Harold E. Paulus

2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease‐modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis

The American College of Rheumatology (ACR) most recently published recommendations for use of disease modifying anti-rheumatic drugs (DMARDs) and biologics in the treatment of rheumatoid arthritis (RA) in 2008 (1). These recommendations covered indications for use, monitoring of side-effects, assessment of the clinical response to DMARDs and biologics, screening for tuberculosis (TB), and assessment of the roles of cost and patient preference in decision-making for biologic agents (1). Recognizing the rapidly evolving knowledge in RA management and the accumulation of new evidence regarding the safety and efficacy of existing and newer therapies, the ACR commissioned an update of the 2008 recommendations in select topic areas. The 2012 revision updates the 2008 ACR recommendations in the following areas: (1) indications for DMARDs and biologics; (2) switching between DMARD and biologic therapies; (3) use of biologics in high-risk patients (those with hepatitis, congestive heart failure, and malignancy); (4) screening for TB in patients starting or currently receiving biologics; and (5) vaccination in patients starting or currently receiving DMARDs or biologics (Table 1). Table 1 Overview Comparison of Topics and Medications Included in the 2008 and 2012 ACR RA Recommendations METHODS We utilized the same methodology as described in detail in the 2008 guidelines (1) to maintain consistency and to allow cumulative evidence to inform this 2012 recommendation update. These recommendations were developed by two expert panels: (1) a non-voting working group and Core Expert Panel (CEP) of clinicians and methodologists responsible for the selection of the relevant topic areas to be considered, the systematic literature review, and the evidence synthesis and creation of “clinical scenarios”; and (2) a Task Force Panel (TFP) of 11 internationally-recognized expert clinicians, patient representatives and methodologists with expertise in RA treatment, evidence-based medicine and patient preferences who were tasked with rating the scenarios created using an ordinal scale specified in the Research and Development/University of California at Los Angeles (RAND/UCLA) Appropriateness method (2–4). This method solicited formal input from a multi-disciplinary TFP panel to make recommendations informed by the evidence. The methods used to develop the updated ACR recommendations are described briefly below. Systematic Literature Review – Sources, Databases and Domains Literature searches for both DMARDs and biologics relied predominantly on PubMed searches) with medical subject headings (MeSH) and relevant keywords similar to those used for the 2008 ACR RA recommendations (see Appendices 1 and 2). We included randomized clinical trials (RCTs), controlled clinical trials (CCTs), quasi-experimental designs, cohort studies (prospective or retrospective), and case-control studies, with no restrictions on sample size. More details about inclusion criteria are listed below and in Appendix 3. The 2008 recommendations were based on a literature search that ended on February 14, 2007. The literature search end date for the 2012 Update was February 26, 2010 for the efficacy and safety studies and September 22, 2010 for additional qualitative reviews related to TB screening, immunization and hepatitis (similar to the 2008 methodology). Studies published subsequent to that date were not included. For biologics, we also reviewed the Cochrane systematic reviews and overviews (published and in press) in the Cochrane Database of Systematic Reviews to identify additional studies (5–8) and further supplemented by hand-checking the bibliographies of all included articles. Finally, the CEP and TFP confirmed that relevant literature was included for evidence synthesis. Unless they were identified by the literature search and met the article inclusion criteria (see Appendix 3), we did not review any unpublished data from product manufacturers, investigators, or the Food and Drug Administration (FDA) Adverse Event Reporting System. We searched the literature for the eight DMARDs and nine biologics most commonly used for the treatment of RA. Literature was searched for eight DMARDS including azathioprine, cyclosporine, hydroxychloroquine, leflunomide, methotrexate, minocycline, organic gold compounds and sulfasalazine. As in 2008, azathioprine, cyclosporine and gold were not included in the recommendations based on infrequent use and lack of new data (Table 1). Literature was searched for nine biologics including abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab; anakinra was not included in the recommendations due to infrequent use and lack of new data. Details of the bibliographic search strategy are listed in Appendix 1.

