Rene Costello

Comparison of Tripterygium wilfordii Hook F Versus Sulfasalazine in the Treatment of Rheumatoid Arthritis: A Randomized Trial

Context In Chinese medicine, extracts of Tripterygium wilfordii Hook F (TwHF, known as lei gong teng or thunder god vine) are used to treat autoimmune and inflammatory conditions. Small clinical trials suggest that TwHF may benefit patients with rheumatoid arthritis. Contribution This trial compared TwHF extract with sulfasalazine in 121 patients with active rheumatoid arthritis who could continue oral prednisone and nonsteroidal anti-inflammatory drugs but not disease-modifying antirheumatic drugs. Among patients who continued treatment for 24 weeks, achievement of 20% improvement in American College of Rheumatology criteria was greater with TwHF than with sulfasalazine. Adverse event rates were similar. Caution Only 62% and 41% of patients continued TwHF and sulfasalazine treatment, respectively, and provided 24 weeks of data. The Editors Rheumatoid arthritis is characterized by chronic inflammation of the joint lining (synovial membrane) (1), which causes pain and swelling of diarthrodial joints. Over time, uncontrolled disease results in progressive joint damage, disability, and increased mortality (2). The evolving understanding of the immune mechanisms that perpetuate the inflammatory response has led to effective targeted therapies, including inhibitors of inflammatory cytokines (tumor necrosis factor, interleukin-1, and interleukin-6), modulators of activation of CD4+ T cells and dendritic cells, and agents that deplete B cells (3, 4). Despite the clinical efficacy of these therapies, many patients have no clinically meaningful response or discontinue treatment because of adverse events. Furthermore, the limited availability of effective biologics in developing countries, the need for parenteral administration of the biologics, and the relatively high cost all restrict access to these therapies in many patients with rheumatoid arthritis around the world (5). In traditional Chinese medicine, extracts of the roots of the medicinal vine Tripterygium wilfordii Hook F (TwHF) (known in China as lei gong teng or thunder god vine) have shown therapeutic promise in treating autoimmune and inflammatory conditions as well as cancer (68). More recently, different extracts of TwHF have been used in Chinese allopathic medicine for the treatment of autoimmune and inflammatory diseases, and small controlled trials reported good responses with TwHF extracts in patients with cadaveric kidney transplants (9, 10) and Crohn disease (11). Of the approximately 380 metabolites isolated from the plant, 95% are terpenoids (12, 13). Three diterpenoidstriptolide, tripdiolide, and triptonide (13)are the most abundant and account for the immunosuppressive and anti-inflammatory effects observed with the root extracts in both in vitro and in vivo studies (6). In 2 previous single-center trials of patients with rheumatoid arthritis, the extract was standardized by the content of triptolide and tripdiolide (14). This made it possible to use optimal doses identified in an open-label trial (15) for the design of a subsequent small placebo-controlled study (16). Although the number of patients was small, the apparent clinical impact and experimental results indicating potent inhibition of the expression of proinflammatory genes both in vitro and in vivo in animal models (1721) provided the rationale for our multicenter, double-blind, active comparator trial of a standardized TwHF extract in patients with active rheumatoid arthritis. Methods Design Overview This randomized, controlled, 24-week study was conducted between March 2004 and October 2005. All participants provided written informed consent to enter the trial, and the institutional review boards at the participating sites approved the protocol. All investigators and outcome assessors were blinded to group assignment of the patients. Our objective was to determine whether therapy with TwHF extract, 180 mg/d, was statistically significantly better than therapy with sulfasalazine, 2 g/d, over 24 weeks in patients with rheumatoid arthritis by using standard outcome measures. Setting and Participants Our study was conducted at 11 U.S. centers: 2 academic centers (National Institutes of Health, Bethesda, Maryland, and University of Texas, Dallas, Texas) and 9 rheumatology subspecialty clinics (1 each in Dallas and Austin, Texas; Tampa and Fort Lauderdale, Florida; Arlington, Virginia; Duncanville, Pennsylvania; Wheaton and Greenbelt, Maryland; and Lansing, Michigan). Eligible patients had to be at least 18 years of age and have established rheumatoid arthritis, defined by the American College of Rheumatology (ACR) classification criteria (22) as rheumatoid arthritis lasting longer than 6 months. Eligible patients had active disease, defined as 6 or more painful and swollen joints, a visual analogue scale score for pain of at least 3 (on a scale of 1 to 10, with 1 being mild), and a C-reactive protein (CRP) level of 57.14 nmol/L or greater (0.6 mg/dL) or an erythrocyte sedimentation rate (ESR) greater than 25 mm/h. Patients who were taking any disease-modifying antirheumatic drug at screening underwent a 28-day washout period. The use of oral prednisone, at stable doses up to 7.5 mg/d, and nonsteroidal anti-inflammatory drugs were allowed as long as the dose was not changed for 28 days before randomization and the patient agreed to continue to take the medication during the study. Table 1 lists baseline patient characteristics. Table 1. Patient Characteristics at Baseline Randomization and Interventions We used a computer-generated, pseudo-random code (with random, permuted blocks) to assign patients to treatment groups across all centers. We assigned eligible patients at a 1:1 ratio to receive either TwHF extract, 180 mg/d, or sulfasalazine, 2 g/d. In the event of gastrointestinal intolerance, the protocol allowed for temporary dose reduction of 50%. As described elsewhere (15, 16), the triptolide and tripdiolide content of the ethanol and ethylacetate extract (measured by high-performance liquid chromatography [22]) was used to standardize the drug preparation for this study. On the basis of data on in vitro activity and in vivo toxicity, 30 mg of TwHF extract were formulated per capsule. Our study was conducted under the U.S Food and Drug Administrationapproved Investigational New Drug application 39191. Outcomes and Measurements Patients were evaluated clinically and by laboratory measures at baseline, 2 weeks, and every 4 weeks for a total of 24 weeks. A rheumatologist or trained staff member masked to treatment allocation assessed the patients. Serum or plasma specimens were obtained from the patients at baseline, 4 weeks, and 24 weeks and stored at 80C until analysis. Radiographs of hands and feet were obtained at baseline and 24 weeks or at study discontinuation. The primary end point was a 20% improvement at 24 weeks, as defined by ACR criteria (ACR 20) (23). To meet criteria, a patient must have 20% or greater improvement in both tender and swollen joints (68 tender and 66 swollen joints were assessed) and 20% or greater improvement in 3 or more of the following: the physicians or patients assessment of global health status, the patients assessment of pain on a visual analogue scale, the patients assessment of function (using a modified version of the Health Assessment Questionnaire [HAQ]), and the serum CRP level. Secondary end points included the efficacy of TwHF in achieving ACR 50 and ACR 70 responses at 24 weeks, the improvement in the European League Against Rheumatism Disease Activity Score 28 (DAS 28) measure, and a change in the Sharpvan der Heijde score of the hand and foot radiographs (24). Radiographs were obtained at baseline and at the end of the study and were scored by 2 independent readers who were blinded to the randomization schedule and the radiograph sequence. Drug adherence was assessed by using a daily diary and by pill counts. Body weight, blood pressure, and serum glucose level were measured at each visit. Laboratory assessments included ESR (Westergren method); high-sensitivity CRP with normal levels up to 38.1 nmol/L (0.4 mg/dL), which was analyzed in a central laboratory; and interleukin-6 levels, which were measured at baseline, 4 weeks, and 24 weeks by using high-sensitivity enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota). Rheumatoid factor was measured by immunonephelometry with a BNII analyzer (Siemens Medical Solutions Diagnostics, Newark, Delaware), cortisol and adrenocorticotropic hormone levels by immunochemiluminescence methods with an Immulite 2500 (Siemens Medical Solutions Diagnostics, Los Angeles, California), and plasma lipids by Synchron LX-20 automated analyzers (Beckman Coulter, Brea, California). Safety assessments consisted of all patients marking adverse events in their drug diaries, which were reviewed on each visit. Vital signs and safety laboratory measures, including a complete blood count and a chemistry profile (electrolyte and liver and kidney function tests), were recorded at each visit. Adverse events were graded by severity according to the National Cancer Institute Common Toxicity Criteria guidelines. An electrocardiogram (ECG) was obtained from all patients at baseline, 2 weeks, and the end of study. After 24 weeks, no follow-up was conducted. Statistical Analysis We designed our study to detect differences in the primary end point with greater than 90% power at a 2-sided level of significance of 0.05. To properly account for missing end point data due to dropouts, we used mixed-effects analyses to predict each patients ACR response at the end of study visit and to properly account for uncertainty in that prediction. The response was categorized according to the ACR 20, ACR 50, and ACR 70 criteria. In a similar manner, we compared changes in DAS 28 from baseline visit between treatment groups. We modeled the treatment group, visit number (2 random-effect terms for visit number and visit nu

