Noreen Fertig

Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis: A Randomized, Placebo-phase Trial

OBJECTIVE To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients. METHODS Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required ≥3 abnormal CSMs, with or without muscle weakness. Patients were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary end point compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary end points were the time to achieve ≥20% improvement in muscle strength and the proportions of patients in the early and late rituximab groups achieving the DOI at week 8. RESULTS Among 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieving the DOI between the rituximab late (n = 102) and rituximab early (n = 93) groups (P = 0.74 by log rank test), with a median time to achieving a DOI of 20.2 weeks and 20.0 weeks, respectively. The secondary end points also did not significantly differ between the 2 treatment groups. However, 161 (83%) of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial. CONCLUSION Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI. The role of B cell-depleting therapies in myositis warrants further study, with consideration for a different trial design.

Systemic sclerosis sine scleroderma: Demographic, clinical, and serologic features and survival in forty‐eight patients

OBJECTIVE To describe the demographic, clinical, and laboratory features and natural history of patients with systemic sclerosis sine scleroderma (ssSSc), and to compare them with those of patients with SSc and limited cutaneous involvement (IcSSc). METHODS The University of Pittsburgh Scleroderma Databank served as the data source. Patients were divided into those who had no skin thickening (ssSSc) and those who had skin thickening only distal to elbows or knees and/or of the face (IcSSc) during their disease course. These two groups were compared with regard to demographic characteristics, clinical, laboratory, and serologic features, and survival rates. Chi-square and Students t-test analyses were performed, and Fishers exact test was used as appropriate. RESULTS Of 555 consecutive patients without diffuse cutaneous SSc, 48 (9%) had ssSSc and 507 (91%) had IcSSc. The ssSSc patients had a mean total disease duration of 18.6 years (15.1 years before study entry and 3.5 years of followup after study entry), and had not developed IcSSc or another connective tissue disease. Other than the absence of skin thickening, the ssSSc group had no significant differences in individual internal organ involvements, laboratory features, serum autoantibody type, or survival rate compared with patients with IcSSc. Within the category of lung involvement, patients with ssSSc had a significantly greater frequency of dyspnea with mild exertion or at rest, and a tendency toward reduced carbon monoxide diffusing capacity (<70% of predicted normal) and primary pulmonary arterial hypertension. Patients with IcSSc had significantly more frequent individual manifestations of digital pitting scars, digital-tip ulcers, telangiectasia, and calcinosis than those with ssSSc, in part related to increased time of observation. Puffy fingers and finger joint contractures were detected significantly more often in IcSSc patients. CONCLUSION Systemic sclerosis sine scleroderma should be included in the spectrum of SSc with limited cutaneous involvement and should not be considered a distinct or separate disorder.

Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma

Objective To examine the association of skin thickness progression rate (STPR) with mortality, and as a predictor of future internal organ involvement in an inception cohort of diffuse cutaneous systemic sclerosis (SSc) patients. Methods Diffuse cutaneous SSc patients older than 16 years of age evaluated at the University of Pittsburgh within 2 years of the first evidence of skin thickening between 1980 and 2005 were eligible. The authors calculated the STPR on these patients, and examined the relationship of this variable to the development of early internal organ involvement and short-term mortality using logistic regression. Results 826 patients were included in the analysis. Patients with a rapid STPR experienced significantly reduced short-term survival at 1 and 2 years from the time of first Pittsburgh evaluation (p=0.002). Patients with a rapid STPR were more likely to develop renal crisis within 1–2 years of follow-up. Rapid STPR was found to be an independent predictor of both mortality (OR 1.72; 95% CI 1.13 to 2.62; p=0.01) and ‘renal crisis’ (OR 2.05, 95% CI 1.10 to 3.85; p=0.02) within 2 years from first evaluation. Conclusion The STPR is an easy measure to perform at the time of initial evaluation for identifying those diffuse cutaneous SSc patients who are at increased risk of mortality and the development of renal crisis during the following 2 years.

In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype.

The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1–0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes.

Patients with non-Jo-1 anti-tRNA-synthetase autoantibodies have worse survival than Jo-1 positive patients

