ABSTRACT
The N-methyl-D-aspartate (NMDA) glutamate receptors function as plasma membrane ionic channels and take part in very tightly controlled cellular processes activating neurogenic and inflammatory pathways. In particular, the NR1 subunit (new terminology: GluN1) is required for many neuronal and non-neuronal cell functions, including plasticity, survival, and differentiation. Physiologic levels of glutamate agonists and NMDA receptor activation are required for normal neuronal functions such as neuronal development, learning, and memory. When glutamate receptor agonists are present in excess, binding to NMDA receptors produces neuronal/CNS/PNS long-term potentiation, conditions of acute pain, ongoing severe intractable pain, and potential excitotoxicity and pathology. The GluNR1 subunit (116 kD) is necessary as the anchor component directing ion channel heterodimer formation, cellular trafficking, and the nuclear localization that directs functionally specific heterodimer formation, cellular trafficking, and nuclear functions. Emerging studies report the relevance of GluN1 subunit composition and specifically that nuclear GluN1 has major physiologic potential in tissue and/or subnuclear functioning assignments. The shift of the GluN1 subunit from a surface cell membrane to nuclear localization assigns the GluN1 promoter immediate early gene behavior with access to nuclear and potentially nucleolar functions. The present narrative review addresses the nuclear translocation of GluN1, focusing particularly on examples of the role of GluN1 in nociceptive processes.
Subject(s)
N-Methylaspartate , Nociception , Humans , Cell Nucleus , Excitatory Amino Acid Agonists , Pain , Receptors, N-Methyl-D-Aspartate/geneticsABSTRACT
OBJECTIVE: This study assessed the impact of pancreatic cancer (PC) pain on associated symptoms, activities, and resource utilization from 2016 to 2020 in an online patient registry. PATIENTS AND METHODS: Responses from PC patient volunteers (N = 1978) were analyzed from online surveys in a cross-sectional study. Comparisons were performed between PC patient groups reporting, (1) the presence vs. absence of pre-diagnosis PC pain, (2) high (4-8) vs. low (0-3) pain intensity scores on an 11-point numerical rating scale (NRS), and (3) year of PC diagnosis (2010-2020). Descriptive statistics and all bivariate analyses were performed using Chi-square or Fisher's Exact tests. RESULTS: PC pain was the most frequently reported pre-diagnosis symptom (62%). Pre-diagnostic PC pain was reported more frequently by women, those with a younger age at diagnosis, and those with PC that spread to the liver and peritoneum. Those with pre-diagnostic PC pain vs. those without reported higher pain intensities (2.64 ± 2.54 vs.1.56 ± 2.01 NRS mean ± SD, respectively, P = .0039); increased frequencies of post-diagnosis symptoms of cramping after meals, feelings of indigestion, and weight loss (P = .02-.0001); and increased resource utilization in PC pain management: (ER visits N = 86 vs. N = 6, P = .018 and analgesic prescriptions, P < .03). The frequency of high pain intensity scores was not decreased over a recent 11-year span. CONCLUSIONS: PC pain continues to be a prominent PC symptom. Patients reporting pre-diagnosis PC pain experience increased GI metastasis, symptoms burden, and are often undertreated. Its mitigation may require novel treatments, more resources dedicated to ongoing pain management and surveillance to improve outcomes.
Subject(s)
Cancer Pain , Gastrointestinal Neoplasms , Pancreatic Neoplasms , Humans , Female , Cross-Sectional Studies , Pain , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/therapy , Palliative Care , Gastrointestinal Neoplasms/therapy , Cancer Pain/diagnosis , Cancer Pain/therapyABSTRACT
Pain is highly prevalent in patients with pancreas cancer and contributes to the morbidity of the disease. Pain may be due to pancreatic enzyme insufficiency, obstruction, and/or a direct mass effect on nerves in the celiac plexus. Proper supportive care to decrease pain is an important aspect of the overall management of these patients. There are limited data specific to the management of pain caused by pancreatic cancer. Here we review the literature and offer recommendations regarding multiple modalities available to treat pain in these patients. The dissemination and adoption of these best supportive care practices can improve quantity and quality of life for patients with pancreatic cancer. IMPLICATIONS FOR PRACTICE: Pain management is important to improve the quality of life and survival of a patient with cancer. The pathophysiology of pain in pancreas cancer is complex and multifactorial. Despite tumor response to chemotherapy, a sizeable percentage of patients are at risk for ongoing cancer-related pain and its comorbid consequences. Accordingly, the management of pain in patients with pancreas cancer can be challenging and often requires a multifaceted approach.