American College of Rheumatology 2008 Recommendations for the Use of Nonbiologic and Biologic Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Guidelines and recommendations developed and/or endorsed by the American College of Rheumatology (ACR) are intended to provide guidance for particular patterns of practice and not to dictate the care of a particular patient. The ACR considers adherence to these guidelines and recommendations to be voluntary, with the ultimate determination regarding their application to be made by the physician in light of each patient’s individual circumstances. Guidelines and recommendations are intended to promote beneficial or desirable outcomes but cannot guarantee any specific outcome. Guidelines and recommendations developed or endorsed by the ACR are subject to periodic revision as warranted by the evolution of medical knowledge, technology, and practice.

Immunosuppressive and corticosteroid therapy of polyarteritis nodosa

The clinical manifestations, treatment and survival of 64 patients with polyarteritis nodosa seen from 1955 to 1977 were evaluated. In general, the patients had multisystem involvement. No patient with cutaneous vasculitis alone was accepted into the study. The clinical diagnosis was confirmed by biopsy in 34 patients, by autopsy in 13 and by angiography in 10. The patients were treated at the discretion of the physicians responsible for their care. Eight of the 64 patients received only supportive therapy (group 1), 34 received corticosteroids alone (group 2), and 22 received both corticosteroids and an immunosuppressive agent (group 3). Five patients in group 2 and one patient in group 3 were excluded from survival studies because of insufficient length of therapy. Patients in the three treatment groups were very similar with respect to 18 clinical and laboratory variables. Median survival times for the three groups were three months, 63 months and 149 months, respectively; 5 year survival rates were 12 per cent, 53 per cent and 80 per cent (p less than 0.05). Despite difficulty in precisely defining polyarteritis nodosa, the data suggest a better prognosis for treated patients than has previously been appreciated, with improvement in outcome when an immunosuppressive agent is added to corticosteroid therapy.

Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: A pilot study

BACKGROUND Because traditional therapies for rheumatoid arthritis (RA) such as methotrexate (MTX) do not produce an adequate response in many patients, newer therapies that block the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) are increasingly being used in combination with MTX. OBJECTIVE This study evaluated the efficacy, pharmacokinetics, and safety profile of adalimumab, a fully human anti-TNF alpha monoclonal antibody, when added to continuing MTX therapy. METHODS This Phase I, randomized, dose-titration study consisted of a 4-week, double-blind, placebo-controlled treatment phase and a 26-month, open-label continuation phase. Patients with RA who had been taking stable doses of MTX (mean dose, 17 mg/wk) for > or =3 months before enrollment with an inadequate response were randomly assigned to receive 2 single doses of either adalimumab 0.25, 0.5, 1, 3, or 5 mg/kg i.v. or placebo in the double-blind phase. In the open-label phase, patients received treatment with 1 of the doses of adalimumab every other week or monthly for 18 months; patients were then switched to adalimumab 40 mg i.v. or SC every other week or monthly. The main efficacy end point was 20% improvement in American College of Rheumatology response criteria (ACR20). Other efficacy end points included 50% (ACR50) and 70% improvements in ACR response criteria. Pharmacokinetic parameters were analyzed for adalimumab and MTX during both phases of the study. Serum adalimumab concentrations were analyzed using a validated enzyme-linked immunosorbent assay relying on the double-antigen principle. Peak and trough concentrations were determined from observed concentration-time data, and a modeling approach was used to estimate total serum clearance, mean apparent terminal half-life, apparent volume of distribution at steady state, and area under the concentration-time curve. RESULTS Sixty patients entered the double-blind phase, 45 receiving adalimumab and 15 receiving placebo; 1 placebo recipient chose not to continue into the open-label phase. Overall, the study population included 47 (78.3%) women and 13 (21.7%) men. The mean age was 52.9 years (range, 24-73 years), and the mean body weight was 69.7 kg (range, 43-98 kg). ACR20 and ACR50 responses were achieved on at least 1 assessment during the 4-week double-blind phase by a respective 29 (64.4%) and 11 (24.4%) of 45 patients receiving active treatment and by 4 (26.7%) and none of the 15 patients receiving placebo. Responses to adalimumab were rapid, with 10 (22.2%) of 45 patients achieving an ACR20 response within 24 hours of dosing. Of 29 adalimumab recipients who had an ACR20 response, 18 (62.1%) had a duration of response (time from first occurrence of a response to first occurrence of a nonresponse) of 1 to 2 weeks, and 11 (37.9%) had a duration of response of 3 to 13 weeks. The pharmacokinetic properties of adalimumab appeared to be linear. The mean apparent terminal half-life after a single intravenous dose of adalimumab ranged from 15 to 19 days in the 5 dose groups. Repeated administration of adalimumab had no statistically significant effect on the pharmacokinetics of MTX, indicating that dose adjustment of MTX is not necessary. Adalimumab was well tolerated, and there were no dose-related adverse events. CONCLUSIONS Among patients with active RA who had not had an adequate response to MTX, addition of adalimumab to MTX achieved statistically significant, long-term improvement compared with placebo plus MTX (P < or = 0.05), as indicated by ACR responses at 26 months. The combination was well tolerated. Adalimumab exhibited linear pharmacokinetics. In this selected patient population, adalimumabs long half-life of 15 to 19 days supports every-other-week dosing. Coadministration of adalimumab did not alter serum levels of MTX.

