Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

scleroderma renal crisis

1st line – ACE inhibitors

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ACUTE
|
scleroderma renal crisis
1st line – 

ACE inhibitors

Severe and life-threatening renal disease develops in 10% to 15% of scleroderma patients.

Scleroderma renal crisis is characterized by: onset of acute renal failure; abrupt onset of moderate or marked hypertension; urinary sediment that is normal or reveals only mild proteinuria with few cells or casts; and microangiopathic hemolytic anemia.

High-dose corticosteroids are associated with an increased risk of renal crisis.[52][53]

Patients are treated with ACE inhibitors titrated to maximum allowable and tolerated dose. Aggressive dose escalation may be required. Consult a specialist for further guidance on dose escalation.

Normotensive renal crisis may occur in a small minority of patients and tends to be less amenable to successful intervention.[52][54]​​[55]

Primary options

captopril: 12.5 to 25 mg orally two to three times daily initially, increase according to response

OR

enalapril: 2.5 to 5 mg orally once daily initially, increase according to response

OR

enalaprilat: 0.625 to 1.25 mg intravenously every 6 hours initially, increase according to response

OR

lisinopril: 5-10 mg orally once daily initially, increase according to response

Plus – additional antihypertensive therapy

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ACUTE
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scleroderma renal crisis
Plus – 

additional antihypertensive therapy

Treatment recommended for ALL patients in selected patient group

The goal is to establish absolutely normal BP, to optimize chances for renal recovery.

ACE inhibitors are most effective in BP lowering but other antihypertensive agents can be added after maximum ACE inhibition is given.

There are many possible agents that may be used. Calcium-channel blockers are appropriate; generally, an angiotensin receptor blocker should be avoided along with maximum dose of ACE inhibitor, to avoid hyperkalemia; nonselective beta-blockers should also be avoided as they can worsen Raynaud phenomenon.

Normotensive renal crisis may occur in a small minority of patients and tends to be less amenable to successful intervention.[52][54]​​[55]

2nd line – renal dialysis or transplant

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ACUTE
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scleroderma renal crisis
2nd line – 

renal dialysis or transplant

Dialysis may only be needed on a temporary basis.

Renal function can recover to nondialysis-requiring levels if BP is well controlled.

Renal transplantation is generally well-tolerated, with scleroderma renal crisis rarely recurring after transplant.

Normotensive renal crisis may occur in a small minority of patients and tends to be less amenable to successful intervention.[52][54]​​[55]

cardiac tamponade

1st line – pericardial window + oral prednisone

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ACUTE
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cardiac tamponade
1st line – 

pericardial window + oral prednisone

Development of tamponade requires an acute pericardial window along with prednisone.

There is a risk of scleroderma renal crisis with this dose of prednisone, so BP should be monitored closely.

ACE inhibitors can be started prophylactically if BP will tolerate it, although there are little data to support this.

Primary options

prednisone: 10 mg orally once daily, increase dose if no response but use for shortest duration possible

Consider – ACE inhibitor prophylaxis

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ACUTE
|
cardiac tamponade
Consider – 

ACE inhibitor prophylaxis

Treatment recommended for SOME patients in selected patient group

ACE inhibitors can be started prophylactically (to reduce the risk of scleroderma renal crisis associated with high doses of corticosteroids) if BP will tolerate it, although there are little data to support this.

Primary options

captopril: 12.5 to 25 mg orally two to three times daily initially, increase according to response

OR

enalapril: 2.5 to 5 mg orally once daily initially, increase according to response

OR

enalaprilat: 0.625 to 1.25 mg intravenously every 6 hours initially, increase according to response

OR

lisinopril: 5 to 10 mg orally once daily initially, increase according to response

ONGOING

Raynaud phenomenon: no ulcers

1st line – lifestyle measures

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ONGOING
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Raynaud phenomenon: no ulcers
1st line – 

lifestyle measures

First-line treatment includes conservative measures such as avoiding cold exposure. Other simple methods include relaxation therapy, hand exercises, biofeedback, and smoking cessation, but the evidence for these measures is lacking.[62]

Consider – calcium-channel blocker

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ONGOING
|
Raynaud phenomenon: no ulcers
Consider – 

calcium-channel blocker

Treatment recommended for SOME patients in selected patient group

Dihydropyridine calcium-channel blockers (e.g., amlodipine, nifedipine) may be used if conservative measures are failing. Dihydropyridine calcium-channel blockers have been found to be an effective treatment in these patients.[24]

Care must be taken with titration, as BP may drop too low.

