Chris T. Derk

Following the Molecular Pathways toward an Understanding of the Pathogenesis of Systemic Sclerosis

Clinical Principles Systemic sclerosis is an autoimmune connective tissue disorder of unknown cause. It is clinically heterogeneous, ranging from limited skin involvement to diffuse skin sclerosis with severe internal organ involvement. The Raynaud phenomenon, swelling of the extremities, and diffuse arthralgias often precede the onset of skin tightness and induration. Visceral involvement with fibrosis, microvascular alterations, and mononuclear cell infiltration of the gastrointestinal tract, lungs, heart, and kidneys is present to a variable extent in most patients. Autoantibodies, some with very high specificity, are present almost universally. Mortality and morbidity are substantial and are directly related to the extent of the fibrotic and microvascular alterations. A better understanding of the pathogenesis of this incurable disorder will help to design effective therapies in the future. Physiologic Principles The pathogenesis of systemic sclerosis is extremely complex; at present, no single unifying hypothesis explains all aspects. Fundamental abnormalities in at least 3 types of cells are intimately involved in the development of the clinical and pathologic manifestations of the disease: 1) fibroblasts; 2) endothelial cells; and 3) cells of the immune system, in particular T and B lymphocytes. The profound functional alterations in these cells result in the characteristic triad of pathologic changes: severe and often progressive cutaneous and visceral fibrosis; obliteration of the lumen of small arteries and arterioles; and humoral and cellular immunologic abnormalities, which include the production of autoantibodies, the chronic mononuclear cell infiltration of affected tissues, and the dysregulation of lymphokine and growth factor production. A crucial component in systemic sclerosis pathogenesis is the persistent and unregulated activation of genes encoding various collagens and other extracellular matrix proteins. Abnormal regulation of transcription of genes encoding various collagens is responsible for tissue and vascular fibrosis. Alterations in the production of cytokines and growth factors, which are capable of modulating the function of fibroblasts and other target cells, appear to play a relevant role. Transforming growth factor- is one of the growth factors intimately involved in the fibrosis that accompanies systemic sclerosis. Systemic sclerosis is a disease of unknown origin characterized by excessive deposition of collagen and other connective tissue macromolecules in skin and multiple internal organs, prominent and often severe alterations in the microvasculature, and humoral and cellular immunologic abnormalities (see Glossary). Systemic sclerosis is a complex and heterogeneous disease. Clinical forms range from limited skin involvement with minimal systemic alterations (limited cutaneous systemic sclerosis) to forms with diffuse skin sclerosis and severe internal organ disease (diffuse cutaneous systemic sclerosis) (1), and occasionally a fulminant course (fulminant systemic sclerosis) (2). The most apparent and almost universal clinical features of systemic sclerosis are related to the progressive thickening and fibrosis of the skin (3). However, multiple internal organs are always involved in some degree even when it is not clinically apparent. The affected skin is tight, indurated, and firmly bound to the subcutaneous tissue. Hair follicles and sweat and sebaceous glands atrophy. The skin over the hands and face is most frequently involved; as the disease progresses, the sclerotic changes extend and may affect the entire body. In many cases, the cutaneous involvement is confined to the digits and the dorsum of the hands and feet (acrosclerosis), and progression of the sclerotic process is relatively slow. This form of disease was previously known as the CREST syndrome (Calcinosis, long-standing Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectases) (4). Skin ulcerations, usually localized to fingertips or knuckles, and peculiar pigmentary changes are frequent. Calcinosis is most commonly found in fingertips and periarticular tissues. The Raynaud phenomenon is the second most common manifestation of systemic sclerosis and is present in more than 85% of patients (5). It usually appears simultaneously with other manifestations but may antedate them by several years. Often, the initial vasoconstriction and blanching are followed by a dusky cyanosis and are accompanied by paresthesias and numbness. With return of blood flow, reactive erythema occurs. In some cases, larger blood vessels are affected and luminal narrowing and occlusion can result in ischemic necrosis. Musculoskeletal symptoms are often the initial manifestations and may vary from mild polyarthralgias to frank arthritis (6). Synovitis with a moderate effusion occurs occasionally; however, the synovial fluid is only mildly inflammatory. In more