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BOTTOM LINE

Systemic sclerosis (aka scleroderma, SSc) is a heterogenous, chronic, and frequently progressive multisystem disease characterized by fibrosis of skin and internal organs with widespread vasculopathy and auto-antibody positivity. Patients are often middle-aged women (80% women); older age is associated with limited subset scleroderma. Common features include skin thickening (either with limited or diffuse cutaneous distribution), Raynaud phenomenon, GERD, and interstitial lung disease. Nearly all patients are ANA positive and need to be screened for interstitial lung disease (UIP or NSIP patterns) and pulmonary hypertension.  Treatment is tailored to individual disease/organ dysfunction with aim to reduce progression or severity of complications.
[🕑 15 minute read ]

CLINICAL FRAMEWORK

Click to Enlarge.

TERMINOLOGY

• Scleroderma refers to fibrosis and hardening of the skin; systemic sclerosis refers to multi-organ fibrosis, vasculopathy, and inflammation. The two terms are usually used interchangeably.
• Scleroderma can be divided into non-systemic (skin only) versus systemic (multi-organ) scleroderma; systemic scleroderma (aka systemic sclerosis) is further subdivided into limited versus diffuse cutaneous Systemic Sclerosis (lcSSc vs. dcSSc).  

Classification of patients as lcSSc or dcSSc predict patients’ expected pattern of organ involvement and disease course.

• “CREST” is itself not a diagnosis. “CREST” usually refers to a subset of lcSSc patients with combination of Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, and Telangiectasia. Many dcSSc patients can also have “CREST” features.
• Systemic sclerosis can also occur as an overlap syndrome with another systemic rheumatic disease (ex: RA, Sjogren’s, SLE).
• If a patient carries a diagnosis of “Mixed Connective Tissue Disease” (MCTD) or undifferentiated Connective Tissue Disease (uCTD, aka undifferentiated systemic autoimmune rheumatic disease or uSARD) yet meets ACR/EULAR classification criteria for scleroderma, this patient can then be labelled as Systemic Sclerosis.

EPIDEMIOLOGY

• Population
  • Incidence ~1-4/100,000 annually
  • Prevalence ~3-35/100,000
    • Highest prevalence in Native Aboriginals (Canada) 47/100,000
    • Greater prevalence in European versus East Asian populations
• Age
  • Age at onset often 40-64 years-old; native aboriginal and African patients typically present younger
    • Younger onset: Higher risk of dcSSc, higher prevalence anti-Scl70 antibodies
    • Older onset: higher risk of lcSSc. More cardiac involvement (heart block, diastolic dysfunction) particularly in older dcSSc patients.
  • Age at onset is getting older, likely due to the aging population in most Western countries or changing epidemiology of disease over time.
• Sex
  • Predominantly female, 4:1
  • Women
    • More likely lcSSc, increased risk of Raynauds Phenomenon with digital ulcers and PAH
  • Men
    • More likely have dcSSc, more ILD, renal crisis, and increased cardiovascular complications
• Risk factors
  • Environmental
    • Silica exposure (ex: miners, construction workers, farmers, certain engineers)
    • Possible risk: Organic solvents (ex: aromatic chlorinated compounds), heavy metals (ex: antimony, cadmium, lead, and mercury)
  • Genetic
    • First degree relatives: RR 13 (95% CI 2.9–48.6; P < 0.001) for developing SSc
    • Various single-nucleotide polymorphisms increase susceptibility, including
      • MHC Class II region:
        HLA-DQ1B, HLA-DQA1, DBP1, DRB1, NOTCH4
      • Non-MHC loci:
        IR56, CD247, STAT4, BANK1, TNIP1, TNFAIP, PTPN22, PPARG, MECP2, IRAK1
    • Various epigenetic modifications described, including varied DNA methylation, histone modifications and microRNAs

CLINICAL MANIFESTATIONS

— Skin

• Early Stage:
  • Pruritis (especially in involved active skin), edematous swelling (“puffy fingers”); often starts in fingers and face
  • Skin induration/thickening starts at fingers and spreads proximally
• Later Stage
  • Skin thickening over finger causes flexion contractures (sclerodactyly: claw hands, atrophy of skin and loss of subcutaneous fat)
  • Face skin thickens, mimic folds disappear, lips thin, nose sharpens, oral aperture decreases
  • Telangiectasias worsen in severity and number on face, lips, tongue, neck, palms, dorsum hands, forearms; sometimes abdomen, breast, shoulders, thighs

If skin thickening does not start at finger tips and face, consider scleroderma mimic

