Scleroderma (Systemic Sclerosis)

Systemic sclerosis (SSc), also called scleroderma, is an uncommon autoimmune connective tissue disease in which three processes — autoimmunity, a small-vessel vasculopathy, and progressive fibrosis of the skin and internal organs — combine in a way no other rheumatologic disease quite replicates.^[1] It is rare (Canadian prevalence estimates are in the range of roughly 1 in 3,000-5,000 adults) but disproportionately morbid, with a female-to-male ratio of roughly 4:1 and typical onset between ages 30 and 50.^[1]

Two cutaneous subtypes with genuinely different natural histories

The single most important organizing framework in this chapter, first proposed by LeRoy and colleagues and still the working clinical classification in daily practice, divides SSc by the extent of skin involvement into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) — a distinction that predicts organ risk, timeline, and prognosis well enough to shape nearly every decision in this chapter.^[2]

CREST — the mnemonic for limited disease, and why it still matters

CREST is more than a memory aid: each letter names a genuinely distinct clinical problem addressed elsewhere in this chapter — Calcinosis cutis, Raynaud's phenomenon (covered in full in the companion Raynaud's Phenomenon chapter), Esophageal dysmotility, Sclerodactyly, and Telangiectasia.^[2] A patient does not need every CREST feature to have limited disease, and the presence of calcinosis or telangiectasia in a patient without diffuse skin involvement should itself raise SSc on the differential rather than being dismissed as an isolated cosmetic finding.

How this chapter fits with the platform's other SSc-related chapters

This chapter deliberately does not repeat what three companion chapters already cover in depth: the companion Raynaud's Phenomenon chapter covers vasospasm mechanism, the drug-culprit table, and the calcium-channel-blocker-first escalation ladder that applies to SSc-associated Raynaud's phenomenon exactly as it does to primary disease; the companion Pulmonary Fibrosis chapter covers antifibrotic pharmacotherapy in depth (this chapter adds only the SSc-ILD-specific evidence not covered there); and the companion Pulmonary Hypertension chapter covers the full PAH diagnostic and treatment pathway, including the DETECT screening algorithm this chapter references for SSc-specific PAH screening. Cross-references to each appear throughout rather than duplicated content.

Limited cutaneous SSc in detail

• Calcinosis cutis — dystrophic calcium deposits in the skin and subcutaneous tissue, most often over the fingertips, forearms, and other pressure points; can ulcerate and extrude chalky white material, and is a genuine source of pain, recurrent local infection, and functional limitation (see Choose Initial Treatment).
• Raynaud's phenomenon — the presenting feature in the great majority of SSc patients, often by years; see the companion Raynaud's Phenomenon chapter for the full diagnostic and management pathway, which applies here without modification.
• Esophageal dysmotility — smooth-muscle atrophy and fibrosis of the distal two-thirds of the esophagus produce weak peristalsis and a hypotensive, incompetent lower esophageal sphincter; the practical consequence is severe, often atypically silent gastroesophageal reflux disease with a real risk of peptic stricture and Barrett's esophagus if under-treated (see Choose Initial Treatment).
• Sclerodactyly — tight, thickened, shiny skin of the fingers, often producing flexion contractures and a tapered, claw-like appearance; a core physical finding in both subtypes, not limited disease alone.
• Telangiectasia — dilated capillaries producing discrete, blanchable red macules, classically on the face, lips, and hands; cosmetically significant and, in the GI tract as gastric antral vascular ectasia, a genuine source of chronic blood loss (see Assessment & Diagnosis and Choose Initial Treatment).