advanced stages, thickening and fibrosis of periarticular tissues result in severe flexion contractures and distal phalangeal resorption. Muscle involvement can reveal either an inflammatory myopathy or a more indolent noninflammatory form due to muscle infiltration with fibrotic tissue. The gastrointestinal tract is the most common internal organ system involved (7). Esophageal symptoms resulting from reduced lower esophageal sphincter pressure and dysmotility of the lower two thirds of the esophagus include reflux, heartburn, and dysphagia to solid foods. In severe cases, chronic esophagitis can lead to stricture and odynophagia. Poor gastric emptying and small intestine involvement may cause abdominal distention, bloating, nausea, and pain, and, in many instances, bacterial overgrowth with secondary malabsorption, diarrhea, and weight loss. Pulmonary involvement has emerged as potentially the most serious visceral lesion in systemic sclerosis. Because no reliable ameliorating treatment is available for such involvement, it frequently leads to severe respiratory disability and often death (8). The most prominent symptoms are tachypnea and exertional dyspnea, secondary to either pulmonary fibrosis or pulmonary hypertension. Many patients remain asymptomatic despite evidence of fibrotic involvement of the lung parenchyma. In some cases, fulminant pulmonary hypertension may lead to rapid death (9). Cardiac involvement is not uncommon (9, 10). Chest pain, arrhythmias, various degrees of heart block, and myocardiopathy with left ventricular or biventricular failure may result from myocardial fibrosis. These alterations occur almost exclusively in patients with diffuse systemic sclerosis. Cor pulmonale can develop in patients with pulmonary hypertension. Pericardial involvement is usually asymptomatic; however, pericardial effusions are found by echocardiography or autopsy examination in approximately one half of patients. Until recently, renal disease was the most rapidly fatal visceral involvement of systemic sclerosis. It is known as scleroderma renal crisis and is typically characterized by the abrupt onset of malignant hypertension and rapidly progressive renal insufficiency (11). It is often heralded by severe headache; visual symptoms from hypertensive retinopathy; seizures and other central nervous system symptoms; or myocardial ischemia, infarction, or left ventricular failure. Prompt aggressive treatment now can usually reverse this process, which otherwise is fatal. Functional thyroid abnormalities, including elevated levels of antithyroid autoantibodies and clinical and subclinical hypothyroidism, are common (12). Impotence caused by erectile failure may be an early feature of systemic sclerosis (13), and some degree of erectile dysfunction ultimately develops in many affected patients. Patients may develop the sicca syndrome (keratoconjunctivitis sicca and xerostomia) caused by fibrosis and lymphocytic infiltration of the salivary and lacrimal glands (14). Unusual clinical manifestations include urinary bladder involvement, pneumatosis cystoides intestinalis with pneumoperitoneum, trigeminal neuralgia, and hoarseness from vocal chord involvement. The pathologic changes in systemic sclerosis encompass a spectrum reflecting variable stages of development and progression of 3 major processes in the affected tissues: 1) severe tissue fibrosis with exaggerated deposition of collagen and other connective tissue components in the extracellular matrix [see Glossary]; 2) chronic inflammation, occurring predominantly in the early stages of disease and characterized by infiltration with mononuclear cells, mostly of the macrophage and T-cell lineages; and 3) microvascular disease, characterized by intimal proliferation, concentric subendothelial deposition of collagen and mucinous material, and narrowing and thrombosis of the vessel lumen. Progression of the vascular and fibrotic changes and a decrease in the inflammatory component lead to end-stage fibrosis and atrophy of the affected organs. The histopathologic findings in the skin include marked thickening of the dermis with massive accumulation of dense collagen, causing epidermal atrophy, flattening of the rete pegs, and replacement of sebaceous and sweat glands as well as hair follicles. A prominent inflammatory infiltrate is often present at the dermaladipose tissue interphase, especially in early lesions (15, 16). The small vessels of the lower dermis show fibrous thickening but no evidence of vasculitis. In the lungs, the architecture of the alveolocapillary membrane and the parenchymal interstitium are markedly disrupted by fibrosis and severe mononuclear-cell infiltration. Prominent vascular abnormalities with intimal proliferation causing narrowing or complete obliteration of small vessels are frequent. The renal lesions display severe narrowing and obliteration of the medium-size arterioles because of subintimal accumulation of loose connective tissue and intimal and perivascular fibrosis. The glo

