Lessons from Carl M. Pearson 1919 - 1981.

Carl M. Pearson was an energetic and exceptional physician-scholar-leader who founded, established, and broadened the Divisions of Rheumatology at University of California in Los Angeles (UCLA) beginning in 1956. His studies to induce myositis by injecting muscle saturated with the heat-killed tubercle bacillus, an emulsifier, and mineral oil (Freund's adjuvant) enabled his report that polyarthritis occurred with Freund's adjuvant alone in certain strains of rat and mice. This model of adjuvant arthritis allowed the next generation of studies to assess therapies for autoimmune diseases.

Targeting inflammatory pathways in axial spondyloarthritis.

The triggers and pathogenesis of axial spondyloarthritis (axSpA) are not yet completely understood. However, therapeutic agents targeting tumor necrosis factor-α and interleukin-17 inflammatory pathways have proven successful in suppressing many of the clinical symptoms and signs of axSpA, giving us an indication of which pathways are responsible for initiating and maintaining the inflammation. The mechanisms that eventuate in syndesmophytes and ankyloses are less clear. This review addresses these two critical pathways of inflammation, discussing their nature and these factors that may activate or enhance the pathways in patients with axSpA. In addition, genetic and other markers important to the inflammatory pathways implicated in axSpA are explored, and prognostic biomarkers are discussed. Treatment options available for the management of axSpA and their associated targets are highlighted.

Genetic and inflammatory factors associated with psoriatic arthritis: Relevance to diagnosis and management.

Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory musculoskeletal condition with complex pathophysiology. In recent years, understanding of the pathogenesis of PsA has improved substantially. Several genetic and inflammatory factors have been identified and studied as targets for new biologic disease-modifying therapies. This review presents findings from a detailed literature assessment conducted to identify genes and biomarkers associated with PsA and its most common comorbidities. This literature assessment identifies genes and biomarkers that may be predictive of the onset and severity of PsA, places them in the context of our understanding of PsA pathogenesis, and explores potential connections between the pathways involved in PsA and current biologic therapeutics used to treat PsA. Knowledge of the genetics and inflammatory factors associated with disease pathogenesis can support the targeted development of new biologic therapies and biomarkers for PsA.

Comparative genomic profiling of synovium versus skin lesions in psoriatic arthritis.

OBJECTIVE: To our knowledge, there is no broad genomic analysis comparing skin and synovium in psoriatic arthritis (PsA). Also, there is little understanding of the relative levels of cytokines and chemokines in skin and synovium. The purpose of this study was to better define inflammatory pathways in paired lesional skin and affected synovial tissue in patients with PsA. METHODS: We conducted a comprehensive analysis of cytokine and chemokine activation and genes representative of the inflammatory processes in PsA. Paired PsA synovial tissue and skin samples were obtained from 12 patients on the same day. Gene expression studies were performed using Affymetrix HGU133 Plus 2.0 arrays. Confirmatory quantitative real-time polymerase chain reaction (PCR) was performed on selected transcripts. Cell populations were assessed by immunohistochemistry and immunofluorescence. RESULTS: Globally, gene expression in PsA synovium was more closely related to gene expression in PsA skin than to gene expression in synovium in other forms of arthritis. However, PsA gene expression patterns in skin and synovium were clearly distinct, showing a stronger interleukin-17 (IL-17) gene signature in skin than in synovium and more equivalent tumor necrosis factor (TNF) and interferon-γ gene signatures in both tissues. These results were confirmed with real-time PCR. CONCLUSION: This is the first comprehensive molecular comparison of paired lesional skin and affected synovial tissue samples in PsA. Our results support clinical trial data showing that PsA skin and joint disease are similarly responsive to TNF antagonists, while IL-17 antagonists have better results in PsA skin than in PsA joints. Genes selectively expressed in PsA synovium might direct future therapies for PsA.

Different tumor necrosis factor α antagonists have different effects on host susceptibility to disseminated and oropharyngeal candidiasis in mice.

