Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension.

N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of neurohormonal activation that is useful in the diagnosis and prognosis of various forms of pulmonary arterial hypertension (PAH). We sought to characterise and compare NT-proBNP in a cohort of PAH related to systemic sclerosis (PAH-SSc) and idiopathic PAH (IPAH) patients. NT-proBNP levels, collected from PAH-SSc and IPAH patients followed prospectively, were compared and correlated with haemodynamic variables. Cox proportional hazard models were created to assess the predictive value of NT-proBNP. 98 patients (55 PAH-SSc, 43 IPAH) were included. Haemodynamics were similar, except for lower mean pulmonary arterial pressure in PAH-SSc. NT-proBNP levels were significantly higher in PAH-SSc (3,419+/-3,784 versus 1,393+/-1,633 pg x mL(-1); p<0.01) and were more closely related to haemodynamics in PAH-SSc than IPAH. 28 patients died. NT-proBNP predicted survival (hazard ratio (HR) 3.18; p<0.01) in the overall cohort; however, when stratified by group, predicted survival only in PAH-SSc (HR 3.07, p<0.01 versus 2.02, p = 0.29 in IPAH). This is the first description showing NT-proBNP levels are 1) significantly higher in PAH-SSc than IPAH despite less severe haemodynamic perturbations, and 2) stronger predictors of survival in PAH-SSc, suggesting that neurohormonal regulation may differ between PAH-SSc and IPAH. Future studies to define pertinent mechanisms are warranted.

Fatigue: an overlooked determinant of physical function in scleroderma.

OBJECTIVES: To examine the frequency and correlates of fatigue and its impact on physical and social functioning in patients with scleroderma, and to investigate whether fatigue mediates an association between pain and physical function. METHODS: One hundred and seven scleroderma patients attending an academic scleroderma specialty centre completed measures of fatigue, sleep, pain, depressive symptoms, and physical and social functioning. Patients had received a comprehensive clinical assessment with a diagnosis of limited or diffuse scleroderma from their attending rheumatologist. RESULTS: In this sample of scleroderma patients, 76% reported experiencing fatigue and 61% of these patients reported fatigue as one of their three most distressing symptoms. Patients endorsing greater pain had higher levels of self-reported fatigue, as did those reporting greater depression and poorer functioning. Multiple regression analyses indicated that global fatigue was a significant cross-sectional correlate of physical, but not social, functioning after controlling for depressive symptoms, level of education, poor sleep quality and disease subtype. However, global fatigue did not predict physical function when pain was included in the analyses. CONCLUSIONS: Our findings indicate that fatigue is common in scleroderma and that pain and fatigue are significant determinants of physical functioning for patients with limited and diffuse disease subtypes. Future research should investigate whether effective pain treatments reduce symptoms of fatigue, as well as identify other possible causes of fatigue in order to improve quality of life for scleroderma patients.

High-dose cyclophosphamide without stem cell rescue in scleroderma.

OBJECTIVE: To investigate the safety and tolerability of high-dose cyclophosphamide without stem cell rescue in scleroderma. METHODS: An open-label, single-site, uncontrolled study design entered patients with active diffuse cutaneous scleroderma. Patients were treated with cyclophosphamide (50 mg/kg) intravenously daily for 4 consecutive days (total 200 mg/kg) followed by granulocyte colony-stimulating factor (5 microg/kg/day). The primary clinical efficacy end point was the modified Rodnan skin score (mRSS). Secondary end points included the Health Assessment Questionnaire-Disability Index (HAQ-DI), physician global assessment (PGA) and pulmonary function tests. RESULTS: Six patients (4 men, 2 women) aged 19-60 years were entered into the study. One patients died early in the protocol, thus five patients had follow-up data. The percentage reduction of the mRSS in these five evaluable patients within 1 month of treatment was 60%, 55%, 41%, 31% and 0%. The patient with no decline in skin score at 1 month showed a decrease in skin score from 41 to 26 by the 3-month visit, a 37% improvement. Three patients sustained the improvement after treatment for 24, 12 and 12 months. Two patients relapsed at 12 and 6 months after treatment. The PGA and HAQ-DI scores improved in five of the six patients by 72% and 79% respectively at 3 months. The only serious adverse event was a death that occurred owing to infection after neutrophil count recovery. CONCLUSIONS: High-dose cyclophosphamide without stem cell rescue can lead to a clinically significant improvement in skin score and measures of disease severity in patients with diffuse cutaneous scleroderma.