A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: The Treatment of Early Aggressive Rheumatoid Arthritis trial†‡

OBJECTIVE To assess whether it is better to intensively treat all patients with early rheumatoid arthritis (RA) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response (as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] of ≥ 3.2 at week 24) to methotrexate (MTX) monotherapy, and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine. METHODS The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study is a 2-year, randomized, double-blind trial. A 2 × 2 factorial design was used to randomly assign subjects to 1 of 4 treatment arms: immediate treatment with MTX plus etanercept, immediate oral triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or step-up from MTX monotherapy to one of the combination therapies (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine) at week 24 if the DAS28-ESR was ≥ 3.2. All treatment arms included matching placebos. The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102. RESULTS At week 24 (beginning of the step-up period), subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P < 0.0001); no differences between the combination-therapy regimens were observed. Between week 48 and week 102, subjects randomized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy, regardless of the treatment arm. There was no significant difference in the DAS28-ESR between subjects randomized to oral triple therapy and those randomized to receive MTX plus etanercept. By week 102, there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy (0.64 versus 1.69; P = 0.047). CONCLUSION There were no differences in the mean DAS28-ESR during weeks 48-102 between subjects randomized to receive MTX plus etanercept and those randomized to triple therapy, regardless of whether they received immediate combination treatment or step-up from MTX monotherapy. At 102 weeks, immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy. Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine (or etanercept, if necessary, after 6 months) is a reasonable therapeutic strategy for patients with early RA. Treatment with the combination of MTX plus etanercept resulted in a statistically significant radiographic benefit compared with oral triple therapy.

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVE To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Cholesterol efflux by high density lipoproteins is impaired in patients with active rheumatoid arthritis

Objectives Reverse cholesterol transport (RCT) is a major antiatherogenic function of high density lipoprotein (HDL). In the current work, the authors evaluated whether the RCT capacity of HDL from rheumatoid arthritis (RA) patients is impaired when compared to healthy controls. Methods HDL was isolated from 40 patients with RA and 40 age and sex matched healthy controls. Assays of cholesterol efflux, HDLs antioxidant function and paraoxanase-1 (PON-1) activity were performed as described previously. Plasma myeloperoxidase (MPO) activity was assessed by a commercially available assay. Results Mean cholesterol efflux capacity of HDL was not significantly different between RA patients (40.2%±11.1%) and controls (39.5%±8.9%); p=0.75. However, HDL from RA patients with high disease activity measured by a disease activity score using 28 joint count (DAS28>5.1), had significantly decreased ability to promote cholesterol efflux compared to HDL from patients with very low disease activity/clinical remission (DAS28<2.6). Significant correlations were noted between cholesterol efflux and the DAS28 (r=−0.39, p=0.01) and erythrocyte sedimentation rate, (r=−0.41, p=0.0009). Higher plasma MPO activity was associated with worse HDL function (r=0.41/p=0.009 (antioxidant capacity); r=0.35, p=0.03 (efflux)). HDLs ability to promote cholesterol efflux was modestly but significantly correlated with its antioxidant function (r=−0.34, p=0.03). Conclusions The cholesterol efflux capacity of HDL is impaired in RA patients with high disease activity and is correlated with systemic inflammation and HDLs antioxidant capacity. Attenuation of HDL function, independent of HDL cholesterol levels, may suggest a mechanism by which active RA contributes to increased cardiovascular (CV) risk.