Starting the medication before sleeping may minimize adverse effects. It is best to start with minimal doses to avoid hypotension.

Primary options

amlodipine: 2.5 to 5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day

OR

nifedipine: 30 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 90 mg/day

Consider – aspirin or pentoxifylline

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ONGOING
|
Raynaud phenomenon: no ulcers
Consider – 

aspirin or pentoxifylline

Treatment recommended for SOME patients in selected patient group

Aspirin (an antiplatelet agent) or pentoxifylline (a blood viscosity-reducing agent) may be used alone, or added to existing calcium-channel blocker therapy.

Primary options

aspirin: 81 mg orally once daily

OR

pentoxifylline: 400 mg orally twice to three times daily

Plus – topical nitrate

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ONGOING
|
Raynaud phenomenon: no ulcers
|
inadequate response to initial treatment, no ulcers
Plus – 

topical nitrate

Treatment recommended for ALL patients in selected patient group

Used in addition to first-line agents when response is inadequate.

The combination of agents may result in unacceptable adverse effects (particularly hypotension), necessitating discontinuation of one of the existing therapies.

Primary options

nitroglycerin transdermal: 0.1 mg/hour patch for 12 hours followed by 12-hour break initially, increase dose according to response, maximum 0.8 mg/hour

Raynaud phenomenon: with digital ulcer development

1st line – phosphodiesterase-5 inhibitor or endothelin-1 receptor inhibitor + lifestyle changes

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ONGOING
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Raynaud phenomenon: with digital ulcer development
1st line – 

phosphodiesterase-5 inhibitor or endothelin-1 receptor inhibitor + lifestyle changes

May be used to treat severe Raynaud phenomenon with digital ulceration.

May be added onto existing therapy, but care is needed to avoid hypotension. Existing therapy may need to be discontinued.

Can only be given for short-term treatment. Assessment for pulmonary hypertension should be performed before initiation. Treatment would need to be continued indefinitely if there is pulmonary hypertension.

Generally, only a prostacyclin agonist, sildenafil, tadalafil, or an endothelial-1 receptor inhibitor would be used at any one time.

PDE-5 inhibitors appear to have moderate, but significant, efficacy in secondary Raynaud phenomenon.​[25][26]​​ Sildenafil may be helpful to decrease the development of new ulcers.[27] There is some evidence to support the use of bosentan (an endothelin-1 receptor antagonist), particularly in people with multiple or recurrent ulcers.[28]

Liver function tests must be monitored throughout treatment with endothelin-1 receptor antagonist therapy (bosentan and ambrisentan).

Conservative measures, such as avoiding cold exposure, are standard for all patients with Raynaud, but the evidence for these measures is lacking.[62]

Primary options

sildenafil: 20-80 mg orally three times daily

OR

tadalafil: 40 mg orally once daily

OR

bosentan: weight <40 kg: 62.5 mg orally twice daily; weight >40 kg: 62.5 mg orally twice daily initially for 4 weeks, followed by 125 mg orally twice daily

OR

ambrisentan: 5 mg orally once daily initially, followed by 10 mg once daily

Consider – calcium-channel blocker as tolerated

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ONGOING
|
Raynaud phenomenon: with digital ulcer development
Consider – 

calcium-channel blocker as tolerated

Treatment recommended for SOME patients in selected patient group

Dihydropyridine calcium-channel blockers (e.g., amlodipine, nifedipine) may be an existing therapy in people presenting acutely with severe Raynaud phenomenon and ulceration.

Existing therapy may be continued but only if tolerated.

Care is needed to observe systemic BP to avoid hypotension, which may occur with a combination of vasodilator therapies.

Primary options

amlodipine: 2.5 to 5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day

OR

nifedipine: 30 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 90 mg/day

Consider – aspirin or pentoxifylline

Back
ONGOING
|
Raynaud phenomenon: with digital ulcer development
Consider – 

aspirin or pentoxifylline

Treatment recommended for SOME patients in selected patient group

Aspirin (an antiplatelet agent) or pentoxifylline (a blood viscosity-reducing agent) may be an existing therapy in people presenting acutely with severe Raynaud phenomenon and ulceration.

Existing therapy may be continued, but only if tolerated.

Care is required to observe for adverse effects.

Primary options

aspirin: 81 mg orally once daily

OR

pentoxifylline: 400 mg orally twice to three times daily

Consider – topical nitrate as tolerated

Back
ONGOING
|
Raynaud phenomenon: with digital ulcer development
Consider – 

topical nitrate as tolerated

Treatment recommended for SOME patients in selected patient group

Topical nitrates may be an existing therapy in people presenting acutely with severe Raynaud phenomenon and ulceration.