Sclerodactyly — dark, shiny, tightly bound skin over the distal phalanges of both hands. The bilateral, symmetric pattern shown here is itself a diagnostic clue distinguishing systemic sclerosis from a unilateral or asymmetric mimic. (Maria Sieglinda von Nudeldorf, CC BY-SA 4.0, Wikimedia Commons)

Diffuse cutaneous SSc in detail

Diffuse disease is defined by skin thickening that extends proximal to the elbows and knees and onto the trunk, and behaves differently from limited disease in three clinically important ways.^[2][1]

• A rapid early tempo — skin thickening typically progresses fastest in the first 1-3 years after onset, sometimes reaching its maximum extent within this window before plateauing or, in some patients, slowly regressing over subsequent years.
• Tendon friction rubs — a genuinely distinctive examination finding: a palpable, sometimes audible leathery or crepitant sensation over tendons (classically the wrists, ankles, and knees) during active or passive joint movement, caused by fibrinous deposits within tendon sheaths. Its presence correlates with more severe diffuse disease, a higher rate of early internal-organ involvement, and worse overall prognosis — actively check for it on examination rather than treating joint stiffness as generic arthralgia.
• A materially higher risk of early major-organ disease — interstitial lung disease and scleroderma renal crisis both cluster in the first several years of diffuse disease specifically, which is exactly why the early diffuse-disease window drives the intensified monitoring detailed in Monitoring & Follow-Up.

The modified Rodnan skin score

Skin involvement is tracked, not just described qualitatively: the modified Rodnan skin score (mRSS) grades skin thickness on a 0 (normal) to 3 (severe) scale across 17 standardized body areas (face, anterior chest, abdomen, and bilaterally the fingers, hands, forearms, arms, thighs, legs, and feet), for a total possible range of 0-51. A rising mRSS over serial visits is a genuine, reproducible marker of active diffuse disease and is the outcome measure most immunosuppressive-therapy trials for skin disease are built around (see Choose Initial Treatment).

Sine scleroderma and overlap syndromes

Two variant presentations are worth recognizing by name rather than dismissing as atypical: SSc sine scleroderma, in which a patient has the vascular, serologic, and internal-organ features of SSc — Raynaud's phenomenon, a positive SSc-specific autoantibody, characteristic organ involvement — without ever developing clinically detectable skin thickening; and overlap syndromes, in which SSc coexists with features of another connective tissue disease (inflammatory myositis, systemic lupus erythematosus, or rheumatoid arthritis), which can blur the clinical picture and typically warrants the same rheumatology-led, multidisciplinary approach as straightforward SSc.^[1]

• Female sex — roughly a 4:1 female predominance.^[1]
• Age of onset typically between 30 and 50 years, though SSc can present outside this range.
• A first-degree relative with SSc or another autoimmune connective tissue disease.
• Occupational silica exposure (classically described in miners and quarry workers) and, less consistently, certain organic solvent exposures.
• African ancestry — associated with earlier onset, a higher proportion of diffuse cutaneous disease, and a disproportionately higher rate of anti-U3 RNP (fibrillarin) antibody positivity, itself linked to a higher risk of pulmonary hypertension, cardiac, and renal involvement.
• Diffuse cutaneous subtype specifically, and particularly its first 1-3 years, as the single most important risk window for scleroderma renal crisis and early interstitial lung disease (see Recognize the Condition and Red Flags & Refer).
• Anti-RNA polymerase III antibody positivity — the single strongest individual risk factor for scleroderma renal crisis, and also associated with a well-documented, time-limited increase in concurrent malignancy risk (see Assessment & Diagnosis and Special Populations).^[3]
• Recent high-dose corticosteroid exposure (see Choose Initial Treatment) — a genuine, modifiable, iatrogenic risk factor for precipitating scleroderma renal crisis, not merely a theoretical concern.^[4]

Beyond renal crisis, the following should also prompt prompt escalation rather than routine follow-up:

• New or worsening exertional dyspnea, dry cough, or a fall in forced vital capacity on screening spirometry — evaluate for interstitial lung disease per the companion Pulmonary Fibrosis chapter's diagnostic pathway.
• Unexplained exertional dyspnea, syncope, or presyncope in a patient with limited cutaneous disease, particularly longstanding disease — evaluate for isolated pulmonary arterial hypertension per the companion Pulmonary Hypertension chapter and its DETECT screening algorithm.
• New iron deficiency anemia, occult or overt GI bleeding, or a falling hemoglobin without an obvious source — evaluate for gastric antral vascular ectasia (see Assessment & Diagnosis).
• Fixed digital pallor/cyanosis unrelieved by warming, a non-healing digital ulcer, or any sign of digital gangrene — this is critical digital ischemia; see the companion Raynaud's Phenomenon chapter's escalation pathway.
• New palpitations, syncope, or signs of pericardial effusion — evaluate for scleroderma-associated myocardial or pericardial disease.
• Rapidly progressive skin thickening in early diffuse disease — this itself signals the highest-risk window for internal-organ involvement and should prompt closer, not routine-interval, monitoring (see Monitoring & Follow-Up).

