Approach
Treatment goals are based on the distribution of organ involvement. Treatment is targeted on disease processes that are potentially reversible (e.g., active inflammation or vasoconstriction) and aims to minimise the patient's functional impairment.
The medical history, physical examination, laboratory tests, and imaging studies that lead to the initial diagnosis provide much of the information necessary to determine the distribution of organ involvement. Functional tests (e.g., PFTs) and additional imaging studies (e.g., high-resolution computed tomography (CT) and echo) may be needed to determine the distribution, severity, and nature of scleroderma-related processes prior to developing a treatment plan.
It is common to describe the treatments for scleroderma according to system involvement. However, as scleroderma may be manifested in a variety of bodily systems, individual patients may require multi-modal therapies. Specialist consultation is necessary.
Raynaud's phenomenon without digital ulcers
Treatment of Raynaud's phenomenon is important to prevent progression to digital ulceration. The goal is vasodilation. First-line treatment includes the avoidance of stimuli (e.g., cold weather). Other simple methods include:
Relaxation therapy
Hand exercises
Biofeedback
Smoking cessation
The evidence for these simple measures is lacking. If conservative measures fail, dihydropyridine calcium-channel blockers are added. Calcium-channel blockers are an effective treatment in these patients.[25][26] Antiplatelet agents (e.g., aspirin) or blood viscosity-reducing agents (e.g., pentoxifylline) can also be used alone or added to calcium-channel blocker therapy.
Topical nitrates may be tried next in people with persisting symptoms, in addition to any existing therapy. However, the combination of agents may result in unacceptable adverse effects, particularly hypotension. This may necessitate the discontinuation of a treatment.
Raynaud's phenomenon with digital ulcer development
If Raynaud's phenomenon becomes more severe and digital ulceration occurs, various therapies may be used to provide maximal vasodilatation. In addition to the treatments mentioned above, these also include:
Phosphodiesterase type 5 (PDE5) inhibitors
Endothelin-1 receptor antagonists
Prostacyclin agonists (in the UK and Europe, prostacyclin agonists are approved for this indication and may be used prior to PDE5 inhibitors or ERAs)
Generally, only one agent from these groups is used at any one time, as a combination is unlikely to be tolerated. Care is provided by a specialist. The drugs for the management of Raynaud's phenomenon with ulceration are not all approved in some countries but are used as standard care. These agents may be added onto existing therapy, but it is necessary to observe systemic BP carefully to avoid hypotension.
PDE-5 inhibitors appear to have moderate but significant efficacy in secondary Raynaud's phenomenon.[26][27] Sildenafil may be helpful to decrease the development of new ulcers.[28] There is some evidence to support the use of bosentan (an endothelin-1 receptor antagonist), particularly in people with multiple or recurrent ulcers.[29] Liver function tests must be monitored frequently throughout treatment in people receiving endothelin-1 receptor antagonist therapy.
Prostacyclin agonists, such as iloprost (inhaled or by intravenous infusion), epoprostenol (intravenous infusion), or treprostinil (subcutaneous or intravenous infusion) may be used.[30] Intravenous epoprostenol may be appropriate for short-term therapy if other measures fail and intravenous iloprost is not available. Close monitoring of blood pressure and heart rate is necessary during the titration of the infusion. Adverse effects are headache and nausea. A short-term infusion should not be given in patients with pulmonary arterial hypertension as this condition can worsen abruptly once the infusion is stopped.
Wound care for ulceration is necessary, along with pain management.[31] Paracetamol or tramadol may be used initially. The use of narcotics should be avoided if possible but may become necessary. Any complicating secondary infection requires prompt therapy with antibiotics.
Digital sympathectomy is a last-resort therapy in people with severe Raynaud's phenomenon with ulceration. The procedure is difficult in this patient population. It should only be done by surgeons experienced in the management of patients with scleroderma.
Generalised skin involvement (e.g., dryness, thickening, pruritus)
Emollients are used to treat skin dryness, but the creams should be used frequently and they have a limited effect. Cyclophosphamide has been the only agent that has some evidence of benefit for improvement in skin thickening.[32][33] Careful selection of patients with early, rapidly progressive diffuse disease may have the highest risk/benefit ratio. These patients should be referred to a scleroderma specialist for management decisions. Risk/benefit ratios need to be considered carefully in each patient. However, 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.[34] For patients 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.[35]
Pruritus can be discomforting early in the disease, before the appearance of skin thickening. Treatments used include emollients, topical corticosteroids, and low-dose oral corticosteroids. Oral antihistamines are usually of limited benefit. This symptom usually improves with time.