Toxicity of a first-generation adenoviral vector in rhesus macaques

We constructed a first-generation adenovirus vector (AVC3FIX5) that we used to assess the rhesus macaque as a nonhuman primate model for preclinical testing of hemophilia B gene therapy vectors. Although we succeeded in our primary objective of demonstrating expression of human factor IX we encountered numerous toxic side effects that proved to be dose limiting. Following intravenous administration of AVC3FIX5 at doses of 3.4 x 10(11) vector particles/kg to 3.8 x 10(12) vector particles/kg, the animals in our study developed antibodies against human factor IX, and dose-dependent elevations of enzymes specific for liver, muscle, and lung injury. In addition, these animals showed dose-dependent prolongation of clotting times as well as acute, dose-dependent decreases in platelet counts and concomitant elevation of fibrinogen and von Willebrand factor. These abnormalities may be caused by the direct toxic effects of the adenovirus vector itself, or may result indirectly from the accompanying acute inflammatory response marked by elevations in IL-6, a key regulator of the acute inflammatory response. The rhesus macaque may be a useful animal model in which to evaluate mechanisms of adenovirus toxicities that have been encountered during clinical gene therapy trials.

Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma.

IMPORTANCE Carfilzomib-lenalidomide-dexamethasone therapy yields deep responses in patients with newly diagnosed multiple myeloma (NDMM). It is important to gain an understanding of this combinations tolerability and impact on minimal residual disease (MRD) negativity because this end point has been associated with improved survival. OBJECTIVE To assess the safety and efficacy of carfilzomib-lenalidomide-dexamethasone therapy in NDMM and high-risk smoldering multiple myeloma (SMM). DESIGN, SETTING, AND PARTICIPANTS Clinical and correlative pilot study at the National Institutes of Health Clinical Center. Patients with NDMM or high-risk SMM were enrolled between July 11, 2011, and October 9, 2013. Median follow-up was 17.3 (NDMM) and 15.9 months (SMM). INTERVENTIONS Eight 28-day cycles were composed of carfilzomib 20/36 mg/m2 on days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on days 1 through 21; and dexamethasone 20/10 mg (cycles 1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, and 23. Patients who achieved at least stable disease subsequently received 24 cycles of lenalidomide extended dosing. MAIN OUTCOMES AND MEASURES Primary end points were neuropathy of grade 3 or greater (NDMM) and at least very good partial response rates (SMM). Minimal residual disease was also assessed. RESULTS Of 45 patients with NDMM, none had neuropathy of grade 3 or greater. Of 12 patients with high-risk SMM, the most common of any-grade adverse events were lymphopenia (12 [100%]) and gastrointestinal disorders (11 [92%]). All patients with SMM achieved at least a very good partial response during the study period. Among the 28 patients with NDMM and the 12 with SMM achieving at least a near-complete response, MRD negativity was found in 28 of 28 (100% [95% CI, 88%-100%]), 11 of 12 (92% [95% CI, 62%-100%]) (multiparametric flow cytometry), 14 of 21 (67% [95% CI, 43%-85%]), and 9 of 12 (75% [95% CI, 43%-94%]) (next-generation sequencing), respectively. In patients with NDMM, 12-month progression-free survival for MRD-negative vs MRD-positive status by flow cytometry and next-generation sequencing was 100% vs 79% (95% CI, 47%-94%; P < .001) and 100% vs 95% (95% CI, 75%-99%; P = .02), respectively. CONCLUSIONS AND RELEVANCE Carfilzomib-lenalidomide-dexamethasone therapy is tolerable and demonstrates high rates of MRD negativity in NDMM, translating into longer progression-free survival in patients achieving MRD negativity. Carfilzomib-lenalidomide-dexamethasone therapy also demonstrates efficacy in high-risk SMM.

The Possible Role of Hepatitis A Virus in the Pathogenesis of Atherosclerosis

The possible association between hepatitis A virus (HAV) infection and coronary artery disease (CAD) was studied. Blood from 391 patients undergoing coronary angiography was tested for serum IgG antibodies to HAV and C-reactive protein (CRP). Of the 391 patients, 205 (52%) had anti-HAV IgG antibodies. CAD prevalence was 74% in HAV-seropositive and 52% in HAV-seronegative patients (P<.0001); significance persisted after adjustment for either traditional CAD risk factors or for risk factors plus other infectious agents (cytomegalovirus, Chlamydia pneumoniae, Helicobacter pylori, and herpes simplex virus). In addition, CRP levels were significantly higher in HAV-seropositive than in HAV-seronegative patients (P=. 013) in both univariate and multivariate analyses. Logistic regression analysis demonstrated that HAV seropositivity is an independent predictor of risk for CAD and elevated CRP levels. HAV infection is therefore associated with CAD, which raises the possibility that this virus may play a causal role in atherogenesis.

