|Year : 2019 | Volume
| Issue : 1 | Page : 34-40
Management of systemic sclerosis: A dermatologist's approach
Deepthi Ravi1, Smitha Prabhu2
1 Cosultant Dermatologist, Deepthi's Derma Care, Chennai, Tamil Nadu, India
2 Department of Dermatology and Venereology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
|Date of Web Publication||14-Feb-2019|
Department of Dermatology and Venereology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal - 576 104, Karnataka
Source of Support: None, Conflict of Interest: None
Systemic sclerosis (SSc) is an autoimmune connective tissue disease affecting the blood vessels, skin, and internal organs. The main pathogenic mechanisms are vascular dysregulation, tissue fibrosis due to collagen and extracellular protein deposition, and autoantibody production due to immune dysfunction. The treatment also targets these mechanisms. Various criteria including the American College of Rheumatology and the European League against Rheumatism are laid down for the clinical diagnosis of scleroderma, and treatment is tailored to the systems involved. In the initial stages of the SSc, immunosuppressants are more useful, whereas in the later stages, antifibrotic therapies are important. Vasospasm and endothelial dysfunction are seen in all stages of the disease, and hence, vascular therapies are needed throughout the course of the disease. Special care should be taken to rule out gastrointestinal, pulmonary, and renal system involvement if the primary treatment is by a dermatologist.
Keywords: Diffuse, limited, management, systemic sclerosis
|How to cite this article:|
Ravi D, Prabhu S. Management of systemic sclerosis: A dermatologist's approach. Clin Dermatol Rev 2019;3:34-40
| Introduction|| |
Systemic sclerosis (SSc) is an autoimmune connective tissue disease affecting the blood vessels, skin, and internal organs such as the lungs, kidneys, gastrointestinal tract, musculoskeletal system, and the heart. It is one of the scleroderma spectrum disorders. Scleroderma is a broad term used for a group of disorders presenting with both localized involvements, i.e., morphea and systemic involvement affecting the internal organs as well as having vascular manifestations referred to as SSc.
SSc is of two types, namely, limited and diffuse. Limited SSc includes calcinosis, Raynaud's phenomenon (RP), esophageal dysmotility, sclerodactyly, and telangiectasia syndrome (CREST) and is characterized by fibrotic skin changes which are limited to the face, hands, and fingers. Diffuse SSc (dSSc) is progressive disorder and initially starts over the hands and fingers but later progresses to involve the forearms, arms, face, lower extremities, and trunk.
Internal organ involvement is the major cause of morbidity and mortality in SSc. The emergencies commonly encountered in SSc include RP, pulmonary artery hypertension (PAH), interstitial lung disease (ILD), and scleroderma renal crisis (SRC).
[TAG:2]Etiology and Predisposing Factors[/TAG:2]
The etiology is unknown. It is three to four times more common in women; however, disease severity is greater in men. The peak ages of the onset are between 30–40 years and 50–60 years.
Poor prognostic factors include black race, male sex, older age, and internal organ involvement at the time of diagnosis, elevated erythrocyte sedimentation rate, and skin fibrosis over the trunk.
| Pathogenesis|| |
The main pathogenic mechanisms are vascular dysregulation, tissue fibrosis due to collagen and extracellular protein deposition, and autoantibody production due to immune dysfunction. The treatment also targets these mechanisms.
There are three major stages of the disease which are vasculopathy followed by inflammation which is followed by fibrosis.
Impaired angiogenesis leads to vascular dysfunction affecting all vessels from small capillaries to large vessels. Endothelial cell injury is the initial stage before fibrosis, and it results in perivascular leak and thus edema. Intimal proliferation leads to occlusion of the lumen which leads to hypoxia which induces profibrotic cytokine synthesis, collagen production, and fibroblast activation. Endothelial cell apoptosis is seen with antiendothelial cell antibodies.