Subject(s)
Cancer Pain , Celiac Plexus , Pancreatic Neoplasms , Cancer Pain/etiology , Cancer Pain/therapy , Humans , Pain Management , Palliative Care , Pancreas , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/therapy , Quality of LifeABSTRACT
In the lumbar spinal cord dorsal horn, release of afferent nerve glutamate activates the neurons that relay information about injury pain. Here, we examined the effects of protein tyrosine kinase (PTK) inhibition on NMDA receptor NR1 subunit protein expression and subcellular localization in an acute experimental arthritis model. PTK inhibitors genistein and lavendustin A reduced cellular histological translocation of NMDA NR1 in the spinal cord occurring after the inflammatory insult and the nociceptive behavioral responses to heat. The PTK inhibitors were administered into lumbar spinal cord by microdialysis, and secondary heat hyperalgesia was determined using the Hargreaves test. NMDA NR1 cellular protein expression and nuclear translocation were determined by immunocytochemical localization with light and electron microscopy, as well as with Western blot analysis utilizing both C- and N-terminal antibodies. Genistein and lavendustin A (but not inactive lavendustin B or diadzein) effectively reduced (i) pain related behavior, (ii) NMDA NR1 subunit expression increases in spinal cord, and (iii) the shift of NR1 from a cell membrane to a nuclear localization. Genistein pre-treatment reduced these events that occur in vivo within 4 h after inflammatory insult to the knee joint with kaolin and carrageenan (k/c). Cycloheximide reduced glutamate activated upregulation of NR1 content confirming synthesis of new protein in response to the inflammatory insult. In addition to this in vivo data, genistein or staurosporin inhibited upregulation of NMDA NR1 protein and nuclear translocation in vitro after treatment of human neuroblastoma clonal cell cultures (SH-SY5Y) with glutamate or NMDA (4 h). These studies provide evidence that inflammatory activation of peripheral nerves initiates increase in NMDA NR1 in the spinal cord coincident with development of pain related behaviors through glutamate non-receptor, PTK dependent cascades.
ABSTRACT
OBJECTIVE: To identify baseline features that predict progression of hand contractures and to assess the effect of contractures on functional status in the prospective GENISOS cohort. METHODS: Rate of decline in hand extension, as an indicator of hand contracture, was the primary outcome. We assessed longitudinal hand extension measurements, modified Health Assessment Questionnaire (MHAQ) score, Medical Outcomes Study Short Form-36 (SF-36) physical function score, and demographic, clinical, and serological variables. Subjects with ≥ 2 hand measurements at least 6 months apart were included. RESULTS: A total of 1087 hand measurements for 219 patients were available over an average of 8.1 ± 4.8 years. Hand extension decreased on average by 0.11 cm/year. Antitopoisomerase I antibody (ATA) positivity and higher modified Rodnan Skin Score (mRSS) were predictive of faster decline in hand extension (p = 0.009 and p = 0.046, respectively). In a subgroup analysis of 62 patients with ≤ 2 years from SSc onset, ATA and diffuse disease type were associated with faster decline in hand extension; anticentromere positivity was associated with slower rate of decline. Although the rate of decline in patients with disease duration ≤ 2 years was numerically higher, the difference was not statistically significant. Hand extension continued to decline in a linear fashion over time and was inversely related to overall functional status. CONCLUSION: ATA was predictive of contracture development in both early disease (≤ 2 yrs) and in the overall cohort. Hand extension declined linearly over time and was inversely associated with MHAQ and SF-36 scores. ATA positivity and higher baseline mRSS were predictive of faster decline in hand extension.
