Efficacy of tofacitinib in patients with rheumatoid arthritis stratified by background methotrexate dose group.

Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This post hoc analysis investigated the effect of methotrexate (MTX) dose on the efficacy of tofacitinib in patients with RA. ORAL Scan (NCT00847613) was a 2-year, randomized, Phase 3 trial evaluating tofacitinib in MTX-inadequate responder (IR) patients with RA. Patients received tofacitinib 5 or 10 mg twice daily (BID), or placebo, with low (≤12.5 mg/week), moderate (>12.5 to <17.5 mg/week), or high (≥17.5 mg/week) stable background MTX. Efficacy endpoints (at months 3 and 6) included American College of Rheumatology (ACR) 20/50/70 response rates, and mean change from baseline in Clinical Disease Activity Index (CDAI), Disease Activity Score in 28 joints (DAS28)-4(erythrocyte sedimentation rate [ESR]), Health Assessment Questionnaire-Disability Index (HAQ-DI), and modified Total Sharp score. 797 patients were treated with tofacitinib 5 mg BID (N = 321), tofacitinib 10 mg BID (N = 316), or placebo (N = 160); 242, 333, and 222 patients received low, moderate, and high MTX doses, respectively. At months 3 and 6, ACR20/50/70 response rates were greater for both tofacitinib doses vs placebo across all MTX doses. At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly greater for both tofacitinib doses vs placebo, irrespective of MTX category; improvements were maintained at month 6. Both tofacitinib doses demonstrated improvements in DAS28-4(ESR), and less structural progression vs placebo, across MTX doses at month 6. Tofacitinib plus MTX showed greater clinical and radiographic efficacy than placebo in MTX-IR patients with RA, regardless of MTX dose.

Patient perceptions concerning pain management in the treatment of rheumatoid arthritis.

Previous qualitative studies have revealed discrepancies between patients' and physicians' perceptions of rheumatoid arthritis (RA) and its treatment. Questionnaires were administered to 2795 patients with RA (756 from Europe; 2039 from the USA) to measure patients' perceptions regarding pain management in RA. Although the majority of patients reported their RA as somewhat-to-completely controlled, 75% of European and 82% of US patients reported their pain as moderate-to-severe in the previous 2 months. The majority of European (60%) and US (65%) patients reported dissatisfaction with their arthritis pain. Patients' pain levels corresponded with their disease severity. A higher percentage of patients who reported severe pain were being treated for depression than those who had moderate or mild pain. Patients in the USA rated pain relief as the top required benefit from their RA medication. A comprehensive examination of patients' perspectives regarding pain could lead to better patient care and pain management strategies.

Inhibition of Amazon deforestation and fire by parks and indigenous lands.

Conservation scientists generally agree that many types of protected areas will be needed to protect tropical forests. But little is known of the comparative performance of inhabited and uninhabited reserves in slowing the most extreme form of forest disturbance: conversion to agriculture. We used satellite-based maps of land cover and fire occurrence in the Brazilian Amazon to compare the performance of large (> 10,000 ha) uninhabited (parks) and inhabited (indigenous lands, extractive reserves, and national forests) reserves. Reserves significantly reduced both deforestation and fire. Deforestation was 1.7 (extractive reserves) to 20 (parks) times higher along the outside versus the inside of the reserve perimeters and fire occurrence was 4 (indigenous lands) to 9 (national forests) times higher. No strong difference in the inhibition of deforestation (p = 0. 11) or fire (p = 0.34) was found between parks and indigenous lands. However, uninhabited reserves tended to be located away from areas of high deforestation and burning rates. In contrast, indigenous lands were often created in response to frontier expansion, and many prevented deforestation completely despite high rates of deforestation along their boundaries. The inhibitory effect of indigenous lands on deforestation was strong after centuries of contact with the national society and was not correlated with indigenous population density. Indigenous lands occupy one-fifth of the Brazilian Amazon-five times the area under protection in parks--and are currently the most important barrier to Amazon deforestation. As the protected-area network expands from 36% to 41% of the Brazilian Amazon over the coming years, the greatest challenge will be successful reserve implementation in high-risk areas of frontier expansion as indigenous lands are strengthened. This success will depend on a broad base of political support.

Possible role for tumour necrosis factor inhibitors in the treatment of resistant dermatomyositis and polymyositis: a retrospective study of eight patients.