• Distribution
  • Limited cutaneous SSc (lcSSc):
    Skin thickening face, hands, feet, but distal to elbows & knees; no truncal involvement
  • Diffuse cutaneous SSc (dcSSc):
    Skin thickening spreads proximal to elbows & knees and/or
    Spreads to trunk, in addition to sclerodactyly and skin thickening of forearms
• Other skin changes
  • Skin hyper/depigmentation (“salt and pepper skin”), hair loss, lipoatrophy, skin ulcers at DIP/PIPs related to microtrauma over tight skin
  • Calcinosis cutis: Up to 25% of SSc
    • Deposition of calcium in subcutaneous tissue
    • Presents as white papules or subcutaneous firm nodules in extremities that can ulcerate.
    • Associated with lcSSc, centromere or PM/ScL antibody; can also be seen with dcSSc
  • Systemic sclerosis sine scleroderma:
    • Clinical and serological features of scleroderma but no significant skin sclerosis.
    • Ex: Raynaud without skin thickening, telangiectasias, dysphagia, ILD with anti-SCL70 antibody
    • Most likely just a mild form of lcSSc rather than a true SSC subtype
    • Rarely in dcSSc, organ involvement (ex: SRC, ILD) can predate skin thickening by a few short weeks/months and appear as Systemic sclerosis sine scleroderma

— Digital Vascular

• Nailfold capillaries
  • Nailfold capillaroscopy can identify dilated nailfold changes that suggest secondary Raynaud (secondary to a systemic rheumatic disease like scleroderma) over idiopathic primary Raynaud phenomenon
  • Often occurs in 3 main phases: early, active, and late patterns (however, patients do not necessarily progress through all stages)
    • Nailfold capillary dilation → dilation + drop-outs → tortuosity + drop-outs
• Raynaud Phenomenon
  • Definition: sequential cold-induced demarcated pallor (vasoconstriction), cyanosis (ischemia), and then erythema (re-perfusion when warming back up) fingers, toes, nipples, tongue caused by vasospasm.
    • Most agree that pallor must be present for the diagnosis and at least one other colour (red or blue)
  • >95% prevalence; remaining patients have abnormal nailfold capillaries if not strict Raynaud Phenomenon
  • Can develop permanently impaired blood flow over time due to vasospasm and abnormal remodelling of digital arteries with possible arterial obliteration
  • Digital ischemia/infarction can cause digital ulcers (~40% patients) or auto-amputation.
    • ~15% of patients develop severe complications
  • Early occurrence and high frequency of digital ulcers is especially seen in patients with dcSSc and/or anti-topoisomerase antibodies.

— Musculoskeletal

• Joints
  • Joint contractures, especially fingers (i.e: fixed inability to fully flex or extend fingers): related to fibrosis of skin and tendons around joint
  • Inflammatory arthritis: not common, usually polyarticular and can be erosive. More common in dcSSc
  • Overlap CTD: RA (if symmetrical erosive arthritis RF/CCP+) and myositis (if proximal muscle weakness)
• Tendons
  • Tendon friction rubs: Crepitus caused by tendon moving inside inflamed tendon sheath.
    • More common in dcSSc
    • Suggests more aggressive and more active disease

— Respiratory: ILD

• Prevalence
  • 30-40% have clinically significant ILD, 30-50% of whom will have progressive lung disease
  • Up to 80% of interstitial lung changes on HRCT
• Risk factors
  • Patient:
    • African ethnicity, male sex, genetic polymorphisms
  • Clinical:
    • dcSSc, dilated nailfolds, digital ulcers, cardiac SSc, longer disease duration (in some patients), severe esophageal involvement/reflux
  • Serology:
    • Anti-SCL70 (aka topoisomerase-I)
    • Also (but not routinely ordered): ANCA, -cardiolipin, -Ro52, -NOR90, -U11/U12, -Th/To, -PM/Scl
    • Rarer in anti-centromere positive patients
• Onset
  • Onset most often within 5 years of first non-Raynaud phenomenon (but can occur at any disease duration)
  • dcSSc: onset earlier in course of disease; lcSSc after years of disease but usually not more than 15 years
• Clinical Presentation
  • Asymptomatic, may progress to subacute dyspnea/cough and fatigue; Velcro-like crackles to auscultation
  • Pulmonary hypertension may occur secondary to hypoxia
• Imaging
  • CT pattern: NSIP 80%, UIP <10%.
  • NSIP is characterized on CT by peripheral ground-glass opacification, basal gradient, subpleural fibrosis; fibrotic NSIP suggested by reticulation, traction bronciectasis, and bronchiolectasis 
  • UIP is characterized on CT by honeycombing, reticular opacities, architectural distortion and lobar volume loss in advanced cases
• PFT
  • Baseline PFT and consider screening q6-12 months for first several years after diagnosis
  • May show restrictive physiology, ↓volumes and ↓DLCO due to parenchymal fibrosis; can also be extra-parenchymal restrictive physiology due to skin thickening of chest wall or concomitant myopathy causing respiratory muscle weakness
• Diagnosis, screening, monitoring
  • Baseline screening: PFT and high resolution CT (HRCT) on most or all patients
  • Monitoring: PFTs q3-6 months first year (especially if baseline ILD and/or Scl70+), then less frequently if stable. Repeat HRCT if clinically indicated
  • Exclude CHF, infection, drug toxicity, aspiration, pulmonary vascular disease
  • Rarely, if ever needed: BAL or tissue biopsy (may be needed to exclude differential)
• Prognosis
  • Independent predictor of mortality. 10-year mortality up to 40%
  • Poor prognosticators
    • Epidemiological:
      • Older, male, smoker
    • Clinical:
      • Early onset ILD, high/progressive skin score, GERD with aspiration, digital ulcers, PAH, SRC, myocardial fibrosis
    • Physiology/imaging characteristics
      • Low baseline FVC <65% and low DLCO ≤55%
      • Decline in DLCO >15%
      • Extent of fibrosis on HRCT

