Search

At least 30% of patients with rheumatoid arthritis (RA) do not respond to biologic agents, which emphasizes the need of predictive biomarkers. We aimed to identify microRNAs (miRNAs) predictive of response to adalimumab in 180 treatment-naïve RA patients enrolled in the OPtimized treatment algorithm for patients with early RA (OPERA) Study, an investigator-initiated, prospective, double-blind placebo-controlled study. Patients were randomized to adalimumab 40?mg (n=89) or placebo–adalimumab (n=91) subcutaneously in combination with methotrexate. Expressions of 377 miRNAs were determined using TaqMan Human MicroRNA LDA, A Card v2.0 (Applied Biosystems). Associations between miRNAs and treatment response were tested using interaction analyses. MiRNAs with a P-value <0.05 using three different normalizations were included in a multivariate model. After backwards elimination, the combination of low expression of miR-22 and high expression of miR-886.3p was associated with EULAR good response. Future studies to assess the utility of these miRNAs as predictive biomarkers are needed.

Objectives. The primary objective was to demonstrate equivalence between a.m. and p.m. dosing of celecoxib 200 mg q.d. An equivalence assessment of q.d. vs b.i.d. dosing was a secondary objective.Methods. In this randomized, double-blind study, patients with symptomatic osteoarthritis of the knee or hip were randomized to receive celecoxib 200 mg q.d. a.m., celecoxib 200 mg q.d. p.m. or celecoxib 100 mg b.i.d. The primary outcome variable, measured at week 12 on a 0- to 10-point integrated scale, was patient satisfaction assessment (pain relief, walking/bending, and willingness to continue medication). Equivalence was declared if the 95% confidence interval (CI) of the difference (a.m. q.d. vs p.m. q.d., b.i.d. vs q.d.) fell within the interval of –2 to +2.Results. A total of 697 patients were enrolled in this trial. For the a.m. vs p.m. comparison, the 95% CIs were within the prespecified equivalence criteria for all three measures of patient satisfaction: pain relief, mean –0.2, 95% CI –0.53 to 0.68; ability to walk and bend, mean –0.2, 95% CI –0.54 to 0.64; willingness to continue medication, mean –0.7, 95% CI –0.98 to 0.49. The 95% CIs for the q.d. vs b.i.d. comparison were also within the –2 to +2 interval.Conclusion. Regardless of the time of day at which celecoxib 200 mg q.d. is administered, patients are equally satisfied with the pain relief, ability to walk and bend, and willingness to continue medication.

Objective: To compare a new MRI scoring system of the sacroiliac joints (SIJs) in early spondylarthropathy (SpA) with clinical and laboratory parameters.Methods: Forty-one patients (24 males, 17 females) with a median age of 26 yr and a median duration of inflammatory low back pain of 19 months were included. They all fulfilled the ESSG-criteria for SpA. The patients were examined by MRI of the SIJs using a new scoring system. Clinical examinations, biochemical tests, functional score (BASFI), and pain score (BASDAI) were also performed.Results: 95% of the patients had inflammation and/or destructive bone changes of the SIJs at MRI. No correlation was found between MRI pathology and clinical findings. MRI demonstrated significantly greater severity of both inflammation and destruction of the SIJs in HLA B27 positive patients than in the HLA B27 negative patients.Conclusions: In patients with early SpA, MRI was able to detect inflammatory and destructive changes of the SIJs, but the changes were not associated to clinical findings. Our results suggest a role of MRI in the detection of early-stage sacroiliitis.

OBJECTIVE: Monocyte chemoattractant protein 1 (MCP-1) level in plasma is described as a marker for joint inflammation in rheumatoid arthritis (RA). METHODS: MCP-1 in plasma and synovial fluid (SF) was quantified by ELISA in 36 RA patients with synovitis of the knee at Day 1 and 30. Disease activity was assessed by the swollen joint count, Ritchie Articular Index (RAI), global assessment, pain on visual analog scale, Health Assessment Questionnaire, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). RESULTS: By linear regression analysis plasma MCP-1 levels correlated significantly with the swollen joint count (Day 1: R = 0.47, p = 0.005; Day 30: R = 0.53, p < 0.001) and the RAI (Day 1: R = 0.37, p = 0.03; Day 30: R = 0.41, p = 0.01). The correlations of swollen joint count and RAI with ESR and CRP were significant only on Day 30 for the ESR (R = 0.40, p = 0.02). No association was found between plasma MCP-1 levels and the ESR/CRP levels. MCP-1 levels in plasma in RA patients were elevated compared to controls (p < 0.001) and MCP-I levels in SF were higher than in plasma (p < 0.001). No correlation was found between SF MCP-1 levels and in vitro migration of mononuclear cells towards SF. MCP-1 appears to participate in the disease process in RA, and plasma MCP-1 may be useful in monitoring joint inflammation.

