MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA).

OBJECTIVE: To identify predictors of radiographic progression in a 2-year randomised, double-blind, clinical study (CIMESTRA) of patients with early rheumatoid arthritis (RA). METHODS: Patients with early RA (n = 130) were treated with methotrexate, intra-articular betamethasone and ciclosporin/placebo-ciclosporin. Baseline magnetic resonance imaging (MRI) of the wrist (wrist-only group, n = 130) or MRI of wrist and metacarpophalangeal (MCP) joints (wrist+MCP group, n = 89) (OMERACT RAMRIS), x-ray examination of hands, wrists and forefeet (Sharp/van der Heijde Score (TSS)), Disease Activity Score (DAS28), anti-cyclic citrullinated peptide antibodies (anti-CCP), HLA-DRB1-shared epitope (SE) and smoking status were assessed. Multiple regression analysis was performed with delta-TSS (0-2 years) as dependent variable and baseline DAS28, TSS, MRI bone oedema score, MRI synovitis score, MRI erosion score, anti-CCP, smoking, SE, age and gender as explanatory variables. RESULTS: Baseline values: median DAS28 5.6 (range 2.4-8.0); anti-CCP positive 61%; radiographic erosions 56%. At 2 years: DAS28 2.0 (0.5-5.7), in DAS remission: 56%, radiographic progression 26% (wrist+MCP group, similar for wrist-only group). MRI bone oedema score was the only independent predictor of delta-TSS (wrist+MCP group: coefficient = 0.75 (95% CI 0.55 to 0.94), p<0.001; wrist-only group: coefficient = 0.59 (95% CI 0.40 to 0.77), p<0.001). Bone oedema score explained 41% of the variation in the progression of TSS (wrist+MCP group), 25% in wrist-only group (Pearson's r = 0.64 and r = 0.50, respectively). Results were confirmed by sensitivity analyses. CONCLUSION: In a randomised controlled trial aiming at remission in patients with early RA, baseline RAMRIS MRI bone oedema score of MCP and wrist joints (and of wrist only) was the strongest independent predictor of radiographic progression in hands, wrists and forefeet after 2 years. MRI synovitis score, MRI erosion score, DAS28, anti-CCP, SE, smoking, age and gender were not independent risk factors. TRIAL REGISTRATION NUMBER: NCT00209859.

Magnetic resonance imaging and bone scintigraphy in the differential diagnosis of unclassified arthritis.

OBJECTIVES: To investigate the value in clinical practice of hand magnetic resonance imaging (MRI) and whole body bone scintigraphy in the differential diagnosis of patients with unclassified arthritis. METHODS: 41 patients with arthritis (> or = 2 swollen joints, > 6 months' duration) which remained unclassified despite conventional clinical, biochemical and radiographic (hands and feet) examinations were studied. Patients who fulfilled the ACR criteria for rheumatoid arthritis (RA) or had radiographic bone erosions were excluded. Contrast enhanced MRI of the wrist and metacarpophalangeal joints of the most symptomatic hand and whole body bone scintigraphy were performed. Two rheumatologists agreed on the most likely diagnosis and the patients were treated accordingly. A final diagnosis was made by another specialist review 2 years later. RESULTS: Tentative diagnoses after MRI and bone scintigraphy were: RA (n = 13), osteoarthritis (n = 8), other inflammatory diseases (n = 11), arthralgias without inflammatory or degenerative origin (n = 9). Two years later 11 of 13 patients with an original tentative diagnosis of RA had fulfilled the ACR criteria while two were reclassified (one to psoriatic arthritis (RF negative + psoriasis); one to non-specific self-limiting arthritis). No patients classified as non-RA at baseline had fulfilled the ACR criteria after 2 years. The presence of MRI synovitis, MRI erosion and bone scintigraphic pattern compatible with RA showed 100% specificity for a diagnosis of RA at 2 year follow-up. CONCLUSIONS: In patients with arthritis unclassified despite conventional clinical, biochemical and radiographic examinations, MRI and scintigraphy allowed correct classification as RA or non-RA in 39 of 41 patients when fulfilment of ACR criteria 2 years later was considered the standard reference.

Low-cost, low-field dedicated extremity magnetic resonance imaging in early rheumatoid arthritis: a 1-year follow-up study.