Objective To compare the cumulative survival and event free survival in patients with Jo-1 versus non-Jo-1 anti-tRNA synthetase autoantibodies (anti-synAb). Methods Anti-synAb positive patients initially evaluated from 1985 to 2009 were included regardless of the connective tissue disease (CTD) diagnosis. Clinical data were extracted from a prospectively collected database and chart review. Survival between Jo-1 and non-Jo-1 was compared by log rank and Cox proportional hazards methods. Results 202 patients possessed anti-synAb: 122 Jo-1 and 80 non-Jo-1 (35 PL-12; 25 PL-7; 9 EJ; 6 KS; 5 OJ). The diagnoses at first visit for Jo-1 and non-Jo-1 patients were myositis in 83% and 40.0%, overlap or undifferentiated CTD in 17% and 47.5%, and systemic sclerosis in 0% and 12.5%, respectively (p<0.001). The median delay in diagnosis was 0.4 years in Jo-1 patients versus 1.0 year in non-Jo-1 patients (p<0.001). The most common causes of death in the overall cohort were pulmonary fibrosis in 49% and pulmonary hypertension in 11%. The 5- and 10-year unadjusted cumulative survival was 90% and 70% for Jo-1 patients, and 75% and 47% for non-Jo-1 patients (p<0.005). The hazard ratio (HR) of non-Jo-1 patients compared with Jo-1 patients was 1.9 (p=0.01) for cumulative and 1.9 (p=0.008) for event free survival from diagnosis. Age at first diagnosis and diagnosis delay but not gender, ethnicity and CTD diagnosis influenced survival. Conclusions Non-Jo-1 anti-synAb positive patients have decreased survival compared with Jo-1 patients. The difference in survival may be partly attributable to a delay in diagnosis in the non-Jo-1 patients.

Genetic Control of Autoimmunity: Protection from Diabetes, but Spontaneous Autoimmune Biliary Disease in a Nonobese Diabetic Congenic Strain

At least 20 insulin-dependent diabetes (Idd) loci modify the progression of autoimmune diabetes in the NOD mouse, an animal model of human type 1 diabetes. The NOD.c3c4 congenic mouse, which has multiple B6- and B10-derived Idd-resistant alleles on chromosomes 3 and 4, respectively, is completely protected from autoimmune diabetes. We demonstrate in this study, however, that NOD.c3c4 mice develop a novel spontaneous and fatal autoimmune polycystic biliary tract disease, with lymphocytic peribiliary infiltrates and autoantibodies. Strains having a subset of the Idd-resistant alleles present in the NOD.c3c4 strain show component phenotypes of the liver disease: NOD mice with B6 resistance alleles only on chromosome 3 have lymphocytic liver infiltration without autoantibody formation, while NOD mice with B10 resistance alleles only on chromosome 4 show autoantibody formation without liver infiltration. The liver disease is transferable to naive NOD.c3c4 recipients using splenocytes from affected NOD.c3c4 mice, demonstrating an autoimmune etiology. Thus, substitution of non-NOD genetic intervals into the NOD strain can prevent diabetes, but in turn cause an entirely different autoimmune syndrome, a finding consistent with a generalized failure of self-tolerance in the NOD genetic background. The complex clinical phenotypes in human autoimmune conditions may be similarly resolved into largely overlapping biochemical pathways that are then modified, potentially by alleles at a few key chromosomal regions, to produce specific autoimmune syndromes.

Clinical and Serologic Characterization of an Argentine Pediatric Myositis Cohort: Identification of a Novel Autoantibody (anti-MJ) to a 142-kDa Protein

Objective. Autoantibodies are frequently found in adult patients with polymyositis (PM), dermato-myositis (DM), and overlap myositis disorders. They are less common in pediatric patients with myositis. We investigated the autoantibody pattern in a pediatric Argentine Caucasian cohort to characterize novel autoantibodies. Methods. Sera from children that satisfied published criteria for idiopathic inflammatory myopathy were analyzed for autoantibodies by RNA and protein immunoprecipitation and immunoblotting techniques. Routine myositis-specific and myositis-associated autoantibodies as well as autoantibody specificities were determined. Results. We tested sera from 64 consecutive pediatric myositis patients, including 40 with juvenile DM, 7 with juvenile PM, and 17 with overlap myositis syndromes. Sixteen (25%) patients were found to have anti-MJ autoantibody exclusively, which appears to identify a subset of pediatric myositis patients with severe disease characterized by muscle contractures and atrophy and significant compromise of functional status. Fourteen (22%) patients were found to have an antibody targeting 2 proteins of 155 and 140 kDa. Other myositis-specific autoantibodies were uncommon in this pediatric cohort. Conclusion. A newly recognized autoantibody, anti-MJ, was the most common antibody found in this Argentine pediatric cohort. The clinical features indicated that this antibody is distinct from other reported antibodies in pediatric patients with myositis.

Characterization and peripheral blood biomarker assessment of anti–Jo‐1 antibody–positive interstitial lung disease

