S. Vinzio

Azathioprine or Methotrexate Maintenance for ANCA-Associated Vasculitis

BACKGROUND Current standard therapy for Wegeners granulomatosis and microscopic polyangiitis combines corticosteroids and cyclophosphamide to induce remission, followed by a less toxic immunosuppressant such as azathioprine or methotrexate for maintenance therapy. However, azathioprine and methotrexate have not been compared with regard to safety and efficacy. METHODS In this prospective, open-label, multicenter trial, we randomly assigned patients with Wegeners granulomatosis or microscopic polyangiitis who entered remission with intravenous cyclophosphamide and corticosteroids to receive oral azathioprine (at a dose of 2.0 mg per kilogram of body weight per day) or methotrexate (at a dose of 0.3 mg per kilogram per week, progressively increased to 25 mg per week) for 12 months. The primary end point was an adverse event requiring discontinuation of the study drug or causing death; the sample size was calculated on the basis of the primary hypothesis that methotrexate would be less toxic than azathioprine. The secondary end points were severe adverse events and relapse. RESULTS Among 159 eligible patients, 126 (79%) had a remission, were randomly assigned to receive a study drug in two groups of 63 patients each, and were followed for a mean (+/-SD) period of 29+/-13 months. Adverse events occurred in 29 azathioprine recipients and 35 methotrexate recipients (P=0.29); grade 3 or 4 events occurred in 5 patients in the azathioprine group and 11 patients in the methotrexate group (P=0.11). The primary end point was reached in 7 patients who received azathioprine as compared with 12 patients who received methotrexate (P=0.21), with a corresponding hazard ratio for methotrexate of 1.65 (95% confidence interval, 0.65 to 4.18; P=0.29). There was one death in the methotrexate group. Twenty-three patients who received azathioprine and 21 patients who received methotrexate had a relapse (P=0.71); 73% of these patients had a relapse after discontinuation of the study drug. CONCLUSIONS These results do not support the primary hypothesis that methotrexate is safer than azathioprine. The two agents appear to be similar alternatives for maintenance therapy in patients with Wegeners granulomatosis and microscopic polyangiitis after initial remission. (ClinicalTrials.gov number, NCT00349674.)

The syndrome of food-cobalamin malabsorption revisited in a department of internal medicine. A monocentric cohort study of 80 patients.

BACKGROUND: To date, only case reports or small studies have documented the syndrome of food-cobalamin malabsorption in specific populations of patients or situations. In this paper, we present the data from 80 unselected patients with cobalamin deficiency related to food-cobalamin malabsorption. METHODS: We studied 80 patients with well-established food-cobalamin malabsorption who were extracted from an observational cohort study (1995-2000) of 127 consecutive patients with cobalamin deficiency and who were followed in a department of internal medicine. RESULTS: The median age of patients was 66 years and the female to male ratio was 1.2. The mean hemoglobin level was 113+/-27 g/l (range 32-159 g/l) and the mean erythrocyte cell volume was 95.4+/-12.3 fl (range 55-140 fl). Mean serum vitamin B12 and homocysteine levels were 153+/-74 pg/ml (range 35-200 pg/ml) and 20.6+/-15.7 μmol/l (range 8-97 μmol/l), respectively. The main clinical findings noted were peripheral neuropathy (46.2%), stroke (12.5%), confusion or dementia (10%), asthenia (18.7%), leg edema (11.2%), and digestive disorders (7.5%). The commonest associated conditions were atrophic gastritis (39%) with evidence of Helicobacter pylori infection (12.2%) and alcohol abuse (13.7%). Three patients had Sjögrens syndrome and one had systemic sclerosis. Ten percent of all patients were on long-term metformin (10%) and 7.5% on acid-suppressive drugs. Correction of the serum vitamin B12 levels and hematological abnormalities was achieved equally well in all patients treated with either intramuscular or oral crystalline cyanocobalamin. CONCLUSION: This study suggests that food-cobalamin malabsorption may be the leading cause of vitamin B12 deficiency in adults. As other studies have also reported, the condition is often associated with neuro-psychiatric findings and with several other conditions. Oral and parenteral cobalamin appear to be equally effective in correcting serum B12 levels and hematological abnormalities and, in many cases, they also relieve symptoms.

