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Biomedical subjects

Christopher T Ritchlin

Publications and source records attributed to Christopher T Ritchlin.

At least 19 recordsLinked to original sources
PubMed2006

Therapies for psoriatic enthesopathy. A systematic review.

Enthesitis is defined as inflammation at sites of tendon, ligament, joint capsule, or fascia insertion sites to bone, and is a hallmark feature of psoriatic arthritis. Several outcome measures have been developed to assess enthesitis, but none have been validated in psoriatic arthritis. In this evidence-based review, we assess the limited data on treatments for enthesitis and make recommendations for further studies in psoriatic enthesitis.

Antirheumatic Agents↗
PubMed2006

Systematic review of treatments for psoriatic arthritis: an evidence based approach and basis for treatment guidelines.

Psoriatic arthritis (PsA) is a chronic systemic inflammatory disorder characterized by the association of arthritis and psoriasis. In addition to a heterogeneous and variable clinical course, PsA is complex and multifaceted and may include prominent involvement in the peripheral and axial diarthrodial joints, the skin and nails, and in periarticular structures such as entheses. A central mission of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) is to develop guidelines, based upon the best scientific evidence, for the optimal treatment of patients with PsA. We outline the specific methods and procedures used in this evidence-based, systematic review of treatments for PsA, which we hope will provide a basis for future treatment guidelines.

Arthritis, Psoriatic↗
PubMed2006

Metabolic disorders in patients with psoriasis and psoriatic arthritis.

Psoriasis is one of the common complex disorders in Western world, affecting 2% to 3% of the population. Recent studies indicate that psoriasis is associated with an increased risk of comorbidity and mortality compared to the general population. It appears that patients with psoriasis have a higher prevalence of metabolic disorders such as diabetes, hypertension, obesity, and hyperlipidemia, as well as a higher frequency of cigarette smoking. These concomitant diseases can complicate the treatment of psoriasis. Even though the etiology of these associations is elusive, physicians should be aware of them and take active steps to reduce the risk profiles of patients with psoriasis and psoriatic arthritis, in order to lessen mortality and comorbidity.

Arthritis, Psoriatic↗
PubMed2006

Autoimmunity and bone.

Focal erosions of cartilage and bone, which occur in the joints of patients with autoimmune inflammatory arthritis (i.e., rheumatoid arthritis (RA) and psoriatic arthritis [PsA]), represent the most debilitating and irreversible components of the disease. Over the last decade, seminal breakthroughs in our understanding of the cells and signal transduction pathways central to this process have been elucidated. From this information an established paradigm has been developed to explain focal erosions in which osteoclasts responsible for erosions are derived from bone marrow-derived myeloid precursors. Using the tumor necrosis factor (TNF) transgenic mouse model of erosive arthritis and anti-TNF clinical trials with PsA patients, we have demonstrated that systemic TNF induces the migration of CD11b+ osteoclast precursors (OCP) from the bone marrow into peripheral blood. These OCP can then enter the joints in blood vessels, translocate across the receptor activator of NF-kappaB ligand (RANKL) rich inflamed synovium, and differentiate into active osteoclasts. In direct contrast to this, systemic lupus erythematosus (SLE) patients appear to have an innate resistance to bone resorption. Our hypothesis to explain this phenomenon is that systemic interferon-alpha (IFN-alpha) diverts the bone marrow-derived myeloid precursors away from the osteoclast lineage and stimulates their differentiation into dendritic cells (DC). In support of this model, several labs have used microarray analyses to define the IFN-induced transcriptome in peripheral blood mononuclear cells (PBMC) from SLE patients. Here we propose the hypothesis that systemic TNF induces osteoclastic differentiation of PBMC in PsA patients that correlates with their erosive disease, and that the innate immune TNF/IFN axis in patients with autoimmune disease dictates their erosive phenotype. To demonstrate this, we injected wild-type C57B/6 and TNF-Tg mice with poly I:C, which is known to induce systemic IFN responses, and show its dominant effects on increasing the number of circulating CD11b+/CD11c+ precursor dendritic cells (pDC), concomitant with a dramatic reduction in CD11b+/CD11c- OCP. Thus, systemic factors produced by autoimmunity have a dramatic impact on active myelopoiesis and bone homeostasis.