2013 ACR/EULAR classification criteria

Skin thickening of the fingers of both hands extending proximal to the metacarpophalangeal joints is, on its own, sufficient to classify a patient as having systemic sclerosis. In its absence, seven additional items are weighted and summed; a total score of 9 or more classifies the patient as having SSc.^[5]

This scoring system replaced the 1980 ACR criteria specifically because those older criteria under-recognized early and limited-cutaneous disease; the 2013 system achieved a sensitivity of 91% and specificity of 92% in its validation cohort.^[5] It is a classification tool for research and structured clinical reasoning, not a substitute for overall clinical judgment in an individual patient.

Autoantibody testing — genuinely useful, not just confirmatory

Antinuclear antibody (ANA) testing is positive in the great majority of SSc patients and is a reasonable first screen, but the real diagnostic and prognostic value comes from the SSc-specific autoantibody pattern, which should be tested in every patient with a new or suspected diagnosis.^[3][1]

Baseline and diagnostic organ screening

Once SSc is diagnosed or strongly suspected, a structured baseline organ evaluation — not a single test — establishes the starting point every subsequent follow-up in Monitoring & Follow-Up is measured against: pulmonary function testing (including DLCO) and high-resolution CT chest for interstitial lung disease (full diagnostic pathway in the companion Pulmonary Fibrosis chapter); echocardiography, applying the DETECT algorithm specifically validated for this population, for pulmonary arterial hypertension screening (full pathway in the companion Pulmonary Hypertension chapter); baseline renal function, urinalysis, and blood pressure, given the disproportionate scleroderma-renal-crisis risk in early diffuse disease; a baseline ECG; nailfold capillaroscopy (full technique in the companion Raynaud's Phenomenon chapter); and a baseline modified Rodnan skin score to track skin involvement over time (see Recognize the Condition).

Gastric antral vascular ectasia ("watermelon stomach")

A distinctive vascular lesion of the gastric antrum, seen almost exclusively on upper endoscopy as parallel, ectatic mucosal vessels radiating from the pylorus in a pattern resembling watermelon rind — hence the common name — and a genuine, sometimes under-recognized cause of chronic occult or overt GI blood loss and iron deficiency anemia in SSc.^[6] Endoscopic evaluation is warranted for any SSc patient with unexplained iron deficiency anemia or GI bleeding rather than attributing this reflexively to reflux esophagitis alone; diagnosis and endoscopic treatment (argon plasma coagulation is the mainstay) belong with gastroenterology, not primary care or community pharmacy (see Choose Initial Treatment and Treatment Failure/Next Step).

Systemic sclerosis has no single approved disease-modifying therapy that halts the disease as a whole — unlike, for example, the biologic and targeted-synthetic options available across rheumatoid arthritis — so treatment targets are necessarily organ-specific and staged by urgency rather than built around one drug or one endpoint.^[7]

• Recognize and treat scleroderma renal crisis immediately — this is the one target in this chapter where delay measured in hours, not weeks, materially changes survival (see Choose Initial Treatment).
• Slow skin and lung fibrosis progression in patients with high-risk features (early diffuse disease, a rapidly rising modified Rodnan skin score, anti-Scl-70 positivity) using immunosuppressive therapy, understanding that this is a rate-of-progression goal, not a cure.
• Prevent, not just treat, digital ulceration through the vasodilator ladder detailed in the companion Raynaud's Phenomenon chapter, plus the SSc-specific prevention evidence for bosentan detailed in this chapter.
• Control esophageal reflux aggressively enough to prevent stricture and Barrett's esophagus, not merely to relieve symptoms.
• Screen for, and act promptly on, interstitial lung disease and pulmonary arterial hypertension — the two largest drivers of SSc mortality — using the companion chapters' full diagnostic and treatment pathways.
• Preserve hand and joint function against the contractures that fibrotic skin and tendon disease otherwise produce.
• Support quality of life and mental health against a disease with a genuinely high, often under-acknowledged, chronic symptom and cosmetic burden.