OBJECTIVE: To understand the use of tumour necrosis factor (TNF)alpha inhibitors in refractory dermatomyositis and polymyositis in an academic centre. METHODS: A retrospective study of eight patients with dermatomyositis or polymyositis refractory to corticosteroids and immunosuppressives who were treated with TNF inhibitors between 1998 and 2004. RESULTS: 8 patients with dermatomyositis or polymyositis who were treated with TNF inhibitors as adjunct treatment were identified. The mean (SD) duration of disease before initiation of TNF inhibitors was 8.5 (4.4) years. The patients failed to respond to treatment with corticosteroids (oral and intravenous); intravenous immunoglobulin and immunosuppressants (methotrexate, azathioprine, mycophenolate mofetil and leflunomide); 4.5 (1.4) immunosuppressants had been used before TNF treatment. Six patients were treated with etanercept alone, one with infliximab and one sequentially with both agents. Of the eight patients, six showed a favourable response with improved motor strength and decreased fatigue after 15.2 (6.5) months. Two of the patients did not respond after 4 (1.4) months and TNF inhibitors were discontinued. Responders showed a 54.4% (27.7%) decrease in serum concentration of creatine kinase, which was grossly abnormal (4463.5 (4036.4) U/l). Non-responders had similar reductions in creatine kinase concentration (56.1% (20.4%)), but their pre-treatment concentrations were in the normal range (118.5 (19.1) U/l). CONCLUSION: Anti-TNF agents may be useful in some patients with refractory dermatomyositis or polymyositis.

Environmental policy. Counting the cost of deforestation.

To halt the dramatic alteration in our climate, there must be a reduction in the emission of greenhouse gases. As Bonnie and colleagues discuss in their Perspective, conservation of forests will increase carbon sequestration and decrease greenhouse gas emissions. In this issue, a cost-benefit analysis by Kremen et al. demonstrates the benefits of forest conservation on a local and global scale.

Ovulation induction and in vitro fertilization in systemic lupus erythematosus and antiphospholipid syndrome.

OBJECTIVE: During ovulation induction (OI), ovarian stimulation is accomplished by hormonal manipulation, which includes administration of gonadotropins, gonadotropin-releasing hormone agonists, follicle-stimulating hormone, and luteinizing hormone. In in vitro fertilization (IVF), progesterone is often added. Because of the possibility of hormone-associated flare or thrombosis, patients with systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (primary APS) undergoing OI/IVF are potentially at increased risk. The present study was conducted in order to assess this risk. METHODS: Nineteen women who underwent 68 cycles of OI/IVF were studied by interview and retrospective chart review. RESULTS: Four OI/IVF cycles (25%) in SLE patients resulted in increased lupus activity and 2 (13%) in ovarian hyperstimulation syndrome. One patient with primary APS who was given heparin during multiple cycles developed osteopenia. No thrombosis occurred. Pregnancy complications included toxemia, lupus flare, gastrointestinal hemorrhage due to Mallory-Weiss tear, polygestation, and diabetes. Postpartum complications included nephritis flare, costochondritis, and suicidal depression. Lupus flares occurred at expected rates. Five of 16 cycles (31%) in 7 SLE patients, 5 of 48 cycles (10%) in 10 primary APS patients, and 0 of 5 cycles in 2 women with antiphospholipid antibody (without SLE or primary APS) resulted in liveborn children, including multiple gestations (3 twin sets with 4 surviving infants and 2 triplet sets with 3 surviving infants). Seven of 14 living children (50%) were premature, 3 had neonatal lupus, and 1 had pulmonic stenosis. Five surviving infants (38%) had complications unrelated to prematurity. CONCLUSION: Although OI/IVF can be successful in SLE and primary APS patients, rates of fetal and maternal complications are high.

Validation of the Sapporo criteria for antiphospholipid syndrome.

OBJECTIVE: To test the Sapporo criteria for the classification of the antiphospholipid syndrome (APS). METHODS: We classified 243 consecutive patients who had clinical diagnoses of primary APS (n = 49), secondary APS (n = 26), systemic lupus erythematosus (SLE) without clinical APS (n = 131), and lupus-like disease without clinical APS (n = 37). RESULTS: Sensitivity, specificity, positive predictive value, and negative predictive value were 0.71, 0.98, 0.95, and 0.88, respectively. False-negative findings were the result of patients being classified on the basis of minor criteria that were not included in the Sapporo criteria, such as livedo reticularis, thrombocytopenia, low-titer IgG or IgM anticardiolipin antibody, IgA anticardiolipin antibody, and anti-beta2-glycoprotein I antibody. Some patients with false-negative results were true seronegative cases. CONCLUSION: The Sapporo criteria for APS compare favorably with the American College of Rheumatology criteria for SLE and are usable for clinical studies.

Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment.

