Systemic scleroderma
Systemic scleroderma, also known as systemic sclerosis, is a rare autoimmune disease characterized by excessive collagen production leading to fibrosis, which causes the hardening and tightening of the skin and connective tissues, and often involves internal organs such as the lungs, heart, esophagus, and kidneys.[1][2][3] This condition arises from a complex interplay of immune system dysfunction, vascular abnormalities, and tissue fibrosis, resulting in progressive damage that can significantly impair quality of life.[3] It affects approximately 50 to 300 people per million worldwide, with a higher prevalence in women (female-to-male ratio of about 4:1 to 5:1) and peak onset between ages 30 and 50.[2][3] The disease is classified into two main subtypes based on the extent of skin involvement: limited cutaneous systemic sclerosis (often associated with CREST syndrome—calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), which typically affects the skin of the face, hands, and forearms with slower progression, and diffuse cutaneous systemic sclerosis, which involves widespread skin thickening and more rapid onset of organ complications.[1][3] A less common variant, systemic sclerosis sine scleroderma, features internal organ involvement without significant skin changes.[2] Systemic scleroderma differs from localized scleroderma (morphea), which is confined to the skin and does not affect internal organs.[1] Common symptoms include Raynaud's phenomenon, affecting over 95% of patients, where fingers and toes turn white, blue, or red in response to cold or stress due to vasospasm; skin thickening starting in the fingers (sclerodactyly) and spreading proximally; and gastrointestinal issues like heartburn, difficulty swallowing, and bloating from esophageal dysmotility.[1][3] Other manifestations involve joint pain, fatigue, digital ulcers, telangiectasias (dilated small blood vessels), and calcinosis (calcium deposits under the skin).[1] Complications can be severe, including interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis (leading to kidney failure), cardiac arrhythmias, and increased risk of malignancy.[1][3] The exact cause remains unknown, but it involves genetic predisposition—such as variations in genes like HLA, IRF5 (linked to diffuse type), and STAT4 (linked to limited type)—combined with environmental triggers like exposure to silica dust, solvents, or certain viruses (e.g., cytomegalovirus).[2][3] Risk factors include female sex, age 30–50, and certain ethnic backgrounds, with Black individuals experiencing earlier onset and more severe disease.[1] Although there is no cure, early diagnosis and management of symptoms and organ involvement are crucial for improving outcomes.[3]Classification
Subtypes
Systemic scleroderma, also known as systemic sclerosis (SSc), is primarily classified into subtypes based on the extent of skin involvement and patterns of organ manifestations, which help predict disease course and guide management.[3] Limited cutaneous systemic sclerosis (lcSSc) is characterized by skin thickening confined to areas distal to the elbows and knees, including the face and hands, while sparing the trunk and proximal limbs.[3] This subtype often includes features of the CREST syndrome, an acronym for calcinosis (calcium deposits in the skin), Raynaud's phenomenon (vasospasm causing color changes in fingers and toes), esophageal dysmotility (impaired swallowing and reflux), sclerodactyly (tightening of skin on fingers), and telangiectasia (dilated small blood vessels on the skin).[3] lcSSc accounts for approximately 60-70% of SSc cases and is associated with a slower disease progression compared to other forms.[4][5] Diffuse cutaneous systemic sclerosis (dcSSc) involves more extensive skin fibrosis, affecting the trunk, proximal extremities (above elbows and knees), and face, leading to greater functional impairment.[3] Patients with dcSSc face a higher risk of early and severe internal organ involvement, such as rapid progression to interstitial lung disease or renal crisis.[3] This subtype comprises about 25-40% of cases and follows a more aggressive course with increased mortality risk.[4][5] Systemic sclerosis sine scleroderma (ssSSc) represents a variant without significant skin thickening, yet it features the hallmark internal organ fibrosis, vascular abnormalities like Raynaud's phenomenon, and serological markers typical of SSc.[3] This form is less common, affecting fewer than 10% of patients, and may be underdiagnosed due to the absence of cutaneous signs.[6] Overlap syndromes occur when SSc coexists with other connective tissue diseases, such as rheumatoid arthritis (leading to inflammatory joint involvement) or myositis (muscle inflammation), and include entities like mixed connective tissue disease characterized by overlapping features and high titers of anti-U1 RNP antibodies.[3] These syndromes account for around 10% of SSc cases and complicate classification due to mixed clinical presentations.[4]Autoantibodies and their implications