Animals↗
PubMed2005

Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: Adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody, was evaluated for its safety and efficacy compared with placebo in the treatment of active psoriatic arthritis (PsA). METHODS: Patients with moderately to severely active PsA and a history of inadequate response to nonsteroidal antiinflammatory drugs were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks. Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter. The primary efficacy end points were the American College of Rheumatology 20% improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 24. Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3% of body surface area. RESULTS: At week 12, 58% of the adalimumab-treated patients (87 of 151) achieved an ACR20 response, compared with 14% of the placebo-treated patients (23 of 162) (P < 0.001). At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was -0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (P < 0.001). Among the 69 adalimumab-treated patients evaluated with the Psoriasis Area and Severity Index (PASI), 59% achieved a 75% PASI improvement response at 24 weeks, compared with 1% of the 69 placebo-treated patients evaluated (P < 0.001). Disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo. Adalimumab was generally safe and well-tolerated. CONCLUSION: Adalimumab significantly improved joint and skin manifestations, inhibited structural changes on radiographs, lessened disability due to joint damage, and improved quality of life in patients with moderately to severely active PsA.

Adalimumab↗
PubMed2005

Treatment update on spondyloarthropathy.

PURPOSE OF REVIEW: The unexpected success of the tumor necrosis factor antagonists in ankylosing spondylitis and psoriatic arthritis has generated considerable enthusiasm regarding the therapeutic potential of these drugs. By contrast, concerns regarding the high cost and long-term safety of the tumor necrosis factor blocking agents have prompted investigators to take a closer look at more traditional anti-inflammatory agents and to explore novel therapeutic targets. The purpose of this review is to summarize treatment advances in spondylarthropathy over the past year and to discuss potential future therapies. RECENT FINDINGS: Recent studies indicate that the morbidity of ankylosing spondylitis and PsA are considerably higher than previously reported. Etanercept, infliximab and adalimumab safely and effectively relieved the signs and symptoms of psoriatic arthritis patients in phase III trials. Etanercept and infliximab were also effective in phase III trials in ankylosing spondylitis. Etanercept slowed radiographic progression in psoriatic arthritis trials, but it is not known whether tumor necrosis factor antagonists can prevent structural damage in ankylosing spondylitis. One trial showed that methotrexate may be effective for relieving the pain of axial disease in ankylosing spondylitis but these findings contradict two previous studies. For reactive arthritis and undifferentiated spondylarthropathy, a combination of antibiotics may be more effective than a single antibiotic for the relief of musculoskeletal symptoms. Last, potential therapeutic targets include interleukin-1, interleukin-12, B lymphocytes, accessory molecules on T lymphocytes, and angiogenic factors. SUMMARY: Phase III trials have confirmed that tumor necrosis factor antagonists are effective and safe for the treatment of ankylosing spondylitis and psoriatic arthritis. For patients who do not respond to tumor necrosis factor blockade, several treatment options are under study. Information from these trials will more clearly define the role of disease-modifying antirheumatic drugs, novel therapeutic agents, and antibiotics in the treatment of spondylarthropathy.

Angiogenesis Inducing Agents↗
PubMed2005

Pathogenesis of psoriatic arthritis.

PURPOSE OF REVIEW: Heterogeneity in clinical presentation and disease course has hindered understanding of disease mechanisms in psoriatic arthritis, but recent studies have provided insights into pathogenesis. This review examines relevant animal models and genetic factors implicated in disease susceptibility. Also, recent reports on mechanisms related to synovial and entheseal inflammation are discussed. RECENT FINDINGS: Two transgenic mouse models (amphiregulin, STAT-3) were reported that have features of psoriatic arthritis and psoriasis respectively. Genetic studies did not find associations between psoriatic arthritis and several class I major histocompatibility complex alleles, the caspase-activating recruitment domain 15 domain, or the major histocompatibility complex class I chain-related gene A9 allele, in sharp contrast to previous reports. The striking association of psoriatic arthritis with mutations in the killer immunoglobulin receptors on natural killer cells is particularly exciting but needs further study. Psoriatic arthritis has histopathologic features that are more characteristic of other forms of spondyloarthritis than rheumatoid arthritis. Moreover, several of these features correlate with clinical disease activity. Matrix metalloproteinases are strongly expressed in psoriatic arthritis synovium, and serum matrix metalloproteinases-3 may be a reliable biomarker for monitoring disease response. Finally, the concept of an 'enthesis organ' may explain the magnetic resonance imaging findings and clinical signs of psoriatic enthesitis and dactylitis. SUMMARY: Recent findings highlight the importance of innate immune mechanisms in disease pathogenesis. Moreover, psoriatic arthritis and rheumatoid arthritis synovium have divergent histopathologic features that indicate distinct disease mechanisms. The generation of appropriate animal models coupled with reliable biomarkers will result in a deeper understanding of disease pathogenesis and will facilitate the identification of new therapeutic targets.

Animals↗
PubMed2005

Outcome measures in psoriatic arthritis.

Recent advances in biologic therapies have provided hope for patients with psoriatic arthritis (PsA). However, studies have been hampered by the lack of acceptable and validated outcome measures. This article reviews outcome measures used in the assessment of both skin and joints in PsA, and provides a summary of the Psoriatic Arthritis Workshop during OMERACT 7. A set of domains to be included in the assessment of patients with PsA was derived, and a research agenda was developed.