It may be continued. However, the combination of agents may result in unacceptable adverse effects, particularly related to hypotension. This may necessitate its discontinuation.

Primary options

nitroglycerin transdermal: 0.1 mg/hour patch for 12 hours followed by 12-hour break initially, increase dose according to response, maximum 0.8 mg/hour

Plus – wound care and analgesia

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ONGOING
|
Raynaud phenomenon: with digital ulcer development
Plus – 

wound care and analgesia

Treatment recommended for ALL patients in selected patient group

Supportive measures include wound care, pain management, and treatment of any secondary wound infection.[30]

Primary options

acetaminophen: 325 to 100 mg orally every 4 to 6 hours when required, maximum 4000 mg/day

Secondary options

tramadol: 50 mg orally (immediate-release) every 6 hours when required, maximum 400 mg/day

2nd line – prostacyclin agonist + lifestyle changes

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ONGOING
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Raynaud phenomenon: with digital ulcer development
2nd line – 

prostacyclin agonist + lifestyle changes

Intravenous prostacyclin agonists such as iloprost,[29] epoprostenol, or treprostinil may be used to treat severe Raynaud phenomenon with digital ulceration. However, intravenous iloprost is not available in the US.

May be added onto existing therapy, but care is needed to observe BP to avoid hypotension.

Admission is required for continuous intravenous infusion.[29].

Epoprostenol (intravenous infusion) may be used if other agents are ineffective. Common rate-limiting adverse effects are headache and nausea. Close monitoring of the blood pressure and heart rate is necessary during titration of infusion.

Intravenous therapy (e.g., epoprostenol) should not be given as a short-term infusion in those with pulmonary hypertension.

Conservative measures, such as avoiding cold exposure, are standard for all patients with Raynaud, but the evidence for these measures is lacking.[62]

Primary options

epoprostenol: consult specialist for guidance on dose

Consider – calcium-channel blocker as tolerated

Back
ONGOING
|
Raynaud phenomenon: with digital ulcer development
Consider – 

calcium-channel blocker as tolerated

Treatment recommended for SOME patients in selected patient group

Dihydropyridine calcium-channel blockers (e.g., amlodipine, nifedipine) may be an existing therapy in people presenting acutely with severe Raynaud phenomenon and ulceration.

Existing therapy may be continued but only if tolerated.

Care is needed to observe systemic BP to avoid hypotension, which may occur with a combination of vasodilator therapies.

Primary options

amlodipine: 2.5 to 5 mg orally once daily initially, increase gradually according to response, maximum 10 mg/day

OR

nifedipine: 30 mg orally (extended-release) once daily initially, increase gradually according to response, maximum 90 mg/day

Consider – aspirin or pentoxifylline

Back
ONGOING
|
Raynaud phenomenon: with digital ulcer development
Consider – 

aspirin or pentoxifylline

Treatment recommended for SOME patients in selected patient group

Aspirin (an antiplatelet agent) or pentoxifylline (a blood viscosity-reducing agent) may be an existing therapy in people presenting acutely with severe Raynaud phenomenon and ulceration.

Existing therapy may be continued, but only if tolerated.

Care is required to observe for adverse effects.

Primary options

aspirin: 81 mg orally once daily

OR

pentoxifylline: 400 mg orally twice to three times daily

Consider – topical nitrate as tolerated

Back
ONGOING
|
Raynaud phenomenon: with digital ulcer development
Consider – 

topical nitrate as tolerated

Treatment recommended for SOME patients in selected patient group

Topical nitrates may be an existing therapy in people presenting acutely with severe Raynaud phenomenon and ulceration.

It may be continued. However, the combination of agents may result in unacceptable adverse effects, particularly related to hypotension. This may necessitate its discontinuation.

Primary options

nitroglycerin transdermal: 0.1 mg/hour patch for 12 hours followed by 12-hour break initially, increase dose according to response, maximum 0.8 mg/hour

Plus – wound care and analgesia

Back
ONGOING
|
Raynaud phenomenon: with digital ulcer development
Plus – 

wound care and analgesia

Treatment recommended for ALL patients in selected patient group

Supportive measures include wound care, pain management, and treatment of any secondary wound infection.[30]

Primary options

acetaminophen: 325 to 100 mg orally every 4 to 6 hours when required, maximum 4000 mg/day

Secondary options

tramadol: 50 mg orally (immediate-release) every 6 hours when required, maximum 400 mg/day

3rd line – digital sympathectomy + wound care and analgesia

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ONGOING
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Raynaud phenomenon: with digital ulcer development
3rd line – 

digital sympathectomy + wound care and analgesia

For refractory ulcers not amenable to other modalities.