Systemic scleroderma, also known as systemic sclerosis (SSc), is characterized by the presence of specific autoantibodies that play a crucial role in serological classification and prognostic assessment. These autoantibodies are detected in over 90% of patients and are generally mutually exclusive, with co-occurrence being rare in more than 90% of cases.[7][8] The major SSc-specific autoantibodies include anti-centromere antibodies (ACA), anti-topoisomerase I antibodies (ATA, also known as anti-Scl-70), and anti-RNA polymerase III antibodies (anti-RNAP3). ACA are found in 50-90% of patients with limited cutaneous SSc (lcSSc) and are strongly associated with pulmonary arterial hypertension (PAH), occurring in 10-20% of ACA-positive cases, as well as calcinosis.[7][8] ATA are present in 30-60% of patients with diffuse cutaneous SSc (dcSSc) and are linked to interstitial lung disease (ILD), digital ulcers, and an increased risk of scleroderma renal crisis (SRC).[7][8][9] Anti-RNAP3 antibodies occur in 20-25% of dcSSc patients and confer a high risk of SRC (up to 50%), rapid skin progression, gastric antral vascular ectasia (GAVE), and malignancy within two years of disease onset in approximately 9% of cases.[7][8] Other relevant autoantibodies include anti-U3 ribonucleoprotein (anti-U3 RNP, or anti-fibrillarin), anti-Th/To, and anti-PM/Scl. Anti-U3 RNP antibodies are detected in 4-10% of SSc patients, predominantly in dcSSc, and are associated with severe disease, including PAH, ILD, and gastrointestinal involvement, particularly in Afro-Caribbean males.[7][8] Anti-Th/To antibodies appear in 4-13% of ACA-negative lcSSc patients and correlate with ILD and PAH.[7][8] Anti-PM/Scl antibodies, found in about 4% of cases, are typically associated with overlap syndromes featuring myositis, ILD, and calcinosis, often with a relatively favorable prognosis for lung involvement.[7][8] These autoantibodies have significant implications for risk stratification and clinical management. For instance, ATA positivity predicts worse outcomes in skin fibrosis and lung involvement, guiding intensified monitoring for ILD, while anti-RNAP3 status prompts early screening for SRC and cancer.[7][8] Prevalence varies by ethnicity; ATA is more frequent and associated with severe disease in African Americans compared to other groups, whereas ACA is more common in Caucasians and anti-U3 RNP in Afro-Caribbean populations.[8][7] Detection of these autoantibodies relies on methods such as indirect immunofluorescence (IIF) on HEp-2 cells for initial antinuclear antibody (ANA) screening, enzyme-linked immunosorbent assay (ELISA) for specific quantification (e.g., anti-RNAP3 and ATA), and line blot assays for multiplex detection.[7][8] Immunoprecipitation serves as the gold standard for confirming specificity. Testing for SSc-related autoantibodies—specifically ACA, ATA, and anti-RNAP3—is recommended at diagnosis as part of the 2013 ACR/EULAR classification criteria, where their presence contributes 3 points toward a total score of ≥9 for definite SSc classification.[7][10][11]Signs and symptoms
Cutaneous and vascular manifestations
Cutaneous manifestations in systemic scleroderma typically begin with an early edematous phase characterized by non-pitting swelling of the fingers and hands, often accompanied by intense pruritus that can significantly impair quality of life.[3] This initial phase progresses to fibrosis, resulting in progressive skin thickening and tightening, particularly affecting the distal extremities.[3] The extent of skin involvement is quantified using the modified Rodnan skin score (mRSS), a validated semiquantitative measure assessing skin thickness at 17 body sites on a scale from 0 (normal) to 3 (severe), yielding a total score ranging from 0 to 51; higher scores correlate with more extensive fibrosis.[12] Skin tightening often manifests as sclerodactyly, involving fibrosis distal to the metacarpophalangeal joints of the fingers, which may extend proximally in diffuse cutaneous systemic sclerosis (dcSSc) to include the forearms, upper arms, trunk, and legs, distinguishing it from the more limited distal involvement in limited cutaneous systemic sclerosis (lcSSc).[3] Additional cutaneous features include hyperpigmentation with a characteristic salt-and-pepper appearance due to areas of hypopigmentation amid hyperpigmented patches, particularly on the trunk and extremities.[3] In later stages, the skin may soften with atrophy, leading to ulceration at sites of trauma, such as over joints.[3] Calcinosis cutis, involving subcutaneous calcium deposits that can cause pain and ulceration, occurs in 18-49% of cases and is more prevalent in lcSSc.