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

ONGOING

all patients

1st line – supportive care + lifestyle changes

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ONGOING
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all patients
1st line – 

supportive care + lifestyle changes

It is essential that all patients be referred to a rheumatologist with experience in managing these conditions. Any patient with evidence of lung disease should be referred to a specialist to evaluate for progressive lung disease.

Patients should be counseled regarding lifestyle changes. These may include patient education to encourage the patient to take responsibility for his/her disease management; advice regarding how to maintain an ideal body weight for their height; reduction of salt intake in the presence of hypertension due to renal disease; and exercise guidelines to maintain optimum cardiovascular fitness.

Patients who smoke should be encouraged to stop.

Plus – nonsteroidal anti-inflammatory drug

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ONGOING
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all patients
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with arthralgias and arthritis
Plus – 

nonsteroidal anti-inflammatory drug

Treatment recommended for ALL patients in selected patient group

Typical small-joint arthralgias of mixed connective tissue disease and other overlap syndromes are managed with the use of nonsteroidal anti-inflammatory drugs at the lowest effective doses, with attention paid to monitoring for, and prevention of, cardiovascular, renal, and gastrointestinal toxicities.

Primary options

naproxen: 500 mg orally twice daily when required, maximum 1500 mg/day

OR

ibuprofen: 400-800 mg orally every 6-8 hours when required, maximum 2400 mg/day

Consider – hydroxychloroquine

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ONGOING
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all patients
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with arthralgias and arthritis
Consider – 

hydroxychloroquine

Treatment recommended for SOME patients in selected patient group

If nonsteroidal anti-inflammatory drugs are found to be inadequate or ineffective, consider adding antimalarial medications, particularly hydroxychloroquine, which has been shown to be effective in systemic lupus erythematosus and may be used in mixed connective tissue disease.[24]

Patients require regular ophthalmologic screening for retinopathy.

Primary options

hydroxychloroquine sulfate: 6.5 mg/kg/day orally given in 1-2 divided doses

Consider – oral corticosteroid

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ONGOING
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all patients
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with arthralgias and arthritis
Consider – 

oral corticosteroid

Treatment recommended for SOME patients in selected patient group

In patients who develop frank synovitis, short courses of corticosteroids are helpful.

Primary options

prednisone: 5-10 mg orally once daily

Consider – methotrexate + folic acid

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ONGOING
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all patients
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with arthralgias and arthritis
Consider – 

methotrexate + folic acid

Treatment recommended for SOME patients in selected patient group

If arthritis is resistant to corticosteroids, synovitis is not adequately controlled on low doses of corticosteroids, or patient has deforming or erosive disease, addition of methotrexate is useful.[24]

Should not be used in patients with renal failure, and should be used cautiously in those with interstitial lung disease.

Folate supplementation should be given simultaneously, and close attention paid to advice on contraception and reproductive health. Monitoring of CBC, renal function, and liver enzymes is recommended.

Primary options

methotrexate: 7.5 mg orally once weekly on the same day of each week, increase by 2.5 mg/week increments every 2 weeks according to response, maximum 25 mg/week

and

folic acid (vitamin B9): 1 mg orally once daily

Plus – avoidance of trigger factors

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ONGOING
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all patients
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with Raynaud phenomenon
Plus – 

avoidance of trigger factors

Treatment recommended for ALL patients in selected patient group

Lifestyle modifications including avoidance of cold or sudden changes in temperature should be advised.

Smoking cessation is essential.

Plus – pharmacotherapy

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ONGOING
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all patients
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with Raynaud phenomenon
Plus – 

pharmacotherapy

Treatment recommended for ALL patients in selected patient group

Treatment is important to prevent progression to digital ulceration.

First line pharmacologic interventions include calcium-channel blockers such as nifedipine. These agents are useful at decreasing the frequency and severity of attacks.[25][26] In patients with Raynaud phenomenon secondary to scleroderma, alpha-1-blocking agents (e.g., prazosin) have been found to be useful.