A case-control study of the pathology of oesophageal disease in systemic sclerosis (scleroderma).

BACKGROUND: Atrophy of the smooth muscle layers of the muscularis propria characterises oesophageal involvement in systemic sclerosis (scleroderma). The aetiology of this atrophy and of the resultant oesophageal dysfunction is unknown. OBJECTIVES: To examine oesophageal tissue for evidence of fibrosis, vascular disease, inflammatory reactions and neural abnormalities to determine the possible causes of this disease process. METHODS: A case-control survey was conducted using oesophageal tissue from 74 scleroderma cases and 74 age, race and sex-matched controls from our autopsy files. Histological evidence of oesophageal muscle atrophy was correlated with the degree of vascular changes, inflammatory infiltration, fibrosis, abnormalities of the myenteric plexus and reduction of interstitial cells of Cajal (ICC) using a predesigned semiquantitative descriptive method. RESULTS: Smooth-muscle atrophy was found in 94% of scleroderma cases, and in 5% of controls (p<0.001). Atrophy was evident in the circular smooth muscle in 93% of cases, and in the longitudinal smooth muscle in 66% of cases. Intimal proliferation of arterioles was found in 38% of cases and in 5% of controls (p<0.001), but was not associated with smooth-muscle atrophy (p = 0.29). Despite these vascular changes, there was no evidence of compromised perfusion, such as findings suggestive of acute ischaemic necroses. Minimal cellular infiltrates were seen in the myenteric plexus in 82% of cases and in 92% of controls (p = 0.091). ICC were found in fewer numbers in areas of atrophic smooth muscle compared with adjacent normal smooth muscle in selected scleroderma cases. CONCLUSION: The pathological findings of oesophageal lesions in scleroderma seem inconsistent with either an ischaemic or an inflammatory process. The loss of circular and longitudinal smooth muscle in the distal scleroderma oesophagus may represent loss of normal neural function followed by secondary tissue atrophy, or may be a primary smooth muscle lesion.

Abnormal exhaled ethane concentrations in scleroderma.

Scleroderma (systemic sclerosis) is a chronic multisystem autoimmune disease in which oxidative stress is suspected to play a role in the pathophysiology. Therefore, it was postulated that patients with scleroderma would have abnormally high breath ethane concentrations, which is a volatile product of free-radical-mediated lipid peroxidation, compared with a group of controls. There was a significant difference (p<0.05) between the mean exhaled ethane concentration of 5.27 pmol ml(-1) CO(2) (SEM=0.76) in the scleroderma patients (n=36) versus the mean exhaled concentration of 2.72 pmol ml(-1) CO(2) (SEM=0.71) in a group of healthy controls (n=21). Within the scleroderma group, those subjects taking a calcium channel blocker had lower ethane concentrations compared with patients who were not taking these drugs (p=0.05). There was a significant inverse association between lung diffusion capacity for carbon monoxide (per cent of predicted) and ethane concentration (b=-2.8, p=0.026, CI=-5.2 to -0.35). These data support the presence of increased oxidative stress among patients with scleroderma that is detected by measuring breath ethane concentrations.

Distinct recognition of antibodies to centromere proteins in primary Sjogren's syndrome compared with limited scleroderma.