Digital sympathectomy is difficult in this patient population and should be done only by surgeons experienced with scleroderma.

Limited data to support efficacy.

Supportive measures include wound care, pain management, and treatment of any secondary wound infection.[30]

Primary options

acetaminophen: 325 to 100 mg orally every 4 to 6 hours when required, maximum 4000 mg/day

Secondary options

tramadol: 50 mg orally (immediate-release) every 6 hours when required, maximum 400 mg/day

generalized skin involvement

1st line – topical emollient

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ONGOING
|
generalized skin involvement
1st line – 

topical emollient

Used to treat skin dryness but should be used very frequently and only has a limited effect.

Plus – low-dose oral corticosteroid or topical corticosteroid

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ONGOING
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generalized skin involvement
|
with pruritus
Plus – 

low-dose oral corticosteroid or topical corticosteroid

Treatment recommended for ALL patients in selected patient group

Treatments that can be beneficial include low-dose prednisone or a topical corticosteroid cream (effect lasts a few hours, so should be used before sleeping). Doses of 15 mg or higher of prednisone should be avoided, due to increased risk of renal crisis.[52][53] Even lower doses of prednisone should be used with caution as these may contribute to an increased risk of renal crisis.

There are numerous options of topical corticosteroids. Initially an over-the-counter hydrocortisone cream (0.5%) can be initiated once or twice daily. If that is not effective, then a lower to mid-strength preparation such as fluocinolone acetonide 0.025%, fluticasone propionate 0.05%, hydrocortisone valerate 0.2%, prednicarbate 0.1%, alclometasone dipropionate 0.05%, desonide 0.05%, fluocinolone acetonide 0.01% can be used once or twice daily.

Skin areas with breakdown can become secondarily infected.

Pruritus usually improves. It is worst in early diffuse disease.

Primary options

prednisone: 5 to 10 mg orally once daily

OR

hydrocortisone topical: (0.5%) apply to affected areas once or twice daily

Secondary options

fluocinolone topical: (0.025 to 0.01%) apply to affected areas once or twice daily

OR

fluticasone propionate topical: (0.05%) apply to affected areas once or twice daily

OR

hydrocortisone valerate topical: (0.2%) apply to affected areas once or twice daily

OR

prednicarbate topical: (0.1%) apply to affected areas once or twice daily

OR

alclometasone topical: (0.05%) apply to affected areas once or twice daily

OR

desonide topical: (0.05%) apply to affected areas once or twice daily

Consider – oral antihistamine

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ONGOING
|
generalized skin involvement
|
with pruritus
Consider – 

oral antihistamine

Treatment recommended for SOME patients in selected patient group

Oral antihistamines are usually of limited benefit. An antihistamine can be used for pruritus but may cause drowsiness. There is no medical reason to choose one over the other, except that diphenhydramine is the most sedating. The combination of these products with pseudoephedrine should be avoided because of the vasoconstrictive nature of pseudoephedrine which can worsen Raynaud’s phenomenon. Also, caution should be avoided if there is renal compromise.

Primary options

cetirizine: 5-10 mg orally once daily

OR

desloratadine: 5 mg orally once daily

OR

diphenhydramine: 25-50 mg orally once or twice daily

OR

fexofenadine: 60 mg orally once or twice daily

OR

levocetirizine: 2.5-5 mg orally once daily

OR

loratadine: 10 mg orally once daily

Consider – cyclophosphamide

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ONGOING
|
generalized skin involvement
|
with thickening
Consider – 

cyclophosphamide

Treatment recommended for SOME patients in selected patient group

Cyclophosphamide has been found to be beneficial, but it is used hesitantly because of its adverse effects.[31][32]

Referral should be made to a scleroderma specialist.

Primary options

cyclophosphamide: consult specialist for guidance on dose

Consider – methotrexate

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ONGOING
|
generalized skin involvement
|
with thickening
Consider – 

methotrexate

Treatment recommended for SOME patients in selected patient group

In a re-analysis of a clinical trial of methotrexate versus placebo, the use of methotrexate was associated with improvement in skin scores and physician global assessment.[33]

Referral should be made to a scleroderma specialist.