Second-line therapies include fluoxetine and the phosphodiesterase-5 inhibitor sildenafil, which has been shown to be effective and may be considered in patients who fail to respond to calcium-channel blockers.[29]

In more severe cases associated with systemic sclerosis, parenteral prostacyclin analogs have been tried with some success. The endothelin receptor antagonist bosentan has been shown to reduce the incidence of new ischemic ulcers.[30] These agents should only be used under the supervision of physicians familiar with their use, as side effects are common.

Primary options

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

OR

prazosin: 1 mg orally twice daily

Secondary options

fluoxetine: 20 mg orally once daily

OR

sildenafil: 50 mg orally twice daily

Tertiary options

bosentan: 62.5 mg orally twice daily for 4 weeks, followed by 125 mg orally twice daily

Plus – nonsteroidal anti-inflammatory drug

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ONGOING
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all patients
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with puffy hands
Plus – 

nonsteroidal anti-inflammatory drug

Treatment recommended for ALL patients in selected patient group

Nonsteroidal anti-inflammatory drugs may improve symptoms and should be used at the lowest effective doses, with attention paid to monitoring for, and prevention of, cardiovascular, renal and gastrointestinal toxicities.

Primary options

naproxen: 500 mg orally twice daily when required, maximum 1500 mg/day

OR

ibuprofen: 400-800 mg orally every 6-8 hours when required, maximum 2400 mg/day

Consider – oral corticosteroid

Back
ONGOING
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all patients
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with puffy hands
Consider – 

oral corticosteroid

Treatment recommended for SOME patients in selected patient group

In patients unresponsive to nonsteroidal anti-inflammatory drugs, low-dose corticosteroids may improve symptoms.

Primary options

prednisone: 5-10 mg orally once daily

Plus – oral corticosteroid

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ONGOING
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all patients
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with myositis
Plus – 

oral corticosteroid

Treatment recommended for ALL patients in selected patient group

Corticosteroid therapy is the mainstay of management of myositis in mixed connective tissue disease and those overlap syndromes in which inflammatory myopathy is a prominent component.​[24][31]

Prednisone, with slow tapering after 4-6 weeks if disease is controlled, is the drug of choice.

Primary options

prednisone: 0.5 to 1 mg/kg/day orally for 4-6 weeks, then taper dose gradually according to response

Consider – alternative immunosuppressant

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ONGOING
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all patients
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with myositis
Consider – 

alternative immunosuppressant

Treatment recommended for SOME patients in selected patient group

For those patients who do not remit with corticosteroid therapy, or in those who continue to require unacceptably high doses for disease control, addition of methotrexate or azathioprine may provide a corticosteroid-sparing effect.

If methotrexate is used, folate supplementation should be given simultaneously, and close attention paid to advice on contraception and reproductive health. Monitoring of CBC, renal function, and liver enzymes is recommended.

Patients with low thiopurine methyltransferase (TPMT) activity are at increased risk of myelosuppression with conventional doses of azathioprine; patients may be tested for TPMT deficiency prior to initiation.

High-dose intravenous immunoglobulin has been used in resistant cases, with reports of efficacy in polymyositis and dermatomyositis.

Primary options

methotrexate: 7.5 mg orally once weekly on the same day of each week initially, increase by 5 mg/week increments every 2 weeks according to response, maximum 25 mg/week

and

folic acid (vitamin B9): 1 mg orally daily

OR

azathioprine: 50 mg orally once daily initially, increase according to response every 4-6 weeks, maximum 2.5 mg/kg/day

Secondary options

immune globulin (human): 400 mg/kg/day intravenously for 5 days each month

Plus – proton-pump inhibitor

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ONGOING
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all patients
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with GERD
Plus – 

proton-pump inhibitor

Treatment recommended for ALL patients in selected patient group

Proton-pump inhibitors are the mainstay of management. Treatment is usually lifelong. See Gastroesophageal reflux disease (Management approach).