Hand, digit, and cold protection

See the companion Raynaud's Phenomenon chapter for whole-body and local warming technique, trigger avoidance, and smoking-cessation counseling — all apply here without modification, since Raynaud's phenomenon is present in the great majority of SSc patients.

Oral and facial care

Facial skin thickening can progressively reduce mouth opening (microstomia), with real downstream consequences for dental hygiene, dental procedures, and nutrition. Daily mouth-opening and facial stretching exercises, started early rather than once microstomia is already significant, help preserve oral aperture; reinforce regular dental care, since a reduced oral opening makes routine dental work progressively harder to access over time.

Skin care

Regular emollient use for the diffuse xerosis and pruritus that frequently accompany fibrotic skin change; gentle, non-abrasive skin care around any area of calcinosis or digital ulceration to avoid precipitating breakdown or infection; consistent sun protection, both for the photosensitivity some patients experience and for general skin health given chronic skin fragility.

Physical and occupational therapy

Regular stretching and range-of-motion exercises for the hands and joints help preserve function against the contractures that skin and tendon fibrosis otherwise produce over time; an occupational therapy referral for adaptive equipment and joint-protection strategies is genuinely useful once hand function is meaningfully affected, not only in advanced disease.

GI lifestyle measures

Small, frequent meals rather than large ones; remaining upright for at least 2-3 hours after eating; elevating the head of the bed (not simply using extra pillows, which does not reliably reduce reflux the same way); avoiding known reflux triggers (caffeine, alcohol, high-fat meals, late-evening eating). These are genuine adjuncts to, not substitutes for, the pharmacotherapy in Choose Initial Treatment.

Nutrition

Proactive dietitian referral for a patient with esophageal dysmotility, SIBO, or unintentional weight loss, rather than waiting until malnutrition is advanced; malabsorption from SIBO in particular can silently drive fat-soluble vitamin deficiency and warrants specific nutritional attention.

Psychosocial support

SSc carries a genuinely high disease burden — visible skin and facial change, chronic pain, functional limitation, and a materially elevated rate of depression and anxiety compared with the general population. Proactively screen for and address mental health alongside physical disease management, and connect patients with SSc-specific patient-support organizations, which offer a kind of peer understanding that generic chronic-illness resources often cannot.

Vaccination

Keep routine immunization current, with particular attention to influenza and age-appropriate pneumococcal vaccination given the added respiratory vulnerability in a patient with any degree of interstitial lung disease.

Pregnancy

Pregnancy in SSc carries genuine, disease-specific risk that is highest in early diffuse disease — the same window carrying the highest scleroderma-renal-crisis risk generally — so conception is best deferred, where feasible, until diffuse disease has stabilized past its most active early years. If scleroderma renal crisis develops during pregnancy, this is a genuine exception to routine ACE-inhibitor teratogenicity counseling: an ACE inhibitor is still used to treat this life-threatening emergency, since the maternal mortality risk of untreated renal crisis outweighs fetal ACE-inhibitor exposure risk in this specific situation — a decision made jointly with maternal-fetal medicine and rheumatology, not deferred. Mycophenolate mofetil and cyclophosphamide are both teratogenic and should be stopped well before a planned conception, with a bridge to a pregnancy-compatible alternative planned in advance rather than reactively. Pulmonary arterial hypertension, covered in the companion Pulmonary Hypertension chapter, is itself a contraindication to pregnancy given its very high associated maternal mortality.

