Cell
Pathogenic effects
Fibroblasts
Produce collagen and other extracellular matrix molecules
Adipocytes, endothelial cells, epithelial cells
Undergo transition to myofibroblasts expressing a smooth actin and producing collagen
T cells
Are oligoclonal-indicative of antigen-driven proliferation in skin lesions
Produce pro-fibrotic IL-4, IL-13 cytokines
Anti-maternal graft-versus-host disease may operate in some cases
B cells
Are activated (hyper-express CD19)
Activate fibroblast to collagen production through cell contact
Plasma cells produce antibodies that promote fibrosis
Produce cytokines promoting fibrosis
IL-10-producing regulatory B cells are decreased
Innate cells
Promote fibrosis through Toll-like receptors(TLRs), such as TLR4
Fibroblasts, T cells, B cells, and innate cells are involved in SSc pathogenesis. Epithelial cells, endothelial cells, and adipocytes can undergo transition to myofibroblasts, expressing α-smooth muscle actin and producing collagen [4]. Anti-maternal graft-versus-host disease may operate in some cases. TGFβ is the master fibrogenic factor in SSc. The Wnt/β-catenin pathway is also involved in fibrogenesis [5–7].
Clinical Manifestations and Assessment Tools
Cutaneous and Musculoskeletal Manifestations
Raynaud’s phenomenon (RP) may appear years before other SSc manifestations. RP, along with the fibrointimal proliferation of digital arteries, may lead to digital ulcers (DUs). DU, a loss of epithelialization, occurs in nearly 50% of patients and may lead to secondary infection, gangrene, and acro-osteolysis . Skin thickening usually begins as puffy fingers (the first non-RP skin change) that gradually evolves into skin tightness and extends proximally. Skin thickening of the face diminishes the mouth aperture. Based on the extent of skin involvement, SSc is divided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc), with lcSSc being more common (59%) than dcSSc (37%). The skin may have a salt and pepper appearance from hypopigmentation/hyperpigmentation changes. In the final atrophic stage, skin softens. Arthralgias and or arthritides are common, usually in small hand joints, and flexion contractures may develop from severe skin thickening. Tendon friction rubs are associated with dcSSc, scleroderma renal crisis (SRC), cardiac, and gastrointestinal complications and reduced survival [8]. Calcinosis of skin and subcutaneous tissues is more frequent in lcSSc (45%) than dcSSc (15%). It may be extensive and may cause skin ulceration and secondary infection. Telangiectasias are common and are commonly found on the face, lips, hands, and chest. In the late atrophic skin stage of SSc, telangiectasias may be the only skin sign of SSc. Histology is dominated by the deposition of collagen, proteoglycans, and other extracellular matrix (ECM) molecules in the dermis which encase sweat glands and replace subcutaneous adipose tissue. Mononuclear cell infiltrates consisting of T cells, macrophages, and few B cells, eosinophils and mast cells appear early and gradually disappear as disease progresses. In small arteries there is fibrointimal proliferation.
Assessment
Typical SSc nailfold capillaroscopy reveals dilated (giant) capillary loops, hemorrhages, and capillary loss. Skin thickening is assessed by the modified Rodnan skin score (mRSS).
Pulmonary Manifestations
Two main entities occur in SSc, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). Other, much less frequent manifestations are pleuritis, endobronchial telangiectasias with hemoptysis, and cryptogenic organizing pneumonia.
ILD
Patients with ILD are asymptomatic at first but gradually develop dyspnea on exertion and dry cough. ILD is an early manifestation of SSc, is more common in dcSSc than lcSSc, and is associated with anti-topoisomerase I Abs (ATA) [9]. ILD can cause secondary pulmonary hypertension (ILD-PH). It is most commonly non-specific interstitial pneumonia (NSIP) with mononuclear cell infiltrates and uniform distribution of fibrosis, and less commonly usual interstitial pneumonia (UIP) with scattered fibroblastic foci. ILD is a major cause of death with survival 58% at 10 years [10].