Subject(s)
Contracture/etiology , Hand/physiopathology , Scleroderma, Systemic/complications , Adult , Contracture/diagnosis , Contracture/physiopathology , Disease Progression , Female , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Risk Factors , Scleroderma, Systemic/physiopathology , Severity of Illness IndexABSTRACT
Development of new pharmacological treatments for osteoarthritis that address unmet medical needs in a competitive market place is challenging. Bayesian approaches to trial design offer advantages in defining treatment benefits by addressing clinically relevant magnitude of effects relative to comparators and in optimizing efficiency in analysis. Such advantages are illustrated by a motivating case study, a proof of concept, and dose finding study in patients with osteoarthritis. Patients with osteoarthritis were randomized to receive placebo, celecoxib, or 1 of 4 doses of galcanezumab. Primary outcome measure was change from baseline WOMAC pain after 8 weeks of treatment. Literature review of clinical trials with targeted comparator therapies quantified treatment effects versus placebo. Two success criteria were defined: one to address superiority to placebo with adequate precision and another to ensure a clinically relevant treatment effect. Trial simulations used a Bayesian dose response and longitudinal model. An interim analysis for futility was incorporated. Simulations indicated the study had ≥85% power to detect a 14-mm improvement and ≤1% risk for a placebo-like drug to pass. The addition of the second success criterion substantially reduced the risk of an inadequate, weakly efficacious drug proceeding to future development. The study was terminated at the interim analysis due to inadequate analgesic efficacy. A Bayesian approach using probabilistic statements enables clear understanding of success criteria, leading to informed decisions for study conduct. Incorporating an interim analysis can effectively reduce sample size, save resources, and minimize exposure of patients to an inadequate treatment.
Subject(s)
Antirheumatic Agents/therapeutic use , Biostatistics/methods , Clinical Trials, Phase II as Topic/statistics & numerical data , Osteoarthritis, Knee/drug therapy , Randomized Controlled Trials as Topic/statistics & numerical data , Research Design/statistics & numerical data , Bayes Theorem , Clinical Trials, Phase II as Topic/methods , Computer Simulation , Data Interpretation, Statistical , Disease Progression , Dose-Response Relationship, Drug , Early Termination of Clinical Trials , Endpoint Determination/statistics & numerical data , Humans , Medical Futility , Models, Statistical , Osteoarthritis, Knee/diagnosis , Randomized Controlled Trials as Topic/methods , Remission Induction , Time Factors , Treatment OutcomeABSTRACT
Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Arthralgia/drug therapy , Celecoxib/pharmacology , Organic Chemicals/pharmacology , Osteoarthritis/drug therapy , Receptors, Prostaglandin E, EP4 Subtype/antagonists & inhibitors , Administration, Oral , Adult , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthralgia/etiology , Celecoxib/therapeutic use , Double-Blind Method , Female , Healthy Volunteers , Humans , Male , Middle Aged , Organic Chemicals/chemistry , Osteoarthritis/complications , Placebos , Young AdultABSTRACT
AIMS: LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile. METHODS: Healthy subjects were randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated. RESULTS: The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing. CONCLUSIONS: This study emphasized the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207.
Subject(s)
Chemical and Drug Induced Liver Injury/etiology , Drug Hypersensitivity/etiology , Enzyme Inhibitors/adverse effects , Imidazoles/adverse effects , Prostaglandin-E Synthases/antagonists & inhibitors , Administration, Oral , Adult , Area Under Curve , Celecoxib/adverse effects , Chemical and Drug Induced Liver Injury/pathology , Cyclooxygenase 2 Inhibitors/adverse effects , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Drug Hypersensitivity/pathology , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Female , Half-Life , Healthy Volunteers , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Liver/drug effects , Liver/immunology , Liver/pathology , Male , Middle Aged , Pain/drug therapy , Withholding TreatmentABSTRACT
BACKGROUND: Chronic Pancreatitis (CP) is a complex and multifactorial syndrome. Many contributing factors result in development of dysfunctional pain in a significant number of patients. Drugs developed to treat a variety of pain states fall short of providing effective analgesia for patients with chronic pancreatitis, often providing minimal to partial pain relief over time with significant side effects. Recently, availability of selective pharmacological tools has enabled great advances in our knowledge of the role of the cannabinoid receptors in pathophysiology. In particular, cannabinoid receptor 2 (CB2) has emerged as an attractive target for management of chronic pain, as demonstrated in several studies with inflammatory and neuropathic preclinical pain models. In this study, the analgesic efficacy of a novel, highly selective CB2 receptor agonist, LY3038404 HCl, is investigated in a chronic pancreatitis pain model, induced with an alcohol/high fat (AHF) diet. RESULTS: Rats fed the AHF diet developed visceral pain-like behaviors detectable by week 3 and reached a maximum at week 5 that persists as long as the diet is maintained. Rats with AHF induced chronic pancreatitis were treated with LY3038404 HCl (10 mg/kg, orally, twice a day for 9 days). The treated animals demonstrated significantly alleviated pain related behaviors after 3 days of dosing, including increased paw withdrawal thresholds (PWT), prolonged abdominal withdrawal latencies (ABWL), and decreased nocifensive responses to noxious 44°C hotplate stimuli. Terminal histological analysis of pancreatic tissue sections from the AHF chronic pancreatitis animals demonstrated extensive injury, including a global pancreatic gland degeneration (cellular atrophy), vacuolization (fat deposition), and fibrosis. After the LY3038404 HCl treatment, pancreatic tissue was significantly protected from severe damage and fibrosis. LY3038404 HCl affected neither open field exploratory behaviors nor dark/light box preferences as measures of higher brain and motor functions. CONCLUSION: LY3038404 HCl, a potent CB2 receptor agonist, possesses tissue protective and analgesic properties without effects on higher brain function. Thus, activation of CB2 receptors is suggested as a potential therapeutic target for visceral inflammation and pain management.
