Distinct clinical trajectories of gastrointestinal progression among patients with systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is heterogeneous in its clinical presentation. Common manifestations cluster together, defining unique subgroups. This investigation aims to characterize gastrointestinal (GI) phenotypes and determine whether they can be distinguished by temporal progression. METHODS: We examine a well-established SSc patient cohort with a modified Medsger GI severity score measured over time to determine heterogeneity in disease progression. Growth mixture models estimate each patient's phenotype and disease severity trajectory over time. We compare the characteristics of estimated phenotypes using non-parametric statistics and linear and logistic regression to compare patient characteristics between phenotypes while adjusting for disease duration. RESULTS: We examined 2696 SSc patients with at least two Medsger GI scores, identifying four unique phenotypes. The most common phenotype (n = 2325) ("Stable") had an average score of 1 that was consistent over time. Two phenotypes were progressive ["Early Progressive" (n = 142) and "Late Progressive" (n = 115)] with an initial average score of 1. The Early Progressive group increased initially and stabilized, and the Late Progressive group worsened slowly over time. A fourth phenotype ["Early Severe GI"; (n = 114)] had an initial average Medsger GI score just below 3 with high mortality and improving GI severity over time. CONCLUSIONS: Clinically distinct GI phenotypes exist among patients with SSc. These phenotypes are not only distinguished by GI and extra-intestinal SSc clinical complications, but they are also temporally distinct. Distinct autoantibody profiles are associated strongly with more severe GI disease.

Renal biopsy in the management of lupus nephritis during pregnancy.

The differential diagnosis of proteinuria and hematuria in pregnancy is broad and includes active lupus nephritis. Identification of the correct diagnosis often has a profound therapeutic impact on not only the mother but also the fetus. To date, relatively few reports exist on the role of renal biopsy during pregnancy among women with systemic lupus erythematosus (SLE). We present a case series of 11 pregnant women with SLE who underwent a renal biopsy to evaluate a presumptive flare of lupus nephritis. The electronic medical record was retrospectively analyzed for pre-biopsy serum creatinine, proteinuria, hematuria, antinuclear antibodies (ANA), and antibodies to double-stranded DNA (anti-dsDNA); histologic findings on renal biopsy; and the clinical course of each mother and fetus. From 2001 to 2012, 11 pregnant women with SLE flares during pregnancy underwent a renal biopsy at an academic tertiary medical center. At the time of biopsy, median gestational age was 16 weeks (range 9 to 27), median serum creatinine was 0.6 mg/dl (interquartile range 0.5 to 0.9), six (55%) had hematuria, and all had proteinuria >500 mg/24 hours. Proliferative lupus nephritis was found in 10 (91%) of 11 biopsies (five with ISN/RPS Class III; five with ISN/RPS Class IV). All but one individual underwent a change in management guided by information gleaned from renal biopsy. No apparent biopsy-related complications occurred to mother or fetus. Three women elected to terminate their pregnancy; although many factors were involved, the findings on renal biopsy informed the decision-making process. Among the remaining cases, there were three pre-term deliveries, one fetus with complete heart block, one in utero demise, and one maternal death. Renal biopsy is helpful at informing the management of patients with lupus nephritis during pregnancy.

Gout and risk for subsequent coronary heart disease. The Meharry-Hopkins Study.

BACKGROUND: Patients with gout are encountered frequently in clinical practice. Previous studies have suggested that hyperuricemia and gout may represent risk factors for coronary heart disease (CHD), the most common cause of death in American men. METHODS: Prospectively collected data from 2 longitudinal cohort studies of former medical students--371 black men in the Meharry Cohort Study and 1181 white men in the Johns Hopkins Precursors Study--were analyzed. The development of gout and of CHD was determined by physician self-report, and validated by using published criteria. The risk for CHD associated with gout was evaluated using Cox proportional hazards analysis. RESULTS: During a median follow-up of 30 years, there were 38 gout cases and 44 CHD events among the Meharry men, and 68 gout cases and 138 CHD events among the Hopkins men. Prior gout was not associated with an increased risk for incident CHD (relative risk = 1.20; 95% confidence interval, 0.37-3.92) among the Meharry men or among the Hopkins men (relative risk = 0.66; 95% confidence interval, 0.24-1.79). Multivariate analysis adjusted for known CHD risk factors did not alter these findings. CONCLUSION: These results, in black and white male physicians, do not suggest a role in men for targeting gout identification in the primary prevention of CHD.

Body mass index in young men and the risk of subsequent knee and hip osteoarthritis.

