Approach
There is a paucity of data from controlled trials to support management strategies specifically in patients with mixed connective tissue disease (MCTD) (or any of the overlap syndromes), in whom the clinical features and need for treatment are highly variable. As such, the treatment of these patients is highly individualised, tailored to the organ systems involved and the severity of involvement. Treatment strategies and the evidence to support specific treatments are borrowed from standard therapies proven to be effective in other well-defined rheumatic conditions. The overall goal of therapy is symptom control, prevention of organ injury, and, where possible, arrest of the underlying autoimmune disease process.
General management
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 consultant to evaluate for progressive lung disease.
For many patients with overlap syndromes, symptomatic benefit is gained by use of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. The long-term side effects of corticosteroid therapy are well documented, and patients should be counselled regarding risk of hypertension, hyperglycaemia, and potential skin changes. Caution is advised regarding corticosteroid use in patients with upper gastrointestinal (GI) symptoms, especially if also taking NSAIDs. The lowest possible dose to control symptoms should be used for the shortest period of time.
General lifestyle modifications should be recommended for all patients. These should include:
Education to encourage the patient to take responsibility for his/her disease management
Maintenance of an ideal body weight for their height
Reduction of salt intake in the presence of hypertension due to renal disease
Exercise guidelines to maintain optimum cardiovascular fitness, in patients with stable disease
Smoking cessation encouraged for patients who smoke.
Arthralgias and arthritis
The typical small-joint arthralgias of MCTD and the other overlap syndromes are managed with the use of NSAIDs (e.g., naproxen) at the lowest effective doses, with attention paid to monitoring for, and prevention of, cardiovascular, renal, and GI toxicities. If NSAIDs 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 MCTD.[24] If this is given, regular ophthalmological screening for retinopathy should be done.
In patients who develop frank synovitis, short courses of low-dose corticosteroids are helpful. If the arthritis is resistant to corticosteroids, synovitis is not adequately controlled on low doses of corticosteroids, or the patient has deforming or erosive disease, the addition of methotrexate is useful.[24] It 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.
Raynaud's phenomenon
Lifestyle modifications including avoidance of cold or sudden changes in temperature should be advised. Smoking cessation is essential.
Treatment is important to prevent progression to digital ulceration. First-line pharmacological interventions include calcium-channel blockers such as nifedipine. These agents are useful at decreasing the frequency and severity of attacks.[25][26][27] In patients with Raynaud's phenomenon (RP) secondary to scleroderma, alpha-1-blocking agents (e.g., prazosin) have been found to be useful.
For patients unable to tolerate or resistant to calcium-channel blockers, fluoxetine has been found to reduce the frequency and severity of attacks in patients with primary RP or RP related to systemic sclerosis.[28] Other second-line therapies include 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 analogues have been tried with some success. The endothelin receptor antagonist bosentan has been shown to reduce the incidence of new ischaemic ulcers.[30] These agents should only be used under the supervision of physicians familiar with their use, as side effects are common.
Puffy hands
NSAIDs such as naproxen may improve symptoms. Low-dose prednisolone may be added if needed.
Myositis
Corticosteroid therapy is the mainstay of management of myositis in MCTD, as well as in antisynthetase syndrome and polymyositis/scleroderma overlap syndrome where an inflammatory myopathy is a prominent component.[24][31] Prednisolone is effective followed by slow tapering after 4 to 6 weeks if the disease has been controlled.
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. High-dose intravenous immunoglobulin has been used in resistant cases, with reports of efficacy in polymyositis and dermatomyositis.
GORD
Treatment of GORD is important, both for patient comfort and to prevent complications (e.g., oesophageal stricture). Proton-pump inhibitors are the mainstay of management.
Lifestyle measures are also recommended. Patients should be counselled to avoid eating food 2 to 3 hours before bedtime, and to avoid drinking caffeinated and carbonated beverages.
Sicca symptoms
Treatment is largely symptomatic. Close ophthalmic and dental follow-up are essential for prevention of complications related to decreased tear and saliva pools. Artificial tears are helpful as initial therapy.
Parasympathomimetic agents such as pilocarpine and cevimeline may improve tear and saliva flow but may have numerous anticholinergic side effects.
A retrospective, open-label study found benefit from hydroxychloroquine in patients with primary Sjogren's syndrome, and this may also be of benefit in patients with sicca symptoms as part of their overlap syndrome.[32] If this is given, regular ophthalmological screening for retinopathy should be done. Immunosuppressive therapies, including TNF-alpha blockers, have been largely disappointing and cannot be routinely recommended for these patients.
Neuropathy
For sensory neuropathy, standard treatment with gabapentin or amitriptyline may be tried first.[33][34] Transcutaneous electrical nerve stimulation may be added on to existing therapy or used alone.[35]
See Chronic pain syndromes (Management approach).
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 drugs should only be used under the care of an experienced rheumatologist.
Serositis
Mild serositis may respond to NSAIDs, but corticosteroids are the mainstay of management for more severe disease.[24] Depending on the severity of the serosal involvement, moderate or high-dose prednisolone may be required; the response is generally good.[39]
Pulmonary hypertension
All patients with MCTD should undergo regular screening for the development of pulmonary hypertension.[40] Treatment should be guided by the results of right-heart catheterisation, including documentation of vasomotor responsiveness to vasodilators. Acute vasodilator response is defined as a fall in mean pulmonary artery pressure of ≥10 mmHg to ≤40 mmHg, with an increased or unchanged cardiac output during acute challenge with inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine. If patients are responsive, they should be treated with optimally tolerated doses of calcium-channel blockers as first-line therapy.[24]
Non-responders to vasoreactivity testing and patients without sustained response to calcium-channel blockers should be started on another pulmonary arterial hypertension-specific therapy. Targeted treatment options include oral phosphodiesterase-5 inhibitors such as sildenafil; oral endothelin receptor antagonists such as bosentan; and parenteral and inhaled prostacyclin analogues, among others.
Sildenafil has been shown to improve symptoms, functional capacity, and haemodynamics when used in patients with primary pulmonary hypertension and in pulmonary hypertension secondary to rheumatic diseases.[41]
Bosentan has also been shown to improve symptoms and functional capacity, but its long-term use and effects on pulmonary haemodynamics are less certain.[42][43] It should be used only by physicians experienced in its use, as very close monitoring for side effects, including hepatotoxicity, is needed.
Epoprostenol, inhaled iloprost, and treprostinil have been tried, singly and in combination regimens.[44][45][46] Close follow up with a respiratory physician with experience in the treatment of pulmonary arterial hypertension is mandatory.
Immunosuppressive agents, alone or in combination with vasodilators, may be used in refractory cases.[47][48] Combination therapy with corticosteroids and cyclophosphamide is somtimes effective.[47]
Interstitial lung disease
There are no randomised controlled trials addressing the optimum timing or regimen for the treatment of interstitial lung disease (ILD) in overlap syndromes, so therapy is based on those agents known to be effective for scleroderma or myositis-associated ILD. High-dose corticosteroid therapy with prednisolone is started, with the subsequent introduction of mycophenolate, which has been shown to be better tolerated and with less toxicity than the alternative, cyclophosphamide.[49][50]
Among patients with antisynthetase syndrome and interstitial lung disease, prednisolone is the most frequently used therapy, although additional immunosuppressive agents are increasingly being used.
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