Intimal proliferation and obstruction of lumen lead to irreversible damage of the arteries which lead to digital ulcers. Reversible spasm of vessels leads to RP. SRC and pulmonary arterial hypertension are due to large vessel dysfunction.
Topoisomerase I antibody binds to the surface of fibroblasts and stimulates adhesion and activation of monocytes. There is increased deposition of collagen, fibronectin, proteoglycans, fibronectin, adhesion molecules, and fibrillins. There is increase in transforming growth factor-β (TGF-β) which in turn stimulates connective tissue growth factor which is responsible for maintaining collagen synthesis.
Cutaneous clinical features include, an early edematous phase in which the patient has pitting edema over the tips of the digits. Later as fibrosis progresses, there is hardening of the skin with the development of shiny taut skin referred to as the indurated phase. Cutaneous ulcers can result from flexion contractures of the digits. A beaked nose and microstomia may be seen because of taut skin over the face.
Pigmentary changes are also commonly seen in the sclerotic areas. The sun-exposed areas and the pressure areas may show a diffuse hyperpigmentation. Central face and the trunk may show leukoderma. This spares the perifollicular skin, and in some cases, the veins which lead to salt-and-pepper appearance of the skin. The face, palms, lips, and nail folds may show telangiectasias. Dystrophic calcinosis cutis may be seen near the joint in the distal extremities.
Secondary RP is seen commonly in SSc. Persistence leads to ischemia and sometimes ulceration. Digital tip ulcers due to ischemia and interphalangeal ulcers due to trauma can be seen in SSc. Osteomyelitis and autoamputation of digits may be seen as a result of persistent ulcers.
The differences between limited and dSSc are given in [Table 1].
Internal organ involvement
SRC was the most common cause of mortality in SSc before the introduction of angiotensin-converting enzyme inhibitors (ACEIs). This develops in 10%–15% of patients and the patients have acute onset renal failure, sudden hypertension, and a urine sediment.
PAH and ILD are seen. ILD presents with dyspnea on exertion and dry cough. Tachypnea and bibasilar rales are seen in PAH.
Right-sided congestive heart failure presenting with dilated neck veins, peripheral edema, and hepatomegaly may also be seen. Pericardial effusion, urinary abnormalities, seizures, and fundoscopic changes may also be seen.
Barrett's esophagus and gastroesophageal reflux disease may be seen which may present with dysphagia, postprandial bloating, and dyspepsia. Motility disturbances including constipation and diarrhea may also be seen.
Widespread symmetric cutaneous induration can be seen in scleredema, scleromyxedema, nephrogenic systemic fibrosis, eosinophilic fasciitis, and generalized morphea.
The diagnosis of SSc needs clinical assessment along with tests that need confirmation of the diagnosis. The American College of Rheumatology and the European League against Rheumatism (EULAR) criteria for diagnosis of SSc are given in [Box 1] and [Table 2], respectively.
|Table 2: European league against rheumatism criteria for the diagnosis of systemic sclerosis|
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The general tests which need to be done include ANA profile, biopsy for histopathological examination, nail-fold capillaroscopy, and investigations to rule out other autoimmune rheumatic diseases such as arthritis and other connective tissue disorders. Routine hematological and biochemical tests and tests to rule out internal organ involvement need to be done.
The patients may have anemia due to chronic disease or gastrointestinal blood loss (iron-deficiency anemia). Intestinal hypermotility may lead to Vitamin B12 or folic acid deficiency; due to secondary bacterial overgrowth, SRC may lead to hemolytic anemia.
Antinuclear antibodies are seen in 75%–95% of patients with SSc which are enumerated in [Table 3].
The stage of the disease can be determined by the histopathological examination. In the early stages, a mild inflammatory infiltrate is seen around the dermal vessels, eccrine ducts, and in the subcutaneous tissue.
