Clinical manifestations

Presentation and course

Progressive systemic sclerosis occurs more frequently in females, especially during the peak incidence years of 30 to 55, where the female:male ratio may be as high as 12:1 (29). African American patients are affected at nearly twice the rate of Caucasian patients with disease often occurring at a younger age and more severe disease manifestations resulting in increased mortality (89). Initial symptoms can be vague and include Raynaud phenomena, malaise, and myalgias. For diffuse cutaneous systemic sclerosis, after the appearance of inflammatory and edematous changes, progressive skin fibrosis can occur, resulting in tight and painful skin involving fingers, proximal extremities, trunk, neck, and face. Painful tendon friction rubs are frequently seen and are a poor prognostic indicator for risk of disease progression. The degree of skin thickening may vary over 2 to 3 years. In some proximal locations, skin remodeling may occur and return towards normal as time progresses. Residual and severe skin fibrosis can cause permanent atrophic digit changes, joint immobility, and limited mouth opening. Subclinical visceral involvement may also be present at disease onset, suggested by esophageal reflux and radiographic pulmonary abnormalities. More widespread visceral involvement often occurs within the initial 10 years, including prominent pulmonary, gastrointestinal, cardiac, and renal complications. Motility dysfunction is the most prevalent esophageal pathology in patients with scleroderma (35). A generalized small vessel vasculopathy affecting small arteries, arterioles, and capillaries is characteristically proliferative and obliterative, thus, contributing to organ dysfunction. Cardiopulmonary complications are the leading causes of death. Prior to the availability of angiotensin-converting enzyme inhibitors, scleroderma renal crisis was a major cause of mortality associated with rapidly progressive hypertension and renal failure. Several reviews have emphasized the multisystem nature and clinical complexity of this disease (78; 82; 91; 116).

Skeletal muscle involvement in scleroderma is common; however, the prevalence can vary widely in published studies due in part to an absence of an established diagnostic criteria as well as overlap of scleroderma with the inflammatory myopathies (71). Objective muscle weakness is present sometime during systemic sclerosis in at least 80% and is usually multifactorial (91). Disuse and deconditioning are responsible in part. Over half demonstrate a mild, nonprogressive myopathy with slight elevations of serum creatine kinase and aldolase levels. Approximately 12% have a more progressive inflammatory myopathy. Inclusion body myositis has been reported rarely (12).

Patients may complain of muscle pain along with weakness, particularly if a scleroderma-myositis overlap is present. Autoantibodies such as the Anti-PM-Scl can help support the diagnoses of a myositis overlap. In a database of 9,165 scleroderma patients, muscle weakness reported by a treating physician was 18.9% in limited cutaneous scleroderma patients and 33.5% in diffuse cutaneous scleroderma patients (71). However, studies have varied widely in prevalence of abnormal manual muscle testing.

The scleroderma-myositis overlap is often part of the antisynthetase syndrome involving scleroderma-like changes in the lung as well as overlap with polymyositis and inclusion body myositis (57).

Clinically apparent neurologic involvement in progressive systemic sclerosis, exclusive of muscular involvement, is infrequent (probably less than 10%) (12). In a systematic review of neurologic involvement in scleroderma, patients with limited cutaneous scleroderma were found to have epilepsy as the most frequent reported neurologic alteration (06). Cranial nerve involvement has been described, with third, sixth, and seventh nerve palsies having been described along with trigeminal neuralgia. Trigeminal sensory neuropathy is found in about 4% and is the most frequently observed focal neurologic problem (75). Trigeminal divisions II and III are involved in 65%, with bilateral distribution in 63%. Trigeminal neuropathy generally occurs later in the disease but may precede or occur simultaneously with other presenting features. The presentation of trigeminal neuropathy in association with Raynaud phenomenon may predict subsequent development of systemic sclerosis. Trigeminal neuralgia may rarely accompany the more common sensory deficits; trigeminal motor function is usually spared (75). In patients with diffuse cutaneous scleroderma, headache was the most prevalent neurologic symptom followed by cognitive impairment (06). Migraine headaches are more common than in rheumatoid arthritis or normal control populations and may be present in at least 30% (88).