Malignancy screening around a new anti-RNA polymerase III-positive diagnosis

The association between anti-RNA polymerase III positivity and concurrent malignancy — typically diagnosed within roughly 2 years before or after SSc onset — is well documented and genuinely actionable.^[3] A new diagnosis of anti-RNA polymerase III-positive SSc is a reasonable trigger to confirm the patient is up to date with age- and risk-appropriate cancer screening, and to maintain a lower threshold for investigating any new, unexplained symptom in the surrounding months rather than attributing everything to the new rheumatologic diagnosis.

Pediatric-onset disease

Juvenile systemic sclerosis is rare and should be managed by pediatric rheumatology; the same subtype and autoantibody framework applies, though organ-involvement patterns and prognosis differ somewhat from adult-onset disease.

Renal and hepatic impairment

Mycophenolate mofetil requires no specific hepatic adjustment but should be used cautiously with close monitoring in significant renal impairment. Methotrexate requires dose reduction and closer monitoring in renal impairment and is contraindicated in significant hepatic impairment. ACE inhibitors used for scleroderma renal crisis are, by definition, being started in a patient with acute kidney injury — this is expected and is not a reason to withhold therapy (see Choose Initial Treatment).

Overlap syndrome patients

A patient with SSc overlapping with inflammatory myositis, lupus, or rheumatoid arthritis features needs the corticosteroid caution in Choose Initial Treatment applied with particular care, since myositis flares in particular can otherwise prompt reflexive high-dose steroid use.

• Home blood pressure monitoring for any patient with early diffuse disease or anti-RNA polymerase III positivity — genuinely useful patient-level surveillance that can catch the earliest signal of scleroderma renal crisis before a scheduled visit would.
• Renal function, urinalysis, and blood pressure at every visit during the early diffuse-disease window (roughly the first 3-5 years), with a lower threshold to check sooner if the patient reports any new headache, visual change, or unusual fatigue.
• Annual pulmonary function testing (including DLCO) and clinical reassessment for interstitial lung disease, per the companion Pulmonary Fibrosis chapter's schedule, more frequently in the first several years of diffuse disease or with anti-Scl-70 positivity.
• Annual echocardiography (or per the DETECT algorithm's specific interval) for pulmonary arterial hypertension screening, per the companion Pulmonary Hypertension chapter — continued long-term even in stable limited disease, since ACA-associated PAH risk persists for years.
• Serial modified Rodnan skin score at routine visits to track skin disease trajectory objectively rather than by impression alone.
• Hemoglobin and iron studies periodically, with a low threshold for endoscopic referral if unexplained iron deficiency emerges (see Assessment & Diagnosis).
• Digit and skin examination at every visit for new calcinosis, digital ulceration, or infection.
• Mycophenolate mofetil and methotrexate: periodic CBC and liver enzymes per each agent's standard immunosuppressive monitoring schedule.
• Bosentan: mandatory monthly liver enzyme monitoring for the full duration of treatment, identical to its use in the companion Pulmonary Hypertension chapter.
• Reconcile the medication list at every visit specifically for recent or escalating corticosteroid exposure in a patient with early diffuse disease.

1. Scleroderma renal crisis not controlled on maximized captopril: add a second and, if needed, a third antihypertensive agent while continuing the ACE inhibitor unchanged; involve nephrology urgently for dialysis planning rather than waiting for a further deterioration.
2. Continued or worsening renal function despite adequate blood pressure control on an ACE inhibitor: this does not automatically mean the ACE inhibitor has failed — renal recovery in scleroderma renal crisis can take months, and dialysis with later recovery is a genuinely expected trajectory in a substantial proportion of patients (see Choose Initial Treatment); do not abandon ACE-inhibitor therapy on this basis alone.
3. Progressive skin or lung disease despite mycophenolate: confirm adherence and an adequate trial duration (benefit can take several months to appear) before concluding failure; reasonable next steps include switching to cyclophosphamide for more severe or rapidly progressive ILD, or considering rituximab or tocilizumab, ideally through a specialized SSc or ILD centre rather than as an isolated primary-care escalation.
4. Recurrent digital ulceration despite the full Raynaud's Phenomenon chapter escalation ladder: add bosentan specifically to prevent new ulcers (see Choose Initial Treatment), while continuing wound care and vasodilator therapy for any ulcer already present.
5. Reflux symptoms or objective findings (stricture, worsening Barrett's changes) not controlled on standard-dose PPI therapy: increase to twice-daily dosing, add a bedtime H2-receptor antagonist, and reassess for a prokinetic if not already trialed; refer to gastroenterology for stricture dilation or closer endoscopic surveillance rather than escalating medical therapy indefinitely.
6. Persistent unexplained iron deficiency anemia: ensure endoscopic evaluation for gastric antral vascular ectasia has actually occurred rather than continuing empiric iron replacement indefinitely (see Assessment & Diagnosis).
7. SIBO symptoms recurring after rifaximin: retreatment with rifaximin, or rotation to an alternative regimen, is reasonable for confirmed recurrence — this is a chronically relapsing problem in SSc given the underlying motility disorder is not itself reversible.