— Respiratory: PAH

• Patients can get any of WHO Group I-V Pulmonary Hypertension (PH).
  • Most common: Group I (PAH) and Group 3 (PH from ILD/hypoxia) 
  • Less common: Group 2 (PH from left heart disease)

• Definition of PAH (via right heart catheterization)
  • Mean pulmonary artery pressure (mPAP) >20mmHg supine
  • Wedge pressures ≤15mmHg
  • Peripheral pulmonary vascular resistance (PVR) ≥3 Wood units
  • Absence of chronic hypoxemia from coexisting ILD in group 1 PAH
    • Hypoxia is associated with Group 3 PH
• Prevalence
  • Prevalence of pulmonary hypertension (all WHO groups): ~5-15%
• Risk Factors
  • Patient profile:
    Older age, late onset disease, longstanding disease, Caucasian ethnicity, African ethnicity (if secondary to ILD)
  • Vascular phenomena:
    Extensive telangiectasias, digital ulcers
  • PFTs:
    DLCO <50%,
    Progressive decline in DLCO,
    FVC/DLCO >1.6
  • Cardiac:
    ↑RSVP >2mmHg/year,
    ↑ NT-proBNP,
    mPAP ≥21mmHg
    TPG (transpulmonary pressure gradient) ≥11mmHg on right heart cath.
  • Serology:
    Anti-centromere, anti-U3-RNP, anti-SCL70, phospholipid antibodies, nucleolar pattern ANA (virtually any serology associated with PAH in SSc).
• Screening
  • Initial visit, could consider:
    • Clinical evaluation (ex: dyspnea, syncope, peripheral edema, loud P2, elevated JVP, and other signs of right heart failure)
    • Consider BNP or NT-proBNP
    • Full PFT (spirometry, lung volumes, DLCO)
    • Echocardiogram for suggestive signs of PH (ex: elevated right ventricular systolic pressure [RVSP] >40mmHg, tricuspid regurgitant velocity [TRV], or right atrial area) or for other cardiac SSc involvement
    • Right heart catheterization: if symptoms, low DLCO, or suggestive echocardiogram
  • Subsequent visits, could consider:
    • PFT q6-12 months; q2 years if asymptomatic, stable normal PFT, and SSc >5 years
    • Echo every 1-2 years if high risk of PAH or low DLCO
    • HRCT chest for concomitant ILD if low DLCO

There is virtually no chance of PAH in SSc if the DLCO is not low

• Diagnosis of PAH
  • Do right heart catheter if clinical features, abnormal PFTs and suggestive echo
  • Work-up for other causes of PH including left heart disease, chronic VTE, obstructive sleep apnea, ILD
• Prognosis
  • PAH is independent risk factor for death (HR 2.50, 95% CI 1.83-3.42, P<0.0001)
  • Poor prognosticators: male, age >60, NYHA Class IV, DLCO <39%, severe PAH, pericardial effusion, anti-U1-RNP negative

— Respiratory: Other

• Vascular
  • Pulmonary thromboembolism: DVT/PE higher risk compared to general population
  • Pulmonary capillary hemangiomatosis/pulmonary veno-occlusive disease (PCH-PCVOD)
• Extrinsic
  • Pleural effusion <10%.
    • Exudative and lymphocytic.
    • Etiology includes pleuritis, CHF, pneumonia, PCH-PVOD, cancer.
    • Asymptomatic to progressive dyspnea/pleurisy depending on etiology
  • Respiratory muscle weakness: hypercapnic failure from overlap myositis
• Exposure/injury
  • Recurrent aspiration: secondary to GERD and esophageal dysmotility; worse lung prognosis
  • Drug-associated pneumonitis: includes methotrexate and other possible drug exposures
• Airway disease
  • Bronchiolitis obliterans/cryptogenic organizing pneumonia: rare, likely related to older treatment penicillamine but can still occur due to SSc
  • Follicular bronchiolitis: hyperplasia of bronchus-associated lymphoid tissue
  • Bronchiectasis
• Other
  • Spontaneous pneumothorax, Lung cancer