Peripheral neuropathy has been noted in less than 5% (06), but most occur at a higher frequency that previously reported. Reduced vibration sense, reduced pinprick, focal atrophy, muscle weakness and decreased deep tendon reflexes are often seen (90). Comprehensive electrophysiological testing using electromyography (EMG) and nerve conduction studies shows distal sensory impairment in as many as 50%, usually subclinical (100). Both symptomatic and asymptomatic carpal tunnel syndrome has been identified, with incidence up to 67% for asymptomatic median nerve abnormalities on ultrasound imaging suggestive of carpal tunnel syndrome (06). Motor conduction abnormalities may occur in up to 44% (72). Nerve entrapment has been detected, notably ulnar nerve entrapment and manifests as large and small fiber abnormalities in a non-length dependent fashion (90; 06). Clinically-evident sensorimotor axonal polyneuropathies occur infrequently, usually later in the disease, but may occur early or precede development of other symptoms (05). Brachial plexopathy has also been reported and thought to be a result of the scleroderma vasculopathy (04). A systematic review of the published cases with peripheral neuropathy and systemic sclerosis identified main risk factors as diffuse systemic disease, calcinosis cutis, and anticentromere antibodies (05).

Autonomic neuropathy may rarely cause symptomatic postural hypotension and gastrointestinal disturbances with features of dysautonomia. Electrophysiological testing has shown frequent autonomic abnormalities, usually subclinical, in up to 80% (50). Autonomic dysfunction probably contributes significantly to esophageal, cardiovascular, gastrointestinal dysmotility, and bladder abnormalities, and may also contribute to impotence (02).

Cerebral blood flow hypoperfusion abnormalities have been found in the majority of neurologically asymptomatic individuals (27). These findings probably relate to intracerebral microangiopathic processes, including cerebrovascular calcinosis (46), and correlate well to focal or diffuse abnormalities noted on cranial MRI, which are observed in over 50% of cases. These findings may also be related to mild cognitive abnormalities noted on neuropsychometric testing (112).

A rare, localized form of scleroderma involving the head (scleroderma "en coup de sabre") may be associated with symptoms such as headaches, seizures, or hemiparesis; it may demonstrate focal cerebral MRI abnormalities, including vasculopathy (111; 65). In a retrospective review, cutaneous severity did not correlate with the severity of neurologic symptoms and imaging findings (22). Scleroderma “en coup de sabre” has been associated with orbital and intracerebral involvement leading to epilepsy and impaired vision (53).

Other limited forms or localized forms of scleroderma demonstrate neurologic involvement even less commonly. Isolated case reports have reported describing intracerebral hemorrhage; ischemic stroke; optic neuropathy; impaired eye movements; hearing loss; facial weakness; vocal cord paresis; tongue fasciculations; subacute combined degeneration from malabsorption and B12 deficiency; multiple sclerosis; myasthenia gravis; acute transverse myelopathy; compressive myelopathy from fibrosis, calcinosis, or atlantoaxial subluxation; compressive radiculopathy or mononeuropathy (ulnar, lateral femoral cutaneous, saphenous); mononeuritis multiplex; brachial and lumbosacral plexopathy; and lumbar radiculopathy (06). Whether these rare clinical events are direct consequences of the underlying pathological processes, indirect consequences, or coincidental associations remains unresolved.

Descriptive studies of pain in systemic sclerosis are very limited. Schieir and colleagues report that the pain symptoms were common in their study of patients with systemic sclerosis and were independently associated with more frequent episodes of Raynaud phenomenon, active ulcers, and worsening synovitis (101).

Neuro-psychiatric manifestations are all common in scleroderma. Patients complain of chronic pain and symptoms of depression and anxiety (14; 06) and may exhibit behaviors not unlike patients with other forms of chronic facial or dental pain. They are often depressed about pain and disfigurement, physical function and social function, and may be candidates for psychologic intervention should be considered (48).

Neurologic and muscular complications of progressive systemic sclerosis are summarized in Table 2.