Primary options

methotrexate: consult specialist for guidance on dose

Consider – high-dose chemotherapy followed by autologous stem cell transplant

Back
ONGOING
|
generalized skin involvement
|
with thickening
Consider – 

high-dose chemotherapy followed by autologous stem cell transplant

Treatment recommended for SOME patients in selected patient group

For individuals with severe skin involvement and internal organ disease, particularly interstitial lung disease (ILD), high-dose chemotherapy followed by autologous stem cell transplant has been demonstrated to improve long-term event-free survival. However, this therapeutic approach is associated with a higher treatment-related mortality than intravenous cyclophosphamide alone in the first year following treatment.[34]

Referral should be made to a scleroderma specialist.

GI involvement

1st line – lifestyle advice plus proton-pump inhibitor

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ONGOING
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GI involvement
|
with GERD
1st line – 

lifestyle advice plus proton-pump inhibitor

Mild symptoms include reflux due to esophageal dysmotility.

Lifestyle advice includes: not eating 2 to 3 hours before bedtime; avoiding caffeine and carbonated beverages; and elevating the head of the bed.

Advice is given in addition to proton-pump inhibitors.

Treatment is usually lifelong.

Primary options

esomeprazole: 40 mg orally once or twice daily

OR

omeprazole: 20 mg orally once or twice daily

OR

lansoprazole: 30 mg orally once or twice daily

OR

rabeprazole: 20 mg orally once or twice daily

OR

pantoprazole: 40 mg orally once or twice daily

OR

dexlansoprazole: 30 mg orally once daily

1st line – prokinetic agent

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ONGOING
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GI involvement
|
with gastroparesis and/or bowel dysmotility
1st line – 

prokinetic agent

If nausea, postprandial bloating, and early satiety are present, gastroparesis and/or bowel dysmotility are likely. This can be evaluated with a barium swallow study.

Promotility agents such as low-dose erythromycin or azithromycin may be helpful.[35]

Octreotide is used in severe cases unresponsive to other promotility agents. Possible disadvantages include inhibitory effects on gastric emptying, pancreatic secretion, and gallbladder contractility.

Metoclopramide may be given intravenously for severe symptoms; however, it should be used with extreme caution due to the risk of tardive dyskinesia. Its use should be limited to as brief a period of time as necessary (usually a maximum of 5 days).

Primary options

erythromycin base: 100-150 mg orally four times daily

OR

azithromycin: 400 mg orally once daily

Secondary options

metoclopramide: 5-10 mg intravenously/orally three times daily

OR

octreotide: 50 micrograms subcutaneously at bedtime

Consider – antibiotics

Back
ONGOING
|
GI involvement
|
with gastroparesis and/or bowel dysmotility
Consider – 

antibiotics

Treatment recommended for SOME patients in selected patient group

In patients with bowel dysmotility, complications of unintentional weight loss with diarrhea are a sign of bacterial overgrowth and malabsorption, and should be treated with antibiotics. Options include cephalexin plus metronidazole, tetracyclines, amoxicillin/clavulanate, rifaximin, nitazoxanide, chloramphenicol, or ciprofloxacin.[35]

Systemic fluoroquinolone antibiotics may cause serious, disabling, and potentially long-lasting or irreversible adverse events. This includes, but is not limited to: tendinopathy/tendon rupture; peripheral neuropathy; arthropathy/arthralgia; aortic aneurysm and dissection; heart valve regurgitation; dysglycemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behavior.[36] Prescribing restrictions apply to the use of fluoroquinolones, and these restrictions may vary between countries. In general, fluoroquinolones should be restricted for use in serious, life-threatening bacterial infections only. Some regulatory agencies may also recommend that they must only be used in situations where other antibiotics, that are commonly recommended for the infection, are inappropriate (e.g., resistance, contraindications, treatment failure, unavailability). Consult your local guidelines and drug formulary for more information on suitability, contraindications, and precautions. 

Treatment duration is for 7 to 21 days.

Primary options

cephalexin: 250 mg orally four times daily

and

metronidazole: 250 mg orally three times daily

OR

minocycline: 100 mg orally twice daily

OR

amoxicillin/clavulanate: 875 mg orally twice daily

OR

tetracycline: 250 mg orally four times daily

OR

doxycycline: 50-100 mg orally twice daily

OR

chloramphenicol: 250 mg orally four times daily

OR

rifaximin: 400 mg orally three times daily

OR

nitazoxanide: 500 mg orally twice daily

Secondary options

ciprofloxacin: 500 mg orally twice daily

1st line – endoscopic coagulation + blood transfusion

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ONGOING
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GI involvement
|
with gastric antral vascular ectasia
1st line – 

endoscopic coagulation + blood transfusion

Also known as watermelon stomach.

Episodic transfusions are required in some chronic cases, but acute or massive bleeding is rare.