OBJECTIVE Using a combination of clinical, radiographic, functional, and serum protein biomarker assessments, this study was aimed at defining the prevalence and clinical characteristics of interstitial lung disease (ILD) in a large cohort of patients with anti-Jo-1 antibodies. METHODS A review of clinical records, pulmonary function test results, and findings on imaging studies determined the existence of ILD in anti-Jo-1 antibody-positive individuals whose data were accumulated in the University of Pittsburgh Myositis Database from 1982 to 2007. Multiplex enzyme-linked immunosorbent assays (ELISAs) for serum inflammation markers, cytokines, chemokines, and matrix metalloproteinases in different patient subgroups were performed to assess the serum proteins associated with anti-Jo-1 antibody-positive ILD. RESULTS Among the 90 anti-Jo-1 antibody-positive individuals with sufficient clinical, radiographic, and/or pulmonary function data, 77 (86%) met the criteria for ILD. While computed tomography scans revealed a variety of patterns suggestive of underlying usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia, a review of the histopathologic abnormalities in a subset of patients undergoing open lung biopsy or transplantation or whose lung tissue was obtained at autopsy (n = 22) demonstrated a preponderance of UIP and diffuse alveolar damage. Analysis by multiplex ELISA yielded statistically significant associations between anti-Jo-1 antibody-positive ILD and elevated serum levels of C-reactive protein (CRP), CXCL9, and CXCL10, which distinguished this disease entity from idiopathic pulmonary fibrosis and anti-signal recognition particle antibody-positive myositis. Recursive partitioning further demonstrated that combinations of these and other serum protein biomarkers can distinguish these disease subgroups at high levels of sensitivity and specificity. CONCLUSION In this large cohort of anti-Jo-1 antibody-positive individuals, the incidence of ILD approached 90%. Multiplex ELISA demonstrated disease-specific associations between anti-Jo-1 antibody-positive ILD and serum levels of CRP as well as the interferon-gamma-inducible chemokines CXCL9 and CXCL10, highlighting the potential of this approach to define biologically active molecules contributing to the pathogenesis of myositis-associated ILD.

Serum Autoantibodies and Their Clinical Associations in Patients with Childhood-and Adult-Onset Linear Scleroderma. A Single-Center Study

Objective To determine the frequency of selected serum autoantibodies and their clinical associations in patients with childhood-onset (ChO) or adult-onset (AO) linear scleroderma (LiScl) evaluated at a single institution. Methods Seventy-two patients (ChO = 40, AO = 32), including 12 with en coup de sabre, were studied. All ChO patients had disease onset before age 16 years. Clinical features (extent of cutaneous disease, activity, and joint contractures) were recorded. Antinuclear antibodies (ANA) were identified by indirect immunofluorescence (HEp-2 cells), and anti-single-stranded DNA (anti-ssDNA), antihistone (AHA), and antichromatin (AChA) autoantibodies were detected by ELISA. Results There were no significant differences between groups in regard to gender, proportion with LiScl/E, or clinical features except joint contractures (ChO > AO; p = 0.04). There were no differences in the frequency of ANA or other autoantibodies between the groups except for AHA (ChO > AO). AHA was more frequently found with anti-ssDNA (p < 0.0001). LiScl patients with positive anti-ssDNA and/or AHA had more extensive cutaneous involvement and more often had joint contractures (p < 0.05). Anti-ssDNAwas present more frequently inAO than in ChO patients with active lesions (p = 0.04). ANA and AChA were not associated with any clinical features. Both AHA and anti-ssDNA levels showed good correlation with disease severity. Conclusion Over two-thirds of LiScl patients had ANA. Patients with ChO were similar to those with AO with regard to the frequency of selected serum autoantibodies. Anti-ssDNA and AHA were frequently found together and both were associated with more extensive skin disease with joint contractures. LiScl disease severity correlated with the serum levels of both these antibodies.

A clinical and serologic comparison of African American and Caucasian patients with systemic sclerosis

OBJECTIVE Epidemiology studies suggest that systemic sclerosis (SSc) is more common, occurs at a younger age, and is more severe in African Americans than Caucasians. However, the scleroderma autoantibody profile is very different between these 2 ethnic groups. This study was undertaken to examine the demographic and disease features, frequency and severity of internal organ system involvement, and survival in African American patients compared to Caucasian patients with SSc, giving particular attention to their serum autoantibody profiles. METHODS Demographic features, clinical characteristics, autoantibody profile, organ involvement, and survival were studied in consecutive African American and Caucasian patients with SSc whose visits were recorded between 1972 and 2007 as part of the Pittsburgh Scleroderma Database. The Medsger Severity Score for SSc was used to determine the severity of disease. RESULTS African American patients were more likely to have anti-topoisomerase I (anti-topo I), anti-U1 RNP, and anti-U3 RNP autoantibodies. In comparing African American and Caucasian patients with these antibodies, pulmonary fibrosis was found to be more frequent and more severe, and the rate of survival was decreased, in African American patients with anti-topo I antibodies compared to Caucasian patients with anti-topo I. Pulmonary fibrosis was also more severe in the anti-U1 RNP-positive patients, but this was not associated with a difference in survival between African Americans and Caucasians. Anti-U3 RNP was associated with more severe gastrointestinal involvement in African Americans compared to Caucasians. CONCLUSION African Americans with SSc have more severe disease complications compared to Caucasians with SSc, and this is associated with both the type of autoantibody present and the severity of interstitial lung disease. Thus, it is hoped that early aggressive intervention in African Americans with interstitial lung disease will improve outcomes.