Table 2. Neurologic and Muscular Abnormalities Seen in Progressive Systemic Sclerosis

Prognosis and complications

The course of systemic sclerosis in an individual can be variable, ranging from minimal symptoms to death. Age-adjusted mortality for progressive systemic sclerosis is approximately 3 in 1 million; rates for women are two to four times higher than for men (81; 60; 78). Black women are more severely affected and have a higher mortality than Caucasian women. For all populations, 5- and 10-year survival rates vary from 60% to 70% and 40% to 50%, respectively. Factors adversely influencing prognosis include female gender; Black race; skin thickening of the trunk; cardiac, renal, or pulmonary involvement at time of diagnosis; heavy alcohol use in Caucasians; heavy cigarette smoking in the first year; and anemia, elevated erythrocyte sedimentation rate, proteinuria, or hypoproteinemia at the time of initial diagnosis. The absence of proteinuria, elevated sedimentation rate, and low carbon monoxide diffusing capacity has been associated with a 93% survival rate at 5 years (17). Patients with systemic sclerosis generally have a worse prognosis than those with limited scleroderma. Severe organ involvement, in those which it occurs, is usually within the first 3 years; the 9-year cumulative survival rate was 38% in those with severe organ involvement versus 72% in those without such involvement (108; 78). Complications arising from renal, cardiac, and pulmonary involvement are the leading causes of death (81; 01; 16; 70).

Pulmonary arterial hypertension, in particular, is an important cause of mortality in systemic sclerosis. Patients with interstitial lung disease and pulmonary arterial hypertension are associated with a high rate of morbidity and mortality (30). Although echocardiography is used as a screen for pulmonary arterial hypertension, right heart catheterization remains the diagnostic gold standard. Earlier treatment with new agents is associated with better treatment outcomes (92). Patients with simple myopathy have a relatively benign muscular course, characterized by minimal progression and waxing and waning symptoms. The muscle weakness of polymyositis progresses rapidly. The course of inclusion-body myositis is more indolent.

Scleroderma renal crisis is one of the most feared complications and can affect patients with both diffuse cutaneous and limited cutaneous scleroderma. However, prevalence has been decreasing with 10% of diffuse patients and 2% of limited cutaneous patients affected (104). Scleroderma renal crisis typically manifests as acute onset of moderate to severe “accelerated” hypertension and oliguric renal failure. Some patients may exhibit hypertensive encephalopathy and retinopathy.

Several studies have reported the association of systemic sclerosis with thyroid autoimmune disorders and thyroid function abnormalities; antithyroid peroxidase autoantibodies and ultrasonography should be tested as part of the clinical profile in systemic sclerosis patients. Females, subjects with positive antithyroid peroxidase and hypoechoic and small thyroid should have thyroid function follow-up and appropriate treatment in due course (07).

Clinical vignette

A 48-year-old woman was in good health until six months prior to her first evaluation when she began to notice excessive tiredness, general but mild muscle aches, and intermittent hand discomfort with mild purplish discoloration on cold exposure. Two weeks before evaluation she developed painless right face numbness.

At the time of the first evaluation, the general physical exam, including vital signs, was normal. In particular, no skin, joint, or vascular abnormalities were detected. Neurologic exam was also normal except for mildly decreased pin sensation in the second and third divisions of the right trigeminal nerve.

Initial laboratory evaluation of routine serum chemistries, complete blood count with differential, thyroid function tests, and serum creatine kinase were normal. Sedimentation rate was mildly elevated at 45. Testing for rheumatoid factor was negative; antinuclear antibodies were present at 1:160. Cranial MRI demonstrated a few punctate white matter T2 hyperintense foci bilaterally that were nonenhancing after gadolinium infusion. Magnetic resonance angiography of the extra- and intra-cranial vasculature was normal. Cerebrospinal fluid analysis was normal.

Over the next nine months the facial numbness improved, but her other mild symptoms continued. In addition, her Raynaud worsened, and sclerodactyly developed involving both hands followed by similar skin tightening of the proximal arms. Repeat antinuclear antibody testing was positive at 1:2560. Anti-RNA polymerase III and anti-topoisomerase I antibodies were present; anti-centromere antibodies were absent.

A diagnosis of systemic sclerosis was made.

Comment. Neurologic complaints, especially at the time of presentation, are uncommon in systemic sclerosis. However, trigeminal sensory neuropathy is the most common focal neurologic event that is seen. In addition, the early presentation of trigeminal sensory neuropathy and Raynaud phenomenon together strongly suggests the subsequent development of typical systemic sclerosis (75).