Sustained Low-Grade Pro-inflammatory State in Unmedicated, Remitted Women with Major Depressive Disorder as Evidenced by Elevated Serum Levels of the Acute Phase Proteins C-reactive Protein and Serum Amyloid A

BACKGROUND Major depressive disorder (MDD) shows increased coronary artery disease (CAD) risk of unknown mechanism(s). MDD is more common in women than men; CAD diagnosis can be difficult in women. Elevations of the inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) predict increased CAD risk in populations; few data on these markers exist in MDD, particularly in remitted patients. METHODS We measured fasting am serum CRP (high sensitivity, CRP(hs)) and SAA in 18 unmedicated, remitted women with MDD (mean age 41 +/- (SD)12, body mass index (BMI) 25.2 +/- 4.1 kg/m(2)) and 18 BMI-matched healthy control subjects (age 36 +/- 10, BMI 25.3 +/- 3.8 kg/m(2)) on 2 separate occasions, > or = 6 days apart. RESULTS Repeat SAA and CRP(hs) measurements strongly correlated across study days (SAA: r = .83, p < .001; CRP(hs): r = .94, p < .001). Both SAA (5.30 +/- 3.39 vs. 2.84 +/- 1.87 mg/L, p < .005) and CRP(hs) (3.23 +/- 3.17 vs. 1.12 +/- 1.45 mg/L; p < .01) were significantly elevated in MDD women versus controls. CONCLUSIONS Elevated SAA and CRP(hs) in remitted, unmedicated women with MDD indicate a pro-inflammatory state unrelated to current depressive symptoms or pharmacotherapy. These findings suggest that inflammatory mechanisms may in part underlie findings of increased CAD risk in MDD.

Metabolic Effects of Liothyronine Therapy in Hypothyroidism: A Randomized, Double-Blind, Crossover Trial of Liothyronine Versus Levothyroxine

CONTEXT Levothyroxine (L-T(4)) therapy is based on the assumption that the conversion of T(4) into T(3) provides adequate amounts of active hormone at target tissues. However, in rodents, L-T(4) alone does not restore a euthyroid state in all tissues. Previous combination L-T(4)/liothyronine (L-T(3)) therapy trials focused on quality-of-life endpoints, and limited information is available on the effects on other measures of thyroid hormone action. OBJECTIVE Our objective was to evaluate the efficacy of thyroid hormone replacement with L-T(4) or L-T(3) at doses producing equivalent normalization of TSH. PARTICIPANTS, DESIGN, AND SETTING Fourteen hypothyroid patients participated in this randomized, double-blind, crossover intervention at the National Institutes of Health Clinical Center. INTERVENTIONS L-T(3) or L-T(4) were administered thrice daily to achieve a target TSH from 0.5-1.5 mU/liter. Volunteers were studied as inpatients after 6 wk on a stable dose and at the target TSH. MAIN OUTCOME MEASURES Serum thyroid hormones, lipid parameters, and indices of glucose metabolism were evaluated. RESULTS No difference was observed in TSH between L-T(3) and L-T(4) treatments. L-T(3) resulted in significant weight loss [L-T(4), 70.6 ± 12.5, vs. L-T(3), 68.5 ± 11.9 kg (P = 0.009)] and in a 10.9 ± 10.0% decrease in total cholesterol (P = 0.002), 13.3 ± 12.1% decrease in low-density lipoprotein-cholesterol (P = 0.002), and an 18.3 ± 28.6% decrease in apolipoprotein B (P = 0.018). No significant differences were observed in high-density lipoprotein-cholesterol, heart rate, blood pressure, exercise tolerance, or insulin sensitivity. CONCLUSIONS The substitution of L-T(3) for L-T(4) at equivalent doses (relative to the pituitary) reduced body weight and resulted in greater thyroid hormone action on the lipid metabolism, without detected differences in cardiovascular function or insulin sensitivity.

Minimal changes in environmental temperature result in a significant increase in energy expenditure and changes in the hormonal homeostasis in healthy adults.