Background:Enkephalins are opioid peptides that can modulate immune responses and inflammatory processes. Furthermore, they inhibit keratinocyte proliferation/differentiation in vitro. Previously, we have shown that enkephalins are present in increased amounts in lesional psoriasis. Objective:To determine the effect of topical treatment with the vitamin D analogue calcipotriol and the corticosteroid mometasone furoate on the level of methionine-enkephalin (enk) in psoriatic lesions. Methods:Twelve psoriatic patients were treated with calcipotriol and mometasone furoate for 14 days without or with hydrocolloid occlusion. Keratome biopsies were obtained from treated and untreated skin, and the extracted enk was quantified by radioimmunoassay. Furthermore, punch biopsies were obtained for immunohistochemical analysis. Results:Clinically, both calcipotriol and mometasone furoate improved psoriasis to the same degree, the effects being more pronounced after occlusion. Histologically, treatment with mometasone furoate without occlusion decreased both the epidermal thickness/parakeratosis and the number of dermal immunocompetent cells (CD3- and CD68-positive cells). In contrast, treatment with calcipotriol without occlusion reduced the epidermal thickness and the degree of parakeratosis but decreased the number of CD3- and CD68-positive cells only slightly. The mean enk level was decreased by 26 and 86% by calcipotriol without and with occlusion and by 16 and 63% by mometasone furoate without and with occlusion, respectively. The decreases in the enk levels corresponded to the degree of clinical improvement but not to the histological changes. Conclusion:The increased levels of enk in psoriatic lesions are reduced in parallel with the clinical improvement induced by a topical vitamin D analogue and a corticosteroid. Because enkephalins can modulate epidermal differentiation and inflammatory processes, the findings indicate that enkephalins may play a role in the pathogenesis of psoriasis.

We report a detailed comparative immunocytochemical mapping of enkephalin, CCK and ACTH/gb-endorphin immunoreactive nerves in the central nervous system of rat and guinea pig. Enkephalin immunoreactivity was detected in many groups of nerve cell bodies, fibers and terminals in the limbic system, basal ganglia, hypothalamus, thalamus, brain stem and spinal cord. ß-endorphin and ACTH immunoreactivity was limited to a single group of nerve cell bodies in and around the arcuate nucleus and in fibers and terminals in the midline areas of the hypothalamus, thalamus and mesencephalic periaqueductal gray with lateral extensions to the amygdaloid area. Cholecystokinin immunoreactive nerve fibers and terminals displayed a distribution similar to that of enkephalin in many regions; but striking differences were also found. An immunocytochemical doublestaining technique, which allowed simultaneous detection of two different peptides in the same tissue section, showed that enkephalin-, CCK- and ACTH/ß-endorphin-immunoreactive nerves although closely intermingled in many brain areas, occurred separately. The distributions of nerve terminals containing these neuropeptides showed striking overlaps and also paralleled the distribution of opiate receptors. This may suggest that enkephalin, CCK, ACTH and ß-endorphin may interact with each other and with opiate receptors.