Although long-term clinical studies have shown no excessive risk of lymphoma in rheumatoid arthritis (RA) patients treated with methotrexate (MTX), an increasing number of reports of this association continue to appear. We describe two cases, review the cases in the world's literature, and summarize their important characteristics. Possible oncogenic mechanisms are discussed. Most lymphoproliferation cases presented here have features of immunosuppression-associated lymphoma. The immunosuppressed state is attributable to a combination of factors, such as RA itself and the actions of MTX. The risk factors for RA patients to develop lymphoma while on MTX include severe disease, intense immunosuppression, genetic predisposition, and an increased frequency of latent infection with prooncogenic viruses such as Epstein-Barr virus (EBV). The spontaneous remission of lymphomas in eight RA patients after MTX was stopped highlights the likely causative role of the drug in the development of these malignancies. If the clinical situation permits, a period of observation for spontaneous remission after MTX is stopped is advisable. The physicians caring for RA patients on MTX should maintain a high surveillance for signs and symptoms suggestive of lymphoma.

Ammonia encephalopathy.

Ureterosigmoidostomy can be complicated by pyelonephritis, renal calculi, hypokalemic hyperchloremic acidosis, and colonic neoplasia. It has been associated with the development of hyperammonemia and encephalopathy in patients with underlying liver disease. We report a rare case of hyperammonemic encephalopathy in a patient with normal liver function.

Carbohydrates on human Fc gamma receptors. Interdependence of the classical IgG and nonclassical lectin-binding sites on human Fc gamma RIII expressed on neutrophils.

To explore the molecular basis for the ability of aggregated IgG to block the phagocytosis by human polymorphonuclear leukocytes of Con A-opsonized E and of nonopsonized Escherichia coli with mannose-binding adhesins, we examined specific aspects of the glycoprotein structure of both the 40- to 43-kDa receptor for the Fc portion of IgG (Fc gamma RII) and the 50- to 78-kDa receptor for the Fc portion of IgG (Fc gamma RIIIPMN) from human polymorphonuclear leukocytes. Fc gamma RIIIPMN isolated by both mAb and ligand affinity chromatography, but not Fc gamma RII, binds Con A in Western blots. This binding is specifically inhibitable by alpha-methylmannoside. Digestion of Fc gamma RIIIPMN by recombinant endoglycosidase H, which is specific for high mannose-type (Con A-binding) oligosaccharides, alters the epitope recognized by mAb 3G8 in or near the IgG ligand-binding site of the receptor. Similarly, the ability of Fc gamma RIIIPMN to bind human IgG ligand is sensitive to endoglycosidase H digestion. Our data indicate that ligands other than the classical IgG opsonins can bind to human Fc gamma RIIIPMN per se through lectin-carbohydrate interactions. Furthermore, Fc gamma RIIIPMN contains a high mannose type oligosaccharide chain which contributes importantly to the integrity of the classical IgG ligand-binding site. Thus, specific glycosylations of the receptor are important for both classical and nonclassical engagement of Fc gamma RIII and may play a role in determining the properties of the ligand-binding site.

Mycotic abdominal aortic aneurysm induced by immunotherapy with bacille Calmette-Guérin vaccine for malignancy.

Successful surgical treatment of a mycotic abdominal aortic aneurysm infected with Mycobacterium bovis is described. The infecting organism can be traced to an intraneoplastic injection of bacille Calmette-Guérin (BCG) vaccine into a cutaneous malignant melanoma nodule 14 months before aneurysm detection (17 months before operation). Treatment consisted of aneurysm excision, in situ prosthetic graft placement, and antituberculous medications. This patient represents the first reported case of BCG-induced mycotic aortic aneurysm.

Interaction between fibronectin and C1q in rheumatoid synovial fluid and normal plasma.

The interaction between fibronectin and C1q was studied in the presence of normal human plasma and rheumatoid synovial fluid by solid phase binding assay. Fibronectin-C1q binding occurred in the presence of rheumatoid synovial fluid but not in the presence of normal plasma. Binding was strongest at 4 degrees C and in the presence of EDTA. Fibronectin-C1q binding could be induced in the presence of normal plasma by hypotonicity, augmentation of the concentration of solution-phase fibronectin or by the addition of heat-aggregated IgG. The C1q present in rheumatoid synovial fluid bound to both aminoterminal collagen-binding and carboxyterminal noncollagen binding fibronectin fragments although binding to the aminoterminal fragment was stronger. The interaction between fibronectin and C1q in rheumatoid synovial fluid may modulate immune-complex deposition and complement activation in the inflamed joint.

Iron deficiency caused by 7 weeks of intensive physical exercise.