Subject(s)
Cannabinoid Receptor Agonists/therapeutic use , Pancreatitis, Chronic/complications , Receptor, Cannabinoid, CB1/agonists , Visceral Pain/drug therapy , Visceral Pain/etiology , Alcohols/toxicity , Animals , Cell Proliferation/drug effects , Dark Adaptation/drug effects , Diet, High-Fat/adverse effects , Disease Models, Animal , Exploratory Behavior/drug effects , Fibrosis/etiology , Fibrosis/pathology , Hyperalgesia/drug therapy , Hyperalgesia/etiology , Male , Pain Threshold/drug effects , Pancreatitis, Chronic/etiology , Pancreatitis, Chronic/pathology , Rats , Rats, Inbred F344 , Reaction Time/drug effects , Severity of Illness IndexABSTRACT
BACKGROUND: Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis. RESULTS: The functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores. CONCLUSIONS: Our present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population.
Subject(s)
Diabetic Neuropathies/genetics , Gene Expression Regulation/genetics , Polymorphism, Single Nucleotide/genetics , Receptors, Purinergic P2X7/genetics , Adenosine Triphosphate/analogs & derivatives , Adenosine Triphosphate/pharmacology , Analysis of Variance , Benzoxazoles/metabolism , Calcium/metabolism , Female , Gene Expression Regulation/drug effects , Genotype , HEK293 Cells , Humans , Male , Middle Aged , Pain Measurement , Platelet Aggregation Inhibitors/pharmacology , Purinergic P2X Receptor Antagonists/pharmacology , Quinolinium Compounds/metabolism , TransfectionABSTRACT
BACKGROUND: The gastrointestinal (GI) dysmotility of systemic sclerosis (SSc, scleroderma) patients requires careful evaluation and intervention. The lack of effective prokinetic drugs motivate researchers to search for alternative treatments. OBJECTIVES: We present an overview of the pathophysiology of SSc GI dysmotility and the advances in its management, with particular focus on acupuncture-related modalities and innovative therapies. DATA SOURCES: Original research articles were identified based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline methodology. We have searched the MEDLINE database using Medical Subject Heading (MeSH) for all English and non-English articles with an English abstract from 2005 to October 2012. RESULTS: Only four original articles of various study designs were found studying Complementary and Alternative Medicine (CAM) therapies for SSc patients. Despite the small patient study numbers, CAM treatments, acupressure, and transcutaneous electroacupuncture, showed self-reported and physiologic evidence of improvement of GI functioning and/or symptoms in SSc patients. CONCLUSIONS: CAM therapies include experimental modalities with the potential to offer relief of symptoms from GI dysmotility. Larger studies are needed to investigate their optimal use in patient subsets to tailor therapies to patient needs.