Biological basis

Etiology and pathogenesis

The pathogenesis of systemic sclerosis is not entirely understood, but it is presumed to be autoimmune (43). Distinct immune profiles are found in patients with the limited cutaneous and progressive forms. An increasing body of work has been focused on the genetic role in the presentation of disease including insulin-like growth factor binding protein 7 and others (30). A complex imbalance of cytokine production is present in patients with scleroderma (58). Environmental or occupational factors such as exposure to silica dust, organic solvents, biogenic amines, vinyl chloride, or urea formaldehyde have been implicated although only silica and solvent exposure has been consistently associated with diffuse cutaneous scleroderma (34). A scleroderma-like condition may also occur after exposure to bleomycin, tainted rapeseed oil, and L-tryptophan. This exposure may alter cytokine production and T cell responses (26). No clear association between silicone breast implants and systemic sclerosis has been found (120).

Major mechanisms accounting for the pathological changes in progressive systemic sclerosis include generalized fibrosis, systemic vasculopathy, and cellular/humoral autoimmunity. The three pathologic processes may occur and progress independently (42). Fibrosis appears to be the consequence of increased synthesis and deposition of collagen, fibronectin, and glycosaminoglycans by fibroblasts activated by products of microangiopathic endothelial cell damage and immune activation. Perivascular mononuclear cell infiltrates consist predominantly of T lymphocytes. They and their pro-inflammatory products can be directly damaging to skin, vasculature, and viscera (43; 120). The causes of immunologic activation or the identity of the inciting autoantigens remains unresolved. The role of infectious agents as instigators is intriguing with the possibility of molecular mimicry and autoimmune disease. Given these environmental factors, it appears that both extrinsic and intrinsic events are necessary for the manifestation of disease.

A general immunoregulatory abnormality may set the stage for the development of scleroderma (97; 113). Transforming growth factor-beta as well as connective tissue growth factor locally induce cytokines within the cellular infiltrate, which promotes fibrosis and angiogenesis. Blockade of these actions may provide a potential therapeutic benefit (56; 115). This approach has successfully prevented pathological fibrosis in a graft-versus-host murine model of scleroderma (80). There is increasing evidence that IFN pathways in SSc play a pivotal pathogenic role (30). Serum levels of tumor necrosis factor and interleukin 13 are elevated in patients with localized scleroderma (87; 98; 124). Moreover, persistent fetal microchimerism after pregnancy in a majority of women with systemic sclerosis suggests that a graft-versus-host mechanism may contribute in some instances to the development of this illness (09; 15; 67).

The pathogenesis of scleroderma also involves a complex genetic relationship. Microchimeric cells, which can be passed from one individual to another during gestation, between twin fetuses, or via blood transfusions, organ donation, have been implicated in the pathogenesis of scleroderma; as noted above, this may be a spectrum of graft verus host disease. It is uncertain if these microchimeric cells are integrally associated with scleroderma or a source of immunologic dysregulation that results in scleroderma. Other genetic factors may be responsible for an increase in cases in families (08; 116). To date, only one study has been published analyzing 42 twin pairs. This study demonstrated a poor correlation between clinical expression of disease, suggesting genetic predisposition alone is not sufficient to manifest disease expression (34). Patients of African American ancestry have a higher predominance of HLA-DRB1*08:04, which has been strongly related to antifibrallin auto antibodies, which could partially explain the increase prevalence among African American patients (30).

The mechanisms underlying the neurologic complications of progressive systemic sclerosis are likely not specific to the central nervous system, peripheral nervous system, or muscular system. Rather, they are similar to those involved in organ damage elsewhere in the body. Pathological reports of epineurial and perineurial thickening suggest that the neuropathy of progressive systemic sclerosis is related to excessive collagen deposition causing compression of myelinated fibers. Interstitial and perivascular fibrosis are the most common pathological findings in patients with progressive systemic sclerosis and uncomplicated myopathy (86). The paucity of connective tissue in the central nervous system may account for the relative rarity of clinically apparent central nervous system involvement (12; 50). Immune-mediated vascular endothelial cell damage induces platelet aggregation and subsequent tissue ischemia, predisposing to ischemic neuropathy and presumed cerebral blood flow abnormalities and strokes. A study comparing vascular retinopathy with capillary nail fold findings demonstrated that retinal changes may reflect vascular damage from scleroderma and does not always correlate with the nailfold capillaroscopic patterns (117). Another study reported that the elastic properties of larger vessels in scleroderma are altered (21). Inflammatory vascular disease may cause some forms of cerebrovascular complications but is an unlikely basis of peripheral neuropathy (50). Increased endothelial growth factor levels are an early marker for subsequent vascular disease (32). There is also concern about defective protective mechanisms of nitric oxide in patients with scleroderma (76). Immune-mediated inflammatory muscle damage underlies the rare cases of aggressive myositis and progressive systemic sclerosis (12).