Early Undifferentiated Connective Tissue Disease: III. Outcome and Prognostic Indicators in Early Scleroderma (Systemic Sclerosis)

Scleroderma, or systemic sclerosis, varies widely in its presentation and course. Many patients with scleroderma have a disease course of 10 to 20 years [1-4], but some patients experience a rapidly progressive form of disease characterized by early organ failure and death. Of 91 patients studied retrospectively by Lally and colleagues [3], 16 developed renal or cardiorespiratory failure (or both) an average of 15.8 months after the onset of symptoms; 11 of these 16 patients died. Retrospective assessments are inherently weighted toward the selection of patients with a longer disease duration, and patients experiencing early death or rapidly progressive disease may be under-represented. A few clinical studies and therapeutic trials have targeted patients with a disease duration of less than 5 years [3-5]; however, additional prospective information on the course and prognosis of patients with early scleroderma is needed to make appropriate risk/benefit decisions about potentially toxic therapies. Recently, a prospective study was done in 410 patients with early undifferentiated or early defined connective tissue disease [6]. Selecting 48 patients with early scleroderma from this cohort, we analyzed short-term outcomes and identified some features occurring within the first year of disease that may be useful in distinguishing patients at high risk for an unfavorable outcome. Methods The Cooperative Systematic Studies of the Rheumatic Diseases Program is funded under a National Institute of Arthritis and Musculoskeletal Diseases contract through the Coordinating Center at the University of Utah, Salt Lake City, Utah, and includes 10 centers participating in the study of early undifferentiated connective tissue disease. Outpatients and inpatients seen at participating centers were eligible for the study if they met diagnostic criteria for rheumatoid arthritis, scleroderma, systemic lupus erythematosus, or poly/dermatomyositis [7-10] and had experienced symptoms for less than 1 year. Patients who had features of a connective tissue disease, including Raynaud phenomenon, unexplained polyarthritis, or 3 of 11 findings characteristic of connective tissue disease, but who did not meet established criteria for a specific connective tissue disease were classified as having undifferentiated connective tissue disease. Patients were evaluated at baseline and at follow-up intervals of 1, 3, and 5 years. Details on data collection and on the clinical and laboratory features of the patients with early undifferentiated connective tissue disease have been described previously [6, 11]. Enrollment for the study began in July 1982 and was completed in June 1987. Survival status was confirmed through at least 5 years after symptom onset in all cases except one (patient lost to follow-up after 1.6 years). A diagnosis of scleroderma was made in 52 patients (in 46 within 1 year of symptom onset and in 6 within 4 years of symptom onset). Four of these patients (including 2 of 6 diagnosed after the baseline evaluation) developed overlap syndromes during the 5-year follow-up period and were excluded from the study, leaving 48 patients for analysis. Deaths and causes of death were reported to the Coordinating Center; every possible effort was made to confirm the cause of death through hospital records and autopsy reports from the participating centers. Five patients died at home, on the way to the hospital, or shortly after arrival at the hospital. Sclerodermatous skin findings on physical examination were categorized as follows: sclerodactyly (involvement distal to the metacarpophalangeal joints); acrosclerosis (involvement distal to elbows and knees); or generalized or diffuse scleroderma. A skin score was not determined. Physical findings for each organ system were recorded as a yes or no response to a list of abnormal findings. Twelve cardiorespiratory signs were assessed on the baseline physical examination: These included the presence or absence of rales, wheezes, pleural or pericardial rubs, pleural effusion, systolic or diastolic murmurs, abnormal second heart sounds, cardiomegaly, arrhythmia, dependent edema, and tachycardia (pulse 100 beats/min). All patients had routine hematology and biochemical laboratory tests. Many patients also had a determination of erythrocyte sedimentation rate (Westergren method) (n = 47), pulmonary function tests (n = 43), an electrocardiogram (n = 40), a chest radiograph (n = 40), and the Schirmer test. Serum specimens from all patients were analyzed for serologic markers of rheumatic disease at the Centers for Disease Control [11]. In addition, frozen serum specimens from 45 of the 48 patients with scleroderma were analyzed at Specialty Laboratories, Inc. (Santa Monica, California): Interleukin-2 levels were assessed by enzyme-linked immunosorbent assay (ELISA); soluble interleukin-2 receptor levels by ELISA; and neopterin levels