Tumor necrosis factor α is important for the host defense against intracellular pathogens. We tested the effect of mouse analogs of human TNF-α antagonists, the rat anti-mouse TNF-α monoclonal antibody (XT22) and the soluble mouse 75 kDa TNF-α receptor fused to the Fc portion of mouse IgG1 (p75-Fc), on the susceptibility of mice to hematogenously disseminated candidiasis (HDC) and oropharyngeal candidiasis (OPC). Both XT22 and p75-Fc significantly reduced mice survival, increased kidney fungal burden, and reduced leukocyte recruitment during HDC. However, only XT22 significantly increased the oral fungal burden and reduced leukocyte recruitment during OPC. This result suggests that XT22 and p75-Fc affect host susceptibility to different types of Candida albicans infections by different inhibitory mechanisms.

Significance of sex in achieving sustained remission in the consortium of rheumatology researchers of North America cohort of rheumatoid arthritis patients.

OBJECTIVE: To determine whether men with rheumatoid arthritis (RA) are more likely to achieve remission compared to women. METHODS: RA patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) cohort between October 2001 and January 2010 were selected for the present analyses. Detailed clinical, demographic, and drug utilization data were available at enrollment (baseline) and at subsequent followup visits. We examined the influence of sex on the Clinical Disease Activity Index remission score (≤2.8) using sustained remission or point remission as the primary outcome measure in multivariate stepwise logistic regression models. We stratified the data by RA duration at baseline (≤2 years or >2 years) to investigate whether RA duration had differential effects on remission in men and women. RESULTS: A total of 10,299 RA patients (2,406 men and 7,893 women) were available for this study. In both early and established RA, women had more severe disease at baseline with worse disease activity measures, modified Health Assessment Questionnaire disability index score, pain on a visual analog scale, and depression. Women were also more likely to have been treated with disease-modifying antirheumatic drugs and anti-tumor necrosis factor therapy compared to men. In the regression models, male sex was associated with sustained remission in early RA (odds ratio [OR] 1.38, 95% confidence interval [95% CI] 1.07-1.78, P = 0.01), but not in established RA. However, for point remission, an inverse association was observed with male sex in established RA (OR 0.65, 95% CI 0.48-0.87, P = 0.005) and not in early RA. CONCLUSION: Within the large real-life CORRONA cohort of RA patients, men were more likely to achieve sustained remission compared to women in early RA, although not in established RA.

Gender and ethnicity differences in patients with diffuse systemic sclerosis--analysis from three large randomized clinical trials.

OBJECTIVE: Although the incidence of dcSSc is higher in African-American and Hispanic populations compared with European Caucasian patients, it is not clear whether there are differences in subsequent disease course. Also, the potential impact of gender on the disease course of dcSSc is not well defined. Our objective was to assess the course of modified Rodnan skin score (MRSS), HAQ-disability index (HAQ-DI) and forced vital capacity per cent (FVC%) predicted between men vs women and three ethnic groups with dcSSc participating in three randomized clinical trials (RCTs). METHOD: Data from RCTs (n = 495) were pooled and analysed. Baseline characteristics were compared in men vs women and among ethnic groups. A linear mixed effects model was used to assess the predictors of MRSS, HAQ-DI and FVC%. The primary independent variables were time-in-study and its interaction with gender and ethnicity. The models were adjusted for other covariates that were significant at baseline between gender and ethnicity analyses. RESULTS: Men had lower HAQI-DI scores compared with women (P < 0.05). Among the three ethnic groups, Caucasians were older, African-Americans had lower FVC% predicted and Hispanics had greater tender joint counts (P < 0.05). The course of MRSS, HAQ-DI and FVC% predicted during the study period was not significantly different between gender and three ethnicities. Time-in-study was an independent predictor of improvement in MRSS and HAQ-DI. CONCLUSION: Our analysis explores the influence of gender and ethnicity on disease course in RCTs. These findings are relevant to issues of future trial design.

Differences in binding and effector functions between classes of TNF antagonists.