Prevalence and factors associated with left ventricular dysfunction in the EULAR Scleroderma Trial and Research group (EUSTAR) database of patients with systemic sclerosis

Objectives: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in systemic sclerosis (SSc). Methods: The EUSTAR database was first searched. A case-control study of a patient subset was then performed to further identify independent factors associated with LV dysfunction by simple and multiple regression. Results: Of 7073 patients, 383 (5.4%) had an LV ejection fraction (EF) of <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension were associated with LV dysfunction. In the second phase, 129 patients with SSc with LVEF <55% were compared with 256 patients with SSc with normal LVEF. Male sex (OR 3.48; 95% CI 1.74 to 6.98), age (OR 1.03; 95% CI 1.01 to 1.06), digital ulcerations (OR 1.91; 95% CI 1.05 to 3.50), myositis (OR 2.88; 95% CI 1.15 to 7.19) and use of calcium channel blockers (OR 0.41; 95% CI 0.22 to 0.74) were independent factors associated with LV dysfunction. Conclusion: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with an increased prevalence of LV dysfunction. Conversely, the use of calcium channel blockers may be protective.

Eosinophilic fasciitis: demographics, disease pattern and response to treatment: report of 12 cases and review of the literature

Backgroundu2002 Eosinophilic fasciitis is a rare scleroderma‐like illness. The clinical spectrum of the disease has evolved since its initial description.

Systemic sclerosis: current views of its pathogenesis.

Systemic sclerosis (SSc) is an autoimmune disorder of unknown etiology characterized by severe and often progressive cutaneous and visceral fibrosis, pronounced alterations in the microvasculature, and numerous cellular and humoral immune abnormalities. Clinically, SSc is very heterogeneous, encompassing a spectrum ranging from mild limited forms of skin sclerosis with minimal internal organ involvement to severe skin and multiple internal organ fibrosis. Mortality and morbidity in SSc are very high and are directly related to the extent of the fibrotic and microvascular alterations. A better understanding of the pathogenesis of this incurable disorder will help to better target and design effective therapy in the future.

A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis

OBJECTIVEnTo evaluate the efficacy and safety of mycophenolate mofetil for the treatment of SSc.nnnMETHODSnWe recruited 15 patients with dcSSc to take part in an open-label study using mycophenolate mofetil to treat their disease over a 12-month period. The primary outcome measure was the modified Rodnan skin score (mRSS), whereas secondary outcomes included the Medsger severity score, pulmonary function studies, 2D echocardiograms and the Short Form Health Survey (SF)-36 questionnaire.nnnRESULTSnThe mRSS significantly improved in those patients who tolerated the medication for >3 months (P < 0.0001), and there was a statistically significant improvement in the Medsger severity scores of the general (P = 0.05), peripheral vascular involvement (P = 0.05) and skin (P = 0.0003) scores. The SF-36 scores improved (P = 0.05) and the pulmonary function studies showed a trend towards improvement, though not of statistical significance. The mean pulmonary artery pressure by 2D echocardiography did not change.nnnCONCLUSIONSnIn this prospective open-label study of mycophenolate mofetil for the treatment of dcSSc, we observed significant improvements in skin scores, peripheral vascular involvement and patient-perceived health status. Pulmonary function studies did not worsen as expected, but instead showed a trend towards improvement. Controlled trials are needed to further investigate this trend for improved pulmonary function studies.

