Step‐down approach using either cyclosporin A or methotrexate as maintenance therapy in early rheumatoid arthritis

Objective

To evaluate the feasibility and outcome of the step‐down approach using either cyclosporin A (CSA) or methotrexate (MTX) as maintenance therapy following 6 months treatment with these 2 agents in combination in early, nonerosive rheumatoid arthritis (RA).

Methods

Fifty‐seven patients younger than 65 years with early, nonerosive RA were first treated with CSA and MTX in combination for 6 months. They were then randomly stepped down to single‐agent maintenance treatment for another 18 months. Safety, clinical efficacy, survival on treatment, and radiographic progression were evaluated.

Results

When being treated with combination therapy, 7 of the 57 patients (12.3%) withdrew because of adverse events. Of the remaining 50 patients, 42 (84.0%) were American College of Rheumatology (ACR) 20% responders, 30 (60.0%) were ACR 50% responders, and 23 (46.0%) were ACR 70% responders. At month 6, 22 patients were randomized to CSA and 27 to MTX. During this trial period, the treatment was discontinued by 16 patients taking CSA (mainly because of loss of efficacy) and by 4 taking MTX. At month 24, the probability (± SEM) of survival on treatment was 0.273 ± 0.09 for CSA and 0.852 ± 0.07 for MTX. Of the 6 CSA patients who completed the trial, 4 (66.7%) were ACR 20% responders, and 3 (50%) were both ACR 50% and ACR 70% responders. Of the 23 completers in the MTX arm, 21 (91.3%) were ACR 20% responders, 18 (78.3%) were ACR 50%, and 10 (43.5%) were ACR 70% responders. The treatment was not responsible for severe adverse events. Radiography showed a slow progression in the damage score and number of eroded joints in both treatment groups.

Conclusion

Stepping down to single agent maintenance therapy following 6 months of combination treatment with CSA and MTX in early RA was only successful with MTX. Because this treatment did not prevent some radiographic progression, other approaches (e.g., step‐up approach) may be more appropriate in early RA.

     

Ovarian steroids modulate the action of calcitonin in women

Slow i.v. infusion of salmon calcitonin into normal women led to a transient increase in plasma concentrations of cyclic AMP and to a decrease in plasma calcium, which was maintained for at least 2 h. These responses were significantly reduced in the same patients after hysterectomy and ovariectomy. In contrast, maintenance of the ovaries at the time of surgery, or substitutive hormonal therapy, seemed to restore the sensitivity to exogenous calcitonin, suggesting a permissive role of ovarian steroids in the effect of calcitonin. The most likely explanation for this phenomenon is that these hormones influence either the number of calcitonin receptors or the coupling of the receptors to the functional unit of bone adenylate cyclase.     

Cuidados paliativos en la enfermedad pulmonar intersticial difusa: resultados de una encuesta de ámbito nacional

Introduction

Interstitial lung diseases (ILD) and, in particular, idiopathic pulmonary fibrosis, may have a significant impact on patient survival. Recent studies highlight the need for palliative care (PC) in the management of ILD patients. The aim of this study was to determine the current situation of PC in patients in Spain.

Toward the development of a test for growth hormone (GH) abuse: a study of extreme physiological ranges of GH-dependent markers in 813 elite athletes in the postcompetition setting