Epidemiology

Estimates indicate an incidence of 20 per million population per year and a prevalence rate of 240 per 1,000,000 adults (78). There is a low concordance of disease in twins but a high concordance for antibodies (40). Distribution is worldwide and appears to be noncontagious but affected by environmental and genetic factors. Female preponderance is noted in all studies. Female to male ratios vary from 5:1 to 12:1 (during mid to late childbearing years) with symptom onset highest in the fourth and fifth decades (78). Age-specific incidence rates are higher in African American women than in white women, especially in women younger than 54 years old. Diffuse disease is more common in black women, and this makes survival lower for African-American women (78).

Prevention

Progressive systemic sclerosis and its potential neurologic complications have no known prevention currently.

Differential diagnosis

Associated or underlying disorders

Diagnostic considerations include: (1) connective tissue disorders that are also characterized by Raynaud phenomenon; (2) connective tissue disorders with similar but nonspecific clinical presentations; (3) scleroderma-like features associated with endocrine disorders (eg, hypothyroidism, diabetes mellitus, paraproteinemias); and (4) disorders with similar visceral (eg, primary pulmonary hypertension, biliary cirrhosis) or dermatological manifestations (eg, eosinophilic fasciitis, eosinophilia-myalgia syndrome) (59).

Diagnostic workup

The clinical diagnosis of progressive systemic sclerosis rests on the demonstration of the typical skin and digit changes in patients with a history of Raynaud phenomenon and positive antinuclear antibodies. Microangiopathic changes can be seen under magnified examination of the nail fold capillaries and careful retinal examination (117). About half will have an elevated sedimentation rate. Serum creatine kinase levels are usually near normal but may be markedly elevated in association with rarely accompanying inflammatory myositis (12).

Serological studies demonstrate high-titer antinuclear antibodies in 90% of patients (81; 93). Patterns of organ involvement may be based on the type of autoantibodies detected, and their titers (51). The absence of antibodies may also occur in a patient otherwise meeting clinical criteria for scleroderma (54). The association of scleroderma with antibodies other than antinuclear antibodies is under investigation (19; 84; 11).

Autoantibody profiles are particularly helpful in the diagnosis. Antinuclear antibodies are detectable in greater than 90% of patients with scleroderma (20). Anti-RNA polymerase III antibodies are found in 45% of patients with systemic sclerosis but rarely in limited cutaneous scleroderma. They are associated with increased risk of cardiac or renal disease (55). Anti-topoisomerase I (Scl70) antibodies are detected in 30% of patients with systemic sclerosis and 15% in limited cutaneous scleroderma. The presence of anti-topoisomerase I antibodies and anti-U1 RNA protein complex antibodies may be associated with higher likelihood of neurologic complications in some patients with systemic sclerosis (52), as well as increased risk for pulmonary disease (82). Anti-PM-Scl antibodies are found in systemic sclerosis patients with associated inflammatory myopathy (103). Anti-centromere antibodies are found in over 70% of patients with limited scleroderma and CREST syndrome but infrequently in those with systemic sclerosis; they strongly correlate with esophageal involvement in systemic sclerosis (45). Localized scleroderma also demonstrates a high incidence of antinuclear antibodies (73%), prominently directed at histones, but low incidence of anti-centromere and anti-topoisomerase I antibodies (99).

Table 3. Disease Manifestations Associated With Autoantibodies

EMG studies demonstrate myopathic features in some muscles in the majority of individuals with systemic sclerosis, particularly with long-standing disease. Nerve conduction studies may indicate a mild distal axonal neuropathy or evidence of nerve entrapment (85; 72).

Muscle biopsy is abnormal in over 50% of patients but is generally heterogenous and non-specific (71). Specimens generally show mild changes with mononuclear inflammation, microangiopathy, increased collagen deposition, nonspecific type II muscle fiber atrophy, and intimal proliferation within endomysial and perimysial vessels. Perivascular cellular infiltrates may be rarely seen and raise the possibility of coexisting inflammatory myopathy. Infrequent reports of nerve biopsies demonstrate intimal thickening, adventitial edema, a reduced number of myelinated fibers, evidence of axonal degeneration, and the relative absence of active inflammatory changes (74). Muscle weakness is likely multifactorial with scleroderma-related heart and lung damage leading to muscle atrophy as well. Patients with a skeletal myopathy do not appear to have a worse prognosis, but there does appear to be an increased risk of myocardial involvement (71).