Subject(s)
Acupuncture Therapy , Connective Tissue/pathology , Gastrointestinal Diseases/therapy , Gastrointestinal Motility , Gastrointestinal Tract/physiopathology , Scleroderma, Systemic/therapy , Electroacupuncture , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/physiopathology , Humans , Outcome Assessment, Health Care , Scleroderma, Systemic/complications , Scleroderma, Systemic/physiopathologyABSTRACT
OBJECTIVE: To examine the prevalence of isolated IgA anti-ß2 -glycoprotein I (anti-ß2 GPI) positivity and the association of these antibodies, and a subgroup that bind specifically to domain IV/V of ß2 GPI, with clinical manifestations of the antiphospholipid syndrome (APS) in 3 patient groups and to evaluate the pathogenicity of IgA anti-ß2 GPI in a mouse model of thrombosis. METHODS: Patients with systemic lupus erythematosus (SLE) from a multiethnic, multicenter cohort (LUpus in MInorities, NAture versus nurture [LUMINA]) (n = 558), patients with SLE from the Hopkins Lupus Cohort (n = 215), and serum samples referred to the Antiphospholipid Standardization Laboratory (APLS) (n = 5,098) were evaluated. IgA anti-ß2 GPI titers and binding to domain IV/V of ß2 GPI were examined by enzyme-linked immunosorbent assay (ELISA). CD1 mice were inoculated with purified IgA anti-ß2 GPI antibodies, and surgical procedures and ELISAs were performed to evaluate thrombus development and tissue factor (TF) activity. RESULTS: A total of 198 patients were found to be positive for IgA anti-ß2 GPI isotype, and 57 patients were positive exclusively for IgA anti-ß2 GPI antibodies. Of these, 13 of 23 patients (56.5%) in the LUMINA cohort, 17 of 17 patients (100%) in the Hopkins cohort, and 10 of 17 patients (58.9%) referred to APLS had at least one APS-related clinical manifestation. Fifty-four percent of all the IgA anti-ß2 GPI-positive serum samples reacted with domain IV/V of anti-ß2 GPI, and 77% of those had clinical features of APS. Isolated IgA anti-ß2 GPI positivity was associated with an increased risk of arterial thrombosis (P < 0.001), venous thrombosis (P = 0.015), and all thrombosis (P < 0.001). The association between isolated IgA anti-ß2 GPI and arterial thrombosis (P = 0.0003) and all thrombosis (P = 0.0003) remained significant after adjusting for other risk factors for thrombosis. In vivo mouse studies demonstrated that IgA anti-ß2 GPI antibodies induced significantly larger thrombi and higher TF levels compared to controls. CONCLUSION: Isolated IgA anti-ß2 GPI-positive titers may identify additional patients with clinical features of APS. Testing for these antibodies when other antiphospholipid tests are negative and APS is suspected is recommended. IgA anti-ß2 GPI antibodies directed to domain IV/V of ß2 GPI represent an important subgroup of clinically relevant antiphospholipids.
Subject(s)
Antibodies, Anti-Idiotypic/blood , Antiphospholipid Syndrome/diagnosis , Autoantibodies/blood , Immunoglobulin A/blood , beta 2-Glycoprotein I/immunology , Animals , Antiphospholipid Syndrome/blood , Antiphospholipid Syndrome/immunology , Humans , Longitudinal Studies , Mice , Prevalence , Thrombosis/diagnosis , Thrombosis/immunologyABSTRACT
BACKGROUND: Previous studies have demonstrated elevated levels of excitatory amino acids (EAA) glutamate (Glu) and aspartate (Asp) in the synovial fluid (SF) of patients with active arthritis. The source of SF EAA concentrations are thought in large part to be secondary to passive diffusion from the plasma across synovial membranes and less so, reflective of local synovial pathology. OBJECTIVE: This descriptive report assesses the hypothesis that the SF EAA levels reflect inflammatory processes of the joint and are not dependent on plasma levels. METHODS: Simultaneously drawn plasma and SF samples were obtained from 14 recently deceased cadavers and 10 patients with active arthritis. Plasma and SF EAA and other amino acid (AA) levels were determined by HPLC. SF: Plasma compartment concentration ratios were calculated to assess if SF EAA levels were similar to plasma levels. RESULTS: In the cadavers with no antemortem arthritis, the mean SF: Plasma ratios for Glu and Asp were 4-5-fold lower than the mean ratios seen for 9 other AAs, showing specific discrepancies of EAA levels between plasma and synovial fluid. In 9 patients with active arthritis, the SF: Plasma concentration ratios were higher in samples derived from inflammatory arthropathies. CONCLUSIONS: Clinical samples demonstrated distinct, independent compartmental EAA concentrations between blood and joint compartments in support that local arthritic processes rather than plasma influence SF EAA concentrations. The SF EAA levels, whether from local cell production, local neurogenic sources, and/or transport-gradient mechanisms, parallel local pathology in the joint compartment and thus serve as surrogate biomarkers of local inflammatory processes.
