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Background and Aims: To evaluate changes in the high-density lipoprotein (HDL) proteome and HDL function in active rheumatoid arthritis (RA) patients initiating therapy with abatacept or adalimumab in the Abatacept Versus Adalimumab Comparison in Biologic-Naïve RA Subjects with Background Methotrexate (AMPLE) study., Methods: Ultra high-pressure liquid chromatography (UHPLC) coupled with ion mobility mass spectrometry (LC-IM-MS) was used to analyze proteins associated with immunoaffinity-captured HDL from plasma of 30 patients with RA randomized to either abatacept (n = 15) or adalimumab (n = 15) therapy. Paraoxonase 1 (PON1) activity, HDL anti-oxidant capacity, cholesterol profiles, and homocysteine levels were also measured at baseline and following treatment. Repeated-measures analyses were performed using mixed-effect linear models to model the within-subject covariance over time., Results: In models controlling for age, sex and treatment group, improvement in inflammation measured by decreases in CRP was associated with improvement in HDL function and changes in several HDL-associated proteins including significant decreases in lipopolysaccharide-binding protein, serum amyloid A-I (SAA-I) and inter-alpha-trypsin inhibitor heavy chain H4 (p values < 0.05). Improvement in disease activity was also associated with changes in multiple HDL-associated proteins. Adalimumab was associated with higher PON1 activity, HDL-associated serotransferrin, and HDL-associated immunoglobulin J chain, and lower HDL-associated SAA-I over time compared with abatacept., Conclusions: Improvement in inflammation associated with treatment of RA, using either abatacept or adalimumab in the AMPLE study, was associated with improvement in HDL function and significant alterations in the HDL proteome, including proteins involved in the immune response, proteinase inhibition, and lipid metabolism., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Missing data are ubiquitous in clinical trials for rheumatic diseases, and it is important to accommodate them using appropriate statistical techniques. We review some of the basic considerations for missing data and survey a range of statistical techniques for analysis of longitudinal clinical trial data with missingness. Using clinical trial data from patients with diffuse systemic sclerosis, we show that different approaches to handling missing data can lead to different conclusions on the efficacy of the treatment. We then suggest how such discrepancies might be addressed. In particular, we emphasize that the commonly used method in rheumatic clinical trials of carrying the last observation forward to impute missing values should not be the primary analysis. We review software for analyzing different types of missing data and discuss our freely available software library for analyzing the more difficult but more realistic situation when the probability of dropout or missing data may depend on the unobserved missing value., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Fetal CD34(+) CD38(+) cells have recently been found to persist in maternal peripheral blood for many years after pregnancy. CD34(+) CD38(+) cells are progenitor cells that can differentiate into mature immune-competent cells. We asked whether long-term fetal microchimerism occurs in T lymphocyte, B lymphocyte, monocyte, and natural-killer cell populations of previously pregnant women. We targeted women with sons and used polymerase chain reaction for a Y-chromosome-specific sequence to test DNA extracted from peripheral blood mononuclear cells (PBMC) and from CD3, CD19, CD14, and CD56/16 sorted subsets. We also asked whether persistent microchimerism might contribute to subsequent autoimmune disease in the mother and included women with the autoimmune disease scleroderma. Scleroderma has a peak incidence in women after childbearing years and has clinical similarities to chronic graft-versus-host disease that occurs after allogeneic hematopoietic stem-cell transplantation, known to involve chimerism. Sixty-eight parous women were studied for male DNA in PBMC and 20 for PBMC subsets. Microchimerism was found in PBMC from 33% (16 of 48) of healthy women and 60% (12 of 20) women with scleroderma, P =.046. Microchimerism was found in some women in CD3, CD19, CD14, and CD56/16 subsets including up to 38 years after pregnancy. Microchimerism in PBMC subsets was not appreciably more frequent in scleroderma patients than in healthy controls. Overall, microchimerism was found in CD3, CD19, and CD14 subsets in approximately one third of women and in CD56/16 in one half of women. HLA typing of mothers and sons indicated that HLA compatibility was not a requirement for persistent microchimerism in PBMC subsets. Fetal microchimerism in the face of HLA disparity implies that specific maternal immunoregulatory pathways exist that permit persistence but prevent effector function of these cells in normal women. Although microchimerism in PBMC was more frequent in women with scleroderma than healthy controls additional studies will be necessary to determine whether microchimerism plays a role in the pathogenesis of this or other autoimmune diseases.