In later stages, there is less amount of blood vessels with thickening and hyalinization of the vessel walls making the lumen narrow. There may be thinning of the epidermis with disappearance of the rete ridges. Deposits of homogeneous collagen in the subcutaneous tissue and the dermis can be seen. Atrophic sebaceous and sweat glands due to surrounding fibrosis may also be seen.
Modified Rodnan skin score can be used for measuring the skin involvement [Box 2]. A durometer (mechanical engineering tool) can also be used to assess the cutaneous induration.
Electromyography abnormalities and creatine phosphokinase elevation are seen in patients having myositis.
The prognosis of SSc depends on the organ system involved, and hence, it is important to screen for various organ involvement and to monitor the disease evolution.
A baseline evaluation of cardiac status by ECG and echocardiography and of the pulmonary system by chest X-ray and pulmonary function tests are needed. Any abnormality needs assessment with high-resolution computed tomography (CT) or cardiac magnetic resonance, stress echocardiography, or rhythm assessment.
Upper gastrointestinal evaluation with barium swallow and small bowel follow through is useful to detect hypomotility, Barrett's esophagus, and fibrotic strictures. Manometry, endoscopy, and malabsorption evaluation also can be done. Sensitive scintigraphic procedures which are noninvasive and quantitative can also be done.
Early diagnosis of lung involvement is necessary to prevent morbidity and mortality.
In case of ILD, high-resolution CT chest and pulmonary function tests need to be done including diffusing capacity of lungs for carbon monoxide.
In case of PAH, an echocardiogram and right heart catheterization are needed to confirm the diagnosis.
Echocardiography, myocardial perfusion scintigraphy, and ventriculography are the most sensitive techniques for diagnosis of cardiac involvement. Conduction abnormalities, signs of infarction, and nonspecific ST and T-wave changes may be seen n ECG.
SRC is a very important complication. Blood pressure was monitored on a regular basis, especially in patients with diffuse skin disease. Plasma creatinine levels and urine protein/creatinine ratio also need to be done to assess the damage.
Fall in the 24-h creatinine clearance of 20 ml/min from the previous value or a creatinine clearance of <60 ml/min and new persistent proteinuria of >500 ml/day indicate impending renal crisis. Other features of SRC include microangiopathic hemolytic anemia, azotemia, microscopic hematuria, elevated plasma renin levels, and hypertension.
| Treatment|| |
Treatment of SSc should target the three underlying pathogenic processes, namely, vasculopathy, fibrosis, and immune cell activation. A combination therapy targeting all the pathogenic processes mentioned above is needed instead of a single line of therapy.
In the initial stages of the SSc, immunosuppressants are more useful, whereas in the later stages, antifibrotic therapies are important. Vasospasm and endothelial dysfunction are seen in all stages of the disease, and hence, vascular therapies are needed throughout the course of the disease.
| Treatment Of Vasculopathy|| |
Vasculopathy leads to digital ulcers, RP, glomerular dysfunction, esophageal dysmotility, and PAH.
Calcium channel blockers
They cause arteriolar dilatation and thus increase peripheral blood flow. It is useful in RP and leads to improvement in the severity and frequency of the ischemic episodes. It is also useful in high doses in PAH and improves early myocardial function and perfusion defects.
ACEIs such as enalapril and angiotensin receptor blockers (ARBs) such as losartan are vasodilators shown to have an evidence-based benefit.
Both these also block the profibrotic renin–angiotensin axis. Angiotensin II-induced collagen production and lung fibroblast proliferation are also reduced by losartan. Losartan also modulates the levels of circulating cell surface adhesion molecules and procollagen peptides. Thus, both ACEI and ARB have additional benefits apart from the vasodilator properties and have shown to be more effective than pure vasodilators like nifedipine.
ACEI reverses SRC and thus has reduced mortality due to scleroderma after its introduction.