An ongoing challenge of systemic sclerosis is early diagnosis before end-organ damage. Progression of nailfold patterns on videocapillaroscopy is indicative of microvascular damage and disease and may have utility for monitoring the efficacy of therapeutic interventions (95).

In patients with systemic sclerosis-related interstitial lung disease, pericardial abnormalities are commonly seen on high-resolution CT, and their presence is strongly associated with echocardiographically defined pulmonary arterial hypertension, with abnormal total pericardial score as the best individual predictor (39). Significantly decreased parasympathetic tone and parasympathetic reactivity had been observed in systemic sclerosis patients than the controls (122).

In patients with progressive systemic sclerosis, high-resolution CT of the chest may reveal numerous signs of scleroderma, such as ground-glass opacities, consolidation, reticulation, nodules, bronchiectasis, and honeycombing (41). Recognizing and understanding the pulmonary findings of scleroderma on CT is important because these findings may indicate the level of disease involvement and dictate whether treatment is indicated. On initial high-resolution CT of the chest, interstitial lung disease is present in more than 50% of patients, including in some patients without symptoms (63).

Hachulla and colleagues in their study show that MRI is a very dependable technique to diagnose heart involvement in systemic sclerosis, including its inflammatory, microvascular, and fibrotic components, by visualizing the myocardial fibrosis and inflammation (47). Right ventricular dilation might suggest a myocardial involvement related to systemic sclerosis.

Neuroimaging by CT and MRI has noted abnormalities in the absence of clear neurologic pathology (06). Imaging by CT has noted cerebral calcifications, extracranial atrophy, and cortical depression. MRI abnormalities include hyperintense white matter lesions and abnormal gyral pattern (102).

Men with systemic sclerosis present an increased risk of erectile dysfunction. Penile thermal abnormalities occur in almost all sclerodermic patients. Non-contact thermal imaging not only identifies thermal alterations but also clearly distinguishes between systemic sclerosis patients and healthy controls. Hence, this imaging could be valuable in identifying early erectile dysfunction in systemic sclerosis patients (83).

Management

The morbidity and mortality of progressive systemic sclerosis are primarily related to the excess accumulation of collagen in various tissues with the ensuing complications, including organ failure. As a general rule, treatment is directed at specific organ involvement. Progressive systemic sclerosis currently has no universally effective treatment and immunosuppression response is disappointing. Management is directed toward staging the severity of the disease and treating its complications (28; 69).

Progressive skin disease without visceral involvement is very often approached with either methotrexate or mycophenolate mofetil. The European League Against Rheumatism supports the use of methotrexate for skin disease. Mycophenolate mofetil is often used when there is combined skin and visceral involvement (66). The effect of tocilizumab in skin fibrosis and systemic sclerosis-associated interstitial lung disease was assessed in a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Tocilizumab was ineffective in improving skin fibrosis, but those patients on tocilizumab had significantly less worsening of the percentage of predicted forced vital capacity compared to placebo and tocilizumab is now FDA approved for systemic sclerosis associated interstitial lung disease (62; 36). IVIG may improve skin involvement in refractory cases (03).

Pulmonary complications of scleroderma, including interstitial lung disease and pulmonary hypertension, are major causes of morbidity and mortality. Cyclophosphamide and rituximab have both shown efficacy in controlling scleroderma interstitial lung disease, at least as measured by pulmonary function testing: cyclophosphamide shows impact on FVC and rituximab on DLCO (123).

Nintedanib has been used for interstitial lung disease in scleroderma with evidence of a modest impact on the decline of forced vital capacity (33). Mycophenolate mofetil can also be considered for interstitial lung disease as there was an even slower progression of forced vital capacity in combination with nintedanib (36).

Reports indicated that tocilizumab might prove beneficial in preventing progression of interstitial lung disease (73; 94), and tocilizumab has now been FDA approved for the treatment of scleroderma associated interstitial lung disease and can preserve lung function and slow progression (64).

