scleroderma
SCLERODERMA
Scleroderma is a connective tissue disorder characterized by skin thickening and fibrosis. It is rare, autoimmune and chronic.
It has an idiopathic cause and not contagious.
Early microvascular damage, mononuclear cell infiltrates and slowly developing fibrosis are the important features of the tissue lesions.
The leading causes of death are pulmonary fibrosis and pulmonary arterial hypertension.

Scleroderma Treatment

Principles of Therapy

  • 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

Pharmacotherapy

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) 

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-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 systemic sclerosis-related skin involvement MRSS of 32, therapeutic agents in preferred order include Mycophenolate mofetil, Methotrexate, IV Cyclophosphamide and hematopoietic stem cell transplantation  
  • Other promising therapies include the following:
    • Morphea: Penicillamine, Penicillin, Bosentan, Colchicine, Cyclosporine, Hydroxychloroquine and Infliximab 
    • Systemic sclerosis-related skin involvement: IV immune globulin (IVIG), Rituximab, Tocilizumab  
  • For active treatment of systemic sclerosis-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 may be considered as 3rd-line agents

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  
  • Standard cardiac treatment is advised for patients with diastolic dysfunction, ischemic cardiopathy or rhythm disturbances

Gastrointestinal

  • For GERD and upper GI dysmotility disorders, 1st-line treatment includes high-dose proton pump inhibitors (eg Esomeprazole, Lansoprazole, Omeprazole, Pantoprazole, Rabeprazole)  
    • Acid-reducing agents reduce the risk of having esophageal strictures
    • 2nd-line agents are prokinetics (eg Metoclopramide, Domperidone) 
    • Please see Gastroesophageal Reflux Disease disease management chart for further information
  • Small bowel disorders such as bacterial overgrowth may be treated with antibiotics and pseudo-obstruction with prokinetic agents  
  • Constipation treatment includes laxatives; 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

  • Induction therapy includes Mycophenolate mofetil, IV Cyclophosphamide, and Rituximab  
    • Select non-responding patients may undergo lung or hematopoietic stem cell transplantation or may be referred for a clinical trial  
  • Maintenance therapy includes Mycophenolate mofetil, Azathioprine and IV or oral Cyclophosphamide
  • Immunosuppressants (eg Azathioprine, Cyclophosphamide) are usually combined with glucocorticoids to prevent further lung deterioration in patients with fibrosing alveolitis
  • 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 kinase inhibitor that slows the rate of pulmonary function decline in patients with systemic sclerosis-associated interstitial lung disease

Pulmonary Arterial Hypertension (PAH)

  • For mild PAH [New York Heart Association (NYHA) functional class I-II], treatment is initiated with a PDE-5 inhibitor followed by the addition of an endothelin receptor antagonist (ERA), then addition of a prostanoid  
  • For severe 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 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 
  • 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  
  • 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

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, Nifedipine) are standard drugs to open blood vessels and improve circulation
  • PDE-5 inhibitors (eg Sildenafil, Tadalafil, Vardenafil) improve peripheral and pulmonary circulation
  • 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 
  • Prostacyclin agonists [eg Epoprostenol, Iloprost, Treprostinil (prostanoids)] dilate the blood vessels and have anti-clotting properties  
  • ERA Bosentan reduces incidence of digital ulceration and ischemia  
  • Other treatment options include Aspirin, statins, Fluoxetine, Pentoxifylline, topical nitrates, botulinum toxin infiltrations  

Non-Pharmacological Therapy

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  

Surgical Intervention

  • 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

Lumbar Sympathectomy

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

Radical Microarteriolysis (Digital Sympathectomy)

  • Relieves severe pain, heals digital ulcers and often reduces the severity of the attacks of Raynaud's phenomenon
  • Complication rates are relatively high

Organ Transplant

  • Renal and lung transplantation is done in severe cases of renal crisis or pulmonary fibrosis, respectively
  • Some studies have shown that non-myeloablative stem cell transplantation is beneficial for patients with systemic sclerosis when compared to treatment with Cyclophosphamide
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