— Cardiac

• Epidemiology
  • 10-30% clinically overt involvement. Up to 70% may have subclinical cardiac SSc.
  • ↑Risk:
    • dcSSc, men, African ethnicity
    • ?anti-U3-RNP and anti-SCL70, concomitant skeletal myopathies
• Vascular
  • Raynaud phenomenon
  • Micro- and macro-vascular cardiac ischemia causing anginal chest pain.
    Can occur more frequently than in age/sex matched population
  • Higher rates DVT/PE
• Pericardial
  • Pericardial effusion (transudative from right-heart failure or exudative from inflammation), pericarditis, constrictive pericarditis, tamponade.
  • Pericardial effusion can be symptomatic or asymptomatic
• Myocardial
  • More common and severe in dcSSc, but still occurs in lcSSc.
  • Recurrent microvascular ischemia and myocardial inflammation leads to ischemic necrosis and patchy fibrosis causing insidious heart failure; some present with acute/subacute myocarditis
  • LV diastolic dysfunction (HFpEF) from fibrosed ventricle; can lead to atrial enlargement, atrial fibrillation, pulmonary edema, and LV systolic dysfunction; Diastolic dysfunction more common than systolic dysfunction
  • RV dysfunction can be caused by HFpEF, HFrEF, RV fibrosis, or secondary to PAH
• Conduction defects
  • 25-75% prevalence of abnormal ECG
  • PVCs, PR prolongation, left anterior fascicular block, intraventricular conduction defects, tachy/bradyarrhythmias, autonomic dysfunction
  • Consider ordering baseline ECG
• Valvular
  • Uncommon. Nodular thickening of mitral and aortic valves +/- regurgitation
• Evaluation
  • History/exam: for features of heart failure, anginal chest pain, palpitations, (pre)-syncope
  • Baseline: (?)ECG, Echo, PFT; consider BNP/NT-proBNP, troponin.
  • Based on clinical suspicion in shared-care model with cardiologist, consider:
    • Arrythmia: Holter monitor
    • Ischemic chest pain: stress testing, cardiac catheterization, cardiac MRI
    • Heart failure, cardiomyopathy: BNP, cardiac MRI, ?left and right heart cath. +/- endomyocardial biopsy

— Scleroderma Renal Crisis

• Epidemiology
  • Approximately 5% prevalence
    • Prevalence much lower in contemporary versus historic cohorts.
    • Often up to 15% of dcSSc and 3% overall in disease registries
• Risk factors
  • Genetic: Male sex,  African ethnicity, HLA-DRB1*1407 and HLA-DRB1*1304 genotypes
  • Cutaneous subtype: early dcSSc, especially rapidly progressive with tendon friction rubs, high Rodnan skin score, pericardial effusion, ILD, cardiac SSc
  • Steroid use: ≥15 mg/day of prednisone or equivalent associated with SRC
  • ACEi: treats SRC,  but prophylactic/baseline ACEi delays SRC recognition, worsens outcome, and does not reduce chances of SRC
  • Antibodies: RNA Polymerase III (OR 5.86, 95% CI 2.6, 13.2), anti-topoisomerase (slight increase)
  • Other: pericardial effusion, CHF, large joint contractures
• Histology
  • Intimal proliferation and thickening/obliteration of small arcuate and interlobular arteries of the glomeruli causing thrombotic microangiopathy.
  • Biopsy rarely required for diagnosis.
• Clinical Presentation
  • Early dcSSc (usually within first 5 years; median ~7months in some studies),
  • AKI with bland sediment or 500-1000mg proteinuria
  • Hypertension: Moderate-severe hypertension, could be normal or slightly elevated
  • Other: Microangiopathic hemolytic anemia and thrombocytopenia, hemoglobinuria, retinal changes of malignant hypertension, flash pulmonary edema

Blood pressure in scleroderma renal crisis could be “normal” or only slightly elevated if the patient’s baseline blood pressures were very low.

• Diagnosis
  • Clinical diagnosis (new hypertension in high risk dcSSc patient)
  • Renal biopsy not routinely needed
• Treatment
  • Must treat with urgent ACE inhibition (not ARB) to reduce blood pressure quickly and reduce chance of chronic kidney disease
• Prognosis
  • 20-40% progress to end-stage renal disease and dialysis
  • 36% mortality at 1 year.