Gastrointestinal involvement
Heartburn and dysphagia are among the most common symptoms described in scleroderma. Oesophageal dysmotility and incompetence of the lower oesophageal sphincter may be found. Treatment of GORD is important, both for the comfort of the patient and to prevent complications, such as stricture, oesophageal ulcers, Barrett's metaplasia, and aspiration pneumonitis. Proton-pump inhibitors are key to effective treatment. Mild symptoms are treated with proton-pump inhibitors. Lifestyle measures are also recommended, including advice to:
Avoid eating food 2 to 3 hours before bedtime
Avoid drinking caffeine and carbonated beverages
Elevate the head of the bed
If nausea, post-prandial 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, azithromycin, or domperidone may be helpful.[36] Following a European review, the Medicines and Healthcare products Regulatory Agency and European Medicines Agency have issued recommendations concerning the use of domperidone. The review found the drug was associated with a small increased risk of potentially life-threatening cardiac effects. As a consequence, the agencies recommend that domperidone should only be used for the treatment of symptoms of nausea and vomiting and is no longer recommended for the treatment of conditions such as heartburn, bloating, or stomach discomfort. The risks and benefits should be weighed carefully before using this drug for this off-label indication. It should be used at the lowest effective dose for the shortest possible duration and the maximum treatment duration should not usually exceed 1 week. The new recommended maximum dose in adults is 30 mg/day. Domperidone is contraindicated in patients with severe hepatic impairment or underlying cardiac disease. It should not be administered with other drugs that prolong the QT interval or inhibit CYP3A4.[37] 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 is no longer recommended by the European Medicines Agency for the treatment of chronic conditions such as gastroparesis.[38]
Complications of unintentional weight loss with diarrhoea are a sign of bacterial overgrowth and malabsorption and should be treated with antibiotics.[36] Options include cephalexin plus metronidazole, tetracyclines, amoxicillin/clavulanate, rifaximin, nitazoxanide, chloramphenicol, or ciprofloxacin.[36]
Systemic fluoroquinolone antibiotics such as ciprofloxacin 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; dysglycaemia; and central nervous system effects including seizures, depression, psychosis, and suicidal thoughts and behaviour.[39]
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.
Patients who have been diagnosed with gastric antral vascular ectasia require referral and management in a specialist centre. They may require episodic transfusions in some chronic cases, but the bleeding is rarely acute and massive. Endoscopic coagulation with heater probe, gold probe, argon plasma coagulator, or laser therapy obliterates the vascular ectasia and can decrease the degree of bleeding.
Musculoskeletal involvement (tendon friction rubs, synovitis, and myopathy)
Treatment of synovitis and friction rubs with weekly methotrexate and low-dose prednisolone can be quite effective. Methotrexate can be problematic in patients with ILD and should be used with caution. Although pulmonary complications are uncommon, methotrexate could cause diagnostic confusion in this setting. Leflunomide, another disease-modifying drug, is an alternative in patients with pulmonary disease.
Another musculoskeletal manifestation of scleroderma is inflammatory myositis, which is differentiated from scleroderma myopathy by the presence of weakness (usually in the proximal muscles) and abnormal electromyogram/nerve conduction study and muscle biopsy findings. Treatment for inflammatory myositis includes corticosteroid therapy. A corticosteroid-sparing agent such as methotrexate may be added if necessary. Referral should be made to a scleroderma specialist.
Treatment of inflammatory arthritis is as for other forms of inflammatory arthritis, with agents such as low-dose corticosteroids and methotrexate.
Interstitial lung disease
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 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.[17]
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 include cyclophosphamide, nintedanib, and azathioprine.[40][41]
For patients who experience disease progression despite initial treatment, adding a treatment or switching treatment should be considered.[40]
Therapies are listed in order of recommendation, but treatment decisions should be based on specific clinical considerations.[40] Whether to switch treatment or add to initial therapy depends on the initial therapy used, and on which therapy is being considered for addition.[40] 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, cyclophosphamide, or referral for autologous haematopoietic stem cell transplant and/or lung transplant.[40]
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.[40]
Treatment with immunosuppression must be weighed against the significant risks with therapy: most notably, increased risk of infections. This is best assessed by a consultant. 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 haematuria.[42]
Mycophenolate
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.[40][41][42][43] Although gastrointestinal adverse effects are common, it may be better tolerated than cyclophosphamide.[44][45]
Tocilizumab
Tocilizumab, an interleukin-6 receptor antagonist monoclonal antibody, has specifically been approved in the US for the treatment of adults with SSc-related ILD. In a phase 3 randomised double-blind trial, tocilizumab appeared to preserve lung function in patients with early SSc-related ILD and elevated acute-phase reactants.[46] This was, however, a secondary endpoint; the primary skin fibrosis endpoint was not met.