Assessment
Pulmonary function tests (PFTs) with spirometry and diffusing capacity for carbon monoxide (DLCO) are routinely used for screening and follow-up in ILD. PFTs typically show a restrictive pattern. DLCO is reduced. High resolution computed tomography (HRCT) of the chest is the best test to detect ILD and reveals thickening of interlobular septa, honeycomb pattern, traction bronchiectasis, and alveolitis (ground glass opacities) [11]. Lung ultrasound can also detect lung fibrosis.
Pulmonary Hypertension
PH is the main prognostic factor for survival in SSc. Precapillary pulmonary hypertension (PH) in SSc is pulmonary arterial hypertension (PAH) and PH associated with ILD (ILD-PH) which is less responsive to treatment. PAH is defined by right-sided heart catheterization as mean pulmonary arterial pressure ≥25 mmHg and normal pulmonary artery wedge pressure (≤15 mmHg) in the absence of significant ILD (only mild ILD on HRCT and FVC >70% of predicted value). PAH is associated with decreased of vasodilatory mediators, NO, and prostacyclin (PGI) and increased vasoconstriction mediator endothelin-1 (ET-1) . Factors associated with increased risk for PAH include FVC(percentage)/DLCO(percentage) ratio of predictive values >1.60, anticentromere antibodies (ACA), telangiectasias, NT proBNP >300 ng/L, pericardial effusion, right axis deviation on ECG, TR jet velocity >2.8 m/s, 6 min walk distance (6 MWD) <440 min. Reduction of nailfold capillary density correlates with severity of PAH. Patients with PAH have dyspnea on exertion, but as the condition worsens, signs of right-sided heart failure develop. FVC(percentage)/DLCO(percentage) ratio of predictive values >1.6 is predictive of PAH. DLCO <45% of predictive value is associated with poor outcome. SSc-PAH carries a poor prognosis and a worse prognosis than idiopathic PAH but ILD-PH carries the worst prognosis.
Assessment
Echocardiography, ECG, serum N-terminal pro-brain natriuretic peptide (NT proBNP) levels, FVC(percentage)/DLCO(percentage), 6 MWD, telangiectasias, and ACA are used to detect PAH early and stratify risks. Right-sided heart catheterization is the gold standard and used to confirm PAH. Cardiac MRI is also a useful method in evaluating PAH. The DETECT algorithm helps detect candidates for right heart catheterization [12]. The 2015 guidelines for the diagnosis and treatment of PAH stratified patients to low, intermediate, and high risk [13]. The low-risk group has (a) WHO functional classes I and II; (b) 6 MWD >440 min; (c) NT proBNP levels <300 ng/L; (d) echocardiography, right atrial area <18 cm2, no pericardial effusion; and (e) hemodynamics, right atrial pressure (RAP) <8 mmHg, cardiac index (CI) ≥2.5 L/min/m2, and venous oxygen saturation (SvO2) >65%.
Risk stratification is very important. The 5-year mortality in patients with PAH and low-risk profile at baseline and follow-up was <10%, whereas patients with high-risk profile at baseline and follow-up had a 1-year mortality around 30% [14]. The 1-, 2-, and 3-year survival of SSc-PAH patients were 93%, 88%, and 75%, respectively [15].
Cardiac Manifestations
Cardiac manifestations include pericardial effusion, left or right diastolic dysfunction, right-sided heart failure from pulmonary hypertension, and arrhythmias. Takotsubo cardiomyopathy is rarely reported. Pericardial effusion is more frequent in dcSSc than lcSSc. Fibrinous pericarditis also develops. Arrhythmias may be caused by fibrosis of the conduction system and are more frequent in dcSSc than lcSSc. Postmortem studies reveal inflammatory infiltrates and fibrosis of the myocardium. Contraction band necrosis with patchy fibrosis may also be observed.
Assessment
Echocardiography is the method of choice for evaluating cardiac function, chamber size, and wall motion abnormalities. Tissue Doppler echocardiography, cardiac MRI, single-photon emission tomography (SPECT), and thallium scanning may also be used. Two-dimensional echocardiography is the method of choice to detect pericardial effusion. ECG and Holter monitoring are used to detect cardiac arrhythmias [9].
