Maternal rheumatoid arthritis during pregnancy and neurodevelopmental disorders in offspring: a systematic review.

Objective: To summarize the available literature on in utero exposure to maternal rheumatoid arthritis (RA) and its influence on the risk of neurodevelopmental disorders (NDDs) in offspring.Method: We conducted a systematic literature review and assessed the internal validity of studies with the Newcastle Ottawa Scale tool.Results: Six studies were included. Three reported on autism spectrum disorders; one cohort study indicated a slightly elevated risk, and two case-control studies reported too few cases for risk assessment. Two large cohort studies reported elevated hazard ratios for epilepsy in offspring, in overlapping populations. One study on attention deficit hyperactivity disorder (ADHD) reported higher odds for maternal RA during pregnancy, among children with ADHD.Conclusion:Few studies were found specifically studying maternal RA during pregnancy and NDDs in offspring. The studies pointed towards a moderately higher risk of these outcomes; however, reporting bias appears to be a problem. Additional studies of appropriate design and power are needed.

Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study.

Objective: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease. Studies suggest that pro-inflammatory cytokines may be attenuated by the vagus nerve through the cholinergic anti-inflammatory pathway. We aimed to evaluate the anti-inflammatory effects of short-term transcutaneous non-invasive vagus nerve stimulation (n-VNS) applied to the cervical vagus nerve in patients with RA. Method: We conducted a single-centre, open-label, preliminary proof-of-concept study of n-VNS in two cohorts of participants with RA: one with high disease activity (n = 16) and one with low disease activity (n = 20). Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines were measured at baseline and after 1 and 4 days of n-VNS. Results: In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02). In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone (p = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02). Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs 4.9 ± 3 linear vagal scale, p = 0.03). Cardiac vagal tone was negatively associated with DAS28-CRP (r = -0.37, p = 0.03). Overall, n-VNS was well tolerated. Conclusion: This study provides preliminary support for an anti-inflammatory effect of n-VNS in patients with RA. These findings warrant further investigation in larger placebo-controlled trials.

Pamidronate in chronic non-bacterial osteomyelitis: a randomized, double-blinded, placebo-controlled pilot trial.

OBJECTIVE: This is the first randomized double-blinded, placebo-controlled pilot trial to investigate the efficacy of pamidronate in reducing radiological and clinical disease activity in chronic non-bacterial osteomyelitis (CNO). METHOD: Patients received pamidronate or placebo at baseline and weeks 12 and 24. Whole-body magnetic resonance imaging was performed at baseline and weeks 12 and 36, and computed tomography of the anterior chest wall (ACW) at baseline and week 36. Radiological disease activity was systematically scored in the ACW and spine. Patient-reported outcomes [visual analogue scale (VAS) pain, VAS global health, Health Assessment Questionnaire (HAQ), EuroQol-5 Dimensions (EQ-5D), and 36-item Short-Form Health Survey (SF-36)] and biomarkers of bone turnover and inflammation were assessed at baseline and weeks 1, 4, 12, 24, and 36. Data are expressed as median [interquartile range]. RESULTS: Fourteen patients were randomized and 12 were analysed. From baseline to week 36, the radiological disease activity score in the ACW decreased from 5 [4-7] to 2.5 [1-3] in the pamidronate group, but did not change in the placebo group (p = 0.04). From baseline to week 36, VAS pain and VAS global health tended to decrease more in the pamidronate than in the placebo group (p = 0.11, p = 0.08). Physical functioning (HAQ) and health-related quality of life (EQ-5D, SF-36) did not change. Biomarkers of bone turnover decreased only in the pamidronate group (p ≤ 0.02). CONCLUSION: Pamidronate may improve radiological and clinical disease activity in CNO. Methods to score radiological disease activity in adult CNO were suggested. Clinical Trials: NCT02594878.

Vagal influences in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease with a prevalence of 0.5-1% in Western populations. Conventionally, it is treated with therapeutic interventions that include corticosteroids, disease-modifying anti-rheumatic drugs, and biological agents. RA exerts a significant socio-economic burden and despite the use of existing treatments some patients end up with disabling symptoms. The autonomic nervous system (ANS) is a brain-body interface that serves to regulate homeostasis by integrating the external environment with the internal milieu. The main neural substrate of the parasympathetic branch of the ANS is the vagus nerve (VN). The discovery of the role of the ANS and the VN in mediating and dampening the inflammatory response has led to the proposal that modulation of neural circuits may serve as a valuable therapeutic tool. Recent studies have explored the role of the VN in this inflammatory reflex and have provided evidence that stimulation may represent a novel new therapeutic intervention. Accumulating evidence suggests that modulation of the parasympathetic tone results in a broad physiological multi-level response, including decreased pro-inflammatory cytokine response in terms of tumour necrosis factor-α, interleukin-1 (IL-1), and IL-6, and may result in an enhanced macrophage switch from M1 to M2 cells and potentially an increased level of the anti-inflammatory cytokine IL-10. Therefore, therapeutic electrical modulation of the VN may serve as an alternative, non-pharmacological, neuroimmunomodulatory intervention in RA in the future. This review gives a focused introduction to the mechanistic link between the ANS and the immune system.

Faecal calprotectin detects subclinical bowel inflammation and may predict treatment response in spondyloarthritis.