— Neuromuscular

• Myositis
  • Possible risk factors: dcSSc, African ethnicity, male gender
  • Presentation: Proximal muscle weakness, mildly ↑CK, myopathic EMG
  • Antibody associations: anti-PM-Scl, U3-RNP, Ku, RuvBL1/2
  • Biopsy: may see necrosis, inflammatory infiltrate, endomysial fibrosis, vasculopathy, MHC-I expression
• Neuropathy
  • Rare poly/mononeuropathies, autonomic neuropathy

— Gastrointestinal

• Oropharyngeal
  • Decreased oral aperture: skin thickening around mouth
  • Oropharyngeal dysphagia: thickened soft palate, larynx, oral mucosa
  • Impaired mastication: thick skin pressing against teeth impairs chewing
  • Sicca: overlap Sjogren’s
• Esophageal
  • GERD in >70-95%: smooth muscle atrophy, decreased peristalsis, fibrosis
    • Worsens respiratory prognosis
    • Muscle atrophy usually starts in smooth muscles (bottom two-thirds of esophagus), however, can involve any part of esophagus (upper third of esophagus is skeletal muscle)
  • Endoscopy: esophagitis, candida, Barrett’s, stricture
  • Manometry: hypotensive esophageal sphincter
  • Imaging: Chest X-ray and CT can show dilated lower esophagus
• Gastric
  • Gastric antral vascular ectasia (GAVE, ~5%): gastric telangiectasia, iron deficiency anemia, melena
  • Gastroparesis 40-50%: early satiety, nausea, bloating
• Small bowel
  • Small bowel overgrowth in 10-30%: bloating, gas, diarrhea, malabsorption
  • Hypomobility/Obstruction: bloating, pain, pseudo-obstruction
  • Malnutrition: due to low appetite, eating challenges, malabsorption
• Large bowel
  • Hypomobility/Obstruction: bloating, pain, pseudo-obstruction
  • Diarrhea, incontinence: from bacterial overgrowth, pancreatic insufficiency, overflow diarrhea, sphincter incompetence/fibrosis
• Hepatic
  • Rare; if ALT elevated, consider co-morbid myositis, drug toxicity, or comorbid primary biliary cirrhosis (PBC)
• Primary biliary cirrhosis (PBC)
  • 2-18% overlap; usually patients with lcSSc or overlap-SSc, anti-centromere positive.
• Pancreatic insufficiency
  • Weight loss and steatorrhea

— Genitourinary

• Erectile dysfunction in men (common), decreased vaginal lubrication, dyspareunia in women

15% RULE IN SCLERODERMA

The Frequency of Severe Organ Complications in SSc is around 5% or 15%

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INVESTIGATIONS

At baseline: Blood pressure (if early dcSSc for SRC), CBC, creatinine, ALT, CK, CRP, urinalysis, HRCT chest, PFT, Echocardiogram

• CBC
  • Anemia: from malabsorption, iron deficiency/GI bleeding (ex: from GAVE), intravascular hemolysis (from scleroderma renal crisis)
• Creatinine, Urinalysis
  • Creatinine may be elevated if scleroderma renal crisis
  • Creatinine may be low from loss of muscle mass or cachexia
• ALT
  • May be elevated if drug-induced liver toxicity, myopathy, or comorbid PBC
• CK
  • May be elevated if overlap myositis or SSc myopathy
• Cardiorespiratory
  • Baseline echo, PFT, HRCT; consider ECG or Holter monitor depending on suspicion
  • Bronchoalveolar lavage or lung biopsy typically not required to diagnosis SSc-ILD
  • Screen traditional cardiovascular risk factors and obtain smoking history
    Screen for chronic PE if hypoxic
• GI
  • Depending on suspicion: EGD/manometry for GERD or GAVE; ALP for PBC (more common if anti-centromere+)
  • Small intestinal bacterial overgrowth (SIBO) is usually treated with high index of suspicion and not with extra GI testing
• Skin biopsy
  • Rarely needed, unless to consider a SSc mimic (ex: scleromyxedema, eosinophilic fasciitis, see below)
• Serology
  • ANA: positive in >95%

SSc antibody	Cutaneous subtype	Clinical correlates
Anti-centromere	lcSSc	PAH
Anti-Th/To	lcSSc	ILD and PAH
Anti-Pm-Scl	lcSSc	Myositis
Anti-RNP (ribonucleoprotein) (anti-U1 ribonucleoprotein)	lcSSc	Mixed connective tissue disease (MCTD)
Anti-fibrillarin (anti-U3 ribonucleoprotein)	dcSSc	PAH, myositis
Anti-SCL70 (anti-topoisomerase 1)	dcSSc	Progressive ILD
Anti-RNA polymerase 3	dcSSc	Renal crisis, malignancy