Subject(s)
Arthritis/metabolism , Aspartic Acid/metabolism , Glutamic Acid/metabolism , Joints/metabolism , Synovial Fluid/metabolism , Adult , Aged , Arthritis/pathology , Aspartic Acid/analysis , Blood Chemical Analysis , Cadaver , Chromatography, High Pressure Liquid , Glutamic Acid/analysis , Humans , Joints/pathology , Middle Aged , Synovial Fluid/chemistryABSTRACT
PURPOSE: We assessed the effects of transcutaneous electrical nerve stimulation (TENS) on neurogastric functioning in scleroderma patients. METHODS: Seventeen SSc patients underwent 30 min TENS treatment >10Hz at GI acupuncture points PC6 and ST36, once (acute TENS) and then after two weeks of TENS sessions for 30 min twice daily (prolonged TENS). Data collected at Visits 1 and 2 included gastric myoelectrical activity (GMA) by surface electrogastrography (EGG), heart rate variability (HRV) by surface electrocardiography (EKG), GI specific symptoms and health related SF-36 questionnaires. Plasma VIP, motilin and IL-6 levels were determined. Statistical analyses were performed by Student's t-test, Spearman Rank and p-values <0.05 were considered significant. RESULTS: 1. Only after prolonged TENS, the percentages of normal slow waves and average slow wave coupling (especially channels 1, 2 reflecting gastric pacemaker and corpus regions) were significantly increased; 2. the percentage of normal slow waves was significantly correlated to sympathovagal balance; 3. Mean plasma VIP and motilin levels were significantly decreased after acute TENS, (vs. baseline), generally maintained in the prolonged TENS intervals. Compared to baseline, mean plasma IL-6 levels were significantly increased after acute TENS, but significantly decreased after prolonged TENS. 4. After prolonged TENS, the frequency of awakening due to abdominal pain and abdominal bloating were significantly and modestly decreased, respectively. CONCLUSIONS: In SSc patients, two weeks of daily TENS improved patient GMA scores, lowered plasma VIP, motilin and IL-6 levels and improved association between GMA and sympathovagal balance. This supports the therapeutic potential of prolonged TENS to enhance gastric myoelectrical functioning in SSc.
Subject(s)
Gastrointestinal Motility/physiology , Gastroparesis/therapy , Scleroderma, Systemic/complications , Stomach/innervation , Stomach/physiology , Transcutaneous Electric Nerve Stimulation/methods , Electrocardiography , Electromyography , Female , Gastroparesis/blood , Gastroparesis/physiopathology , Health Status , Heart Rate/physiology , Humans , Interleukin-6/blood , Male , Middle Aged , Motilin/blood , Patient Satisfaction , Scleroderma, Systemic/blood , Scleroderma, Systemic/physiopathology , Treatment Outcome , Vasoactive Intestinal Peptide/bloodABSTRACT
OBJECTIVE: Illness behaviors (cognitive, affective, and behavioral reactions) among individuals with systemic sclerosis (SSc; scleroderma) are of clinical concern due to relationships between these behaviors and physical and mental quality of life, such as pain and symptoms of depression. Self-report measures with good psychometric properties can aid in the accurate assessment of illness behavior. The Illness Behavior Questionnaire (IBQ) was designed to measure abnormal illness behaviors; however, despite its longstanding use, there is disagreement regarding its subscales. The goal of the present study was to evaluate the validity of the IBQ in a cohort of patients with SSc. METHODS: Patients with SSc (n = 278) completed the IBQ at enrollment into the Genetics Versus Environment in Scleroderma Outcome Study. Structural validity of previously derived factor solutions was investigated using confirmatory factor analysis. Exploratory factor analysis was utilized to derive SSc-specific subscales. RESULTS: None of the previously derived structural models were supported for SSc patients. Exploratory factor analysis supported an SSc-specific factor structure with 5 subscales. Validity analyses suggested that the subscales were generally independent of disease severity, but were correlated with other health outcomes (i.e., fatigue, pain, disability, social support, and mental health). CONCLUSION: The proposed subscales are recommended for use in SSc, and can be utilized to capture illness behavior that may be of clinical concern.