Primary options

esomeprazole: 20 mg orally once or twice daily

OR

omeprazole: 20 mg orally once or twice daily

OR

lansoprazole: 30 mg orally once or twice daily

Plus – dietary modification

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ONGOING
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all patients
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with GERD
Plus – 

dietary modification

Treatment recommended for ALL patients in selected patient group

Dietary lifestyle measures are recommended.

Patients should be counseled to avoid eating food 2-3 hours before bedtime, and to avoid drinking caffeinated and carbonated beverages.

Plus – artificial tears/saliva

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ONGOING
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all patients
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with sicca symptoms
Plus – 

artificial tears/saliva

Treatment recommended for ALL patients in selected patient group

Artificial tears are helpful as initial therapy. Artificial saliva preparations may be required for those with dry mouth.

Close ophthalmologic and dental follow-up are essential to prevention of complications related to decreased tear and saliva pools.

Plus – cholinergic drug

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ONGOING
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all patients
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with sicca symptoms
Plus – 

cholinergic drug

Treatment recommended for ALL patients in selected patient group

Parasympathomimetic agents such as pilocarpine and cevimeline may improve tear and saliva flow.

Primary options

pilocarpine: 5 mg orally four times daily

OR

cevimeline: 30 mg orally three times daily

Consider – hydroxychloroquine

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ONGOING
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all patients
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with sicca symptoms
Consider – 

hydroxychloroquine

Treatment recommended for SOME patients in selected patient group

A retrospective, open-label study found benefit from hydroxychloroquine in patients with primary Sjogren syndrome, and this may also be of benefit in patients with sicca symptoms as part of their overlap syndrome.[32]

If given, regular ophthalmologic screening for retinopathy should be done.

Primary options

hydroxychloroquine sulfate: 6.5 mg/kg/day orally given in 1-2 divided doses

Plus – gabapentin or amitriptyline

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ONGOING
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all patients
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with neuropathy
Plus – 

gabapentin or amitriptyline

Treatment recommended for ALL patients in selected patient group

For sensory neuropathy, standard treatment with gabapentin or amitriptyline may be used as first-line therapy.[33][34]​ See Chronic pain syndromes.

Primary options

gabapentin: 300-1800 mg/day orally daily given in 3 divided doses

OR

amitriptyline: 25-50 mg orally once daily at night

Consider – immunosuppressant

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ONGOING
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all patients
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with neuropathy
Consider – 

immunosuppressant

Treatment recommended for SOME patients in selected patient group

In more severe cases with motor neuropathy or transverse myelitis, immunosuppressive therapy with high-dose corticosteroids and, rarely, cytotoxic agents may be required.[36][37][38]​​ Of the cytotoxic drugs, cyclophosphamide has been the most frequently employed agent; the roles of less toxic regimens using mycophenolate are under investigation. All should only be used under the care of an experienced rheumatologist.

Primary options

prednisone: 0.5 to 1 mg/kg/day orally for 4-6 weeks, then taper dose gradually according to response

Secondary options

cyclophosphamide: consult specialist for guidance on dose

Consider – transcutaneous electrical nerve stimulation

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ONGOING
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all patients
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with neuropathy
Consider – 

transcutaneous electrical nerve stimulation

Treatment recommended for SOME patients in selected patient group

May be added on to existing therapy or used alone.[35]

Plus – nonsteroidal anti-inflammatory drug or oral corticosteroid

Back
ONGOING
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all patients
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with serositis
Plus – 

nonsteroidal anti-inflammatory drug or oral corticosteroid

Treatment recommended for ALL patients in selected patient group

Mild serositis may respond to nonsteroidal anti-inflammatory drugs.