Endoscopic coagulation with heater probe, gold probe, argon plasma coagulator, or laser therapy obliterates the vascular ectasia and can decrease the degree of bleeding.

myopathy

1st line – observation

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ONGOING
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myopathy
|
without weakness
1st line – 

observation

Elevated muscle enzymes without progressive muscle weakness is relatively common and is referred to as scleroderma myopathy.

This is best observed, as no specific treatment is required.

1st line – oral corticosteroid + close BP monitoring

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ONGOING
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myopathy
|
with associated weakness
1st line – 

oral corticosteroid + close BP monitoring

Inflammatory myositis may be seen in a subset of patients with scleroderma, and is differentiated from scleroderma myopathy based on the presence of weakness (usually in the proximal muscles) and EMG/nerve conduction study and muscle biopsy findings.

Patients with inflammatory myositis may have anti-PM/Scl and anti-Sm/RNP antibodies.

Referral should be made to a scleroderma specialist.

Treatment includes corticosteroid therapy, with careful monitoring of the BP because of the risk of scleroderma renal crisis with corticosteroids.[52][53]

Primary options

prednisone: 20 to 60 mg orally once daily, taper dose gradually as condition permits

Consider – corticosteroid-sparing agent

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ONGOING
|
myopathy
|
with associated weakness
Consider – 

corticosteroid-sparing agent

Treatment recommended for SOME patients in selected patient group

Methotrexate may be considered as a corticosteroid-sparing agent to minimize corticosteroid dose and permit early tapering. It should not be used in patients with renal failure.

Methotrexate can be problematic in those with ILD and should be used with caution.

Although pulmonary complications of methotrexate are uncommon, it could cause diagnostic confusion in this setting. Folic acid should be given daily to prevent adverse effects in people taking methotrexate.

Azathioprine, mycophenolate, and leflunomide, other disease-modifying drugs, are alternatives in patients with pulmonary disease.

Intravenous immune globulin can also be used in methotrexate-resistant cases.

Primary options

methotrexate: see local specialist protocol for dosing guidelines

and

folic acid (vitamin B9): see local specialist protocol for dosing guidelines

OR

azathioprine: see local specialist protocol for dosing guidelines

OR

mycophenolate mofetil: see local specialist protocol for dosing guidelines

OR

leflunomide: see local specialist protocol for dosing guidelines

Secondary options

immune globulin (human): see local specialist protocol for dosing guidelines

synovitis, tendon friction rub, or inflammatory arthritis

1st line – low-dose oral corticosteroid

Back
ONGOING
|
synovitis, tendon friction rub, or inflammatory arthritis
1st line – 

low-dose oral corticosteroid

The presence of tendon friction rubs is a poor prognostic sign. These patients should be evaluated early for immunomodulatory agents.

An inflammatory arthritis is seen in some patients.

Synovitis can be difficult to identify as independent from the diffuse hand swelling and overlying thickened skin.

Joint tenderness on compression or squeezing should be present.

Primary options

prednisone: 5 mg orally once daily

Consider – methotrexate or leflunomide

Back
ONGOING
|
synovitis, tendon friction rub, or inflammatory arthritis
Consider – 

methotrexate or leflunomide

Treatment recommended for SOME patients in selected patient group

Methotrexate may be considered as a corticosteroid-sparing agent to minimize corticosteroid dose and permit early tapering. It should not be used in patients with renal failure.

Methotrexate can be problematic in those with ILD and should be used with caution in this patient population.

Although pulmonary complications of methotrexate are uncommon, it could cause diagnostic confusion in this setting. Folic acid should be given daily to prevent adverse effects in people taking methotrexate.

Leflunomide, another disease-modifying drug, is an alternative in patients with pulmonary disease.

Primary options

methotrexate: see local specialist protocol for dosing guidelines

and

folic acid (vitamin B9): see local specialist protocol for dosing guidelines

OR

leflunomide: see local specialist protocol for dosing guidelines

interstitial lung disease

1st line – observation ± immunomodulator therapy

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ONGOING
|
interstitial lung disease
1st line – 

observation ± immunomodulator therapy

Yearly pulmonary function tests (spirometry, lung volumes and diffusion capacity measurement) should be done with no treatment necessary, if the results are stable.

Any patient with evidence of lung disease should be referred to a specialist to evaluate for progressive lung disease. Not all scleroderma patients with early restrictive lung disease will progress. No treatment is necessary with stable pulmonary function results. An initial high-resolution computed tomography (CT) scan of the chest should be done to establish the diagnosis of ILD and may be repeated for declining lung volumes or functional status.[16]

If active ILD develops (as indicated on high-resolution CT), immunomodulator therapy should be started.