Advances in our understanding of rheumatoid synovitis have been coupled with increasingly refined methods from biotechnology to produce promising therapeutic agents. Monoclonal antibodies (MoAbs), recombinant cytokines, cytokine receptor fusion proteins and other biologics have been elevated from the status of novel reagents applied in phase I toxicity trials to, in some cases, substantially evaluated and validated tools awaiting federal regulatory approval. Biologic agents will soon be released for the treatment of patients with RA. We review some of the most promising preclinical work that supports a position of optimism regarding the future of RA. We also speculate on the potential role for biologics in future management of patients with RA.

Background: Fetal cells can be found in the maternal circulation in most pregnancies. Fetal progenitor cells have been found to persist in the circulation of women many years after childbirth. We tested the hypothesis that microchimerism is involved in the pathogenesis of scleroderma. Scleroderma is of interest because of a strong female predilection, an increased incidence in the years after childbearing, and clinical similarities between scleroderma and chronic graft-versus-host disease after allogeneic bone-marrow transplantation. We also investigated whether HLA-compatibility of a child was associated with later development of scleroderma in the mother., Methods: We enrolled 40 women who had previously given birth to at least one son--16 healthy controls, 17 scleroderma patients, and seven healthy sisters of patients. We used quantitative PCR to amplify a Y-chromosome-specific sequence in whole peripheral blood from these women. Also 32 controls with 58 children, and 21 scleroderma patients with 47 children were HLA genotyped., Findings: The mean number of male cell DNA equivalents among controls was 0.38 cells per 16 mL whole blood (median 0 [range 0-2]) and 11.1 (6.0 [0-61]) among scleroderma patients (p = 0.0007). Controls' youngest sons were born a mean of 15.4 years previously, and scleroderma patients' sons 18.5 years previously. Some scleroderma patients had concentrations of male DNA higher than those found in most pregnant women. HLA-class II compatibility of a child from the mother's perspective was more common among scleroderma patients than among controls, but was not essential for persistence of male DNA in maternal peripheral blood., Interpretation: Low concentrations of male DNA can be detected in healthy women decades after the birth of a son. Microchimerism in scleroderma patients could be secondary to the underlying disease. However, the finding that HLA class II compatibility of a child was more common for scleroderma patients than for controls, supports the possibility that microchimerism may be involved in the pathogenesis of scleroderma.

Methotrexate (MTX) is among the most effective drugs for treatment of rheumatoid arthritis and has been proven valuable in the treatment of multiple other disorders of immune regulation. MTX has been administered at a wide range of doses and dose intervals, in conjunction with multiple other drugs, and in patients with a broad range of concomitant disorders. To design a safe and effective MTX treatment plan for an individual patient, the provider must have knowledge of the pharmacology and drug interactions of this effective but potentially dangerous medication. The first section of the article reviews MTX structure, pharmacology pharmacokinetics, and mechanisms of action in rheumatic disease. The second section examines factors that can be used to increase MTX efficacy and decrease toxicity.

Predictors of disease activity severity and outcome have both been reviewed. Although data to date have usually examined one predictor at a time, it is likely that a combination of genetic factors (HLA-DR4 or its subsets), joint tenderness or swelling, RF positivity, presence of erosions early in disease, and gender can be combined to predict disease activity/severity. The precise "mix" and contribution of these factors, however, still needs to be determined. Longer-term functional outcome can best be predicted by accounting for baseline functional disability (which reflects disease activity/severity), disease severity per se, and psychologic variables (such as depression). Again, the precise variables of most importance still need some research. Finally, mortality appears to be predicted by functional factors (thus also by disease severity), but medications (e.g., prednisone), social factors, and age (not surprisingly) also contribute to mortality.

The purpose of this study was to determine whether selected antirheumatic drugs would suppress elevated circulating interleukin-6 (IL-6) levels in patients with rheumatoid arthritis (RA). The 267 patients who enrolled in a double-blind randomized protocol received placebo, naproxen (1500 mg/day), or prinomide (1500 mg/day) for up to 16 weeks. Serum samples from 143 of the patients completing the trial and from 135 normal donors were analyzed by quantitative sandwich enzyme-linked immunosorbent assay for IL-6 concentrations. A mean normal IL-6 value was determined to be 3 pg/ml (95th percentile value = 10 pg/ml). IL-6 levels at baseline for the patients with RA were significantly higher than those for control subjects (p < 0.0001). Elevated IL-6 levels (> 10 pg/ml) at baseline were found in 80% of subjects with RA (median = 36 pg/ml, range 12 to 403). For patients with elevated levels of either IL-6, C-reactive protein (CRP), or erythrocyte sedimentation rate (ESR) at baseline, initial median values of IL-6, CRP, and ESR were compared with those from the final visit for each treatment group. There was no significant decrease in IL-6 levels with treatment. Median CRP levels decreased significantly, from 1.9 to 0.8 mg/dl (p = 0.002), as did median ESR (37 to 34 mm/hr, p = 0.013), only in the prinomide-treated group.