The present study was designed to evaluate the effect of an intensive physical training program involving both isometric and isotonic activities on the body iron status of 8 females and 11 males (age 20 +/- 1 year). The training was carried out over a 7 week period and included 8 h of varying physical activities each day. Venous blood samples were obtained from the subjects prior to the beginning of the training, on day 2 and in weeks 2, 4, 6 and 7 of the program. Blood samples were analyzed for iron, ferritin and hemoglobin (Hb) concentrations, total iron binding capacity (TIBC) and red blood cell count (RBC). Iron levels of males and females decreased 65% after 2 weeks of training (p less than 0.001). At the end of the training program 5 males and 6 females had lower than normal iron values (less than 13.4 mumol.l-1). TIBC increased 25% in women and 18% in men following 2 and 4 weeks of training (p less than 0.001) and remained at this elevated level throughout the training period. Ferritin levels decreased 50% in both sexes after 4 weeks of exercise (p less than 0.05) and remained at this level until the end of the training. Hb and RBC decreased 8-10% in both sexes during the training period. In two of the women anemia occurred after 4 weeks of training. The development of latent iron deficiency in a substantial number of participants after a relatively short period of training is uncommon and may reflect the high intensity of exercise required in this program.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effect of muramyl dipeptide analogs in combination with trehalose dimycolate against aerogenic influenza virus and Mycobacterium tuberculosis infections in mice.

The effects of two aminobutyryl and four seryl analogs of the synthetic muramyl dipeptide (MDP) against aerosol infections with influenza virus and Mycobacterium tuberculosis were studied. Regardless of the MDP analog employed, there was no evidence that the resistance against viral and bacterial aerosol infections was enhanced in the treated mice. In parallel studies, significant protection against influenza virus and M. tuberculosis infections was induced by the combination of MDP or analogs with the mycobacterial glycolipid trehalose dimycolate (TDM). Resistance conferred by the MDP + TDM combination against influenza virus was present 1 week after pretreatment and could be abrogated by macrophage inhibitory agents silica, dextran sulfate, and carrageenan. Splenic cells from MDP + TDM-pretreated animals generated markedly enhanced levels of luminol-dependent chemiluminescence in response to influenza A and B viruses.

The prognostic value of serum acetylcholinesterase in myocardial infarction. Theoretical and clinical considerations.

The aim of the present work was to determine experimentally the prognostic value of reduced activity of serum acetylcholinesterase (ACE) in cases of acute myocardial infarction (AMI). In the first part of the research we studied the mechanism of this reduction by comparing the serum results with the levels of the enzyme in cardiac tissue in such cases. It was found that ACE activity is reduced in serum and also in cardiac tissue in AMI, in contrast to creatine kinase (CK) that is augmented in serum but reduced in cardiac tissue. This fact was interpreted as a "reduced cardiac flow of ACE," in contrast to the "augmented cardiac clearance of CK" in similar cases. In the second part of our research, 50 patients, admitted in our hospital for AMI, were examined and their blood analysed mainly for ACE and CK at brief intervals (every 2-3 days), during hospitalization, and thereafter every 1-2 weeks for 1-4 months. From the results of ACE activity it was possible to classify these variations into four groups, each of them having a defined prognostic value for the evolution of the AMI, a persistent reduced serum activity being interpreted as a bad, severe prognosis, with high morbidity or mortality (groups II and III). We suggest, therefore, that the determination of ACE in serum in cases of AMI, especially before discharge home of such patients, may be an additional useful laboratory test in such cases.

Some properties of acid and alkaline phosphatase in seminal fluid and isolated sperm.

Activities of acid and alkaline phosphatases were examined in spermatozoa isolated from 177 semen samples differing in sperm counts. Alkaline phosphatase was also determined in seminal fluid. The enzymes were assayed using disodium p-nitrophenyl phosphate as substrate and were studied with respect to susceptibility to various concentrations of tartrate (acid) and to heat (alkaline). Electrophoretic separation of alkaline phosphatase from seminal fluid was performed using an Helena apparatus. The results showed that acid phosphatase activity in spermatozoa decreased with increase in sperm densities and that elevation of tartrate from 0.028 to 0.17 M usually correlated an inhibition of the enzyme from 72% to 78% (mean values). Alkaline phosphatase was very low in sperm and generally below the sensitivity of the method used. Activity of alkaline phosphatase in seminal fluid showed a tendency to increase with the increase in sperm counts, but the significance of differences between groups was not statistically valid. Exposure of seminal fluid to 55 degrees C for 16 min resulted in enzyme inactivation of about 90% and in this respect the alkaline phosphatase resembles the enzyme of bone origin. The electrophoretic pattern, however, did not confirm this view and the type of alkaline phosphatase in seminal fluid is not clear.

Regression of tumors in guinea pigs after treatment with synthetic muramyl dipeptides and trehalose dimycolate.

A high incidence of tumor regression was observed in guinea pigs bearing transplantable, line-10 hepatocellular carcinomas when synthetic muramyl dipeptides combined with trehalose dimycolate in oil-in-water emulsions were injected directly into the tumors. These compounds are promising candidates to replace viable bacillus Calmette-Guérin in cancer immunotherapy in humans and animals.