Opioid receptors can be localized to the hippocampal formation of the rat by autoradiography. The binding of 3H-enkephalinamide to fixed and mounted tissue sections has all the characteristics associated with binding to opioid receptors. It is saturable, of high affinity and displays stereospecificity. The opioid receptor distribution shows striking regional variation throughout the hippocampal formation. Areas with high density include the pyramidal cell layer of both regio superior (CA1) and regio inferior (CA3), stratum moleculare of the hippocampus, the cell layer of subiculum, the superficial part of presubiculum and the deep layer (VI) of the medial and lateral entorhinal cortices. Areas with low to medium densities include regions corresponding to the dendritic field of the pyramidal cells (str. oriens, str. radiatum and the mossy fiber zone), the dentate granule cell layer and the molecular layer of the dentate area. Enkephalin-like immunoreactivity is detected in both intrinsic neuronal systems: 1) the mossy fibers which terminate on the proximal part of the CA3 pyramidal cell dendrites and on CA4 pyramidal cells, 2) cell bodies with multiple short processes, probably interneurons, dispersed throughout the hilus of the dentate area, the pyramidal cell layer of hippocampus, the str. radiatum, and occasionally in the str. moleculare and in the str. oriens, and extrinsic neuronal systems: 1) the lateral perforant path and 2) the lateral temporo-ammonic tract. Thus, the hippocampus contains intrinsic systems of enkephalin-like immunoreactive nerve terminals which may exert their effect on the opioid receptors with a localization corresponding to the pyramidal cells and their apical dendrites. Extrinsic enkephalinergic systems corresponding to the terminal fields of the lateral perforant path and the temporoammonic tract, both of entorhinal origin, may influence the opioid receptors located in the molecular layer of the dentate area, and in the molecular layer of the hippocampus and the subiculum. Thus, the enkephalinlike immunoreactive nerve terminals are all located in areas which contain opioid binding sites. This suggests that the “opioid peptide-opioid receptor” systems may regulate hippocampal neuronal activity via neurotransmission or neuromodulation. However, a high or medium number of opioid binding sites occur over the pyramidal cell bodies and the dentate granule cell bodies, and these opioid binding sites are not in close contact with the major enkephalinergic systems. Such binding sites could represent newly synthesized opioid receptors ready for the enkephalinergic synapses of the cells and/or internalization of opioid receptors after stimulation at the synapses. Another possibility is the existence of cytoplasmic opioid binding sites (possibly t-RNA synthetase) with specific intracellular functions.

Abstract:  A 25-year-old woman with recurrent pronounced enlargement of the iliopsoas bursae is described; her hips were evaluated by ultrasonography and MRI. They appeared normal and communications to the iliopsoas bursae were demonstrated. During the preceding 8 years she had intermittent seronegative non-erosive arthritis of the knee and finger joints and her disease was classified as juvenile chronic arthritis.

The aim of the study was to evaluate the effects of treatment with methotrexate, sulphasalazine and aurothiomalate on polymorphonuclear leucocytes (PMN) in rheumatoid arthritis (RA). Circulating PMNs from 58 RA patients treated with either methotrexate (n = 27), sulphasalazine (n= 16) or aurothiomalate (n = 15) were assayed for their chemotactic capacity and generation of superoxide anions. The expression of CD18/CDllb was measured for 17 RA patients treated with methotrexate. Chemotaxis and generation of superoxide anions were not affected by any of the three drugs. We found no difference in the expression of CD18/CDllb in RA patients treated with methotrexate compared to healthy subjects. Further methotrexate and aurothiomalate did not in vitro alter chemotaxis, generation of superoxide anion or expression of CD18/CDllb on normal PMNs.In conclusion we found no evidence that the effect of methotrexate, aurothiomalate or sulphasalazine in RA can be explained by modulation of chemotactic ability or superoxide anion generation of peripheral circulating PMNs.

In order to investigate whether soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) were present in scleroderma skin, and to compare their levels to concentrations measured in plasma and clinical parameters, we examined suction blister fluid and plasma from 13 patients with systemic sclerosis and 11 healthy volunteers. Suction blisters and biopsies were from the transition zone between normal skin and scleroderma, and uninvolved abdominal skin. The levels of sICAM-1 and sIL-2R were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy volunteers. ICAM-1 was localized to vessels and perivascular mononuclear infiltrates by immunohistochemical methods. IL-2R was expressed by CD3-positive cells. The elevated levels of sICAM-1 and sIL-2R in suction blister fluid point towards activation of endothelial cells and T cells in both the transition zone and uninvolved skin of systemic sclerosis patients.Keywords:Cell adhesion molecules, sICAM-1, sIL-2R, Interleukin-2 receptors, Systemic sclerosis, CD54, CD25.

In order to investigate whether soluble intercellular adhesion molecule-1 (sICAM-1) and soluble interleukin-2 receptors (sIL-2R) were present in scleroderma skin, and to compare their levels to concentrations measured in plasma and clinical parameters, we examined suction blister fluid and plasma from 13 patients with systemic sclerosis and 11 healthy volunteers. Suction blisters and biopsies were from the transition zone between normal skin and scleroderma, and uninvolved abdominal skin. The levels of sICAM-1 and sIL-2R were significantly increased in both plasma and suction blister fluid from systemic sclerosis patients compared with healthy volunteers. ICAM-1 was localized to vessels and perivascular mononuclear infiltrates by immunohistochemical methods. IL-2R was expressed by CD3-positive cells. The elevated levels of sICAM-1 and sIL-2R in suction blister fluid point towards activation of endothelial cells and T cells in both the transition zone and uninvolved skin of systemic sclerosis patients.
Keywords:Cell adhesion molecules, sICAM-1, sIL-2R, Interleukin-2 receptors, Systemic sclerosis, CD54, CD25.