[13] Vascular manifestations are prominent and often precede other symptoms, with Raynaud's phenomenon affecting over 95% of patients and serving as an initial hallmark.[3] This vasospastic disorder features triphasic color changes in the digits—pallor due to ischemia, followed by cyanosis from deoxygenation, and rubor upon reperfusion—typically triggered by cold exposure or emotional stress.[3] Chronic vascular damage contributes to digital ulcers in 20-60% of patients, which are painful ischemic lesions primarily on the fingertips, and may heal with pitting scars.[14] Telangiectasias, dilated superficial capillaries appearing as red spots on the skin of the face, hands, and mucous membranes, are common and more frequent in patients with anticentromere antibodies (ACA).[3][15] Nailfold capillaroscopy reveals characteristic microvascular abnormalities, including giant capillaries (dilated loops >50 micrometers), hemorrhages, and avascular areas indicating capillary dropout, which reflect ongoing vasculopathy and correlate with digital ulcers.[16] Pruritus in the early phase remains a persistent challenge, exacerbating discomfort during skin remodeling.[3]Musculoskeletal involvement
Musculoskeletal involvement is a common feature of systemic scleroderma (SSc), affecting 40-90% of patients and serving as a major contributor to functional disability, particularly in hand mobility and daily activities.[17] This involvement encompasses abnormalities in joints, muscles, and bones, often manifesting early in the disease course and progressing to irreversible changes that impair quality of life.[18] Joint symptoms are prevalent, with arthralgias reported in 60-80% of patients, often accompanied by non-erosive arthritis and flexion contractures that limit range of motion.[19] Tendon friction rubs, a characteristic finding in diffuse cutaneous SSc (dcSSc), occur in 20-65% of cases and are associated with skin thickening and reduced joint function.[20] Early inflammatory arthritis in SSc frequently mimics rheumatoid arthritis, presenting as symmetric polyarthritis, and is more common in overlap syndromes such as scleromyositis.[21] These joint changes profoundly impact hand function, leading to decreased grip strength and dexterity.[22] Muscle involvement affects 10-20% of patients with SSc, typically manifesting as proximal muscle weakness and inflammatory myositis, which may overlap with conditions like polymyositis and is linked to autoantibodies such as anti-PM/Scl.[23] Muscle atrophy can result from disuse secondary to joint contractures or direct fibrotic changes, further exacerbating weakness and fatigue.[24] Bone alterations include acro-osteolysis, characterized by resorption of the distal phalanges, observed in approximately 20% of patients and particularly associated with digital ulcers and severe Raynaud's phenomenon.[25] Radiographic findings often show joint space narrowing without erosions, reflecting soft tissue fibrosis rather than destructive arthropathy.[26] These skeletal changes contribute significantly to hand deformity and overall disability in SSc.[27]Gastrointestinal tract
Gastrointestinal tract involvement is one of the most common manifestations of systemic scleroderma (SSc), affecting up to 90% of patients and contributing significantly to morbidity through motility disorders and nutritional deficits.[28][29] Esophageal dysfunction is particularly prevalent, occurring in 70-90% of cases, and is more frequent in limited cutaneous SSc (lcSSc), including the CREST syndrome variant where esophageal dysmotility is a defining feature.[28][29] Esophageal involvement typically results from smooth muscle atrophy and fibrosis, leading to aperistalsis and impaired lower esophageal sphincter function.[28] This dysmotility manifests as dysphagia, odynophagia, and severe gastroesophageal reflux disease (GERD), which can progress to erosive esophagitis, Barrett's esophagus, or peptic strictures in advanced cases.[28][29] Esophageal manometry often reveals absent peristalsis in the distal two-thirds of the esophagus, with reduced or absent contractility noted in over 50% of affected patients.[28] A major complication is aspiration pneumonia, arising from chronic reflux and impaired clearance, which increases the risk of respiratory infections.[28][29] Gastric and small bowel complications affect 40-70% of SSc patients, primarily through hypomotility and stasis.[28] Gastroparesis, characterized by delayed gastric emptying, occurs in approximately 47-70% of individuals and leads to symptoms such as nausea, early satiety, and bloating.[28] In the small intestine, reduced peristalsis promotes bacterial overgrowth in 30-62.5% of cases, resulting in malabsorption, diarrhea, and unintended weight loss.[28][29] Pseudo-obstruction, a severe form of intestinal hypomotility mimicking mechanical blockage, develops in approximately 4% of patients, more common in diffuse cutaneous systemic sclerosis.[30][29] Large bowel involvement is less dominant but impacts 20-50% of SSc patients, often presenting with colonic inertia and wide-mouth diverticula.[28] These diverticula, observed in about 42% of cases, arise from smooth muscle atrophy and increase the risk of perforation or bleeding.[28] Common symptoms include severe constipation due to delayed transit, affecting 20-50% of individuals, alongside fecal incontinence in 20-70%, which stems from weakened internal anal sphincter tone.[28][29] Overall, these gastrointestinal changes contribute to chronic malnutrition and reduced quality of life in SSc.[28][29]Pulmonary and cardiac systems