Purpose: (1) To evaluate the relationship between the degree of pulmonary involvement by systemic sclerosis (SSc) and the degree of involvement of other organ systems by SSc at baseline. (2) To assess the degree of impairment in lung function at presentation and the annual rate of change in lung function to predict the rate of progression of involvement of extrapulmonary organ systems by SSc over time. (3) To determine whether survival in patients with SSc can be predicted from the degree of lung function impairment at baseline or from the annual rate of change in lung function., Methods: Semiquantitative indices of pulmonary and extrapulmonary involvement and pulmonary function tests (PFTs) were analyzed and compared in 62 nonsmoking scleroderma patients enrolled in a 3-year prospective drug trial, vs 47 in a "study group" who underwent serial evaluation. The other 16 "early withdrawals" withdrew prior to the second evaluation. The indices of organ system involvement were based on clinical, physiologic, and biochemical findings as previously published. The PFTs included total lung capacity (TLC), forced vital capacity (FVC), FEV1, and single-breath diffusing capacity for carbon monoxide (Dsb). Annualized rates of change in PFTs and indices of extrapulmonary involvement were calculated for each subject from data collected on at least 2 separate occasions at least 6 months apart. Spearman rank correlations were performed between individual baseline PFTs (expressed as percent predicted) and (a) indices of extrapulmonary involvement at baseline, (b) annualized rates of change in PFTs, and (c) annualized rates of change in indices of extrapulmonary involvement. Correlations also were performed between the rate of change in each lung function measure and rates of change in indices of extrapulmonary involvement. The ability of PFTs at baseline and their rates of change to predict cumulative survival was assessed by Cox stepwise regression., Results: The degree of impairment in baseline PFTs was related to involvement of the right side of the heart but not to other extrapulmonary system involvement. Baseline PFTs were not related to the rate of subsequent decline of lung function or worsening of extrapulmonary organ system involvement. Subsequent annual rates of decline in lung function were related to worsening skin and upper gastrointestinal involvement. Cumulative survival may be related to the rate of decline in DCO, TLC, and FVC, but was not predicted by impairment in any measure of lung function., Conclusion: With the exception of involvement of the right side of the heart consistent with cor pulmonale, the degree of pulmonary involvement by SSc was not correlated with the extent of extrapulmonary involvement. The degree of pulmonary involvement by SSc did not predict subsequent worsening of either pulmonary or extrapulmonary involvement. Worsening pulmonary involvement by SSc, in general, does not correlate with worsening involvement of extrapulmonary organ systems, except for the skin and upper gastrointestinal tract. A rapid decline in DCO or lung volumes may predict poor survival.

The pharmacokinetics of low dose methotrexate (MTX) were evaluated in 12 rheumatoid arthritis patients in the presence and absence of steady-state levels of salicylic acid (ASA) and sulindac (SU). Using a Latin square design, patients were given MTX plus ASA (mean 3.4 g/day), MTX plus SU (mean 400 mg/day), or MTX alone. On a background of at least one year of regular MTX therapy, patients received 10 mg/m2 MTX iv (mean 17.8 mg) given after at least 2 weeks of treatment with each of the above regimens. Plasma concentrations of MTX and 7-hydroxymethotrexate (7-OH-MTX) were measured using HPLC. No differences in MTX clearance (Cl) were found comparing MTX alone, MTX + ASA, and MTX + SU. However, if one particular subject that had a very low clearance when receiving MTX alone was excluded, there was a statistically significant decrease in MTX clearance when either ASA or SUL were present. It is also noteworthy that ASA significantly increased the exposure of the subject to 7-OH-MTX and, to a lesser extent, so did sulindac. Since 7-OH-MTX has been shown to be an active metabolite when given for cytotoxic effects at higher doses and because it has been show to be nephrotoxic at doses a thousand-fold greater than used in rheumatoid arthritis, nonsteroidal anti-inflammatory drugs should be used cautiously with MTX until further large scale safety studies are conducted. The data indicate that if a clinically significant interaction were to occur, ASA is more likely than SU to interact with MTX.