Arthritis, Psoriatic↗
PubMed2004

Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice.

OBJECTIVE: To investigate the mechanisms whereby tumor necrosis factor alpha (TNFalpha) increases osteoclastogenesis in vivo. METHODS: TNFalpha-transgenic (TNF-Tg) and wild-type mice injected with TNFalpha were studied. In vitro osteoclastogenesis assays, monocyte colony-forming assays, and fluorescence-activated cell sorting were performed using splenocytes, peripheral blood mononuclear cells (PBMCs), and bone marrow cells to quantify and characterize osteoclast precursors (OCPs). Etanercept, a TNFalpha antagonist, was used to block TNFalpha activity in vivo. The effects of TNFalpha on proliferation, apoptosis, and differentiation of OCPs were assessed using 5-bromo-2'-deoxyuridine labeling, annexin V staining, and reverse transcriptase-polymerase chain reaction. RESULTS: OCP numbers were increased 4-7-fold in PBMCs and spleen, but not in bone marrow of TNF-Tg mice. The OCPs in spleen were in the CD11b(high) population and contained both c-Fms- and c-Fms+ cells. The increased number of OCPs correlated with the initiation of detectable TNFalpha in serum and the onset of inflammatory arthritis in TNF-Tg mice. Etanercept eliminated the increase in peripheral OCPs. TNFalpha did not affect proliferation, survival, or differentiation of CD11b(high) splenocytes in vivo or in vitro, but caused a rapid increase in CD11b+ cells in blood within 4 hours of a single injection and an accumulation of CD11b(high) OCPs in spleen after 3 days of multiple injections. CONCLUSION: Systemic TNFalpha induces a marked increase in circulating OCPs that is reversible by anti-TNF therapy and may result from their mobilization from bone marrow. Our findings provide a new mechanism whereby TNFalpha stimulates osteoclastogenesis in patients with inflammatory arthritis, suggesting that CD11b+ PBMCs could be used to evaluate a patient's potential for erosive disease and the efficacy of anti-TNF therapy.

Animals↗
PubMed2004

Pathogenesis of psoriatic arthritis.

PURPOSE OF REVIEW: Psoriatic arthritis is an inflammatory arthritis associated with psoriasis that is more common and severe than initially appreciated. The success of biologic agents in psoriatic arthritis has sparked great interest in this disorder, although the disease pathogenesis is poorly understood. This review focuses on recent advances in the genetic factors and immune pathways that have been implicated in susceptibility to disease. In addition, recent studies examining the mechanisms that underlie angiogenesis, enthesitis, and bone resorption in psoriatic arthritis are discussed. RECENT FINDINGS: Studies performed on several different populations indicate that the MHC class I allele Cw6 is associated with both early-onset psoriasis and psoriatic arthritis. Mutations in the caspase-activating recruitment domain 15 locus on chromosome 16 are also associated with psoriatic arthritis, providing support for a model involving innate immune mechanisms. Evidence for a CD8 antigen-driven acquired immune response in psoriatic synovium and blood was reported. The finding of elevated levels of vascular endothelial growth factor and angiopoietin 2 in psoriatic arthritis synovial vasculature may provide insights into events responsible for the tortuous vessel morphology, a histologic feature characteristic of psoriatic joints. Tumor necrosis factor (TNF)-alpha is a critical factor mediating inflammation in the synovium, enthesis, and bone. In particular, osteoclasts resorb bone via a receptor activator of nuclear factor kappaB-receptor activator of nuclear factor kappaB ligand signaling pathway that is potentiated by TNF-alpha. The lessening of bone marrow edema after anti-TNF therapy provides further support for the importance of this cytokine in disease pathogenesis. SUMMARY: Recent studies provide additional support for distinct pathogenetic mechanisms in psoriatic arthritis that arise from a complex interplay between genetic and environmental factors. Histopathologic data and results from clinical trials highlight the predominance of TNF-mediated inflammation in psoriatic joint tissues.

Arthritis, Psoriatic↗
PubMed2004

Treatment update on spondyloarthropathy. From NSAIDs and DMARDs to anti-TNF-alpha agents.

Traditionally, nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic agents (DMARDs) have been used to control the symptoms of spondyloarthropathy. With the advent of anti-tumor necrosis factor alpha (anti-TNF-alpha) agents, however, it is now possible to slow disease progression, improve overall function, and provide symptomatic relief of arthritis, skin lesions, and bowel inflammation associated with these disorders. Here, Drs Anandarajah and Ritchlin explore the effectiveness of conventional therapies as well as biologic agents that are currently available or under development.

Anti-Inflammatory Agents, Non-Steroidal↗