Effects of oral crystalline cyanocobalamin 1000 μg/d in the treatment of pernicious anemia: An open-label, prospective study in Ten Patients.

BACKGROUND Standard treatment of cobalamin (vitamin B12) deficiency involvesregular (1000 μg/mo) IM cyanocobalamin administration. It has been suggested that high-dose (>2000 μg/d) oral cyanocobalamin may be effective in patients with pernicious anemia. OBJECTIVE The aim of this study was to assess the efficacy and tolerability of oral crystalline cyanocobalamin 1000 μg/d in patients with cobalamin deficiency related to established pernicious anemia. METHODS This open-label, prospective study was conducted at StrasbourgUniversity Hospital, Strasbourg, France. Patients aged ≥18 years with well-documented cobalamin deficiency related to pernicious anemia were enrolled. Patients received crystalline cyanocobalamin 1000 μg QD PO (capsule) for at least 3 months. Serum cobalamin, folate, iron, and homocysteine concentrations were measured, and a complete blood count was obtained, before (month 0; baseline) and after treatment. RESULTS Ten patients (7 women, 3 men; mean [SD] age, 72.1 [15.5] years) entered the study. After 3 months of treatment, serum cobalamin concentration increased in all 9 patients in whom it was measured (mean [SD] increase, 117.4 [30.8] pg/mL; P < 0.001 vs baseline). Serum cobalamin concentrations were normalized (>200 pg/mL) in 6 patients. The serum cobalamin concentration was unavailable in 1 patient because of technical problems. Eight patients had increased hemoglobin concentrations (mean [SD] increase, 2.5 [2.4] g/dL; P < 0.01 vs baseline). All 10 patients had decreased mean erythrocyte corpuscular volumes (mean [SD] decrease, 10.4 [6.2] fL; P < 0.003 vs baseline). Four patients received concomitant blood transfusions or folate and iron supplementation. Three patients experienced clinical improvement in paresthesia, reflex abolition, or combined medullary sclerosis (each, 1 patient). CONCLUSION The results of this small study in patients with cobalamin deficiencyrelated to pernicious anemia suggest that oral crystalline cyanocobalamin 1000 μg/d may be an effective treatment.

Actigraphic assessment of the circadian rest–activity rhythm in elderly patients hospitalized in an acute care unit

Abstract Hospitalization for acute illness is a major risk factor of rest–activity rhythm disturbance among elderly subjects. The rest–activity rhythm is disturbed by the acute illness, aging and hospital environment. The purpose of this study is to assess the rest–activity rhythm and light exposure (using a wrist worn actigraph) of 10 patients (mean age 81 years, seven females) admitted on an acute care unit, suffering from cardiac, respiratory or renal acute disease. A non‐parametric method was used to analyze activity data. With an improvement of the underlying diseases, the mean relative amplitude of rhythm increased from 0.31 ± 0.19 for the first 5‐day period after admission to 0.54 ± 0.21 for the second period before discharge (P < 0.05). The amount of time at night spent above a lighting threshold of 50 lux decreased from 31.4 to 12.3 min between the two periods. The rhythm of elderly subjects hospitalized in the acute care unit is severely altered during the initial period and is progressively resynchronized following clinical improvement. Under the acute underlying disease and/or aging, environmental conditions (light, noise) should be considered to maintain regular rest–activity rhythm.