Over the years, many encouraging uncontrolled studies extolling treatments of SSc have appeared, but initial impressions were not corroborated when controlled trials were done. This article points out that certain recent studies have effectively ruled out the use of some specific therapies for the general treatment of systemic sclerosis. Thus, sufficient data has been generated to rule out the use of n-acetylcysteine, colchicine, chlorambucil, cyclofenil, and DMSO, at least in disease of longer duration. Ketanserin and prostaglandin infusions probably also belong in this group, as they affect only Raynaud's phenomenon. Angiotensin enzyme inhibitors, while probably life-saving in renal crises, do not seem to affect the underlying systemic sclerosis per se. Another group of drugs has only limited supportive data and await well-controlled trials to prove or disprove their effectiveness. These include: 5-fluorouracil, D-penicillamine, drugs affecting platelet function (dipyridamole), and para-aminobenzoic acid. There are a few treatments which have potential. Factor XIII has only limited data using controlled trials, but what does exist seems positive. Apheresis is encouraging, although the success of this treatment modality may be dependent upon a "combination" approach. Ongoing studies with gamma-interferon, photopheresis, and the mast cell stabilizer ketotifen appear exciting, and we await reports of their use in scleroderma. On another level, new insights into genomic alterations in skin fibroblasts and T-cell proto-oncogene expression have contributed to the understanding of the pathogenesis of this disease at the cellular level and new methods to measure change in disease will help gauge response to therapy. Thus, we look forward to more definitive treatment of SSc in the future.

Sizable volume shifts can occur during equilibrium dialysis. This net movement of water, presumably caused by the osmotic effect of plasma proteins, reduces the concentration of binding proteins. In this paper the theory of protein binding estimation is extended, equations are developed for calculating the unbound and bound drug concentrations at dialysis equilibrium by correcting for the dilution of the proteins, and the equations are applied to a study of prednisolone. To demonstrate the importance of correcting for the volume shift, the parameters of a model in which prednisolone binds to corticosteroid-binding globulin, a protein with a limited capacity, and albumin were estimated. Unbound and bound concentrations were determined by correcting for both volume shifts (average 31%) and loss of drug to the buffer side, by correcting only for loss of drug to buffer side, and by making no correction at all (the usual method of treating equilibrium dialysis data). The error introduced by neglecting volume shifts was analyzed by comparing the parameter values obtained using the three methods. The results confirm the need to adjust for volume shifts and imply that reported binding constants obtained by equilibrium dialysis may be in error for many substances.

The metabolism of salsalate (I) was characterized in two normal volunteers. The drug was almost completely absorbed and was excreted primarily in the urine; only approximately 1% of the total dose was found in the stools. Although I is a salicylate derivative, which on hydrolysis yields two molecules of salicylic acid (II), approximately 7-10% of the dose was not hydrolyzed to salicylic acid and appeared in the urine either as unchanged drug or glucuronide conjugates. Thus, the incomplete availability of salicylate from salsalate that has been previously reported may not be due to incomplete absorption of the drug but to incomplete hydrolysis to salicylic acid.

The formation of the methyl ester of salicyluric acid was observed during the quantitation of salicyluric acid and other salicylate metabolites in urine by high-pressure liquid chromatography. This methyl ester formation caused artificially low values for salicyluric acid and high values for salicylic acid.

The pharmacokinetics and bioavailability of low-dose methotrexate (MTX) (10 mg/m2) were evaluated in 41 subjects who had definite or classical rheumatoid arthritis as defined by the American Rheumatism Association criteria. Subjects received 10 mg/m2 (to the nearest 2.5 mg) of MTX in a single oral dose and a single intravenous (iv) dose one week apart. Serum concentrations for this low-dose regimen were monitored using a radiochemical ligand binding assay. The results indicate the MTX is cleared from the plasma at a rate of 84.6 mL/min/m2. The terminal half-life was approximately 6 h. The volumes of distribution at steady state and for the central compartment were 22.2 and 13.5 L/m2, respectively. The mean residence time in the body, in the systemic circulation, and in the periphery were estimated to be 4.7, 3.0, and 1.7 h, respectively, with a peripheral single-pass mean transit time of 6.0 h and an intrinsic mean residence time in the periphery of 7.9 h. The mean absorption time was 1.2 h and the oral bioavailability was 0.70. The ratio of synovial fluid concentration to serum concentration 4 and 24 h after a dose was found to be approximately 1.0, indicating that at least within that time range serum and synovial fluid concentrations are approximately equal. Because of conflicting results and insufficient data from previous high-dose pharmacokinetic studies, it is difficult to say whether or not low-dose MTX pharmacokinetics differs from those of high-dose MTX.

Intraoral and panoramic radiographs were made of 35 patients with progressive systemic sclerosis. Of those patients, 13 (37%) were found to have abnormally thickened periodontal ligament spaces. Six of the 35 demonstrated mild to significant resorption of the posterior mandibular angle. Three patients, including two showing angle resorption also had some degree of coronoid process destruction. All patients with this disease should receive initial and follow-up panoramic radiographic examinations to determine any osseous changes.