OBJECTIVE: To study the ability of low-cost low-field dedicated extremity magnetic resonance imaging (E-MRI) to assess and predict erosive joint damage in the wrist and metacarpophalangeal (MCP) joints of patients with early rheumatoid arthritis. METHODS: 24 previously untreated patients with rheumatoid arthritis with joint symptoms for <1 year were evaluated at the time of diagnosis and after 6 and 12 months of methotrexate treatment with conventional clinical or biochemical examinations, x rays of both hands and wrists, and E-MRI of the dominant wrist and MCP joints. RESULTS: At baseline, all patients showed magnetic resonance imaging (MRI) synovitis, and MRI erosions were detected in 21 bones (10 patients). 6 (29%) of these, distributed among two patients, were seen on x ray. One x ray erosion was not detected by MRI. At 1 year, MRI and x ray detected 15 and 8 new erosions, respectively, and 19% of MRI erosions at baseline had progressed to x ray erosions. In bones with MRI erosions at baseline, the relative risk of having x ray erosions at the 1-year follow-up was 12.1, compared with bones without baseline MRI erosions (lesion-centred analysis). If bones with baseline x ray erosions were excluded, the relative risk was 5.2. In patients with baseline MRI bone erosion or oedema, the relative risk of having x ray erosions at 1 year was 4.0, compared with patients without these signs at baseline (patient-centred analysis). CONCLUSION: In this group of patients with early rheumatoid arthritis who were treated uniformly, baseline E-MRI erosions in MCP or wrist bones markedly increased the risk of x ray erosions at the 1-year follow-up. Low-cost, low-field dedicated extremity MRI is promising for assessment and prognostication of early rheumatoid arthritis.

Low field dedicated magnetic resonance imaging in untreated rheumatoid arthritis of recent onset.

OBJECTIVE: To compare a low field dedicated extremity magnetic resonance imaging system (E-MRI) with x ray and clinical examination, in the detection of inflammation and erosive lesions in wrist and metacarpophalangeal (MCP) joints in newly diagnosed, untreated rheumatoid arthritis (RA). PATIENTS AND METHODS: Twenty five patients (disease duration < or =1 year) and three healthy controls entered the study. An x ray examination and MRI (before and after intravenous injection of a contrast agent) of the 2nd-5th MCP joints and the wrist was performed. The number of erosions on x ray examination and MRI was calculated, and synovitis in the MCP joints and wrists was graded semiquantitatively. RESULTS: E-MRI detected 57 bone erosions, whereas only six erosions were disclosed by x ray examination (ratio 9.5:1). Synovial hypertrophy grades were significantly higher in RA joints with clinical signs of joint inflammation-that is, swelling and/or tenderness (median 3, 5th-95th centile 1-4) than without these clinical signs (median 2, 5th-95th centile 1-3), p < 0.001. 51% of the joints without clinical signs of synovitis showed synovial hypertrophy on E-MRI. There was a positive correlation between MRI scores of synovitis and the number of erosions detected by MRI in the MCP joints (Spearman r(s) = 0.31, p < 0.01). No healthy controls had erosions or synovitis on MRI. CONCLUSION: Joint destruction starts very early in RA and E-MRI allows detailed evaluation of inflammatory and destructive changes in wrists and MCP joints in patients with incipient RA.

Insulin and glucose administration stimulates Fos expression in neurones of the paraventricular nucleus that project to autonomic preganglionic structures.

Insulin and glucose play a key role in the control of body energy homeostasis. However, the anatomical organization of the network of central insulin and glucose sensitive areas is still unclear. In the present study, we used a multiple-labelling technique combining retrograde tracing and Fos-like immunohistochemistry, to analyse the anatomical projections from hypothalamic neurones activated by the combined stimulus of insulin and glucose. After intraperitoneal injections of a bolus of insulin plus glucose, Fos-like immunoreactive neurones were observed in the paraventricular nucleus (PVN), ventromedial and arcuate nuclei, as well as the lateral hypothalamic area. In addition, neurones projecting to the autonomic preganglionic levels in the brainstem and spinal cord potentially involved in the control of glucose metabolism were identified by injections of fluorochrome tracers. Thus, Fluorogold was injected into the intermediolateral cell column of the lower spinal cord and Fast Blue was injected into the dorsal motor nucleus of the vagus. Perikarya of descending neurones were detected chiefly in the dorsal, medial and lateral parvocellular subnuclei and also in the posterior magnocellular subnucleus of the PVN. In contrast, insulin-glucose activated neurones in the PVN were observed mainly in the medial parvocellular and posterior magnocellular subnuclei. Fluorogold/Fos double-labelled neurones were only observed in the ventral zone of the medial parvocellular subnucleus. These data indicate that, within the PVN, there could be neurones responding to insulin-glucose administration, which are involved in the sympathetic control of the classical regulatory structures of body energy homeostasis, such as the liver and pancreas, and which could play a role in the output of the neuronal circuitry controlling food intake.

Neuroimaging findings in twins discordant for Alzheimer's disease.