• Additional serology, depending on suspicion for overlap or differential diagnosis:
  • RF, anti-CCP, dsDNA, Smith, myositis antibody panel

• Other screening
  • Malignancy: age appropriate screening; periodic urinalysis if cyclophosphamide exposure, consider further investigation depending on clinical suspicion (ex: elderly patient with weight loss and rapidly progressive dcSSc)
  • Osteoporosis: bone density scan depending on clinical suspicion and risk factors
  • TSH if autoimmune thyroid disease suspected
  • Other: screen for depression, erectile dysfunction in men, nutritional deficiencies if malabsorption suspected (ex: Vitamin A/D/E/K, B1 (thiamine), B12, albumin, iron, Calcium)

DIAGNOSIS

Suspect SSC in adult patient, more often female, with Raynaud phenomenon and abnormal nailfold capillaries followed by skin thickening. Screen for cardinal end-organ manifestations such as GERD, ILD, and PAH.  Classify patients by cutaneous subtype and antibody profile, which may prognosticate pace of disease progression and expected pattern of organ involvement. ANA should be positive. Screen all patients for ILD and PAH at baseline with at least Echo, HRCT, and PFT. Beware of scleroderma mimics.

DIFFERENTIAL DIAGNOSIS

SCLERODERMA MIMICS

Red Flags for Scleroderma Mimic

· Lack of Raynaud Phenomenon or GERD · Lack of nailfold capillary abnormalities including dilatation and dropout. · Lack of sclerodactyly or involvement of skin of the fingers. · Lack of auto-antibody formation (ANA, scleroderma-associated antibodies)

• Localized Scleroderma
  • Morphea, Linear:
    • Skin-limited scleroderma; does not progress to systemic sclerosis
    • Morphea = patch of skin thickening, Linear = band of skin thickening
• Infection, metabolic
  • Scleredema
    • Skin thickening trunk, nape, shoulders, upper back, face. Spares fingers
    • Associations: Monoclonal gammopathy, post-infxn (strep) , diabetes, hypothyroid
  • Diabetic Cheiro-arthroapthy
    • Thickening and contracture of skin over fingers
    • Association: Long-standing insulin-dependent diabetes mellitus
• Hematological
  • Amyloid
    • Skin thickening and stiffness due to amyloid accumulation
    • Association: Usually AL amyloid, due to plasma cell dyscrasia
  • Scleromyxedema
    • Generalized papules/plaques of skin thickening face/neck/forearms/hands
    • Associations: monoclonal gammopathy (often IgG Lambda), myeloma
  • Eosinophilic fasciitis
    • Woody indurated skin, usually spares hands/feet, from skin adhered to fascia, usually in 3 or 4 limbs
    • May see Peau d’orange, groove or riverbed sign; deep skin/fascia biopsy required
    • Associations: Aplastic anemia, myeloma, hematologic malignancy, PNH
• Exposure
  • Nephrogenic systemic fibrosis
    • Thickening of skin over extremities and trunk ; looks like eosinophilic fasciitis
    • GAD-contrast for MRI in patient with advanced renal failure (though this type of GAD is no longer used)
  • Toxic Oils
    • Scleroderma-like skin thickening from organic solvents, petroleum, L-tryptophan contaminants, adulterated cooking oils (historic outbreaks).
  • Drug-induced
    • · Scleroderma-like skin with Bleomycin, docetaxel, IV Vitamin K/B12, pentazocine
• Other
  • Chronic Graft versus host after hematopoietic transplant or transfusions
  • POEMS: polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes
  • Late-stage CRPS
  • Porphyria cutanea tarda

CLASSIFICATION CRITERIA

Classification criteria are not meant as diagnostic criteria to diagnose disease in a single specific patient. Classification criteria are a standardized way of recruiting a well-defined homogenous population of patients in research studies in order to ensure comparability across studies of a heterogenous disease.

Criteria are only to be applied if SSc is suspected.
A score of 9 or more is strognly associated with a diagnosis of SSc

Click to Enlarge

TREATMENT

SSc is treated by an organ-based approach tailored to each patient’s individual organ manifestations. Goal of therapy is to reduce progression or severity of SSc complications. General approach described below.

— Skin

For progressive/diffuse skin thickening; most treatments only have modest benefit

• Initial
  • Mycophenolate mofetil 750-1500mg BID, or
  • Methotrexate 15-25mg/week
• Subsequent
  • Rituximab 1g IV Day 0/14, then 1g IV q6mo, or
  • Tocilizumab 162mg SC weekly, or
  • Cyclophosphamide PO or IV
• Severe, rapid dcSSc
  • Autologous hematopoietic stem cell transplant in very select patients (see below)
  • Largest effect on skin fibrosis
  • Role of CAR-T and other investigational treatments is unknown

Calcinosis:  little data for minocycline, methotrexate, JAKi (such as tofacitinib and upadacitinib) TNF, and rituximab, surgical debulking, sodium thiosulfate

—Respiratory

GENERAL MEASURES

• Exercise as tolerated with aim to increase exercise capacity
• Smoking cessation
• Routine vaccinations (including pneumococcal, COVID, influenza; encourage and RSV and HZ vaccination)
• Oxygen if indicated
• GERD: rigorous therapy and treatment of GERD and dysphagia likely reduces worsening of ILD
• Close co-management with respirology; PAH usually managed in tertiary care setting.