Subject(s)
Illness Behavior , Mental Health , Quality of Life , Scleroderma, Systemic/psychology , Sick Role , Female , Humans , Male , Middle Aged , Pain Measurement , Prospective Studies , Psychometrics/methods , Scleroderma, Systemic/diagnosis , Severity of Illness Index , Surveys and QuestionnairesABSTRACT
OBJECTIVES: Longitudinal studies examining the baseline predictors of fatigue in SSc have not been reported. Our objectives were to examine the course of fatigue severity over time and to identify baseline clinical, demographic, and psychosocial predictors of sequentially obtained fatigue scores in early SSc. We also examined baseline predictors of change in fatigue severity over time. METHODS: We analyzed 1090 longitudinal Fatigue Severity Scale (FSS) scores belonging to 256 patients who were enrolled in the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS). Predictive significance of baseline variables for sequentially obtained FSS scores was examined with generalized linear mixed models. Predictors of change in FSS over time were examined by adding an interaction term between the baseline variable and time-in-study to the model. RESULTS: The patients' mean age was 48.6 years, 47% were Caucasians, and 59% had diffuse cutaneous involvement. The mean disease duration at enrollment was 2.5 years. The FSS was obtained at enrollment and follow-up visits (mean follow-up timeâ=â3.8 years). Average baseline FSS score was 4.7(±0.96). The FSS was relatively stable and did not show a consistent trend for change over time (pâ=â0.221). In a multivariable model of objective clinical variables, higher Medsger Gastrointestinal (pâ=â0.006) and Joint (pâ=â0.024) Severity Indices, and anti-U1-RNP antibodies (pâ=â0.024) were independent predictors of higher FSS. In the final model, ineffective coping skills captured by higher Illness Behavior Questionnaire scores (p<0.001), higher self-reported pain (pâ=â0.006), and higher Medsger Gastrointestinal Severity Index (pâ=â0.009) at enrollment were independent predictors of higher longitudinal FSS scores. Baseline DLco % predicted was the only independent variable that significantly predicted a change in FSS scores over time (pâ=â0.013), with lower DLco levels predicting an increase in FSS over time. CONCLUSIONS: This study identified potentially modifiable clinical and psychological factors that predict longitudinal fatigue severity in early SSc.
Subject(s)
Fatigue/complications , Fatigue/diagnosis , Scleroderma, Systemic/complications , Severity of Illness Index , Demography , Fatigue/psychology , Female , Humans , Longitudinal Studies , Male , Middle Aged , Multivariate Analysis , Prospective Studies , Time FactorsABSTRACT
Gastrointestinal (GI) hypomotility and symptoms are common in Scleroderma (SSc) patients yet so far uncorrelated. Eight SSc patients and matched controls were queried about their GI dysmotility symptoms and quality of life (QoL) and underwent anorectal motility and sensory tests. Specific scoring systems were developed for anorectal symptoms and anorectal dysmotility. We found that (1) the SSc patients showed low QoL and marked overall GI symptoms. The most common anorectal symptom was incomplete bowel movement (50%). (2) Compared to normal controls, SSc patients showed impaired anorectal pressures, sensations, and rectal compliance (P ≤ .01 for each). (3) The anorectal motility/sensation abnormality score was robustly correlated with the total anorectal symptom score (r(s) = .78, P = .02). In conclusion, scleroderma patients have impaired anorectal motor and sensory functions, and the abnormality score of these anorectal functions is correlated with the total anorectal symptoms score. These scoring systems may assist clinicians in predicting dysmotility based on patient symptoms.
ABSTRACT
OBJECTIVE: To investigate the association of cigarette smoking with susceptibility to systemic sclerosis (SSc) in a large, well-defined patient population. METHODS: We conducted a review of 1,379 patients with SSc enrolled in the Scleroderma Family Registry and DNA Repository and/or the Genetics versus Environment in Scleroderma Outcome Study cohort. Smoking history was obtained from chart review or via telephone interview. Patients with SSc were subsequently categorized as never smokers or ever smokers. Patients with SSc for whom smoking data were available were matched 2:1 by age, sex, ethnicity, and state of residence to control subjects, using the Behavioral Risk Factor Surveillance System. RESULTS: The majority of patients were white (74.2%), with Hispanics and blacks representing 11.3% and 9.7%, respectively. Most patients had limited cutaneous involvement (54%). For our comparative analyses, 621 patients were matched with control subjects. There was no significant difference in age, sex, ethnicity, and SSc subtype between matched versus unmatched patients. The majority of patients had never smoked (57%), while 43% of patients were classified as ever smokers. The patients with SSc did not differ from control subjects in terms of their smoking behavior (odds ratio [OR] 1.020, 95% confidence interval [95% CI] 0.839-1.240, P=0.842). Anti-topoisomerase I antibody-positive patients were more likely to be never smokers (OR 0.648, 95% CI 0.421-0.998, P=0.049), whereas no such association was observed with anticentromere and anti-RNA polymerase III antibodies. CONCLUSION: Unlike its role in rheumatoid arthritis, smoking does not confer a risk for development of SSc, although it may impact disease severity.
