Scleroderma Treatment

• No drug has been clearly proven that would stop or reverse the skin thickening and tightening manifestation of scleroderma
• Primarily for symptomatic treatment and prevention of complications of scleroderma

Dermatological

Topical Therapy

• First-line option for dermal (superficial) and localized dermatological manifestations of scleroderma
• Topical Tacrolimus
  
  • Effective for active inflammatory morphea
• High-potency corticosteroids 
  • Usually applied with occlusion  
  • Topical treatment should be discontinued if no response has been observed after 10-12 weeks of use as it can cause renal crisis
  • Intralesional corticosteroids (eg Triamcinolone) are effective treatment for circumscribed and localized deep morphea; also used as adjuvant therapy for recalcitrant lesions in patients receiving phototherapy or systemic treatment
• Topical Vitamin D
  
  • Inhibits fibroblast proliferation, collagen synthesis and activation of T lymphocyte
  • Treatment combination of Calcipotriol and Betamethasone dipropionate ointment has been reported to show improvement in skin lesions 
• Imiquimod 
  • An immune response modifier that downregulates interleukin-4 (profibrotic cytokine) and induces interferon-gamma (cytokine which inhibits production of extracellular matrix proteins and transforming growth factor-beta) 
• Use of lanolin-based skin moisturizers and antihistamines may also be considered

Systemic Therapy

• For severe, disabling, progressive deep lesions
• Methotrexate
  • Most appropriate agent for systemic therapy of morphea and the 1st-line agent for systemic sclerosis (SSc)-related skin involvement [modified Rodnan skin thickness score (MRSS) of 24]  
  • An alternative option to phototherapy in patients with generalized disease  
• Mycophenolate mofetil
  • 2nd-line agent in those who cannot tolerate or have contraindications to Methotrexate  
• Concomitant use of systemic glucocorticoids may be considered  
  • May be combined with Methotrexate in patients with rapidly progressive or acute generalized disease
• For SSc-related skin involvement MRSS of 32, therapeutic agents in preferred order include Mycophenolate mofetil, Methotrexate, IV Cyclophosphamide and autologous hematopoietic stem cell transplantation (HSCT)  
• Other promising therapies include the following:
  • Morphea: Penicillamine, Penicillin, Bosentan, Colchicine, Cyclosporine, Hydroxychloroquine and Infliximab 
  • SSc-related skin involvement: IV immune globulin (IVIg), Rituximab, Tocilizumab  
• For active treatment of SSc-related digital ulcers, 1st- and 2nd-line treatments are calcium channel blockers (CCBs) (eg Nifedipine) and phosphodiesterase-5 (PDE-5) inhibitors (eg Sildenafil), respectively
  • Prostanoids and endothelin receptor antagonists (ERAs) (eg Bosentan) may be considered as 3rd-line agents
    • IV prostanoids (eg IV Iloprost) should be considered in patients with severe active digital ulcers
    • Therapy with Bosentan is recommended for patients with multiple digital ulcers despite treatment with CCBs, PDE-5 inhibitors and Iloprost; may also be used to prevent ulcer recurrence
    • For patients with recurrent/refractory digital ulcers, a PDE-5 inhibitor or IV prostanoid and an ERA should be considered

Cardiac

• For patients with symptomatic pericardial involvement, 1st-line treatment includes use of low-dose steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), Colchicine or Hydroxychloroquine  
  • May consider adding Methotrexate or Mycophenolate mofetil as 2nd-line agent if unresponsive to above treatment  
  • Pericardial window (1st-line option if with tamponade) or pericardiocentesis may be considered in select patients  
• For patients with myocarditis, initial treatment includes Mycophenolate mofetil or high-dose steroids and standard heart failure treatment  
  • 2nd-line treatment agent is IV Cyclophosphamide or Rituximab  
• For patients with systolic heart failure, immunosuppressants with or without a pacemaker, implantable cardioverter defibrillator, angiotensin-converting enzyme (ACE) inhibitors and Carvedilol may be considered
• For patients with diastolic heart failure with preserved left ventricular ejection fraction, diuretics and CCBs may be considered 
• Standard cardiac treatment is advised for patients with ischemic cardiopathy or rhythm disturbances