Pulmonary artery hypertension is often responsive to endothelin receptor agonists (ambrisentan, bosentan, macitentan), PDE-5 inhibitors (sildenafil, tadalafil), and riociguat. Prostacyclin analogues (iloprost, treprostinil) have been successfully employed, too.

Renal disease in the form of scleroderma renal crisis is heralded by rapid skin involvement, autoantibodies to RNA polymerase III, rising blood pressure, and proteinuria. Glucocorticoids are traditionally used for complications such as arthritis and inflammatory myopathy, but enthusiasm for their use has been limited because they potentially precipitate scleroderma renal crisis when used at higher doses (44; 68). Renal crisis can be significantly ameliorated through the use of angiotensin-converting enzyme inhibitors (28; 121).

Progressive systemic sclerosis involves the gastrointestinal tract from the mouth to the anus, causing significant morbidity (37). Involvement of the gastrointestinal tract in progressive systemic sclerosis may occur in two stages, a neuropathic disorder followed by a myopathy. Gastric emptying is delayed and compliance of the fundus is increased, causing myoelectric abnormalities that result in reduced or absent migrating motor complexes predisposing to bacterial overgrowth. Malabsorption may also be due to pancreatic insufficiency. Pancolonic involvement occurs in 10% to 50% of patients with progressive systemic sclerosis with wide-mouthed diverticula, involving all layers of the intestinal wall, in addition to pseudoobstruction, pneumatosis cystoides intestinalis, stercoral ulcerations, and perforation. Fecal incontinence may be due to dysfunction of the internal anal sphincter. Treatments include biofeedback, sacral nerve stimulation, and surgery. Treatments for gastroparesis include metoclopramide, cisapride, and erythromycin. Bleeding from telangiectasias and watermelon stomach is treated endoscopically. Pseudoobstruction may respond to octreotide or prucalopride therapy. Treatments for rectal incontinence might include biofeedback, sacral nerve stimulation, and surgery.

Christopeit and colleagues describe marked improvement of severe progressive systemic sclerosis after transplantation of mesenchymal stem cells from an allogeneic haploidentical-related donor mediated by ligation of CD137L (23).

Autologous hematopoietic stem cell transplantation has evolved as a therapeutic option for patients with early diffuse cutaneous systemic sclerosis (31). Systemic sclerosis is the most common autoimmune disorder treated with autologous hematopoietic stem cell transplantation, accounting for 20% of all transplants done in autoimmune diseases. An open-access position statement has been published to provide plainly worded guidance for patients and nonspecialist clinicians considering hematopoietic stem cell transplantation for an autoimmune disease (61). There is a definite treatment-related mortality increase in the first year of therapy but a significant survival and quality-of-life benefit (119). Careful patient selection is key to outcome. In a randomized study, adult patients with severe scleroderma were assigned to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). As expected, treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group (114). In a European Society for Blood and Marrow Transplantation multicenter, prospective, noninterventional study between December 2012 and February 2016, 80 patients underwent autologous stem cell transplantation. At two years, progression-free survival was 81.8%, and overall survival was 90%. Five (6.25%) patients died from complications in the first 100 days post transplantation (49).

An expert opinion consensus paper suggesting treatment algorithms for various clinical manifestations of systemic sclerosis has been published (38).

Raynaud phenomenon may respond to calcium channel blockers, but they may also aggravate esophageal reflux.

The treatment of existing digital ulcers includes hydrocolloid occlusion, wound care, pain control, antibiotics, and the use of vasodilating medications, and possibly digital or cervical sympathectomy (24).

Special considerations

Pregnancy

Pregnancies generally have good outcomes but should be considered high-risk owing to an increased incidence of pre-term births and the infrequent occurrence of renal crisis (105; 105; 96). Fertility does not appear to be diminished, but the risk of complications is higher in the first few years after symptom onset and decreases with disease stabilization. One large study concluded that during pregnancy of affected women, 72% remained stable, whereas 14% worsened and 14% improved (96; 10). Pregnancy in systemic sclerosis may be complicated by serious cardiopulmonary and renal problems. Careful monitoring is essential in patients with pulmonary arterial hypertension due to high maternal and neonatal mortality, as well as renal crisis (106; 25).

Anesthesia

Despite advances in medical management, perioperative management also remains complicated due to airway challenges from possible perioral skin thickening, pulmonary arterial hypertension, interstitial lung disease, and increase risk of perioperative myocardial infarction (18).