BACKGROUND: Anticentromere antibodies are characteristically observed in scleroderma but have recently been reported in other autoimmune rheumatic disorders, including Sjögren's syndrome. It is not known whether distinct centromere proteins (CENP) are targeted in primary Sjögren's syndrome (pSS) and scleroderma. OBJECTIVE: To determine whether antibodies to CENP-B and CENP-C are present in these two disorders. METHODS: Sera from 45 patients with pSS and 33 with limited scleroderma were studied. All patients met classification criteria for pSS and scleroderma, respectively. Sera were used to immunoprecipitate in vitro translated CENP-B and CENP-C. The proportions recognising CENP-B or CENP-C were compared. RESULTS: 10 of 45 patients (22%) with pSS and 18 of 33 (55%) with scleroderma had antibodies recognising CENPs (p = 0.004). Seven of 10 (70%) CENP positive patients with pSS recognised CENP-C alone, compared with one of 18 (6%) CENP positive patients with scleroderma (odds ratio (OR) = 40 (95% confidence interval (CI), 3.5 to 450) (p = 0.003). In contrast, the majority (15 of 18 (83%)) of CENP positive scleroderma sera recognised both CENP-B and CENP-C, compared with none of 10 pSS sera (OR = 93 (95% CI, 4.4 to 1979) (p = 0.0001). CONCLUSIONS: The pattern of CENP recognition differs markedly in pSS and limited scleroderma. While patients with pSS predominantly recognise CENP-C alone, dual recognition of CENP-B and CENP-C is most frequent in scleroderma. These findings suggest that obtaining antibodies to specific centromere antigens is useful diagnostically, and imply that distinct mechanisms underlie the unique patterns of centromere autoreactivity in pSS and scleroderma.

Recurrent transverse myelitis associates with anti-Ro (SSA) autoantibodies.

Transverse myelitis (TM) is an idiopathic inflammatory disorder of the spinal cord. The authors observed cases of recurrent TM in patients where anti-Ro (SSA) antibodies were present and therefore performed a case-control study to examine the frequency of anti-Ro autoantibodies in patients with recurrent TM and control subjects. Antibodies to 52-kd Ro were demonstrated in 77% of cases (10/13) compared with only 33% of control subjects (4/12).

Primary pulmonary hypertension is not associated with scleroderma-like changes in nailfold capillaries.

STUDY OBJECTIVES: To determine whether primary pulmonary hypertension (PPH) is associated with scleroderma-like changes in nailfold capillaries. DESIGN: Blinded, prospective, case-control study. SETTING: University medical centers in Baltimore, MD. PATIENTS: Thirty-seven patients with PPH, 15 patients with scleroderma, and 13 healthy control subjects. MEASUREMENTS: Subjects underwent nailfold capillary videomicroscopy of the fourth digits of both hands. Capillary images were evaluated by two blinded, trained graders according to standardized criteria for the presence of scleroderma nailfold changes. RESULTS: The prevalence of scleroderma-associated nailfold changes in patients with PPH (1 of 37 patients) was dramatically lower than that in patients with scleroderma (9 of 15 patients; p < 0.0001). The distribution of nailfold grades for the PPH patients was indistinguishable from that of the healthy control subjects. CONCLUSION: PPH is not associated with scleroderma-like vasculopathy of nailfold capillaries.

A deceptive case of amyloid myopathy: clinical and magnetic resonance imaging features.

Amyloid myopathy is a well-described, increasingly recognized clinical entity. Similar to inflammatory myopathies, amyloid myopathy presents with proximal muscle weakness and can be associated with elevated levels of muscle enzymes. We report the case of a 58-year-old woman who, at presentation to her physician with proximal muscle weakness and congestive heart failure, was antinuclear antibody positive and had muscle biopsy findings "consistent with inflammatory myopathy." She was referred to Johns Hopkins University Medical Center with the diagnosis of polymyositis. Further investigation revealed a monoclonal gammopathy, a unique patterning of subcutaneous fat reticulation and hypodense bone marrow changes on magnetic resonance imaging (MRI), and an endocardial biopsy sample that was positive for light chain amyloid deposition. Paraffin sections of the muscle biopsy sample from the time of her original presentation were obtained, and Congo red staining showed diffuse amyloid deposition throughout the sample, but no inflammation. This case not only illustrates that proximal muscle weakness due to primary amyloid myopathy (as found in light chain amyloidosis and transthyretin amyloidosis) can mimic that of polymyositis, but also shows that unique findings on MRI can alert the clinician to the diagnosis of amyloidosis prior to muscle biopsy.