PURPOSE: Obesity in middle age is associated with an increased risk of osteoarthritis of the knees in later life. We sought to determine whether body mass index in young men was a risk factor for the subsequent development of osteoarthritis of the knee and hip. SUBJECTS AND METHODS: Body mass index was assessed in 1,180 male medical students at age 23 +/- 2 (mean +/- SD) years and at several times during follow-up. The incidence of knee and hip osteoarthritis was ascertained by self-report and corroborated with information on symptoms and radiographic findings. RESULTS: During a median follow-up of 36 years, 62 participants developed knee osteoarthritis and 27 developed hip osteoarthritis. The incidence of knee, but not hip, osteoarthritis was strongly associated with body mass index assessed at ages 20 to 29 years and 30 to 39 years (both P <0.001). For body mass index assessed at ages 20 to 29 years, the incidence of knee osteoarthritis at age 65 years was 12.8% among the heaviest subjects (range 24.7 to 37.6 kg/m2), threefold greater than the incidence of 4.0% in the leanest (15.6 to 22.8 kg/m2) category of body mass index (P = 0.0001). Thus, for a man who was 180 cm (5'11") tall, each 8 kg (18 lb) greater weight at ages 20 to 29 years was associated with an increased risk of subsequent knee osteoarthritis (relative risk = 1.7, 95% confidence interval 1.3 to 2.1), after adjustment for year of birth, physical activity, and knee injury. Body mass index at ages 20 to 29 years was more predictive of future osteoarthritis than at ages 30 to 39 or 40 to 49 years. CONCLUSION: Greater body mass index in young men ages 20 to 29 years is associated with an increased risk of subsequent knee, but not hip, osteoarthritis, suggesting that cumulative exposure to greater weight during young adult life is an important cause of osteoarthritis.

Symptoms of Raynaud's phenomenon in an inner-city African-American community: prevalence and self-reported cardiovascular comorbidity.

The objective of this study was to determine the prevalence of symptoms and the morbidity associated with Raynaud's phenomenon (RP) among African Americans. A total of 2196 randomly selected residents of an inner-city community, in Baltimore, completed a health-assessment survey. Symptoms of RP consisted of cold sensitivity plus cold-induced white or blue digital color change. One third (n = 703) reported cold sensitivity and 14% (n = 308) reported digital color change; 84 residents with symptoms of RP were identified, yielding an overall prevalence rate of 3.8% (95% confidence interval [CI] 3.0-4.6). RP was associated with poor or fair health status (odds ratio [OR] = 1.82, CI 1.18-2.81), heart disease (OR = 2.32, CI 1.39-3.87), and stroke (OR = 2.20, CI 1.17-4.15), after adjustment for age, gender, and physician-diagnosed arthritis. The prevalence of symptoms of RP in this African-American community is comparable to published reports from other populations. These community-based data suggest that identification of RP among African Americans should raise consideration of possible comorbidity, particularly cardiovascular disease.

Behçet's disease complicated by pylephlebitis and hepatic abscesses.

A 22 year old man presented with fever, abdominal pain, weight loss and diarrhea. Past medical history revealed recurrent aseptic meningitis, uveitis, and erythema nodosum. Further inquiry unveiled a prominent history of oral aphthous ulcers; all features of Behçet's disease. Imaging revealed mesenteric arteritis and pylephlebitis, septic thrombophlebitis of the portal vein, a previously unrecognized complication of Behçet's disease, with multiple intrahepatic abscesses. Portal venography demonstrated an extensively diseased, expanded, and obstructed portal venous system. Blood cultures and portal vein aspirate yielded polymicrobial flora. Percutaneous intraportal thrombolytic therapy and mechanical thrombectomy were attempted to restore flow to the portal venous system. This distinctly rare manifestation of Behçet's Disease, pylephlebitis, may result from ischemic injury and structural compromise of the bowel mucosa, resulting from underlying vasculitis.

Obesity and approaches to weight in an urban African-American community.

OBJECTIVES: To describe the prevalence of obesity, associated factors, and current approaches to weight in an inner city African-American community. DESIGN: In-home survey by community health interviewers. SETTING: Baltimore, Maryland. PARTICIPANTS: 2196 community residents identified in a probability sample of census blocks. MAIN OUTCOME MEASURES: Self-reported height and weight and calculated Body Mass Index (BMI), category of BMI, and stated weight goals. RESULTS: Sixty percent of participants were overweight (BMI> or =25 kg/m2), and 31% were obese (BMI> or =30 kg/m2). In multivariate analysis, women, those earning $15,000-30,000, and those aged 45-60 were more likely to be obese; less likely to be obese were smokers, daily drinkers, and those with "good" or "excellent" health. Sixty-one percent of obese participants reported trying to lose weight, while 36% of normal weight participants were trying to gain weight. Of those trying to lose weight, 35% were using recommended approaches, and 26% received "the professional help they needed to control their weight." CONCLUSIONS: Although obesity was prevalent, few were using recommended weight loss strategies and a significant minority of normal weight participants were trying to gain weight, indicating a need for improved weight management and obesity prevention in the African-American community.

Community health survey in an urban African-American neighborhood: distribution and correlates of elevated blood pressure.