PULMONARY ARTERIAL HYPERTENSION (PAH)

• PAH treatment usually directed by tertiary centre respirology in collaboration with rheumatology
• Risk stratify patients with risk calculator (ex: REVEAL 2.0 calculator) or functional score (WHO Functional Class)
  • Low/intermediate risk
    • Combination ETR antagonist + PDE5 inhibitor
      (ex: Ambrisentan + Tadalafil; Macitentan + Sildenafil)
    • Monotherapy ETR antagonist or PDE5 inhibitor if very mild PAH
      (ex: WHO Functional Class I).
    • Possibly use riociguat instead of PDE5i in some circumstances
  • High risk
    • Combination ETR antagonist + PDE5 inhibitor + Prostacyclin analogue
    • Consideration of combining with sotatercept, if available
    • Role of immune suppression is unknown
  • Transplant
    • Double-lung or heart-lung transplant may be reasonable for patients failed medical therapy
• Anti-coagulation not routinely administered in SSc-PH due to no evidence of survival risk and high bleed risk in SSc

ETR (endothelin receptor) antagonist	Ambrisentan, bosentan, macitentan
PDE (phosphodiesterdase) 5 inhibitor	Sildenafil, tadalafil; N.B.: Bosentan reduces plasma concentration of Sildenafil
Prostacyclin analogues	Epoprostenol IV, Selexipag oral, Treprostinil inhaled/SC Less effective: iloprost inhaled/IV
Soluble guanylate cyclase stimulator	Riociguat
anti TGF-β	Sotatercept (fusion protein Fc domain of IgG linked to ActRIIA, which is a ligand trap for some types of TGF-β)

INTERSTIAL LUNG DISEASE (ILD)

• ILD treated in collaboration with respirology; suggested approach below. Treat comorbid GERD.
• Screen for ILD regularly with PFTs ?q6-12months for first few years of disease. ?baseline HRCT chest at SSc diagnosis

• Indication
  • Consider treating at diagnosis if high risk features
    Ex: Recent diagnosis of Ssc (<5 years), FVC <70%, >20% lung involved on HRCT
  • Treat if evidence of progression on serial PFTs q6-12 months
    ΔFVC >10% over <12 months, ΔDLCO >15% over <12 months, CT progression
• 1st Line
  • Mycophenolate Mofetil 1000-1500mg BID
• 2nd Line
  • Tocilizumab 162mg SC/wk or IV 4-8mg/kg/month, or
  • Rituximab 1g IV Day 0/14 then 1g IV q6mo, or
  • Cyclophosphamide IV 600mg/m² qweeks or
    Cyclophosphamide PO 1-2mg/kg/day or 50-100mg/d not exceeding 200mg/d
  • If progressive fibrosis: Add Nintendanib 150mg BID, or if not tolerated, consider pirfenidone
• 3rd Line
  • Lung or autologous hematopoietic stem cell transplant
• Potential future therapy
  • Addition of Nerandomilast, a PDE4i, to antifibrotic therapy
  • Enrollment in ILD randomized control trial

—Raynaud, Digital ulcers

• 1st Line
  • Lifestyle modifications (keeping extremities and core temperature warm)
  • Smoking cessation
  • Calcium channel blocker (CCB) (dihydropyridine-type, ex Nifedipine)
• Refractory
  • PDE5 inhibitor or IV prostacyclin analogues
  • Bosentan (ETR antagonist) prevents new ulcers, does not heal existing ulcers
• Ancillary/refractory
  • For Raynaud: Nitroglycerine, ARB, ASA, botulinum toxin, fluoxetine, pentoxifylline, other topical or oral vasodilators (ex: topical compounded tadalafil, if available)
  • For Digital ulcers: Digital sympathectomy or sympathetic nerve blocks, atorvastatin, botulinum toxin,
• Other
  • Uncertain benefit: anticoagulation, digital sympathectomies for Raynaud, fat grafting

—Renal

• Treatment
  • Urgent ACE inhibitor; historically captopril, though any ACEi effective
  • Captopril 6.25-12.5mg increasing 12.5-25mg q4-8h to max 300-450mg/d
  • Goal: return to normal or pre-morbid baseline BP within 72 hours.