There is a need to develop a test to detect GH abuse by elite athletes. Measured levels of GH in blood or urine, however, provide little information on the GH-IGF-I axis. Previous studies have identified a series of indirect markers of GH action that are markedly altered by the administration of GH, but to a lesser degree by acute exercise. This study was undertaken to determine the physiological range of these GH-dependent variables in elite athletes after a competitive event to determine whether such values differ from resting values in normal and athletic subjects and to establish whether any adjustments to this range are required on the basis of age, gender, demographic characteristics, or the nature of the exercise performed. Serum samples were collected from 813 elite athletes (537 males and 276 females; age range, 17-64 yr) from 15 sporting disciplines within 2 h of completion of a major competitive event. IGF-I, IGF-binding protein 2 (IGFBP-2), IGFBP-3, acid-labile subunit, and the bone and soft tissue markers, osteocalcin, carboxyl-terminal propeptide of type I procollagen, carboxyl-terminal cross-linked telopeptide of type I collagen, and procollagen type III were measured. Sporting category, gender, age, height, weight, body mass index (BMI), and racial group of the athlete were documented, and results were compared both to normative data and to values obtained from elite athletes under resting conditions. Forty-one percent of IGF-I values in male athletes and 41% of values in female athletes were above the upper limits of 99% reference ranges derived from resting values in a normal population. Postcompetition levels of all variables except carboxyl-terminal propeptide of type I procollagen and carboxyl-terminal cross-linked telopeptide of type I collagen differed from resting values. There was a consistent age-dependent fall in measured levels of all variables (P < 0.0001) with the exception of IGFBP-2, which increased with age (P < 0.0001). BMI, but not height, exerted a small, but significant, influence on several variables. After adjustment for age, there were no significant differences in the levels of any of the measured variables between sporting categories. IGFBP-2 and IGFBP-3 were lower in 35 black athletes compared with those in 35 white athletes matched for age, gender, height, BMI, and sporting category. We have demonstrated that there are predictable age-dependent levels of GH-dependent markers in elite athletes that are consistent even at the extremes of physical exertion and that these are independent of sporting category. Normative data applicable to white athletes are provided. This provides important groundwork for the development of a test for GH abuse, although these values may be specific for the reagents and assays used.     

Congenital prothrombin defects: they are not only associated with bleeding but also with thrombosis: a new classification is needed

Objective: Congenital prothrombin deficiency is one of the rarest clotting disorders. It is commonly subdivided in Type I defects or cases of ‘true’ prothrombin deficiency characterized by a concomitant decrease in FII activity and antigen and in Type II or dysprothrombinemias, in which FII activity is low but FII antigen is normal or near normal. A bleeding tendency, often a severe one, is the hallmark of the two-defects even though the bleeding is usually less severe in the Type 2 defects or dysprothrombinemias.

Patients and Methods: An extensive search of published cases of prothrombin deficiency was carried out in Pubmed and Scopus. The search started in 2012, after the publication of the first family with dysprothrombinemia and venous thrombosis. A few additional families were found.

Results: Recent studies have demonstrated that the Type 2 defects are heterogeneous. Several heterozygous mutations involving the Arg596 residue of exon 14 have been demonstrated not be associated with a bleeding tendency but, surprisingly, with venous thromboses. Mutations in close areas of prothrombin have failed to show the same pattern.

Conclusions: These observations have required a reclassification of prothrombin defects. To the Type I and Type II defects, a Type III has to be added characterized by the absence of bleeding and the presence of venous thrombosis. It is not clear yet if this special variant of Type II defect is limited to the Arg596 mutations or if other residues may be involved.     

Inhibitory effect of clofibrate on arginine-induced insulin secretion in chemical diabetes

Summary Clofibrate, 3g/die for 10 consecutive days, significantly reduced arginine-induced IRI release in chemical diabetics and in normal controls, whether of normal body weight or obese. Blood glucose levels were not affected by clofibrate. In agreement with previous findings, it would appear that clofibrate, administered for short periods, does not lead to a decrease in glucose tolerance. However, studies relating to the effect of chronic clofibrate administration in chemical diabetes are needed in order to be sure that prolonged inhibition of IRI secretion does not lead to overt diabetes.     