Pulmonary involvement is a leading cause of morbidity and mortality in systemic scleroderma (SSc), manifesting primarily as interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH).[31] ILD affects 40-80% of patients, with higher prevalence in diffuse cutaneous SSc (dcSSc) at approximately 53%, compared to 35% in limited cutaneous SSc.[31] Common symptoms include progressive dyspnea on exertion and non-productive cough, often developing insidiously in the early disease course.[32] The predominant histological and radiographic pattern is nonspecific interstitial pneumonia (NSIP), observed in up to 76% of biopsied cases.[32] Anti-topoisomerase I antibodies (ATA) are strongly associated with ILD development and progression, particularly in dcSSc patients.[32] Screening for ILD typically involves serial pulmonary function tests (PFTs) to assess restrictive patterns and reduced diffusing capacity for carbon monoxide (DLCO), alongside high-resolution computed tomography (HRCT) for early detection of ground-glass opacities and reticular abnormalities.[31] PAH occurs in 8-12% of SSc patients, confirmed by right heart catheterization, and carries a poor prognosis due to progressive right ventricular strain.[32] Symptoms overlap with ILD but emphasize exertional dyspnea and fatigue, often without prominent cough. Anti-centromere antibodies (ACA) confer increased risk for PAH, contrasting with the ILD association of ATA.[32] PAH can lead to cor pulmonale, characterized by right heart failure from chronic pulmonary vascular resistance, with right ventricular dysfunction evident in up to 38% of affected individuals.[33] Cardiac involvement in SSc primarily affects the myocardium through patchy fibrosis and microvascular ischemia, occurring in 15-35% of patients and independently worsening survival.[33] This fibrosis disrupts conduction pathways, resulting in arrhythmias such as ventricular tachyarrhythmias in about 15% of cases, and bradyarrhythmias requiring pacing.[33] Systolic dysfunction is less common at around 5-6%, while diastolic dysfunction predominates at 30-35%, contributing to heart failure symptoms like orthopnea and peripheral edema.[33] Palpitations, syncope, and exertional intolerance are key clinical signs, often detected via electrocardiography or echocardiography. Pericarditis remains rare, with effusions noted in only 5-16% without hemodynamic compromise.[33]Renal and other organs
Scleroderma renal crisis (SRC) affects approximately 10 to 15 percent of patients with diffuse cutaneous systemic sclerosis (dcSSc), occurring less frequently in limited cutaneous systemic sclerosis (lcSSc).[34] This condition is particularly prevalent in patients with anti-RNA polymerase III antibodies, where the risk is substantially elevated compared to those without these autoantibodies.[35] SRC typically involves a hypertensive crisis with malignant hypertension, often accompanied by thrombotic microangiopathy featuring endothelial damage, platelet-fibrin thrombi in renal arterioles, and microangiopathic hemolytic anemia in nearly half of cases.[36] A rare normotensive variant of SRC exists but occurs infrequently, without the hallmark severe hypertension.[34] Onset of SRC generally occurs within the first 4 to 5 years after systemic sclerosis diagnosis, underscoring the need for vigilant monitoring through regular home blood pressure measurements and serum creatinine assessments to facilitate early detection.[37] Hepatic involvement in systemic sclerosis is uncommon and typically mild, with primary biliary cholangitis (PBC) overlap syndrome observed in 10 to 20 percent of patients with limited cutaneous systemic sclerosis (lcSSc), often linked to anticentromere antibodies.[38] This overlap presents with cholestatic liver enzyme elevations and antimitochondrial antibodies, distinguishing it from direct fibrotic changes in systemic sclerosis.[39] Nodular regenerative hyperplasia, a vascular liver lesion driven by microvascular alterations, represents another rare manifestation, potentially leading to non-cirrhotic portal hypertension without significant fibrosis.