While considerable improvements have been made over the last 30 years in hypertension (HTN) awareness, treatment, and control, a recent reversal of these trends has been documented with African-American adults, particularly among those continuing to suffer from uncontrolled hypertension and its adverse consequences. This paper presents data from a cross-sectional representative survey of the health status of an urban African-American community. The study was designed in partnership with community leadership to improve HTN care and control. The baseline survey was a face-to-face interview (including blood pressure [BP] measurements) of 2,196 adults residing in randomly selected blocks in the Sandtown-Winchester neighborhood in Baltimore City. These sample data were compared with national data from the NHANES III survey, and demonstrated similar awareness of hypertension. However, hypertension control rates among treated hypertensives were significantly lower in the study community (28%) than in the national survey (44%). Compared with normotensive individuals, those with HTN were significantly older, had less education, were less likely to be employed, and had lower annual incomes. Individuals with HTN were also significantly more likely to rate their health as poor/fair, to report a history of heart disease, stroke, diabetes, kidney disease, obesity, high cholesterol, and lack of exercise, as well as to be at greater risk of alcoholism or alcohol problems. Hypertensive individuals (88% with reported prior history, 12% newly detected) were significantly more likely to have a usual source of care, have seen a health professional in the last 12 months, and to be extremely satisfied with the provider; however, 20% of individuals with hypertension reported no health insurance. These data indicate the need for focused interventions to enhance hypertension maintenance of care and adherence to treatment.

Arterial stiffness and hand osteoarthritis: a novel relationship?

OBJECTIVE: Osteoarthritis (OA) and vascular stiffening may share elements of common pathogenesis, but their potential relatedness has been the focus of little prior inquiry. We tested the hypothesis that these two aging-associated conditions are related to each other. METHOD: We analyzed cross-sectional data from 256 participants of the Baltimore Longitudinal Study of Aging (BLSA), a study of normative aging. All underwent measurement of arterial pulse wave velocity (PWV), an index of vascular stiffness, as well as hand radiographs that were graded for evidence of OA. Twenty total joints across three joint groups (distal interphalangeal [DIP], proximal interphalangeal [PIP], carpal-metacarpal [CMC]) were each assigned a Kellgren-Lawrence grade (K-L) of 0 (normal) through 4 (severe), with K-L grades >or=2 considered evidence of definite OA. Radiographic hand OA was defined as definite OA changes in at least two of the three anatomic hand sites (DIP, PIP, CMC). OA burden was represented by the total number of affected OA joints, and a cumulative K-L grade was aggregated across all hand joint groups. The relationship of PWV with these three measures of hand OA was assessed by linear regression. RESULTS: Upon univariate analysis, the presence of radiographic hand OA (beta=218.1, P<0.01), the total number of OA joints (beta=32.9, P<0.01), and the cumulative K-L grade across all joint groups (beta=12.2, P<0.01) were each associated with increased PWV. These associations, however, were no longer significant in age-adjusted models. CONCLUSION: Although significant individual relationships between PWV and several measures of hand OA were observed, these associations were largely attributable to the confounding effect of age.

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.

Central nervous system lymphoma associated with mycophenolate mofetil in lupus nephritis.

Lymphomas, both within and outside the central nervous system, are uncommon among patients with systemic lupus erythematosus (SLE). We describe a 58-year old Korean woman with SLE who presented with acute headache and confusion in the setting of prednisone and mycophenolate mofetil (MMF) therapy used to treat focal proliferative and membranous lupus nephritis. Three-dimensional brain magnetic resonance imaging (MRI) showed two peripherally ('ring') enhancing lesions within the basal ganglia, bilaterally, with associated mass effect and subfalcine herniation. A brain biopsy revealed an Epstein-Barr virus (EBV)-positive diffuse large B cell lymphoma. This is the first description of CNS lymphoma in a patient treated with MMF for lupus nephritis. While intracerebral lymphoma in the immunocompromised patient with lupus is rare, this disorder should be considered in the differential diagnosis of new-onset neurological symptoms among such patients.

Treatment of scleroderma.

Although no new agents were studied in the treatment of scleroderma this year, major steps were taken to improve our investigative approach to this disease. The American College of Rheumatology Committee on Design and Outcomes in Clinical Trials in Systemic Sclerosis (Scleroderma) published guidelines for clinical trials in scleroderma. These guidelines suggest that great care should be taken in the design of therapeutic trials in scleroderma so that the clinical impact of new treatments can be properly understood. Excellent reviews were published this year on how to manage scleroderma and its complications, particularly in the area of gastrointestinal involvement. The need to better understand the treatment of lung disease in scleroderma was emphasized in several reports. Provocative new insight into the pathogenesis of scleroderma has suggested several potential targets for novel approaches to treatment. The challenge for scleroderma clinical researchers in the future is to prioritize treatment options and organize large collaborative studies that are prospective, controlled, and well designed.

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.

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.

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.