Interleukin-8 (IL-8) may play an important role in the development of synovitis in rheumatoid arthritis (RA), in that it is a powerful chemoattractant for neutrophils and T cells. The aim of this study was to examine the distribution of IL-8 in the synovial membrane and cartilage, from RA, osteoarthritis (OA) and normal joints.By immunohistochemical techniques, IL-8 was shown to be present in the lining layer cells in RA (87%) and in OA (62%). By contrast, only a few of the normal synovial lining layer cells (14%) contained IL-8. Deeper in the membrane the number of IL-8 positive cells decreased. Only vessels were highly positive for IL-8. At the RA cartilage-pannus junction 26% of the cells contained IL-8, whereas at the OA cartilage-pannus junction 8% of the cells were IL-8 positive (P < 0.05). Chondrocytes present in joint surface cartilage stained positive for IL-8 in an average of 20% of the cells of both RA and OA. These results provide histological evidence that IL-8 is present in the arthritic synovial tissue and cartilage, and is distributed in a manner that may form a chemotactic gradient, which favours localisation of neutrophils to the joint lumen.

This study deals with the nutritional status of Danish RA patients and address the question of whether or not RA can be directly influenced by dietary manipulation. In a prospective, single-blinded study of 6 months duration, 109 patients with active RA were randomly assigned to either treatment with or without a specialized diet. The energy consumption was adjusted to normal standards of body weights and the intake of fish meals and antioxidants were increased. A daily food diary was completed by the patients, and the total intake of 47 different food-elements was calculated. Nutritional status together with disease activity parameters were recorded. At baseline, the Danish RA-patients had neglected food habits with a significant reduction in intake of total energy, of D-vitamin and of E-vitamin. A very low intake of n-3 fatty acids was also found. During the study, 28 of the 109 patients dropped out, introducing a confounding effect on the overall result. In the remaining 81, those following the diet demonstrated a significant improvement in the duration of morning stiffness, number of swollen joints, pain status, and reduced cost of medicine, while doctors global assessment, laboratory data, X-ray, and daily activities were unaltered. In conclusion, dietary analysis and appropriate, corrective advice should be offered to Danish RA patients.

Previously, we have reported that enkephalins, cholecystokinin, and heavy metals show roughly parallel distributional patterns in the hippocampus. A substantial body of evidence indicates that cholecystokinin-octapeptide (CCK-8) and enkephalins act as neurotransmitters. A CCK-8 degrading enzyme was recently detected in brain synaptosomes. Its activity depended on free thiol groups and the presence of a heavy metal. Since the heavy metal-containing neuropil is closely related to CCK-immunoreactive nerve terminals, we have investigated the effect of metal chelation on CCK components in the rat hippocampus. In vivo treatment of rats with a single dose of the chelating agent diethyldithiocarbamate caused a reversible chelation of heavy metals in the hippocampus. This effect was paralleled by a 3-fold increase in hippocampal content of CCK-8 and a smaller increase in the intermediate forms of CCK (CCK-58, CCK-39, CCK-33). Diethyldithiocarbamate also decreased the spontaneous motility and aggressiveness of the rats. These data show reversible changes of neuronal CCK processing by a drug, and hence they provide additional evidence that CCK is involved in the regulation of neuronal activities.

Gastrins occur in the hypothalamo-hypophyseal neurons of all mammalian species examined. In addition, human, bovine, and murine hypothalamo-hypophyseal neurons contain the homologous cholecystokinins (CCKs). CCK also occurs in neurons innervating bovine melanotrophs. Although the concentration of gastrin is of the same magnitude (15-30 pmol/g) in all neural lobes, the concentration of CCK varies from undetectable in pig and cat to 1 nmol/g in the cow. The constant occurrence of neurohypophyseal gastrin suggests a role different from that of the species-dependent CCK.

Nine normotensive healthy females received timolol 5 mg daily for a 4-day period and subsequently 20 mg daily for another 4-day period. None of the two dosages of timolol caused significant changes in serum uric acid or 24-h urinary fractional excretion of uric acid. Thus the increments of serum uric acid previously found in hypertensive patients is not likely to be caused by beta-adrenoceptor blockade per se.