Gastric antral vascular ectasia in systemic sclerosis: demographics and disease predictors.

Objectives. To evaluate patients with systemic sclerosis (SSc) who have gastric antral vascular ectasia (GAVE), to further characterize this disease association, and to identify factors that may predict which patients with SSc are at greatest risk for the development of GAVE. Methods. Patients with a diagnosis of both SSc and GAVE were identified from the Division of Rheumatology at Georgetown University and Thomas Jefferson University. A chart review was conducted to obtain the demographic data. Results. Twenty-eight patients were included in this analysis, including 17 with diffuse cutaneous (dcSSc) and 11 with limited cutaneous SSc (lcSSc). The mean disease duration at diagnosis with GAVE was 21.5 months for dcSSc and 84.3 months for lcSSc (p = 0.025). Seventy-six percent of patients with dcSSc developed GAVE within 18 months of first scleroderma symptom onset. Over half of patients with early GAVE also had rapidly progressive cutaneous disease. Only 4% had antitopoisomerase I antibody. Although only 1 patient was tested and had positive RNA polymerase (RNAP) III, RNAP III may be overrepresented in this GAVE population. Mean hematocrit levels were 23.8% in dcSSc and 29% in lcSSc. Conclusion. dcSSc is associated with earlier development of GAVE, as well as more severe anemia requiring more therapeutic interventions. Rapid progression of cutaneous disease may suggest earlier development of GAVE. Absence of antitopoisomerase I antibodies and presence of antibodies to RNAP III/speckled antinuclear antibody pattern may be useful to identify the subset of patients with SSc with increased risk for GAVE.

Exposure to ACE inhibitors prior to the onset of scleroderma renal crisis-results from the international scleroderma renal crisis survey

OBJECTIVEnTo determine whether exposure to angiotensin-converting enzyme (ACE) inhibitors prior to the onset of scleroderma renal crisis (SRC) leads to worse outcomes of SRC.nnnMETHODSnProspective cohort study of incident SRC subjects. The exposure of interest was ACE inhibitors prior to the onset of SRC. The outcomes of interest were death or dialysis during the first year after the onset of SRC.nnnRESULTSnA total of 87 subjects with incident SRC were identified and 1-year follow-up data were obtained in 75 (86%) subjects. Overall, 27 (36%) subjects died within the first year and an additional 19 (25%) remained on dialysis 1 year after the onset of SRC. In adjusted analyses, exposure to ACE inhibitors prior to the onset of SRC was associated with an increased risk of death (hazard ratio 2.42, 95% CI 1.02, 5.75, p < 0.05 in the primary analysis and 2.17, 95% CI 0.88, 5.33, p = 0.09 after post-hoc adjustment for pre-existing hypertension).nnnCONCLUSIONnOverall, the 1-year outcomes of SRC were poor. Prior exposure to ACE inhibitors was associated with an increased risk of death after the onset of SRC, although there was uncertainty around the magnitude of the risk and the possibility of residual confounding could not be ruled out. Further studies will be needed to confirm these findings.

Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: results from the PHAROS registry