A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS).

OBJECTIVE: To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's granulomatosis (WG). METHODS: Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. RESULTS: We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43-0.83). CONCLUSION: The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.

The DNA mismatch repair enzyme PMS1 is a myositis-specific autoantigen.

OBJECTIVE: The specificity of the autoantibody response in different autoimmune diseases makes autoantibodies useful for diagnostic purposes. It also focuses attention on tissue- and event-specific circumstances that may select unique molecules for an autoimmune response in specific diseases. Defining additional phenotype-specific autoantibodies may identify such circumstances. This study was undertaken to investigate the disease specificity of PMS1, an autoantigen previously identified in some sera from patients with myositis. METHODS: We used immunoprecipitation analysis to determine the frequency of autoantibodies to PMS1 in sera from patients with myositis, systemic lupus erythematosus, or scleroderma and from healthy controls. Additional antigens recognized by PMS1-positive sera were further characterized in terms of their susceptibility to cleavage by apoptotic proteases. RESULTS: PMS1, a DNA mismatch repair enzyme, was identified as a myositis-specific autoantigen. Autoantibodies to PMS1 were found in 4 of 53 patients with autoimmune myositis (7.5%), but in no sera from 94 patients with other systemic autoimmune diseases (P = 0.016). Additional mismatch repair enzymes (PMS2, MLH1) were targeted, apparently independently. Sera recognizing PMS1 also recognized several other proteins involved in DNA repair and remodeling, including poly(ADP-ribose) polymerase, DNA-dependent protein kinase, and Mi-2. All of these autoantigens were efficiently cleaved by granzyme B, generating unique fragments not observed during other forms of cell death. CONCLUSION: PMS1 autoantibodies are myositis specific. The striking correlation between an immune response to a group of granzyme B substrates (functioning in DNA repair and remodeling) and the myositis phenotype strongly implies that tissue- and event-specific biochemical events play a role in selecting these molecules for an autoimmune response. Understanding the role of granzyme B cleavage in this response is an important priority.

Novel therapy in the treatment of scleroderma.

While the biology of the pathogenesis of scleroderma is continually being better understood, there still is no single agent or therapeutic combination that has a clear impact on the disease process. Traditional medications (colchicine, potassium aminobenzoate (potaba), D-penicillamine) are disappointing in clinical practice despite anecdotal evidence of benefit. Furthermore, the most popular traditional drug, D-penicillamine, failed to clearly show benefit when tested in a well-designed clinical trial comparing conventional high dose with a very low dose (125 mg po. every other day [corrected]) [1]. Currently, most success in managing scleroderma and improving quality of life is secondary to organ-specific therapy, such as management of a renal crisis with an ACE inhibitor, treatment of Raynaud's phenomenon with calcium channel blockers, or control of serious gastrointestinal reflux disease with a proton pump inhibitor. In this review we will focus on novel therapies that are currently being tested in the treatment of scleroderma and have the potential of modifying the disease process and overall clinical outcome. We have attempted to review the rationale for each agent, recognising that its true biological effect will only be determined in clinical trials.

Joint injury in young adults and risk for subsequent knee and hip osteoarthritis.