Effect of captopril on renal function in patients with essential hypertension

The glomerular filtration rate (creatinine clearance), glomerular permeability (qualitative and quantitative proteinuria), tubular reabsorption (k-λ chains of immunoglobulins and lysozyme) and indexes of tubular cell lysis (alpha-glucosidase and gamma-glutamyltranspeptidase) were measured in the urine of 10 patients with moderate, uncomplicated essential hypertension during placebo therapy and after captopril given at increasing doses of 25, 50, 100 and 200 mg twice daily, the first three doses being given for 3 days and the last one for 4 weeks in all patients and for an additional 6 months in 5 patients. During placebo therapy, proteinuria was absent in eight patients and detectable (glomerular and selective) in two; selective proteinuria appeared in two and a decrease in selectivity was observed in two patients with previous proteinuria after 4 weeks of captopril therapy. No proteinuria was detectable in the five patients followed up for 6 months, not even in the one in whom a decrease in glomerular selectivity had occurred after 4 weeks. The glomerular filtration rate was unchanged as were lysozyme and gamma-glutamyltranspeptidase values, while light chains were always undetectable. Alpha-glucosidase showed some increase; however, increments were transient and always much lower than those observed with known tubular toxic drugs. These data show that under our experimental conditions captopril caused no evident changes in glomerular and tubular function.     

Comparison of an intravenous pulse of methylprednisolone versus oral corticosteroid in severe acute rheumatic carditis: a randomized clinical trial

OBJECTIVES: To compare the short-term prognosis of patients with severe acute rheumatic carditis when treated with an intravenous pulse of methylprednisolone in comparison with conventional treatment using oral prednisone. METHODS: We designed a randomized clinical trial in the setting of a university general hospital in Brazil. We randomly allocated 18 patients with the diagnosis of severe acute rheumatic carditis and congestive heart failure to receive an intravenous pulse as opposed to oral prednisolone. Methylprednisolone was administered in a dose of 1 g intravenously for 3 consecutive days in the first and second weeks, for two days in the third, and one day in the fourth week. Prednisone was administered in a dose of 1.5 mg/kg/day over the period of 4 weeks. RESULTS: The mean age of the patients was 11.1 +/- 3.7 years, with a median of 12 years. Patients on oral treatment showed a more pronounced decrease in the heart rate, sedimentation rate, and in the titres of C-reactive protein than those receiving intravenous therapy. At the end of treatment, a mild decrease in the left ventricular end-systolic dimension was found in those having oral treatment, compared to an increase in the group having intravenous treatment (p = 0.036). The ejection fraction showed a median increase of 5% in those undergoing oral treatment, and a median decrease of 6% in the group with intravenous therapy (p = 0.009). There were 5 therapeutic failures in those receiving intravenous therapy (56%), including 1 death. Therapeutic failures were not observed in those treated orally (p = 0.03). CONCLUSION: Intravenous treatment of methylprednisolone, as a single anti-inflammatory agent, was inferior to conventional treatment with oral prednisone in the control of severe rheumatic carditis.     

The Valsalva maneuver in Chagas disease patients without cardiopathy.

BACKGROUND: The Valsalva maneuver is a simple and reliable test of parasympathetic heart control that can also be used as a trigger of cardiac arrhythmia. Few studies are available about the Valsalva maneuver in Chagas disease patients without cardiac involvement and their results are contradictory. In a cross-sectional study, we compared Chagas disease patients without cardiac involvement and normal individuals using the Valsalva maneuver in order to study the vagal cardiac control and the occurrence of cardiac arrhythmia in the early phase of Chagas disease. METHODS: Fifty-nine patients with Chagas disease without cardiac involvement and 37 controls were submitted to a carefully standardized Valsalva maneuver. Cardiac vagal control was assessed by the Valsalva ratio and the occurrence of cardiac arrhythmia was recorded and coded. RESULTS: The two groups were comparable in terms of left ventricular ejection fraction and left ventricular end-diastolic dimension. When compared to the control group, patients with Chagas disease had significantly lower Valsalva ratios (1.81+/-0.41 versus 2.01+/-0.41, P=0.017) which were not significantly correlated with age, left ventricular function or the presence of radiological esophageal abnormalities. Atrioventricular block (mainly 2nd degree Mobitz type I) occurred exclusively in Chagas disease patients (15,6%, P=0.021) and may indicate an early involvement of the AV node. Premature ventricular contraction was more frequent in Chagas disease patients (16.9% versus 8.1%, P=0.217), although the difference was not statistically significant. CONCLUSION: The Valsalva maneuver is a useful test to detect early vagal dysfunction in Chagas disease patients without cardiac involvement.