Corticosteroids are the mainstay of management for more severe disease.[24]​

Depending on the severity of the serosal involvement, moderate or high doses of prednisone may be required; the response is generally good.[39]

Primary options

naproxen: 500 mg orally twice daily when required, maximum 1500 mg/day

OR

ibuprofen: 400-800 mg orally every 6-8 hours when required, maximum 2400 mg/day

Secondary options

prednisone: 0.5 to 1 mg/kg/day orally for 4-6 weeks, then taper dose gradually according to response

Plus – pulmonary vasodilator

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ONGOING
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all patients
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with pulmonary hypertension
Plus – 

pulmonary vasodilator

Treatment recommended for ALL patients in selected patient group

Treatment should be guided by results of right-heart catheterization, including documentation of vasomotor responsiveness to vasodilators.

If responsive, patients should be treated with optimally tolerated doses of calcium-channel blockers as first-line therapy.[24]

Nonresponders to vasoreactivity testing and patients without sustained response to calcium-channel blockers should be started on another pulmonary arterial hypertension-specific therapy.

The oral phosphodiesterase-5 inhibitor sildenafil has been shown to improve symptoms, functional capacity, and hemodynamics when used in patients with primary pulmonary hypertension and in pulmonary hypertension secondary to rheumatic diseases.[41]

The endothelin receptor antagonist bosentan has also been shown to improve symptoms and functional capacity, but its long-term use and effects on pulmonary hemodynamics are less certain.[42][43] It should be used only by physicians experienced in its use, as very close monitoring for adverse effects, including hepatotoxicity, is needed.

The prostacyclin analogs epoprostenol, inhaled iloprost, and treprostinil have been tried singly and in combination regimens.[44][45][46] Close follow up with a pulmonologist with experience in the treatment of pulmonary arterial hypertension is mandatory.

Primary options

nifedipine: 30-60 mg orally (extended-release) once daily, increase according to response, maximum 90-120 mg/day depending on formulation used

Secondary options

sildenafil: 20-80 mg orally three times daily

OR

bosentan: 62.5 mg orally twice daily for 4 weeks, then increase to 125 mg twice daily

Tertiary options

epoprostenol: consult specialist for guidance on dose

OR

iloprost inhaled: consult specialist for guidance on dose

OR

treprostinil: consult specialist for guidance on dose

Consider – immunosuppressant

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ONGOING
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all patients
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with pulmonary hypertension
Consider – 

immunosuppressant

Treatment recommended for SOME patients in selected patient group

Immunosuppressive agents, alone or in combination with vasodilators, may be used in refractory cases.[47][48]

Combination therapy with corticosteroids and cyclophosphamide is effective.[47]

Primary options

methylprednisolone: 500 mg intravenously once daily for 3 days, followed by oral prednisone

and

prednisone: 0.5 to 1 mg/kg/day orally following methylprednisolone, maximum 80 mg/day

and

cyclophosphamide: 600 mg/square meter of body surface area intravenously once monthly

Plus – immunosuppressant

Back
ONGOING
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all patients
|
with interstitial lung disease
Plus – 

immunosuppressant

Treatment recommended for ALL patients in selected patient group

Immunosuppressive treatment for interstitial lung disease in the overlap syndromes is similar to that used in systemic sclerosis and systemic lupus erythematosus.

In patients with mixed connective tissue disease, high-dose corticosteroid therapy with prednisone is started, with the subsequent introduction of either mycophenolate or monthly intravenous or daily oral cyclophosphamide.

Careful monitoring for side effects, including cytopenia, hematuria, and the subsequent development of malignancy, is indicated. Advice on contraception and reproductive health should be given.

Among patients with antisynthetase syndrome and interstitial lung disease involvement, corticosteroids have been the most frequently used therapy, although additional immunosuppressive agents are increasingly being used.

Primary options

Overlap connective tissue disease

prednisone: 1-2 mg/kg/day orally

-- AND --

mycophenolate mofetil: 1 to 1.5 g orally twice daily

or

cyclophosphamide: 1-2 mg/kg/day orally; or 600 mg/square meter of body surface area intravenously once monthly

OR

Antisynthetase syndrome

prednisone: 1 mg/kg/day orally, taper dose according to response

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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

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