[40] Unlike the biliary destruction in PBC overlap, hepatic fibrosis in systemic sclerosis alone is generally less pronounced, with moderate fibrosis detectable in only a subset of cases on biopsy.[41] Neurological involvement in systemic sclerosis primarily affects the peripheral nervous system, with trigeminal neuropathy being the most common cranial manifestation, causing sensory loss in the trigeminal distribution due to ischemic or fibrotic nerve compression.[42] Carpal tunnel syndrome frequently arises from perineural fibrosis and synovial thickening, contributing to median nerve entrapment and hand symptoms.[43] Central nervous system vasculitis is rare, occasionally presenting with headache, seizures, or cognitive impairment, but it lacks the widespread prevalence seen in other vasculitides.[43] Other organ systems can exhibit involvement, including sicca syndrome in 60 to 80 percent of patients, characterized by dry eyes and mouth from glandular fibrosis akin to Sjögren's syndrome features.[44] Thyroid autoimmunity is also common, with autoimmune thyroid disease prevalent in up to 25 percent of systemic sclerosis cases, often manifesting as hypothyroidism and overlapping with sicca symptoms.[45]Pathogenesis
Etiology and risk factors
The etiology of systemic scleroderma, also known as systemic sclerosis (SSc), remains incompletely understood, with no single causative agent identified. Instead, it is considered a multifactorial disease arising from complex interactions between genetic predisposition, environmental triggers, and immune dysregulation.[3][2] Genetic factors contribute significantly to susceptibility, with associations observed in the human leukocyte antigen (HLA) complex. For instance, the HLA-DRB1*1104 allele is linked to increased risk, conferring an odds ratio of approximately 2.8 overall and up to 4-fold in anti-topoisomerase I positive cases compared to non-carriers. Familial clustering occurs in about 1-2% of cases, indicating a heritable component, while monozygotic twin concordance is low at around 4%, underscoring the role of non-genetic influences. Epigenetic modifications, such as DNA methylation and histone alterations, are also suspected to play a part in modulating gene expression relevant to disease onset, though their precise contributions require further elucidation.[46][47][48] Environmental exposures represent key triggers, particularly occupational ones, with prevalence varying by cohort and exposure type. Crystalline silica dust is a well-established risk factor, with odds ratios ranging from 3 to 5 in exposed individuals, often seen in mining or construction workers. Organic solvents (e.g., trichloroethylene, toluene) and vinyl chloride exposure have similarly been associated with elevated risk, with odds ratios of 2-3 reported in systematic reviews. Infections may also contribute, as evidenced by higher prevalence of parvovirus B19 DNA in SSc tissues, though no specific infectious agent has been confirmed as causative.[47][49][50] Demographic factors further modulate risk, with females experiencing disease onset at a rate 4- to 10-fold higher than males, possibly linked to hormonal or X-chromosome influences. Incidence peaks between ages 30 and 50, though some cohorts report a slightly later onset around 45-64 years. Ethnic variations influence severity rather than incidence, with African Americans showing more diffuse cutaneous involvement and poorer prognosis compared to other groups.[47][3][51]Pathophysiological mechanisms
Systemic scleroderma, also known as systemic sclerosis (SSc), is characterized by a complex interplay of vascular, immune, and fibrotic processes that drive disease progression. The canonical three-phase model describes the pathogenesis as an initial vascular phase involving endothelial damage, followed by an inflammatory phase with immune cell activation, and culminating in a fibroproliferative phase marked by excessive tissue remodeling. This sequential progression underscores the interconnectedness of these mechanisms, where early vascular injury perpetuates immune dysregulation and fibrosis across multiple organs. Recent studies as of 2025 have further elucidated fibroblast subpopulations via single-cell analyses and potential contributions from gut microbiome alterations to immune-fibrotic crosstalk.[52] The vascular phase initiates with endothelial cell (EC) injury, often triggered by oxidative stress or infectious agents, leading to EC apoptosis and progressive microvascular loss. This is accompanied by intimal proliferation, where fibroproliferative changes thicken arterial walls, impairing vascular permeability and tone. Perivascular inflammation, involving infiltration of CD4+ and CD8+ T cells around apoptotic ECs, further exacerbates damage. Endothelin-1 (ET-1), a potent vasoconstrictor, is upregulated in this phase, promoting sustained vasoconstriction and endothelial-to-mesenchymal transition (EndoMT), which contributes to vessel wall fibrosis and ischemia.