OBJECTIVE Resting energy expenditure (EE) is a major contributor to the total EE and thus plays an important role in body weight regulation. Adaptive thermogenesis is a major component of EE in rodents, but little is known on the effects of exposure of humans to mild and sustainable reduction in environmental temperature. DESIGN To characterize the dynamic changes in continuously measured resting EE, substrate utilization, and hormonal axes simultaneously in response to mild reduction in environmental temperature, we performed a cross-over intervention. METHODS Twenty-five volunteers underwent two 12-h recordings of EE in whole room indirect calorimeters at 24 and 19 °C with simultaneous measurement of spontaneous movements and hormonal axes. RESULTS Exposure to 19 °C resulted in an increase in plasma and urine norepinephrine levels (P<0.0001), and a 5.96% (P<0.001) increase in EE without significant changes in spontaneous physical activity. Exposure to the lower temperature resulted in a significant increase in free fatty acid levels (P<0.01), fasting insulin levels (P<0.05), and a marginal decrease in postprandial glucose levels. A small but significant (P<0.002) increase in serum free thyroxine and urinary free cortisol (P<0.05) was observed at 19 °C. CONCLUSIONS Our observations indicate that exposure to 19 °C, a mild and tolerable cold temperature, results in a predictable increase in EE driven by a sustained rise in catecholamine and the activation of counter-regulatory mechanisms.

Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock

Objective:l-arginine supplementation in sepsis is controversial. Septic shock has been alternatively viewed as an l-arginine-deficient state or as a syndrome caused by excess nitric oxide, an end-product of l-arginine metabolism. Design:Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists). Setting:Laboratory. Subjects:Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles. Interventions:The effects of parenteral l-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis. Two doses were studied that delivered approximately 1.5-fold (10 mg·kg−1·hr−1) and 15-fold (100 mg·kg−1·hr−1) the l-arginine dose typically administered with standard total parenteral nutrition. Animals in the low- and high-dose l-arginine arms were further randomized to receive vehicle alone or N-acetylcysteine (20 mg·kg−1·hr−1) as an antioxidant to prevent peroxynitrite formation. Measurements and Main Results:The main measurements were hemodynamics, plasma arginine and ornithine, serum nitrate/nitrite, laboratory studies for organ injury, and survival. Both doses of l-arginine similarly increased mortality (p = .02), and worsened shock (p = .001 for reduced mean arterial pressure). These effects were associated with significant increases in plasma arginine (p = .0013) and ornithine (p = .0021). In addition, serum nitrate/nitrite (p = .02), liver enzymes (p = .08), and blood urea nitrogen/creatinine ratios (p = .001) rose, whereas arterial pH (p = .001) and bicarbonate levels (p = .001) fell. N-acetylcysteine did not significantly decrease any of the harmful effects of l-arginine. Thus, parenteral l-arginine monotherapy was markedly harmful in animals with septic shock. Conclusions:These findings suggest that supplemental parenteral l-arginine, at doses above standard dietary practices, should be avoided in critically ill patients with septic shock.

A phase II trial of pan-KIR2D blockade with IPH2101 in smoldering multiple myeloma

Natural killer (NK) cells are involved in immune surveillance of various malignancies, including multiple myeloma (MM).[1][1] IPH2101 is a fully human monoclonal antibody that blocks HLA-C binding KIR2D receptors (KIR2DL/DS-1, -2 -3) expressed on the surface of NK-cells, enhancing their cytotoxicity

Modeling progression risk for smoldering multiple myeloma: results from a prospective clinical study

Abstract The risk of progression to multiple myeloma (MM) from the precursor condition smoldering MM (SMM) varies considerably among individual patients. Reliable markers for progression to MM are vital to advance the understanding of myeloma precursor disease and for the development of intervention trials designed to delay/prevent MM. The Mayo Clinic and Spanish PETHEMA have proposed models to stratify patient risk based on clinical parameters. The aim of our study was to define the degree of concordance between these two models by comparing the distribution of patients with SMM classified as low, medium and high risk for progression. A total of 77 patients with SMM were enrolled in our prospective natural history study. Per study protocol, each patient was assigned risk scores based on both the Mayo and the Spanish models. The Mayo Clinic model identified 38, 35 and four patients as low, medium and high risk, respectively. The Spanish PETHEMA model classified 17, 22 and 38 patients as low, medium and high risk, respectively. There was significant discordance in overall patient risk classification (28.6% concordance) and in classifying patients as low versus high (p < 0.0001), low versus non-low (p = 0.0007) and high versus non-high (p < 0.0001) risk. There is a need for prospectively validated models to characterize individual patient risk of transformation to MM.