There are currently two Food and Drug Administration-approved classes of biologic agents that target tumor necrosis factor-alpha (TNF-alpha): anti-TNF monoclonal antibodies (mAbs) (adalimumab and infliximab), and soluble TNF receptors (etanercept). This study examined the ability of the TNF antagonists to: (1) bind various polymorphic variants of cell surface-expressed Fc receptors (FcgammaRs) and the complement component C1q, and (2) mediate Ab-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity (CDC) killing of cells expressing membrane-bound TNF (mTNF) in vitro. Both mAbs and the soluble TNF receptor demonstrated low-level binding to the activating receptors FcgammaRI, FcgammaRIIa, and FcgammaRIIIa, and the inhibitory receptor FcgammaRIIb, in the absence of exogenous TNF. However, upon addition of TNF, the mAbs, but not etanercept, showed significantly increased binding, in particular to the FcgammaRII and FcgammaRIII receptors. Infliximab and adalimumab induced ADCC much more potently than etanercept. In the presence of TNF, both mAbs bound C1q in in vitro assays, but etanercept did not bind C1q under any conditions. Infliximab and adalimumab also induced CDC in cells expressing mTNF more potently than etanercept. Differences in the ability to bind ligand and mediate cell death may account for the differences in efficacy and safety of TNF antagonists.

Neutralization of tumor necrosis factor (TNF) by antibody but not TNF receptor fusion molecule exacerbates chronic murine tuberculosis.

Tumor necrosis factor (TNF) plays an essential role in the immunologic maintenance of Mycobacterium tuberculosis infection. Although an increased rate of tuberculosis has been reported in humans treated with anti-TNF biological agents, disparate rates of disease have been observed between those treated with infliximab, an anti-TNF antibody, and etanercept, a TNF-neutralizing TNF receptor (TNFR) fusion molecule. We compared the effects of anti-TNF antibody and soluble TNFR fusion molecule in the murine model of tuberculosis. Systemic TNF neutralization was equivalent between these molecules, and both resulted in rapid morbidity at the initiation of infection. During chronic infection, administration of the receptor fusion molecule allowed the control of infection, whereas antibody treatment caused mice to die within a month. We provide evidence of decreased penetration into the granulomas by the receptor fusion molecule, compared with antibody. These findings begin to clarify the mechanistic difference between anti-TNF agents and their role in the exacerbation of tuberculosis.

Binding characteristics of tumor necrosis factor receptor-Fc fusion proteins vs anti-tumor necrosis factor mAbs.

Tumor necrosis factor (TNF) antagonists are efficacious in the treatment of various autoimmune diseases. Two classes of TNF antagonists are currently commercially available: soluble TNF receptor-Fc fusion proteins (etanercept) and anti-TNF mAbs (adalimumab and infliximab). The classes differ in molecular structures and mechanisms of action. The interactions between TNF antagonists with TNF molecules were characterized. The anti-TNF mAbs, but not the soluble TNF receptor, formed visible lines of precipitation in Ouchterlony assays. The molecular weights of complexes formed by TNF (52 kDa) with either etanercept (130 kDa), adalimumab (150 kDa), or infliximab (average 165 kDa) were determined by size exclusion chromatography-light-scattering assays. Etanercept and TNF formed complexes of 180 and 300 kDa, representing one and two etanercept monomers bound to a TNF trimer, respectively. Adalimumab and infliximab formed a variety of complexes with TNF with molecular weights as high as 4,000 and 14,000 kDa, respectively, suggesting the presence of complexes with a wide range of sizes and stoichiometries. The absence of large complex formation with the binding of soluble receptor-fusion proteins to TNF may account for the different clinical efficacy and safety profiles of the two classes of TNF antagonists.

Structural-functional relationships of TNF-alpha antagonists: next steps.

The balance between effective tumor necrosis factor (TNF) blockade to control aggressive autoimmune disease states and adequate remaining TNF activity to confer immunoprotection against infections such as tuberculosis is an important and complex issue. An increased scientific understanding of how each of the TNF antagonist agents affects the complex interactions of the inflammation cascade and apoptosis, and whether the effects are modulatory or destructive, is needed. The data presented in this supplement highlight the need for further research into these key areas, and illustrate our current understanding of the mode of action of TNF blockers as only the tip of the iceberg.

Patient's ethnicity does not influence utilization of effective therapies in rheumatoid arthritis.