Gastrointestinal Tract (GIT) Manifestations
The entire GIT can be affected with equal frequency in dcSSc and lcSSc. Fibrosis, smooth muscle atrophy, and autoAbs against muscarinic M3 receptor all contribute to GIT dysmotility. Dry mouth may be due to fibrosis or Sjogren’s syndrome. Esophageal involvement occurs in nearly all patients and often is the first non-RP manifestation. Lower esophageal sphincter pressure is reduced and leads to gastro-esophageal reflex, esophagitis, stricture, and dysphagia. There is delayed gastric emptying, and there may be vascular ectasia (watermelon stomach) which can cause bleeding. Intestinal involvement is reported in 23% of patients but by specific tests it occurs in up to 88% of patients. Intestinal dysmotility causes post-prandial bloating and constipation and may cause pseudo-obstruction (around 5% of patients). Stasis causes small intestinal bacterial overgrowth (SIBO) which in turn causes diarrhea, malabsorption, malnutrition, and oxalate nephropathy. Wide mouthed diverticula at the antimesenteric aspect of large bowel may occur. Anorectal involvement is very frequent (50–70% of patients) and may cause rectal incontinence in 24% of patients.
Assessment
Barium esophagography is used to detect esophageal dysmotility. Esophageal manometry is used to detect lower esophageal sphincter pressure as an early esophageal involvement. Small intestinal hypomotility is assessed by the lactulose hydrogen breath test which allows estimation of oral-cecal transit time and the detection of SIBO. SIBO can also be detected by calprotectin levels but the gold test for SIBO is culture of jejunal fluid. Malabsorption is assessed by the malnutrition universal screening tool (MUST) to detect nutritional status, and by measurement of serum vitamin B12, folic acid, 25(OH) D, and prothrombin time [16].
Scleroderma Renal Crisis (SRC)
SRC is characterized by marked increase in blood pressure and rapidly progressive renal failure with or without thrombotic microangiopathy. The latter manifests with thrombocytopenia and intravascular hemolytic anemia. Normotensive SRC may occasionally occur. SRC most frequently occurs in dcSSc during the first 4 years of the disease. Risk factors include anti-RNA polymerase III (anti-RNAp3) antibodies, and use of prednisolone >7.5 mg/day, or cyclosporine. Histology shows changes of malignant hypertension in small arteries. Stenosis of interlobular and arcuate renal arteries activates the renin-angiotensin system. SRC has a poor outcome [17].
Diagnosis
The 2013 EULAR/ACR criteria for the classification of SSc
Item | Score |
|---|---|
1. Skin thickening proximal to metacarpophalangeal joints | 9 |
2. Skin thickening of fingers (use the maximum score) | |
Puffy fingers | 2 |
Skin thickening distal to metacarpophalangeal joints | 4 |
Fingertip ulcers | 2 |
Fingertip pitting scar | 2 |
3. Telangiectasias | 2 |
4. Abnormal nailfold capillaroscopy | 2 |
5. Pulmonary arterial hypertension and/or interstitial lung disease | 2 |
6. Raynaud’s phenomenon | 3 |
7. SSc-related autoantibodies (anticentromere, anti-topoisomerase I, anti-RNA polymerase III Abs) (score 1 for each antibody) | 3 (maximum) |
The European scleroderma trials and research (EUSTAR) group, proposed and validated a 0–10 scale SSc activity index with six items, skin worsening during the previous month as evaluated by the patient, tendon friction rubs, DUs, mRSS, CRP, and DLCO. A score ≥2.5 identified active/very active disease [20]. The differential diagnosis includes various sclerotic disorders.
Scleredema
Scleredema is a skin mucin deposition disorder (produced by epithelial cells and fibroblasts) in the skin. It is associated with acute respiratory infection mostly due to streptococcus, diabetes mellitus, and monoclonal gammopathy of unknown significance (MGUS). It manifests with woody induration of skin that begins in the neck and back, and spares hands and feet. There is no Raynaud’s phenomenon, nailfold capillaroscopy changes, or SSc-related autoAbs, and no internal organ involvement [21]. Skin biopsy shows mucin deposition (stain with Asian blue or colloidal iron) in the dermis between collagen bundles without spindle fibroblasts.
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