BACKGROUND: Knee and hip injuries have been linked with osteoarthritis in cross-sectional and case-control studies, but few prospective studies have examined the relation between injuries in young adults and risk for later osteoarthritis. OBJECTIVE: To prospectively examine the relation between joint injury and incident knee and hip osteoarthritis. DESIGN: Prospective cohort study. SETTING: Johns Hopkins Precursors Study. PARTICIPANTS: 1321 former medical students. MEASUREMENTS: Injury status at cohort entry was recorded when the mean age of participants was 22 years. Injury during follow-up and incident osteoarthritis were determined by using self-administered questionnaires. Osteoarthritis was confirmed by symptoms and radiographic findings. RESULTS: Over a median follow-up of 36 years, 141 participants reported joint injuries (knee alone [n = 111], hip alone [n = 16], or knee and hip [n = 14]) and 96 developed osteoarthritis (knee alone [n = 64], hip alone [n = 27], or knee and hip [n = 5]). The cumulative incidence of knee osteoarthritis by 65 years of age was 13.9% in participants who had a knee injury during adolescence and young adulthood and 6.0% in those who did not (P = 0.0045) (relative risk, 2.95 [95% CI, 1.35 to 6.45]). Joint injury at cohort entry or during follow-up substantially increased the risk for subsequent osteoarthritis at that site (relative risk, 5.17 [CI, 3.07 to 8.71] and 3.50 [CI, 0.84 to 14.69] for knee and hip, respectively). Results were similar for persons with osteoarthritis confirmed by radiographs and symptoms. CONCLUSIONS: Young adults with knee injuries are at considerably increased risk for osteoarthritis later in life and should be targeted in the primary prevention of osteoarthritis.

Increased alpha2-adrenergic constriction of isolated arterioles in diffuse scleroderma.

OBJECTIVE: Vasospasm and ischemic organ injury are important in the pathogenesis of systemic sclerosis (SSc; scleroderma). The present study was performed to determine whether SSc arterioles have an intrinsic disturbance in vasoconstrictor activity. METHODS: Skin biopsy samples were obtained from the upper arm of 11 patients with diffuse SSc (clinically uninvolved skin) and 8 age- and sex-matched control subjects. Dermal arterioles were dissected from the biopsy sample and mounted in a myograph for continuous monitoring of arteriolar diameter. The resting internal diameter of control and SSc arterioles was similar (mean +/- SEM 164+/-15 micro and 166+/-18micro, respectively). RESULTS: Dermal arterioles displayed no spontaneous constrictor activity in the absence of stimulation. Vasoconstriction in response to KCI, a receptor-independent activator of smooth muscle, or to phenylephrine, a selective alpha1-adrenergic receptor (alpha1-AR) agonist, was similar in control and SSc arterioles. However, constrictor responses to UK 14,304, a selective alpha2-AR agonist, were increased in SSc compared with control arterioles (maximal constriction responses of 25+/-5% and 67+/-4% [mean +/- SEM] in control and SSc arterioles, respectively; P = 0.000014). Mechanical denudation of the endothelium did not alter reactivity to alpha2-AR activation, indicating that the enhanced constriction in SSc was not mediated by changes in endothelial dilator activity. Indeed, in arterioles constricted with phenylephrine, the endothelial stimuli acetylcholine or bradykinin evoked endothelium-dependent relaxation that was similar in control and SSc arterioles. CONCLUSIONS: Vascular smooth muscle in SSc arterioles displayed a selective increase in alpha2-AR reactivity. The endothelial dilator function appeared normal. Altered activity of smooth muscle alpha2-ARs may contribute to the vasospastic activity that is a prominent feature of the SSc disease process.