Prostacyclin (PGI2) and its analogs (Iloprost) have been used to RP and PAH. Intravenous iloprost improves kidney function, decreases frequency and severity of RP, and has a preventive role on PAH.,
Phosphodiesterase inhibitor (PDE-I) enhances nitric oxide-mediated vasodilation. Sildenafil and Tadalafil are oral PDE-I which can be used in PAH, prevention and healing of digital ulcers, and improvement in RP. Sildenafil is given in a dosage of 12.5 mg to 100 mg once a day for a period of 1–5 months for the treatment of digital ulcers. Tadalafil has a longer half-life and hence is given in a dose of 5–20 mg on alternate days for a period of 1–3 months.
Endothelin-1 is a vasoconstrictor and blocks both endothelin receptor Types A and B. It is related to the pathogenesis of PAH. Bosentan is an endothelial receptor antagonist which helps in PAH and helps in reducing the mean pulmonary arterial pressure and delays the progression of PAH and improves exercise capacity. It is also useful in the prevention of ischemic ulcers and is helpful in patients with recurrent ulcers.
Riociguat which is a guanylate cyclase stimulator in a dose of 1.5–2.5 mg thrice daily has also shown to be useful in the treatment of PAH and in improving the exercise capacity.
| Antifibrotic Agents|| |
Proliferation of fibroblasts and increase in collagen and extracellular matrix proteins is seen in SSc. TGF-β and platelet-derived growth factor (PDGF) are the two main cytokines involved in these effects. Imatinib mesylate inhibits both PDGF and TGF-β pathways.
| Immunomodulators|| |
Since both cell-mediated and humoral immunity is active in SSc, immunosuppressants will be useful as in other connective tissue disorders.
It interferes with the cross-linking of collagen and increases soluble collagen and thus reduces skin thickening. It also has an immunomodulatory effect and also reduces the chance of SRC. A dose of 125 mg alternate days has been as effective as a dose of 750–1000 mg/day in early diffuse cutaneous SSc. A dose of 750 mg/day in patients with diffuse rapidly progressive SSc has been effective in reducing skin thickness, improvement of pulmonary, renal, and cardiac involvement.
Steroids are used in the early edematous phase and do not have much use when fibrosis happens. It is useful in arthritis, inflammatory myositis, serositis, and ILD. Pulse steroid therapy has been useful in active ILD. An improvement of RP, skin thickness, calcinosis, and pulmonary function has also been seen with pulse steroids.
Caution must be exerted while giving steroids since it has a potential to precipitate SRC.
Improvement in skin thickening and global assessment has seen with methotrexate. It is cost-effective and well tolerated and has been recommended by EULAR for the treatment of early dSSc [Table 4].
|Table 4: European league against rheumatism recommendations for systemic sclerosis treatment|
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Intravenous cyclophosphamide is useful in patients with ILD and alveolitis. It also reduces skin thickening in patients with rapidly progressive early dSSc.
It has been useful in pulmonary, esophageal involvement, and skin thickening in doses of 2–5 mg/kg/day.
Autologous stem cell transplant
It can be used in severe SSc where high-dose chemotherapy is used to eradicate immunocompetent cells mainly the T-cells and replace it with autologous stem cells which are naïve to the implicated autoantigens.
Hematopoietic autologous stem cell transplant has shown to improve pulmonary function and skin, prevent worsening of organs, and improve the long-term survival in patients with SSc.
Infliximab in combination with methotrexate has been useful in CREST syndrome and refractory ulcers with healing of the ulcers.
It has been useful in digital ulcers, skin induration, and gastroesophageal reflux. It inhibits TNF-α production and stimulates a Th-1 type of response.
| Organ-Based Treatment|| |
It presents with pain and ischemic demarcation in the digit. Immediate vasodilator therapy is needed. If the ischemic area advances, heparin is given. PGI2s such as iloprost infusion (0.5–2 ng/kg/min) or epoprostenol (0.5–2 ng/kg/min) infusion for 1–3 days can be given. When all these fail, surgical intervention is needed.