• Stopping or reducing an ACE inhibitor in scleroderma renal crisis because creatinine is rising — this is the single most dangerous, avoidable error in this chapter; uncontrolled hypertension, not the ACE inhibitor, drives ongoing renal injury (see Choose Initial Treatment).^[8]
• Starting an ACE inhibitor prophylactically in an asymptomatic, normotensive, high-risk SSc patient hoping to prevent renal crisis — the available evidence associates this with worse, not better, outcomes.^[9]
• Reaching for a high-dose corticosteroid in early diffuse disease for a co-existing symptom without recognizing this as a genuine, modifiable renal-crisis risk factor.^[4]
• Dismissing a normotensive or only mildly hypertensive presentation as "not renal crisis" in an at-risk patient — roughly 1 in 10 cases present without significant hypertension.
• Treating SSc-associated Raynaud's phenomenon and digital ulceration as a separate, unrelated condition rather than using the companion Raynaud's Phenomenon chapter's full escalation pathway.
• Starting bosentan for an existing digital ulcer expecting it to speed healing — RAPIDS-2 showed a new-ulcer-prevention benefit, not a healing benefit.^[11]
• Duplicating interstitial lung disease or pulmonary arterial hypertension work-up and treatment reasoning instead of using the companion Pulmonary Fibrosis and Pulmonary Hypertension chapters' full pathways.
• Attributing new iron deficiency anemia in an SSc patient to "just reflux" without endoscopic evaluation for gastric antral vascular ectasia.
• Not checking for a tendon friction rub or a rapidly rising modified Rodnan skin score as prognostic markers, and instead treating early diffuse-disease joint stiffness as generic arthralgia.
• Missing the malignancy-screening opportunity that a new anti-RNA polymerase III-positive diagnosis genuinely represents.
• Assuming limited cutaneous disease is permanently lower-risk and relaxing long-term pulmonary arterial hypertension screening — anti-centromere-associated PAH risk persists for years to decades after diagnosis.
• Cycling a patient with symptomatic calcinosis through multiple unproven medical therapies indefinitely instead of a timely surgical referral for a functionally limiting or recurrently infected lesion.

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Scleroderma Renal Crisis — ACE Inhibitor Therapy

Captopril is preferred acutely for its short half-life and rapid titratability; do not substitute a longer-acting ACE inhibitor during the initial titration phase.

Disease-Modifying Immunosuppression and SSc-ILD-Specific Antifibrotic/Biologic Therapy

No single agent is approved as disease-modifying therapy for systemic sclerosis as a whole; choice is individualized by dominant organ involvement. See Choose Initial Treatment for the trial evidence behind each option.

Gastrointestinal Motility, Reflux, and Small Intestinal Bacterial Overgrowth

Reflux in SSc is frequently more severe, and more often silent, than routine GERD given true lower esophageal sphincter incompetence rather than simple over-relaxation.

Calcinosis Cutis — Limited-Evidence Medical Options

No medical therapy has robust evidence of effectiveness; set expectations accordingly and do not delay surgical referral for a symptomatic, recurrently infected, or functionally limiting lesion.