Recombinant human relaxin in the treatment of scleroderma. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Relaxin is a pregnancy-related hormone that has tissue remodeling and antifibrotic effects. Systemic sclerosis (scleroderma) is characterized by fibrosis of the skin, vasculature, and internal organs. OBJECTIVE: To assess the efficacy, safety, and dose-response effect of recombinant human relaxin in patients with scleroderma. DESIGN: Multicenter, parallel-group, randomized, double-blind, placebo-controlled trial. SETTING: Academic referral centers. PATIENTS: 68 patients who had had stable, diffuse scleroderma (moderate to severe) for less than 5 years. INTERVENTION: Recombinant human relaxin, 25 or 100 microg/kg of body weight per day, or placebo administered by continuous subcutaneous infusion over 24 weeks. MEASUREMENTS: Modified Rodnan skin score was the primary efficacy measure. Secondary measurements were pulmonary function, the Health Assessment Questionnaire, and other measures of scleroderma that reflected fibrosis. RESULTS: Patients who received 25 microg/kg of recombinant human relaxin per day had significantly lower skin scores than those who received placebo (mean change, -3.6 at 4 weeks [P = 0.021], -7.5 at 12 weeks [P < 0.001], and -8.7 at 24 weeks [P = 0.040]). Similar trends were noted in other outcome measures, including forced vital capacity, measures of oral aperture and hand extension, functional status, and global assessment. Patients who received 100 microg/kg of relaxin per day did not differ from those who received placebo. Drug-related adverse events included menometrorrhagia, reversible anemia, and complications of the subcutaneous drug administration system (site irritation and local infection). CONCLUSIONS: Twenty-four weeks of recombinant human relaxin, 25 microg/kg per day, is associated with reduced skin thickening, improved mobility, and improved function in patients with moderate to severe diffuse scleroderma.

Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis.

BACKGROUND: Lung inflammation (alveolitis) may cause lung fibrosis in scleroderma. OBJECTIVE: To determine whether cyclophosphamide treatment is associated with retention of lung function and improved survival in scleroderma patients with alveolitis. DESIGN: Retrospective cohort study. SETTING: Johns Hopkins and University of Maryland Scleroderma Center. PATIENTS: 103 patients with scleroderma who had bronchoalveolar lavage or lung biopsy. INTERVENTION: Cyclophosphamide therapy. MEASUREMENTS: 1) Serial measurement of forced vital capacity (FVC) and carbon monoxide diffusing capacity and 2) survival. RESULTS: During a median follow-up of 13 months after bronchoalveolar lavage or biopsy, patients with alveolitis who did not receive cyclophosphamide therapy experienced a decrease in FVC (mean difference, -0.28 L [95% Cl, -0.41 to -0.16 L] and -7.1% of the predicted value [Cl, -10.9% to -4.0%]). Carbon monoxide diffusing capacity also decreased in these patients (mean difference, -3.3 x mmol min(-1) x kPa(-1) [Cl, -4.6 to -2.1 mmol x min(-1) x kPa(-1)] and -9.6% of the predicted value [Cl, -16.7% to -2.4%]). During a median follow-up of 16 months, patients with alveolitis who received cyclophosphamide were more likely to have a good outcome (stabilization or improvement) in FVC (relative risk, 2.5 [Cl, 1.5 to 4.1]) and diffusing capacity (relative risk, 1.5 [Cl, 1.0 to 2.2]). These patients also had improved survival; the median survival rate was 89% (25th, 75th percentiles, 84%, 94%) compared with 71% (25th, 75th percentiles, 55%, 86%) in untreated patients (P = 0.01, log-rank test). CONCLUSIONS: The presence of lung inflammation identifies patients with scleroderma who are more likely to have worsening lung function. Lung function outcomes and survival are improved in patients with alveolitis who receive cyclophosphamide.

Mycophenolate mofetil in the treatment of severe skin manifestations of dermatomyositis: a series of 4 cases.

Four cases with classic skin manifestations and histologic evidence of dermatomyositis are presented. No occult malignancies were found. After conventional therapy with corticosteroids, hydroxychloroquine and/or methotrexate proved to be limited by side effects or an inadequate clinical response, a therapeutic trial of mycophenolate mofetil was instituted. This relatively new drug, which inhibits lymphocyte proliferation, was effective [with a mean duration of treatment of 13 months (range 6-20)] at controlling cutaneous disease activity, resulting in a decrease of the steroid dose.