Obésité et cancer

Obesity which is now well recognized as a public health problem increases the risk of developing cancers. Some systematic review and meta-analyses assessed the strength of associations between body mass index and common cancers such as breast, endometrial, colon and adenocarcinoma of oesophagus. The causal mechanisms remain unexplained. However, epidemiological data and animal models have provided some evidence that hormonal alteration linked to obesity, such as hyperinsulinism, high insulin-like growth factor (IGF-1) levels or biodisponibility, low adiponectin serum level and high oestradiol serum level resulting from an enhanced aromatase activity may have mitogenic and antiapoptotic effects. The inflammation associated with visceral adiposity is another factor which promotes cancer. To date, there are no convincing data that weight loss could improve the prognosis of treated neoplasia. However, a regular physical activity and a limited caloric intake are probably safe in healthy subject to prevent cancer and also in cancer survivors.

Pituitary Involvement in Granulomatosis With Polyangiitis: Report of 9 Patients and Review of the Literature

AbstractPituitary dysfunction is a rare manifestation of granulomatosis with polyangiitis (GPA) (Wegener). The main aim of this multicenter retrospective study was to describe the characteristics and outcomes of pituitary manifestations in patients with GPA included in the French Vasculitis Study Group database.Among the 819 GPA patients included in the database, 9 (1.1%) had pituitary involvement. The median age at diagnosis of GPA and pituitary involvement was 46 and 50.8 years, respectively. Pituitary involvement was present at onset of GPA in 1 case and occurred later in 8 patients after a median follow up of 58.5 months. When pituitary dysfunction occurred, 8 patients had active disease at other sites including ENT (n = 6), eye (n = 4), or central nervous system (n = 3) involvement. The most common hormonal dysfunctions were diabetes insipidus (n = 7) and hypogonadism (n = 7). Magnetic resonance imaging was abnormal in 7 patients. The most common lesions were an enlargement of the pituitary gland, thickening of the pituitary stalk, and loss of posterior hypersignal on T1-weighed images. All patients were treated with corticosteroid therapy and 8 patients received immunosuppressive agents for the pituitary involvement, including cyclophosphamide (n = 3), rituximab (n = 2), and methotrexate (n = 3). After a median follow-up of 9.2 years, GPA was in complete remission in 7 patients, but 8 patients were still under hormone replacement therapy. Among the 5 patients who had a subsequent MRI, 2 had complete resolution of pituitary lesions.By combining our study and the literature review, the frequency of hypogonadism and diabetes insipidus, among the patients with pituitary dysfunction, can be estimated at 78% and 71% respectively. Despite a high rate of systemic disease remission on maintenance therapy, 86% of the patients had persistent pituitary dysfunction. The patients who recovered from pituitary dysfunction had all been treated by cyclophosphamide.Pituitary disease in GPA occurs mostly several months or years after diagnosis. There is no correlation between hormonal, radiologic, and systemic outcome. Although immunosuppressive drugs improve the systemic disease, hormonal deficiencies usually persist. It is therefore important to shorten diagnostic delays and treat these patients early in the course of disease before irreversible damage occur.

Sympathovagal response to orthostatism in overt and in subclinical hyperthyroidism

Heart rate variability (HRV) is a measure of the physiological variation of R-R intervals, reflecting the sympathovagal balance. In both overt and subclinical hyperthyroidism, a relative increase in sympathetic activity has been demonstrated, mainly due to a decrease in vagal activity. The modifications of HRV during orthostatism in normal subjects resemble those seen in hyperthyroidism. We have studied the response of 19 patients with overt hyperthyroidism and 12 with subclinical hyperthyroidism during orthostatism using HRV and compared the results to those of 32 healthy controls. In the three groups, the R-R intervals decreased in the same proportion after orthostatism. The low frequency power (LF)/[LF + high frequency power (HF)] ratio, which reflects the sympathetic tone, also increased in the same proportion in the three groups. However, the mechanisms of the modulation of the sympathovagal balance during orthostatism were different among the three groups. In controls, the relative increase of sympathetic tone after orthostatism was due principally to a decrease in vagal tone (reflected by decreased power in the HF band), while in overt hyperthyroidism, where the power in the HF band was already minimal in the lying position, there was a clear increase in the LF band power during orthostatism. The results were intermediate in the subclinical hyperthyroidism group, reflecting a continuum of effects of the thyroid hormone excess on the autonomic nervous system. Our study shows that despite an apparent normal cardiovascular adaptation to orthostatism in hyperthyroidism, the modulation of the autonomic nervous system is profoundly modified.