[52][53] These vascular alterations form the foundation for tissue hypoxia and set the stage for subsequent immune and fibrotic responses.[54] Immune activation in the inflammatory phase features prominent T-cell infiltration into affected tissues, with increased CD4+ and CD8+ T cells producing pro-fibrotic cytokines such as IL-13 and IFN-γ. B cells contribute through dysregulated autoantibody production and elevated IL-6 secretion, while reduced regulatory B cells fail to dampen inflammation. Key cytokines like transforming growth factor-β (TGF-β) and IL-6, derived from these immune cells, bridge inflammation to fibrosis by activating downstream signaling pathways such as SMAD and MAPK.[55][52] This immune dysregulation sustains a Th2-skewed response, with IL-4 and IL-13 enhancing collagen synthesis and fibroblast recruitment.[54] In the fibrotic phase, resident fibroblasts undergo activation and differentiation into myofibroblasts, characterized by expression of alpha-smooth muscle actin (α-SMA) and excessive production of extracellular matrix (ECM) components, particularly collagen types I and III. TGF-β is central here, inducing fibroblast proliferation and inhibiting ECM degradation via matrix metalloproteinases. Platelet-derived growth factor (PDGF) further amplifies this process by stimulating fibroblast and smooth muscle cell proliferation, leading to persistent ECM accumulation.[52][55] These mechanisms extend to multi-organ involvement; for instance, alveolar fibrosis in interstitial lung disease (ILD) arises from similar myofibroblast activation and cytokine-driven ECM deposition in pulmonary tissues, while scleroderma renal crisis (SRC) stems from renal vasculopathy with intimal proliferation and ischemic fibrosis.[54]Diagnosis
Clinical evaluation
Clinical evaluation of systemic scleroderma begins with a detailed history and physical examination to identify characteristic features suggestive of the disease. Patients often report Raynaud's phenomenon as an initial symptom, which involves episodic color changes in the fingers or toes triggered by cold or stress, and it frequently precedes the formal diagnosis by several years (median 2.8 years overall after Raynaud's onset, IQR 0.7–10.0 years; longer in limited cutaneous forms, e.g., median 4.6 years for women), with a median time of approximately 4.6 years from onset to diagnosis overall, though it can extend to 8-10 years or more in limited cutaneous forms.[56] Other key historical elements include the development of puffy fingers, often described as a non-pitting edema affecting the hands, followed by progressive skin tightening starting distally and potentially spreading proximally. Inquiry into family history is essential, as it represents the strongest known risk factor, with first-degree relatives having a 13- to 15-fold increased relative risk compared to the general population.[57] Environmental exposures, such as silica dust or organic solvents, should also be explored, as occupational or environmental triggers are associated with disease onset in susceptible individuals.[58] The physical examination focuses on assessing skin involvement and vascular changes. Skin thickness is evaluated using the modified Rodnan skin score (mRSS), a validated semiquantitative tool that grades firmness and tethering on a scale of 0 (normal) to 3 (sclerosed) across 17 body sites, yielding a total score from 0 to 51; higher scores correlate with more extensive fibrosis and poorer prognosis.[3] Nailfold capillaroscopy, a non-invasive bedside technique, reveals microvascular abnormalities crucial for early suspicion of systemic scleroderma. Characteristic patterns include the "early" scleroderma pattern with giant capillaries greater than 50 micrometers, the "active" pattern featuring hemorrhages and capillary loss alongside giants, and the "late" pattern marked by severe avascularity and ramified/bushy capillaries, reflecting progressive vascular damage.[59] Classification relies on the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria, an additive scoring system where a total score of 9 or greater indicates definite systemic scleroderma; these criteria demonstrate 91% sensitivity and 92% specificity.[60] Skin thickening of the fingers extending proximal to the metacarpophalangeal joints alone suffices for classification (9 points). Absent this, points are assigned as follows:| Item | Subitem | Points |
|---|---|---|
| Skin thickening | Puffy fingers (scleroderma pattern) | 2 |
| Sclerodactyly (distal to metacarpophalangeal joints but proximal to proximal interphalangeal joints) | 4 | |
| Fingertip lesions (digital tip ulcers or pitting scars) | 2 | |
| Telangiectasia | - | 2 |
| Abnormal nailfold capillaries | - | 2 |
| Pulmonary arterial hypertension and/or interstitial lung disease | Maximum extent on either | 2 |
| Raynaud's phenomenon | - | 3 |