Background Patients with normal (mean pulmonary arterial pressure (mPAP) ≤20 mm Hg) and borderline mean pulmonary pressures (21–24 mm Hg) are “at risk” of developing pulmonary hypertension (PH). The objectives of this analysis were to examine the baseline characteristics in systemic sclerosis (SSc) with normal and borderline mPAP and to explore long-term outcomes in SSc patients with borderline mPAP versus normal haemodynamics. Methods PHAROS is a multicentre prospective longitudinal cohort of patients with SSc “at risk” or recently diagnosed with resting PH on right heart catheterisation (RHC). Baseline clinical characteristics, pulmonary function tests, high-resolution CT, 2-dimensional echocardiogram and RHC results were analysed in normal and borderline mPAP groups. Results 206 patients underwent RHC (results showed 35 normal, 28 borderline mPAP, 143 resting PH). There were no differences in the baseline demographics. Patients in the borderline mPAP group were more likely to have restrictive lung disease (67% vs 30%), fibrosis on high-resolution CT and a higher estimated right ventricular systolic pressure on echocardiogram (46.3 vs 36.2 mm Hg; p<0.05) than patients with normal haemodynamics. RHC revealed higher pulmonary vascular resistance and more elevated mPAP on exercise (≥30; 88% vs 56%) in the borderline mPAP group (p<0.05 for both). Patients were followed for a mean of 25.7 months and 24 patients had a repeat RHC during this period. During follow-up, 55% of the borderline mPAP group and 32% of the normal group developed resting PH (p=NS). Conclusions Patients with borderline mPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and the presence of exercise mPAP ≥30 mm Hg.

Systemic lupus erythematosus and acute pancreatitis: a case series

The aim of this study was to evaluate whether corticosteroid use is the etiological agent in acute pancreatitis in patients with systemic lupus erythematosus, or whether it is related to the underlying connective tissue disorder. Hospital admissions at Thomas Jefferson University Hospital between 1982 and 2002 that carried the dual diagnosis of systemic lupus erythematosus and pancreatitis were identified, and demographic data, clinical interventions and parameters of clinical progression of their disease were identified. From 2947 admissions with systemic lupus erythematosus 25 (0.85%) were diagnosed as having acute pancreatitis; 76% of cases had active systemic lupus erythematosus on presentation, with an average of 4.4 organ involvement, and a clustering of renal disease (56%), pleural effusion (48%) and arthritis (44%) in these patients. Fifteen patients with active disease and three whose disease was inactive received increased doses of corticosteroids, and four active cases and one inactive one stayed on the same doses. Two inactive patients received no corticosteroids before or after the diagnosis of pancreatitis. Eighty-two percent of patients had clinical and laboratory improvement on the higher or maintenance dose of corticosteroids. We therefore concluded that acute pancreatitis is a rare manifestation of systemic lupus erythematosus, and corticosteroids do not appear to be the etiological agent.

Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) cohort study.

OBJECTIVESnPHAROS registry is a prospective longitudinal cohort study to understand the natural history of pulmonary hypertension (PH) in systemic sclerosis (SSc).nnnMETHODSnAt-risk pulmonary arterial hypertension (PAH) is defined by these entry criteria: echocardiogram (echo) systolic pulmonary arterial pressure (sPAP) >40 mmHg, diffusion lung capacity of carbon monoxide (DLco) <55% predicted, or ratio of percentage forced vital capacity (FVC)/percentage DLco >1.6, as measured by pulmonary function testing (PFT). Patients were followed up annually and right heart catheterization (RHC) performed if PH was suspected. We used descriptive statistics and Kaplan-Meier estimate of time to PH diagnosis.nnnRESULTSnA total of 251 at-risk subjects were enrolled between 2005 and 2012 and followed up for mean of 2.5 ± 1.2 years. The mean age at entry was 56.7 ± 11.0 and disease duration was 9.9 ± 8.7 years. Overall, 82 patients had RHC, and 35 were confirmed to have new PH. There were no differences in age, gender, SSc subtypes, antibodies, and disease duration between the at-risk and new PH groups. Using Kaplan-Meier survival, the time to PH was 10% at 2 years, 13% at 3 years, and 25% at 5 years. Most new PH patients at entry met the PFT criteria (76%), had significantly higher sPAP (p = 0.013), had shorter 6-min walk distance, and had exercise-induced hypoxia (p = 0.003) than at-risk PAH group.nnnCONCLUSIONSnA low DLco, high FVC/DLco, exercise-induced hypoxia and entry echo sPAP > 40 were strongly associated with future PH, though RHC was necessary to confirm PH. This ongoing prospective study confirms that these high-risk factors do predict future PH.