Risk of hypoperfusion injury from rapidly decreasing BP in scleroderma renal crisis is lower, since renal crisis presents as acute hypertension

• Prevention
  • Consider home BP monitoring in early dcSSc patients. Provide a target blood pressure with action plan if blood pressure greatly increases
  • Avoid steroids; if needed use <15mg/d (ex concomitant myositis, inflammatory arthritis, active skin involvement)

Avoid ACEi/ARB for routine primary hypertension treatment: can delay recognition of SRC onset and worsen outcomes

—Gastrointestinal

• Esophageal
  • GERD: PPI daily or BID-QID, H2 blockade. Surgery usually has poor outcomes.
  • Stricture: endoscopic dilatation
  • Dysmotility: prokinetic agents (ex domperidone, metoclopramide, prucalopride, erythromycin)
• Gastric
  • GAVE: endoscopic coagulation as needed of each lesion, usually with argon plasma coagulation.  Antrectomy reserved for patients failing multiple sessions.
  • Gastroparesis: dietary modification, hydration and glycemic control, prokinetic agents
    (ex: metoclopramide, domperidone, erythromycin)
• Small intestine
  • Bacterial overgrowth: antibiotics, example
    • Rifaximin 550mg TID x 14d, or
      Cipro 500mg daily x 10d, or
      Metronidazole 250mg TID x 10d
      Amoxicillin 250-500mg TID x 7d
  • Motility: prokinetics may help but can also worsen contractility and constipation.
  • Nutrition/malabsorption: Nutritional support, consider dietician referral
• Large intestine
  • Fecal incontinence: fiber, loperamide, cholestyramine. GI referral for testing (manometry, imaging), biofeedback, sphincteroplasty.
  • Constipation: laxatives (PEG)
• Hepatobiliary
  • Primary Biliary Cirrhosis: referral and treatment with GI (ex: ursodiol, obeticholic acid)
• Pancreatic
  • Pancreatic enzymes for pancreatic insufficiency

—Musculoskeletal

• Inflammatory arthritis
  • Minimize steroid use (prednisone <10-15mg/d for 2-4 weeks)
  • csDMARD: Hydroxychloroquine, methotrexate (unless significant concerns about pulmonary toxicity from respirology)
  • bDMARD: could favour JAKi, tocilizumab, abatacept, rituximab
• Inflammatory myositis
  • Minimize steroid use (prednisone <15-20mg/d)
  • cs/bDMARD: methotrexate, mycophenolate mofetil, azathioprine, rituximab
  • IVIG if severe and refractory

—Cardiac

• Pericarditis
  • Per usual pericarditis treatment: NSAIDs, Colchicine, avoid steroids if possible
  • Adjunctively: pericardial drainage and pericardiectomy
• Myocarditis/Myocardial fibrosis
  • Heart failure treatment: per routine systolic/diastolic heart failure treatment
  • New heart failure with ↑CK/Trop and other imaging (ex MRI) suggesting active carditis/fibrosis may require steroids, cyclophosphamide, mycophenolate mofetil, or methotrexate

—Genitourinary

• Erectile dysfunction:
  • Oral sildenafil, tadalafil, topical agents, alprostadil injections, penile implants
  • Treat underlying cardiovascular risk factors (ex: smoking, hypertension, diabetes, hyperlipidemia)
  • Counselling

—Autologous Hematopoietic Stem Cell Transplant (AHSCT)

• Can decrease disease progression of SSc, reduce mortality, and improve skin, lung function, functional ability, quality of life
• High incidence of treatment-related morbidity and mortality (treatment mortality 5-10%)

Candidate patients for AHSCT have a balance of early/severe dcSSc, but not so severe organ dysfunction to increase treatment-related morbidity and death

• AHSCT candidates may include:
  • Younger patients <60-65 years
  • Early dcSSc <4-5 years
  • Very high skin score with worsening and/or moderate ILD
  • Absence of
    • Pulmonary hypertension
    • Active GAVE
    • Cardiac involvement (ex: LVEF <50%)
    • Severe ILD (ex: DLCO <40, FVC <45%)
    • Severe renal involvement (ex: CrCl <40mL/min)
• Must have pre-transplant evaluation in tertiary centre with expertise with scleroderma patients
• Need for immunosuppression post-transplant and relapse rates unclear

PROGNOSIS

• Risk factors for disease progression: older age, active digital ulcers, lung fibrosis, muscle weakness, elevated CRP
• Standardized mortality ratio (SMR) ~4X age/sex-matched controls.
• SMR higher for dcSSc than lcSSc
• Most common cause of death: ILD/PAH, cardiac scleroderma, renal disease.
• Risk factors for death: African ethnicity, ILD, PAH, cardiac involvement, renal disease, extensive skin involvement

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