by radioimmunoassay; anti-Scl-70 antibody levels by ELISA; and anticentromere antibody titer by immunofluorescence assay. Lung diffusing capacity was considered to be abnormal if it was less than 70% of the predicted diffusing capacity. Chest radiographs were considered to be abnormal if infiltrates, effusions, pleural thickening, or heart enlargement was present. Electrocardiograms were considered to be abnormal if evidence of arrhythmia, heart block, ventricular enlargement, repolarization abnormalities, significant shift in axis, or infarction was found. For the purposes of our study, nonspecific ST or T-wave abnormalities were not considered to be abnormal. Baseline clinical, laboratory, and other features of patients with early death were compared with those of survivors. Mean values were compared using the Student t-test. Comparisons between dichotomous variables were done using chi-square distribution with Yates correction. Life-table analyses using Kaplan-Meier survival estimation [12] and Mantel-Haenszel statistics [13] were done to predict survival rates for the group of patients with early scleroderma and the various subgroups generated by stratification based on selected variables. Variables were evaluated using univariate Cox proportional-hazards analysis for their ability to predict survival [14]. The variables found to be most significant, as determined by univariate Cox proportional-hazards analysis, and for which less than 10% of data were missing, were then evaluated by multivariate Cox analysis with stepwise regression modeling. We did not apply the Bonferroni correction to our results; however, because of the many variables compared, we defined statistical significance by a probability level of 0.01. Results Forty-eight patients with scleroderma were enrolled in the study. One patient was lost to follow-up 1.6 years after symptom onset, and the data gathered on her were used only in the survival and Cox analyses. During the 5-year follow-up period, 15 of the 47 evaluable patients with early scleroderma died. Kaplan-Meier estimation yielded overall survival rates at 1, 3, and 5 years after symptom onset of 92%, 75%, and 68%, respectively (Figure 1). Five patients died within 1 year of symptom onset. The cohort of patients with scleroderma accounted for 41% of all early deaths recorded for the entire study population of 410 patients. The causes of death are summarized in Table 1. Multiorgan involvement was frequently observed at the time of death, although pulmonary or cardiac system failure (or both) was thought to be the immediate cause of death in 8 of the 15 patients who died. Renal crisis was substantiated or suspected in 4 of the patients who died. The time from symptom onset to death was similar for those dying of renal causes (21 11 months) and those dying of cardiopulmonary causes (25 17 months). Table 1. Suspected Immediate Causes of Death, Average Age at Death, and Survival in Patients with Early Scleroderma* Figure 1. Cumulative survival probabilities: Kaplan-Meier survival curve with Greenwood confidence limits from onset of symptoms for the 48 early scleroderma patients. Clinical Features In Table 2, baseline characteristics of patients who died within 5 years after symptom onset are compared with those of the survivors. Twelve of the 15 (80%) patients who died had at least one abnormal cardiopulmonary sign at baseline compared with 13 of 32 (41%) survivors (P = 0.03). Among individual cardiopulmonary findings, resting heart rate was significantly different between survivors (79 13 beats/min; range, 50 to 110 beats/min) and patients who died (93 12 beats/min; range, 70 to 120 beats/min) (P = 0.001). Baseline blood pressure was similar in the subgroups (survivors: 120 17/76 12 mm Hg; patients who died: 127 27/78 16 mm Hg; P > 0.3), as was the frequency of chest radiographic, pulmonary function, and electrocardiographic abnormalities (P = 0.09). Table 2. Baseline Features of Patients with Early Scleroderma Who Survived and of Those Who Died* Chest pain, dyspnea, orthopnea, dependent edema, cough, and wheezing were common complaints; 57% of the entire group had at least one symptom. Dyspnea was the most common single cardiorespiratory complaint (36%). No significant difference in frequency of cardiopulmonary symptoms was detected between those who died and those who survived. Ninety-two percent of our patients developed skin involvement within 1 year of symptom onset, implying that patients with gradual-onset scleroderma were not included in our study. Four of the 48 patients did not have diagnosable scleroderma at their first visit, but they did develop skin disease within 3 years of follow-up (or within 4 years of disease onset). At entry, two patients had Raynaud phenomenon only and two were diagnosed with undifferentiated connective tissue disease. When baseline variables for these 4 patients with intermediate-onset scleroderma were compared with those of the remaining 44 patients with earlier-onset disease, no significant differences were

Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis.

OBJECTIVE To characterize the antiinflammatory function of high-density lipoprotein (HDL) in patients with rheumatoid arthritis (RA) and to identify specific differences in HDL-associated proteins and enzymes that distinguish proinflammatory HDL from normal, antiinflammatory HDL. METHODS We studied 132 RA patients. The antiinflammatory function of HDL was assessed by a cell-free assay, and proinflammatory HDL was defined by an HDL inflammatory index > or =1. Plasma and HDL-associated protein levels of apolipoprotein A-I (Apo A-I), haptoglobin, hemopexin, hemoglobin, and myeloperoxidase (MPO) were measured by direct and sandwich enzyme-linked immunosorbent assays, respectively. Lecithin:cholesterol acyltransferase (LCAT) activity was measured by a commercially available assay. RESULTS Age, disease activity, the presence of erosive disease, non-Caucasian race, and smoking were significantly associated with proinflammatory HDL on multivariate analysis. Patients with proinflammatory HDL had higher measures of systemic inflammation, and a significant correlation was observed between RA disease activity (using the Disease Activity Score in 28 joints) and the HDL inflammatory index (r = 0.54, P < 0.0001). Compared with patients with antiinflammatory HDL, patients with proinflammatory HDL had significantly higher levels of haptoglobin, hemoglobin, Apo A-I, and MPO associated with HDL (P < 0.05 for all comparisons except MPO, which was P = 0.05). LCAT activity was lowest in patients with proinflammatory HDL, but was also significantly reduced in RA patients with antiinflammatory HDL as compared with healthy controls (P = 0.001). CONCLUSION Proinflammatory HDL in this RA patient cohort was associated with active disease and an altered protein cargo as compared with antiinflammatory HDL in RA patients and in healthy controls. The antiinflammatory function of HDL was inversely correlated with systemic inflammation in RA patients and may warrant further investigation as a mechanism by which active RA increases cardiovascular morbidity and mortality.

The relationship of arrhythmias and conduction disturbances to other manifestations of cardiopulmonary disease in progressive systemic sclerosis (PSS)

Disorders of rhythm and conduction are characteristic of the cardiac involvement in progressive systemic sclerosis (PSS), but their over-all frequency in PSS is not well established. Therefore, 46 ambulatory patients with PSS underwent several tests of cardiopulmonary function, including a 24-hour continuous electrocardiogram (Holter monitor). Conduction disturbances (sinus node dysfunction, first-degree heart block, pre-excitation), supraventricular arrhythmias (supraventricular tachycardia, atrial fibrillation, premature contractions of atrial or junctional origin) and ventricular arrhythmias (ventricular tachycardia, multifocal premature contractions) were observed on Holter monitoring in 26 subjects. Although these arrhythmias and conduction disorders were predictably observed in patients who complained of palpitations or syncope, or who had an electrocardiogram which showed first-degree heart block, ventricular bigeminy, left anterior superior hemiblock, prolonged p wave, right or left axis deviation, right or left ventricular hypertrophy, pathologic Q waves or low voltage, they were often found in patients who lacked other clinical evidences of heart disease. Arrhythmias and conduction disturbances were not significantly more frequent among patients with cardiomegaly or interstitial change on chest roentgenogram nor were they related to the presence or severity of abnormal lung function. This study suggests that Holter monitoring may be a valuable adjunct in evaluating heart disease in PSS.