SRC is mainly caused by high-dose corticosteroid use. Early introduction of ACEI along with other antihypertensive agents like calcium channel blocker (CCB) is useful in reducing the mortality of the condition.
ILD is treated with immunosuppressants mainly cyclophosphamide and mycophenolate mofetil.
PAH is treated with vasodilators, especially endothelin receptor antagonists, especially bosentan, ambrisentan, and sitaxsentan, PGI2 analogs such as inhaled iloprost, epoprostenol, and treprostinil, and phosphodiesterase-5 inhibitors such as sildenafil and tadalafil and warfarin and CCBs.
Rituximab given for four cycles with each cycle consisting of two infusions in a dose of 1000 mg with a gap of 2 weeks has shown to prevent the decline in pulmonary function tests in patients with ILD in SSc.
Phototherapy with photochemotherapy therapy, UVA1 therapy, D-penicillamine, relaxin, and photopheresis are the various modalities which can be tried in reducing the cutaneous induration.
Targeted molecular therapy can also be given to reduce immunologically mediated fibrosis. The molecular targets include interleukin 4 and 6, β-fibroblast growth factor, TGF-β, and intercellular adhesion molecule-1.
The patients should be instructed to keep warm and avoid smoking to prevent aggravation of the condition.
CCB (nifedipine), ARB (losartan), PDE-5 inhibitors (sildenafil and tadalafil), topical nitroglycerine paste, and oral 5-HT blockers can be given. Low-dose aspirin and pentoxifylline to increase blood supply to the compromised areas can be given. Fluoxetine which is a selective serotonin reuptake inhibitor in a dose of 20 mg once a day for a period of 6 weeks has also shown to reduce the severity and frequency of RP as well as showed an improvement in thermographic response on cold challenge.
In severe cases, sympathectomy is also useful.
Occlusive dressings such as moist hydrocolloid dressings for autolytic debridement can be done. Enzymatic debriders such as collagenase and growth factors such as topical PDGF can be used. A small plastic cage can be used to protect digital tip ulcers.
Endothelial receptor antagonist (oral bosentan) and oral PGI2 analogs (oral iloprost) can be used to prevent new digital ulcers. Nerve blocks and sympathectomies can be done in refractory cases.
Skin lubrication by means of moisturizers is necessary.
Inflammatory changes with calcium deposits can be reduced by low-dose warfarin. Saline compresses can help to reduce the swelling and pain till extrusion of calcium. Colchicine also helps to reduce inflammation caused to calcium deposition and helps in healing.
Extracorporeal shock wave lithotripsy and surgical removal of the calcium deposits can be done if necessary.
Depending on the indication ACEI, ARB, aldosterone antagonists, diuretics, and beta-blockers can be given.
In case of reflux, patients should be instructed to take small, frequent meals, in a sitting position and to avoid coffee, tea, chocolate, and alcohol, and proton-pump inhibitors can be given. For bloating and motility improvement, cisapride, mosapride, domperidone, and metoclopramide can be given.
In case of secondary malabsorption, antibiotics such as doxycycline and tetracycline may be necessary.
Nonsteroidal anti-inflammatory drugs such as indomethacin can be used to manage arthralgias and arthritis. Daily physical therapy with a full range of motion of all joints to prevent the development of contractures is necessary.
Low levels of Vitamin D in SSc have shown to be associated with a more aggressive form of the disease with multiple and more severe organ involvement, particularly cardiac and lung involvement. Vitamin D is known to have antifibrotic, cardioprotective, and immunomodulatory actions and hence could possibly help in combating each of the pathogenic mechanisms in SSc. Therefore, correction of Vitamin D deficiency could possibly help patients with SSc. However, the usual dose of Vitamin D is not quite helpful in correcting this deficiency. Supraphysiological doses of Vitamin D along with UVB light exposure can be considered in such cases.
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[Table 1], [Table 2], [Table 3], [Table 4]