First-line preferred options include mycophenolate, tocilizumab, and rituximab. Additional treatment options for first-line treatment include cyclophosphamide, nintedanib, and azathioprine.[37][38]

For patients who experience disease progression despite initial treatment, adding a treatment or switching treatment should be considered.[37]​ Therapies are listed in order of recommendation, but treatment decisions should be based on specific clinical considerations.[37]​ Whether to switch treatment or add to initial therapy depends on initial therapy used, and on which therapy is being considered for addition.[37]​ Cyclophosphamide is not typically used in combination with other therapies, while others may be used individually or in combination.

Second-line therapies may include mycophenolate, rituximab, nintedanib, tocilizumab, or cyclophosphamide.[37]​ The decision on the use of nintedanib instead of immunosuppression in the second-line setting depends on the pace of progression and amount of fibrotic disease or the presence of a usual interstitial pneumonia pattern on chest CT.[37]

Treatment with immunosuppression must be weighed against the significant risks with therapy: most notably, increased risk of infections. This is best assessed by a specialist. If cyclophosphamide is used, bronchoscopy may be necessary prior to initiation of therapy, to rule out infection. Also, white blood cell count (WBC) should be monitored two weeks post infusion of cyclophosphamide and urine analysis should be monitored for the development of hematuria.[39]

Mycophenolate is recommended over all other treatments for patients with systemic sclerosis with ILD as it has the strongest evidence of benefit for this indication.[37][38]​​[39][40]​​​​​​​ Although gastrointestinal adverse effects are common, it may be better tolerated than cyclophosphamide.​[41][42]

In a phase 3 randomized double-blind trial, tocilizumab appeared to preserve lung function in patients with early SSc-related ILD and elevated acute-phase reactants.[43]​ This was, however, a secondary endpoint; the primary skin fibrosis endpoint was not met. Tocilizumab is associated with an increased risk of developing serious infections (especially in patients taking concomitant immunosuppressants). Check absolute neutrophil count, platelet count, and liver function tests before starting treatment.

In one observational study, patients with SSc-related ILD who received rituximab showed improved forced vital capacity (FVC) at 2 and 7 years treatment compared to baseline and the standard treatment control group.[44]​ Rituximab has been associated with serious and sometimes fatal infusion reactions, severe mucocutaneous reactions, hepatitis B virus reactivation, and cases of progressive multifocal leukoencephalopathy.

Cyclophosphamide has been found to be beneficial but is associated with significant adverse effects.[32][45]​ Decisions concerning the initiation of cyclophosphamide should be made by a scleroderma specialist. Bronchoscopy may be necessary prior to initiation of therapy to rule out infection. WBC count should be monitored two weeks post infusion of cyclophosphamide; urine analysis should be monitored for the development of hematuria.

Nintedanib has been demonstrated to reduce functional decline and disease progression in idiopathic pulmonary fibrosis, and effectiveness in SSc-related ILD has been reported.[46][47]​ In a phase 3 randomized trial of 576 patients with systemic sclerosis-associated ILD, annual decline in FVC was reduced with nintedanib compared with placebo, no significant difference in any other manifestation of SSc was found.[47]​ Post hoc analyses indicated that fewer patients randomized to nintedanib had a decrease in FVC ≥3.3% predicted compared with placebo (proposed minimally clinically important difference for worsening FVC; 34.5% vs. 43.8%); more patients receiving nintedanib had an increase in FVC ≥3.0% predicted (23.0% vs. 14.9%).[48]

Azathioprine is not a preferred first-line option, but can be used as first-line therapy if the preferred options are not appropriate.[37]

Primary options

mycophenolate mofetil: 500 mg orally twice daily initially, increase gradually according to response, maximum 3000 mg/day

OR

tocilizumab: 162 mg subcutaneously once weekly

OR

cyclophosphamide: 1-2 mg/kg/day orally, maximum 200 mg/day; 600 mg/square meter of body surface area intravenously once every 4 weeks

OR

nintedanib: 150 mg orally twice daily

OR

rituximab: consult specialist for guidance on dose

OR

azathioprine: consult specialist for guidance on dose

Consider – continuous oxygen therapy

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interstitial lung disease
Consider – 

continuous oxygen therapy

Treatment recommended for SOME patients in selected patient group

In the US, assessment for continuous oxygen therapy should be done according to the Health Care Financing Administration recommendations, based on oxygen saturation at rest and with activity.[63]