Isolated microcytic anemia disclosing a unicentric Castleman disease: The interleukin-6/hepcidin pathway?

Castleman disease (CD) is a rare lymphoproliferative disorder of uncertain origin. Anemia is commonly reported and is related to an inflammatory mechanism. Occasionally an autoimmune hemolytic anemia appears as the leading clinical feature. Three histological types have been differentiated, a hyaline-vascular type (HV), a plasma cell type (PC), and a mixed type. Clinically CD is separated into unicentric (localized) or multicentric (generalized) forms. The former is most frequently of HV type (80-90%), affecting a single lymph node. The PC type is encountered in 10-20% of the unicentric CD and in almost all of the multicentric cases. Numerous systemic manifestations have been described usually associated with PC type. An isolated and markedly microcytic anemia revealing a unicentric CD has never been reported in English literature. Recent data concerning iron metabolism, interleukin-6 and hepcidin provide interesting clues to understand the particular microcytic anemia of CD.

Increased reverse triiodothyronine is associated with shorter survival in independently-living elderly: the Alsanut study

OBJECTIVE Increased reverse tritiodothyronine (T(3)) used to be described as a part of euthyroid sick syndrome (ESS). It was demonstrated to be associated with increased mortality in acutely ill patients. It can also be found with low or normal T(3) in non-severely ill subjects but its significance remains unclear. PATIENTS AND DESIGN The Alsanut study included a representative sample of 440 independently-living subjects aged 65 or over constituted between January 1988 and September 1989. Past and current medical history and nutritional data were collected at inclusion. Baseline thyroid hormone (TSH, FT(4), FT(3) and rT(3)) serum levels were measured. Life status was determined on 1 December 2005. RESULTS Of the 374 elderly subjects included in the final analysis, 52 had abnormal TSH (43 with hyperthyroidism, nine with hypothyroidism) and 80.7% had died by 1 December 2005. There was no statistical difference in survival between subjects according to thyroid function (P=0.54). Of the 322 elderly subjects with normal TSH, mortality rate was 81.1%. ESS was found in 3.4%, whereas 8.1% of the participants displayed elevated rT(3) with normal FT(3). Time to death was strongly related to rT(3) (P<0.0001) and FT(3) (P<0.0001) in a univariate analysis. After adjusting for other confounding variables, rT(3) was the only thyroid hormone associated with shorter survival (P=0.014). CONCLUSIONS RT(3) was the only thyroid hormone associated with shorter survival in a representative population of independently-living elderly. In these subjects, isolated elevated rT(3) might be an equivalent of ESS, reflecting declining health.

Répercussions cardiaques des dysthyroïdies frustes: Données expérimentales, cliniques et épidémiologiques

Points essentiels ● Alors que les consequences cardiovasculaires des dysthyroidies dites averees sont largement connues et que leur traitement est globalement bien etabli, les dysthyroidies frustes demeurent a l’origine d’interrogations et de controverses concernant leur impact cardiovasculaire et leurs modalites de prise charge. ● L’hyperthyroidie fruste est une situation frequente chez le sujet âge, le plus souvent en rapport avec un goitre multinodulaire. ● Meme si plusieurs etudes epidemiologiques ont montre que l’hyperthyroidie fruste etait associee a une augmentation du risque de fibrillation auriculaire et a une mortalite cardiovasculaire accrue, il n’y a actuellement pas de donnees pratiques solides sur lesquelles fonder la prise en charge de ces patients. ● Concernant l’hypothyroidie fruste, le risque semble surtout vasculaire, mais son appreciation definitive necessite encore la realisation d’enquetes epidemiologiques rigoureuses.