OBJECTIVE: Biological agents have revolutionized the treatment of rheumatoid arthritis (RA). Given the previously documented ethnic disparity in the health service literature, we sought to determine if ethnic difference exists in the lag time between the diagnosis of RA and use of first biological agent. METHODS: RADIUS 1 and 2 are observational studies designed to document how rheumatologists treat RA across the United States. The sample analyzed here included early patients with RA who entered RADIUS with the initiation of the first biological agent. Ethnic status was categorized as White (W), African American (AA), and Hispanic (H). Lag time (months from RA diagnosis to initiation of the first biological agent) was the principal outcome variable. RESULTS: Compared to W (n=1616), AA (n=147) and H (n=116) were more likely to be female, younger, and have less than a high school education. Despite similar swollen and tender joint counts, AA and H had more active disease on the basis of Health Assessment Questionnaire and patient global assessments. Almost 97% of patients had some type of insurance coverage. On multivariable analysis, ethnic affiliation was not associated with lag time (14.5 months W vs 14.9 AA vs 14.3 H; p=NS). Similarly, there were also no significant ethnic differences in time to first DMARD (e.g., methotrexate) initiation. CONCLUSION: In a national sample of patients with RA, most of whom were insured, the length of time from diagnosis of RA to initiation of the first biological agent was not significantly different among Whites, African Americans, and Hispanics.

Blockade of plasmid replication mediated by peptide nucleic acids.

Because peptide nucleic acids (PNAs) are capable of blocking amplification of deoxyribonucleic acid (DNA) by Taq DNA polymerase in vitro, we postulated that PNAs might be able to block replication in vivo. To explore this possibility, we assessed the ability of PNA to specifically block the replication of pUC19 plasmids by allowing a PNA, directed against segments of the Ampr sequence to bind to pUC19 prior to electroporation into Escherichia coli, strain DH10B. Colonies produced by this maneuver not only remained sensitive to ampicillin but were also incapable of blue color production on X-gal-containing media, thus demonstrating true blockade of pUC19 replication, rather than antisense activity. The ability of the PNA to prevent pUC19 replication in these experiments was shown to be dose related. Attempts to prevent the replication of E. coli using a PNA directed against a portion of the lac Z sequence found within the bacterial genome were not uniformly successful. Subsequent experiments showed that the electroporated PNA did not consistently enter a sufficient number of cells for an effect to be demonstrated in the assays used. Nonetheless, this is the first demonstration of in vivo complete replication blockade by a PNA and opens up the potential for new forms of specific antibiosis in both prokaryotic and eukaryotic cells.

Etanercept ameliorates sarcoidosis arthritis and skin disease.

Sarcoidosis is a systemic disorder of unknown etiology characterized by its pathological hallmark, the noncaseating granuloma. In granulomatous diseases, the proinflammatory peptide mediators, including tumor necrosis factor-alpha (TNF-alpha), are increased in the blood and fluids surrounding the activated macrophages. We describe a patient with chronic sarcoidosis arthropathy and lupus pernio resistant to corticosteroids and disease modifying antirheumatic agents, who responded to the addition of etanercept. We discuss the possible mechanisms of action of anti-TNF agents in granulomatous diseases and suggest that chronic, resistant sarcoidosis requires combination immunosuppressive therapy.

Effects of disease management programs on functional status of patients with rheumatoid arthritis.

OBJECTIVE: To perform a systematic review of the published literature on disease management of rheumatoid arthritis (RA) and to use meta-analysis to estimate the magnitude of benefit these programs have on functional status in patients with RA. METHODS: Computerized databases for English articles from 1966 to September 2001 were searched. Two reviewers evaluated 1,029 published titles, identified 11 studies meeting explicit inclusion criteria, and extracted data about study characteristics, interventions used, and outcomes measured. Pooled effect sizes for functional status were calculated using a random-effects model. RESULTS: Four out of 8 disease management programs showed significant improvements in functional status; however, the pooled effect size (ES) was small and statistically non-significant (ES 0.27; 95% confidence interval [95% CI] -0.01, 0.54). Studies with longer intervention durations (>5 weeks) had significantly improved patient functional status (ES 0.49; 95% CI 0.12, 0.86), compared with studies with shorter intervention durations (