Data from computed tomography (CT) scans of 12 twin pairs in which one partner had Azheimer's disease (AD) and the other partner is cognitively intact were analyzed to study structural brain features associated with AD while controlling for familial factors. Visual ratings and analysis of quantified areas and volumes indicated that AD twins showed more dilation of temporal horns, lateral ventricles and third ventricle, and more atrophy of temporal lobes, particularly in the anterior temporal/perisylvian area, than their healthy cotwins. Demented twins did not have smaller intracranial areas or overall brain volumes than their intact partners. The apolipoprotein sigma-4 allele was associated with greater dilation of lateral ventricles and ventricular volume. Significant intrapair correlations were found for total intracranial area and volume, cerebellar area and white matter lesions.

Separate populations of neurons within the paraventricular hypothalamic nucleus of the rat project to vagal and thoracic autonomic preganglionic levels and express c-Fos protein induced by lithium chloride.

The role of different hypothalamic nuclei, particularly the paraventricular nucleus (PVN), in the control of food intake and feeding behaviour is well known. It is also well established that lithium chloride (LiCl) causes various disorders in feeding behaviour. In this study, we analyzed the precise distribution of hypothalamic neurons activated by i.p. LiCl administration (LCA neurons) and compared it to that of hypothalamic neurons which project to autonomic preganglionic levels (HAP neurons). We also analysed the possibility that some neurons belong to both populations of nerve cells. To this end, a multiple-labelling technique, using two retrograde fluorescent tracers together with c-Fos-like immunohistochemistry, was performed. Fast Blue was injected in the dorsal motor nucleus of the vagus and Fluorogold (FG) in the thoracic intermedial-lateral cell column, to trace parasympathetic and sympathetic pathways, respectively. LiCl was used as stimulus for c-Fos-like immunohistochemistry. HAP neurons were located mainly in the dorsal, ventral and lateral regions of the parvocellular PVN, while LCA neurons were observed predominantly in the magnocellular region of the PVN rostrally to HAP neurons. A significant number of FG/Fos double-labelled neurons were located in the dorsal parvocellular subnucleus of the PVN (dp) in the LiCl-stimulated rats. We concluded that there is a clear segregation of LCA neurons from HAP neurons within the PVN. The presence of FG/Fos double-labelled neurons in the dp suggests that this nucleus could mediate a sympathetic response after LiCl administration.

c-fos expression in the rat hypothalamic paraventricular nucleus induced by LiCl: descending projections to the dorsal vagal motor nucleus.

Anorexia inducing lithium chloride is believed to involve descending projections from hypothalamus to preganglionic autonomic output neurons. A multiple-labelling technique has presently been used to analyze the anatomical projections of lithium chloride sensitive neurons in the hypothalamus. Immunolabelling of c-fos was performed to stain neurons activated after LiCl administration, while neurons projecting toward vagal parasympathetic preganglionic levels were identified by injection of diamidino yellow in the dorsal motor nucleus of the vagus. Perikarya of descending neurons were mainly observed in the ventral and lateral areas of the paraventricular hypothalamic nucleus. In contrast, lithium chloride activated neurons were observed mainly in the magnocellular division of the paraventricular nucleus and supraoptic nucleus. Double-labelled neurons were not observed. These data provide evidence that lithium chloride sensitive neurons in the paraventricular nucleus are clearly different from those descending toward preganglionic vagal outflow neurons.

Hypothalamic neuron projection to autonomic preganglionic levels related with glucose metabolism: a fluorescent labelling study in the rat.

The location of hypothalamic paraventricular neurons projecting to sympathetic preganglionic levels and related to the autonomic regulation of various organs involved in glucose metabolism (OGM) was determined by ipsilateral injections of two fluorescent tracers, Diamidino Yellow into the left dorsal motor nucleus of the vagus and Fast Blue into the left intermediolateral cell column of the T8-T9 spinal cord. Hypothalamospinal neurons were mainly located in the dorsal part of the paraventricular hypothalamic nucleus (PVH) and the hypothalamobulbar neurons were most abundant in the ventral, medial and extreme lateral parts of the PVH. No double-labelled neurons were found in the hypothalamus. These results can help the knowledge of the neural hypothalamic network related with the autonomic hypothalamic control.

HLA-A, B, DR antigens and insulin-dependent diabetes in Algerians.

HLA-A, B and DR antigens have been investigated in insulin-dependent diabetics and compared to controls in a population of Algerians. A decrease of A1 and DR2 and an increase of Aw 19.2; B8, B18 and especially DR3 were found in diabetics in comparison to controls. The strongest association was found for DR3, which is a good genetic marker of IDD (RR = 8.50) in this population. The frequency of some HLA antigen associations in IDD suggests that the diabetic gene(s) is linked to 2 main haplotypes: Aw 19.2; B18; DR3 and Aw 19.2; B8; DR3. Antigen DR4 was equally represented in IDD (21%) and controls (28.4%), but heterozygote DR3-DR4 was more frequent in diabetics. The relation between IDD and HLA antigens found in the Algerian population is very similar to that described in diabetic Caucasian populations of southern Europe, except for the lack of association with DR4.