Gastrointestinal

• Enteral and parenteral feeding for patients with swallowing disorders or severe small intestine damage
• For GERD and upper GI dysmotility disorders, 1st-line treatment includes high-dose proton pump inhibitors (eg Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole)
  • 2nd-line agents include histamine₂-receptor antagonists (H₂RAs) and prokinetic drugs (eg Metoclopramide, Domperidone) 
  • Acid-reducing agents reduce the risk of having esophageal strictures
  • Please see Gastroesophageal Reflux Disease disease management chart for further information
• Small bowel disorders such as bacterial overgrowth may be treated with broad-spectrum oral antibiotics and pseudo-obstruction with prokinetic agents  
• Constipation treatment includes laxatives and enemas; incontinent patients may be treated with biofeedback

Musculoskeletal

• NSAIDs (eg Ibuprofen) are used in patients with arthralgia but without arthritis to relieve pain, inflammation, swelling and stiffness
  • Paracetamol may be an alternative agent if NSAIDs are ineffective or are contraindicated  
• For patients with inflammatory arthritis, therapeutic agents in preferred order include Methotrexate, low-dose glucocorticoids (≤10 mg daily dose of Prednisone or equivalent), Hydroxychloroquine, and Rituximab or Tocilizumab  
  • Patients with persistent arthritis unresponsive to above treatment may be given other drugs for rheumatoid arthritis [eg Abatacept, Leflunomide, anti-tumor necrosis factor (TNF), Janus kinase (JAK) inhibitors] in overlap cases or refer patient for a clinical trial
  • Due to concerns about pulmonary toxicity, avoid giving Methotrexate to patients with severe lung fibrosis

Pulmonary

Interstitial Lung Disease (ILD)

• Induction therapy includes Mycophenolate mofetil, IV Cyclophosphamide, and Rituximab  
  • Select non-responding patients may undergo lung or autologous HSCT or may be referred for a clinical trial  
• Maintenance therapy includes Mycophenolate mofetil, Azathioprine and IV or oral Cyclophosphamide
• Cyclophosphamide should be considered for the treatment of SSc with progressive ILD
• Immunosuppressants (eg Azathioprine, Cyclophosphamide) are usually combined with glucocorticoids to prevent further lung deterioration in patients with fibrosing alveolitis
• Low-dose glucocorticoids are generally administered in combination with Cyclophosphamide in the treatment of pulmonary fibrosis
  • Monotherapy is not recommended as it can increase the risk of renal crisis
• Nintedanib is a tyrosine kinase inhibitor that slows the rate of pulmonary function decline in patients with SSc-associated ILD
• Annual flu and anti-pneumococcal vaccinations are recommended

Pulmonary Arterial Hypertension (PAH)

• For mild (low-intermediate risk) PAH [New York Heart Association (NYHA) functional class II-III], treatment is initiated with combination therapy composed of an ERA and a PDE-5 inhibitor (eg Ambrisentan/Tadalafil, Macitentan/Sildenafil), then addition of a prostanoid or Selexipag
  • Combination therapy with Riociguat and Bosentan may also be considered
• For severe (high-risk) PAH (NYHA functional class III-IV), treatment is initiated with prostanoids followed by an ERA plus PDE-5 inhibitor, then ERA plus a prostanoid  
  • Selexipag plus ERA and/or PDE-5 inhibitor can be alternate combination regimens in patients unsuited to the Ambrisentan and Tadalafil combination 
  • Lung transplantation with or without heart transplantation may be advised to patients unresponsive to maximum medical treatment  
• Monotherapy occasionally with ERAs, PDE-5 inhibitors or oral prostacyclin agonists (Selexipag) may be appropriate for patients with very early class I-III disease with a low-risk profile 
• ERAs (eg Ambrisentan, Bosentan, Macitentan) antagonize endothelin which mediates vasoconstriction  
• PDE-5 inhibitors (eg Sildenafil, Tadalafil) increase the production or function of nitric oxide which is a potent vasodilator  
• Prostacyclin agonists [eg Epoprostenol, Treprostinil, Iloprost (prostanoids) and Selexipag] decrease pulmonary vascular resistance 
  • IV Epoprostenol is the treatment of choice in patients with severe, therapy-resistant, SSc-related PAH
• Riociguat, a soluble guanylate cyclase stimulator, is a treatment option used to improve exercise capacity, time to clinical worsening, and hemodynamic parameters
• Flu, anti-pneumococcal and coronavirus disease 2019 (COVID-19) vaccinations are recommended
• Please see Pulmonary Arterial Hypertension disease management chart for further information