Subject(s)
Scleroderma, Systemic/etiology , Smoking/adverse effects , Autoantibodies/immunology , DNA Topoisomerases, Type I/immunology , Female , Humans , Male , Middle Aged , Registries , Risk Factors , Scleroderma, Systemic/immunology , Severity of Illness IndexABSTRACT
OBJECTIVE: Anti-U3-RNP, or anti-fibrillarin antibodies (AFA), are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. We examined the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc. METHODS: Overall, 278 AA patients with SSc and 328 unaffected AA controls were enrolled from 3 North American cohorts. Clinical features, autoantibody profile, and HLA class II genotyping were determined. To compare clinical manifestations, relevant clinical features were adjusted for disease duration. Cox proportional hazards regression was used to determine the effect of AFA on survival. RESULTS: Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR 11.5, p < 0.0001) and AFA-negative SSc patients (OR 5.2, p = 0.0002). AFA-positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger perivascular and lower Medsger lung severity indices (p = 0.004, p = 0.014, p = 0.019, p = 0.092, p = 0.006, and p = 0.016, respectively). After adjustment for age at enrollment, AFA-positive patients did not have different survival compared to patients without AFA (p = 0.493). CONCLUSION: Our findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. Presence of AFA did not change survival.
Subject(s)
Antibodies, Antinuclear/genetics , Antibodies, Antinuclear/immunology , Autoantibodies/genetics , Autoantibodies/immunology , Black or African American/genetics , Chromosomal Proteins, Non-Histone/immunology , Scleroderma, Systemic/immunology , Adult , Chromosomal Proteins, Non-Histone/genetics , Female , Gene Frequency , HLA-DRB1 Chains/immunology , Histocompatibility Antigens Class II/genetics , Histocompatibility Antigens Class II/immunology , Humans , Immunogenetics/methods , Male , Middle Aged , Scleroderma, Systemic/genetics , Scleroderma, Systemic/pathology , Scleroderma, Systemic/physiopathology , Survival AnalysisABSTRACT
OBJECTIVES: To determine the prevalence, correlates, and predictors of work disability (WD) in the Genetics versus ENvironment In Scleroderma Outcome Study (GENISOS). We hypothesized that WD in systemic sclerosis (SSc) is a function of demographic, clinical, and psychosocial factors. METHODS: Patients enrolled in the GENISOS cohort were subdivided in 3 groups: work disabled, working, and retired or homemakers. The latter group (n = 29) was excluded from further analysis. We used logistic regression analysis with a forward hierarchical variable selection strategy to investigate the independent correlates of WD at enrollment. Cox regression proportional Hazard's model with a similar variable selection strategy was utilized to determine the predictors of WD in those working at enrollment. RESULTS: Overall, 284 patients with a mean age of 48.7 years and disease duration of 2.5 (±1.6) years were enrolled into the GENISOS cohort, consisting of 83.5% female, 46.8% white, 28.9% Hispanic, and 20.4% African American. Patients were longitudinally followed in 1438 study visits. At enrollment, 124 patients (43.7%) were work disabled, whereas 131 (46.1%) were working. Lower level of education (P < 0.001), higher Medsger Lung Severity Index (P = 0.012), higher Fatigue Severity Score (P = 0.008), and less social support (P < 0.001) correlated independently with WD. Of those working at baseline, 35 (26.7%) eventually developed WD. Non-white ethnicity (P = 0.038), lower DLCO % predicted value (P = 0.038), and higher Fatigue Severity Score (P = 0.009) at enrollment independently predicted WD on follow-up visits. CONCLUSIONS: WD is a major problem among SSc patients and its prevalence is substantially higher than other rheumatic conditions. Demographic, clinical, and psychosocial factors correlate with WD cross-sectionally and predict WD longitudinally in these patients.