Consider – referral for autologous hematopoietic stem cell transplant and/or lung transplantation

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interstitial lung disease
Consider – 

referral for autologous hematopoietic stem cell transplant and/or lung transplantation

Treatment recommended for SOME patients in selected patient group

Referral for autologous hematopoietic stem cell transplant and/or lung transplantation should be made for lung involvement not amenable to treatment.[37]

Survival rates are similar to those with idiopathic pulmonary fibrosis and pulmonary hypertension: 5-year survival 50% to 60%.[49][50]

pericardial effusion

1st line – observation

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pericardial effusion
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not causing marked symptoms
1st line – 

observation

Should be monitored for symptoms, which are based on the rate of accumulation of effusion.

1st line – oral prednisone + close BP monitoring

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pericardial effusion
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causing marked symptoms
1st line – 

oral prednisone + close BP monitoring

Moderate pericardial effusion causing marked symptoms and signs (e.g., dyspnea and pulsus paradoxus) is a poor prognostic sign as it can progresses to tamponade.

Treatment is with prednisone, although there is a risk of renal crisis so BP requires close monitoring.

If there is no response to 10 mg prednisone, higher doses may be used for the shortest duration possible, with careful monitoring of BP for scleroderma renal crisis.

Primary options

prednisone: 10 mg orally once daily, increase dose if no response but use for shortest duration possible

pulmonary arterial hypertension

1st line – endothelin receptor antagonist or phosphodiesterase-5 inhibitor or prostacyclin analog or riociguat

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pulmonary arterial hypertension
1st line – 

endothelin receptor antagonist or phosphodiesterase-5 inhibitor or prostacyclin analog or riociguat

Early identification of pulmonary hypertension is crucial, with periodic echocardiograms for screening​ and right heart catheterization to confirm the diagnosis. Multiple therapies are currently available including endothelin receptor antagonists (bosentan, ambrisentan, macitentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil), and prostacyclin analogs (iloprost, treprostinil, epoprostenol).[56][57][58][59][60]

Sildenafil or tadalafil treatment would need to be continued indefinitely if there is pulmonary hypertension.

Generally, only a prostacyclin agonist, a phosphodiesterase inhibitor, or an endothelial-1 receptor inhibitor would be used at any one time. However, combination therapy may be used if there is deterioration on monotherapy.[64] Consult specialist for guidance on drug combinations and doses.

In use of prostacyclin analogs care is needed to observe BP to avoid hypotension.

Admission is required for intravenous infusion.[29]

Epoprostenol (intravenous infusion) may be appropriate when admission is needed. Common rate-limiting adverse effects are headache and nausea. Continuous telemetry monitoring is necessary during titration of infusion.

Treprostinil (subcutaneous infusion) necessitates admission. It is essential to have immediate access to back-up pump, infusion sets, and medicine to prevent treatment interruptions, which can be fatal.

Continuous therapy (e.g., epoprostenol and treprostinil) should not be given as a short-term infusion in those with pulmonary hypertension.

Riociguat is an oral medication for the treatment of pulmonary arterial hypertension and for chronic thromboembolic pulmonary hypertension. It is a stimulator of soluble guanylate cyclase, which results in vasodilation.

Some medications for pulmonary arterial hypertension have been demonstrated to improve 6-minute walk time and/or time to clinical worsening.[61]

Primary options

sildenafil: 20-80 mg orally three times daily

OR

tadalafil: 40 mg orally once daily

OR

vardenafil: 10-15 mg orally once daily

OR

bosentan: weight <40 kg: 62.5 mg orally twice daily; weight >40 kg: 62.5 mg orally twice daily initially for 4 weeks, followed by 125 mg orally twice daily

OR

ambrisentan: 5 mg orally once daily initially, followed by 10 mg once daily

OR

macitentan: 10 mg orally once daily

OR

iloprost inhaled: consult specialist for guidance on dose

OR

epoprostenol: consult specialist for guidance on dose

OR

treprostinil: consult specialist for guidance on dose

OR

riociguat: consult specialist for guidance on dose

Consider – supplemental oxygen

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pulmonary arterial hypertension
Consider – 

supplemental oxygen

Treatment recommended for SOME patients in selected patient group

Nocturnal oxygen therapy may be required, with supplemental oxygen given during the day if desaturation is demonstrated with activity.

Consider – referral for lung transplant

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pulmonary arterial hypertension
Consider – 

referral for lung transplant

Treatment recommended for SOME patients in selected patient group

Patients who are unresponsive to medical treatment (including combination therapy) should be referred for a double lung transplant.[49]

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