Renal

• ACE inhibitors (eg Captopril) are 1st-line antihypertensive agents used to prevent scleroderma renal crisis  
  • Immediate initiation of high-dose ACE inihibitor therapy is recommended as a key step for better clinical outcome
• CCB may be added to ACE inhibitors to achieve rapid hypertension control  
• Addition of angiotensin receptor blockers (ARBs) and alpha blockers may be considered as 3rd- and 4th-line treatments, respectively
• Scleroderma renal crisis is a medical emergency; thus, patient should be hospitalized for medical resuscitation or admitted to the intensive care unit for appropriate treatment 
• Avoid Prednisone >15 mg/day due to risk of scleroderma renal crisis

Raynaud’s Phenomenon

• For mild symptoms (<5 attacks/week), initiate treatment with a CCB, then add a PDE-5 inhibitor, then add an ARB or switch to another CCB  
• For severe symptoms (>25 attacks/week), initiate treatment with a CCB, then add a PDE-5 inhibitor or a prostanoid, then add a PDE-5 inhibitor or prostanoid (if not yet added as 2nd-line treatment), then switch to another CCB  
• CCBs (eg Amlodipine, Diltiazem, Felodipine, Isradipine, Nicardipine, Nifedipine, Nimodipine) are standard drugs to open blood vessels and improve circulation
  • Also used for preventing ulcer recurrence
• PDE-5 inhibitors (eg Sildenafil, Tadalafil, Vardenafil) improve peripheral and pulmonary circulation and heal digital ulcers; recommended for patients with severe disease and/or those unresponsive, intolerant or resistant to CCB therapy 
• Prostacyclin agonists [eg Epoprostenol, Iloprost, Treprostinil (prostanoids)] dilate the blood vessels and have anti-clotting properties  
  • IV Iloprost is recommended for patients with recurrence despite oral therapy with CCBs and PDE-5 inhibitors and for patients with severe Raynaud’s phenomenon with progressive trophic disorders 
• ERA Bosentan reduces incidence of digital ulceration and ischemia  
• ARBs (eg Losartan) may be used in patients who are intolerant of CCBs or have other indications (eg heart failure, hypertension, proteinuric chronic kidney disease) that may benefit from its use
• ACE inhibitors (eg Captopril, Enalapril) may be used in patients who are intolerant of CCBs or those with associated PAH 
• Selective serotonin reuptake inhibitor Fluoxetine may be used as an alternative in patients who are intolerant of or have failed vasodilator therapy
• Other treatment options include Aspirin, statins, Fluoxetine, Pentoxifylline, topical nitrates, Prazosin, Moxisylyte hydrochloride, botulinum toxin infiltrations  

Phototherapy

• First line of therapy for localized scleroderma and relieving skin thickening
• Whole-body phototherapy may be given to generalized, dermal, active morphea
• Ultraviolet (UV) light therapy
  
  • UVA1 is most preferred but if not available may use broadband UVA, narrowband UVB or psoralen plus UVA (PUVA)
  • Studies show that it helps in the fibroblast production of enzymes that promotes collagen breakdown as well as UV-induced immunomodulation
• Likely to be ineffective for morphea which involves the subcutaneous tissue, muscle or bone  

• An option for patients who do not respond to medical therapy
• Considered for pain reduction, severe fixed deformities, ulceration and calcinosis
• If there is severe digital gangrene and debridement and removal of the nails did not cause relief, amputation of the affected limb may be done

Debridement

• Surgical debridement and split-thickness skin grafts or full-thickness skin graft may be considered for persistent digital ulcers 
• Mechanical debridement may be performed for a fibrinous or necrotic base or a hyperkeratosis covering a digital ulcer

Lumbar Sympathectomy

• Provides long-term beneficial effect to severe vasoconstriction of the feet

Radical Microarteriolysis (Digital Sympathectomy)

• May be considered in severe and/or refractory disease; to be performed with or without Botulinum toxin injection 
• Relieves severe pain, heals digital ulcers and often reduces the severity of the attacks of Raynaud's phenomenon
• Complication and recurrence rates are relatively high

Organ Transplant

• Renal and lung transplantation is done in severe cases of renal crisis or pulmonary fibrosis, respectively
• Autologous HSCT should be considered in patients with poor-prognosis diffuse SSc without severe internal organ manifestations and those with rapidly progressive SSc at risk of organ failure 
  • Some studies have shown that non-myeloablative stem cell transplantation is beneficial for patients with SSc when compared to treatment with Cyclophosphamide