust therapy as needed; monitor for
disease activity, progression, and new complications.