Rituximab
Rituximab is a monoclonal antibody directed against the CD20 antigen on the surface of B-lymphocytes. In one observational study, patients with SSc-related ILD who received rituximab showed improved forced vital (FVC) capacity at 2 and 7 years treatment compared to baseline and the standard treatment control group.[47]
Cyclophosphamide
Cyclophosphamide has been found to be beneficial but is associated with significant adverse effects.[33][48] Decisions concerning the initiation of cyclophosphamide should be made by a scleroderma consultant. 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 haematuria.
Nintedanib
Nintedanib is a tyrosine kinase inhibitor that is approved in the US and Europe for the treatment of adults with SSc-associated ILD to slow the rate of decline in pulmonary function. Nintedanib is the only drug specifically approved for this indication. It is not an immunosuppressant, like other recommended drugs for ILD.
Nintedanib has been demonstrated to reduce functional decline and disease progression in idiopathic pulmonary fibrosis, and effectiveness in SSc-related ILD has been reported.[49][50] In a phase 3 randomised 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.[50] Post hoc analyses indicated that fewer patients randomised 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%).[51]
Azathioprine
Azathioprine is not a preferred first-line option, but can be used as first-line therapy if the preferred options are not appropriate.[40]
Referral for autologous haematopoietic stem cell transplant and/or lung transplant
Referral for lung transplantation should be made for lung involvement not amenable to treatment. Survival rates following lung transplantation are similar to those with idiopathic pulmonary fibrosis and pulmonary hypertension (5-year survival 50% to 60%).[52][53]
Corticosteroids
Corticosteroids are not recommended for the treatment of ILD in patients with systemic sclerosis.[40]
Renal involvement
Severe and life-threatening renal disease develops in 10% to 15% of scleroderma patients, and was the largest cause of mortality before the introduction of ACE inhibitors. Patients at highest risk are those with early diffuse disease. Consultation with a rheumatologist/scleroderma specialist and nephrologist is required if there is suspicion of scleroderma renal crisis. Patients with early diffuse disease should be given strict instructions on BP monitoring, as early initiation of therapy is key to preventing irreversible renal failure.[54]
Scleroderma renal crisis is characterised by:
Onset of acute renal failure
Abrupt onset of moderate or marked hypertension
Urinary sediment that is frequently normal, or reveals only mild proteinuria with few cells or casts
Micro-angiopathic haemolytic anaemia.
Hypertension is treated with ACE inhibitors, titrated to maximal allowable and tolerated dose. A mild decrease in glomerular filtration rate (about 10%) with initiation of ACE inhibitor therapy should not cause alarm or discontinuation of therapy. The goal is to establish absolutely normal BP, to optimise 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 and various possible agents that may be used. More specifically, calcium-channel blockers are appropriate; generally an angiotensin-II receptor antagonist should be avoided along with maximum dose of ACE inhibitor, to avoid hyperkalaemia. Non-selective beta-blockers should also be avoided as they can worsen Raynaud's phenomenon. Prednisone (prednisolone) (15 mg/day or greater) has been associated with increased risk of renal crisis, so this should be avoided if possible.[55][56]Ciclosporin (cyclosporine) has also been reported to trigger renal crisis so its use should be avoided in all people with scleroderma as well.
Normotensive renal crisis may occur in a small minority of patients and tends to be less amenable to successful intervention.[55][57][58]
Pericardial effusion or cardiac tamponade
Small, asymptomatic pericardial effusions may occur if there is cardiac involvement and should be observed. Oral prednisolone should be given for patients with pericardial effusions causing marked symptoms. These patients are at risk of developing cardiac tamponade. They require close monitoring of BP and renal function as scleroderma renal crisis may be precipitated by high-dose corticosteroids. ACE inhibitors can be instituted in order to prevent scleroderma renal crisis. Patients with tamponade should receive a pericardial window and systemic corticosteroids.
Pulmonary arterial hypertension
Complications often require management at the same time as general treatment and need to be monitored for. Of particular importance is the early identification and management of pulmonary artery hypertension.
Early identification of pulmonary hypertension is crucial, with periodic echocardiograms for screening in appropriate patients and right heart catheterisation to confirm the diagnosis. Multiple therapies are currently available including endothelin receptor antagonists (bosentan, ambrisentan, macitentan), phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil), riociguat, and prostacyclin agonists (iloprost, treprostinil, epoprostenol).[59][60][61][62][63] Some medications for pulmonary arterial hypertension have been demonstrated to improve 6-minute walk time and/or time to clinical worsening.[64] Oxygen therapy may also be required. Patients who are unresponsive to medical treatment should be referred for a double lung transplant.[52]
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