OBJECTIVE: Intestinal inflammation is frequent in patients with spondyloarthritis (SpA). Here, we test the validity of faecal calprotectin as a marker of intestinal inflammation in SpA patients and evaluate the response of adalimumab in patients with and without intestinal lesions. METHOD: Patients were included on the basis of active SpA with a Bath Ankylosing Spondylitis Disease Activity Index ≥ 4. After a 4 week non-steroidal anti-inflammatory drug washout period, patients were divided into two groups based on faecal calprotectin level (> 100 mg/kg, n = 15, and < 50 mg/kg, n = 15). Adalimumab 40 mg every other week was initiated. Patients with calprotectin >100 mg/kg received an additional 40 mg of adalimumab at baseline. Patients were followed with clinical examination at weeks 12, 20, and 52; magnetic resonance imaging (MRI) at weeks 0, 20, and 52; and endoscopy at weeks 0 and 20. RESULTS: The groups were similar with regard to clinical disease activity measures at baseline. Faecal calprotectin above 100 mg/kg accurately identified patients with intestinal inflammation. Twelve of the 15 patients with elevated calprotectin had bowel lesions, compared to only one patient in the control group. On MRI, the group with elevated calprotectin had more inflammation in the sacroiliac joints. Finally, the group with intestinal inflammation had a better clinical response to adalimumab, as evaluated by the Ankylosing Spondylitis Disease Activity Score. CONCLUSION: Elevated faecal calprotectin accurately identified SpA patients with bowel inflammation and more inflammation on MRI. Elevated faecal calprotectin at baseline may predict a better treatment response.

Hepcidin plasma levels are not associated with changes in haemoglobin in early rheumatoid arthritis patients.

OBJECTIVE: A reduction in haemoglobin level is a frequent complication among rheumatoid arthritis (RA) patients. Hepcidin has been linked to disturbed erythropoiesis. The objective of this study was to investigate the longitudinal changes in hepcidin in patients with early RA. METHOD: Hepcidin plasma concentrations were measured by enzyme-linked immunosorbent assay in patients with early RA (n = 80) and healthy volunteers (HV, n = 40). Haemoglobin and other iron-related proteins were also measured. At baseline, all patients had active disease and were treatment naïve. Patients were treated with disease-modifying anti-rheumatic drugs (DMARDs) and with additional adalimumab (ADA, n = 42) or placebo (PLA, n = 38) during 52 weeks, using a treat-to-target strategy, aiming for a 28-joint Disease Activity Score (DAS28) < 3.2. RESULTS: At baseline, hepcidin levels [median (interquartile range)] were 9.7 ng/mL (5.2-19.4 ng/mL) in DMARD + ADA and 11.3 ng/mL (5.9-19.1 ng/mL) in DMARD + PLA. Both were significantly higher than seen in HV (6.0 ng/mL (3.3-9.3 ng/mL) (p < 0.001). After 12 months, both treatment regimens resulted in normalization of hepcidin. DAS28 correlated with hepcidin at baseline (r = 0.48, p < 0.001). No correlation was observed between levels of haemoglobin and hepcidin at baseline or during the 52 week follow-up. No change in haemoglobin levels was seen as a function of hepcidin changes. In a mixed statistical model, no single factor was connected with the regulation of haemoglobin in early RA. CONCLUSION: The changes in hepcidin were not associated with changes in haemoglobin levels. Thus, hepcidin could not be used as a prognostic marker in patients with early RA.

Antibiotic treatment in patients with low-back pain associated with Modic changes Type 1 (bone oedema): a pilot study.

OBJECTIVE: The aim of this study was to assess the clinical effect of antibiotic treatment in a cohort of patients with low-back pain (LBP) and Modic changes Type 1 (bone oedema) following a lumbar herniated disc. DESIGN: This was a prospective uncontrolled trial of 32 LBP patients who had Modic changes and were treated with Amoxicillin-clavulanate (500 mg/125 mg) 3 x day for 90 days. All patients had previously participated in a randomised controlled trial (RCT) that investigated active conservative treatment for a lumbar herniated disc (n = 166). All patients in that RCT who had Modic changes and LBP at 14 months follow-up (n = 37) were invited to participate in this subsequent antibiotic trial but five did not meet the inclusion criteria. RESULTS: 29 patients completed the treatment, as three patients dropped out due to severe diarrhoea. At the end of treatment and at long-term follow-up (mean 10.8 months) there was both clinically important and statistically significant (p

[NSAID--COX-2-inhibitors, where is the difference? Focus on the modes of action]. / NSAID--COX-2-inhibitorer, hvor er forskellen? Fokus på virkningsmekanismerne.

Non-steroidal anti-inflammatory drugs (NSAID) induce their action by inhibiting prostaglandin synthesis via the cyclooxygenase enzymes (COX). COX has recently been shown to have at least two isoforms, termed COX-1 and COX-2. The life-threatening gastrointestinal side effects of NSAID are caused by their inhibition of COX-1, which results in increased gastrointestinal bleeding and decreased ability to induce platelet aggregation. Highly specific COX-2 inhibitors are now available. These have the same ability to relieve pain, but do not cause gastrointestinal bleeding or prolong bleeding time. However, many other side effects caused by NSAID are due to COX-2 inhibition and COX-2 inhibitors should still be used with caution when patients suffer from lung, heart, or kidney diseases.

[Heavy white coats are not the cause of physicians' headaches and shoulder pain]. / Tunge kitler er ikke årsag til laegernes hovedpine og nakkemyoser.

The weight of doctors' white coats was examined and correlated to the degree of headache and muscle pain in the shoulders. The coat weight of doctors was 1.5 kg (1.1 kg-1.9 kg) (median with 25%-75% in parenthesis). The highest weight was found in the coats of young physicians 2.0 kg (1.7 kg-2.2 kg), which was higher than those of young surgeons. No correlation was seen in the degree of headache and muscle pain in the shoulders. With the long walking distances in hospitals, it would seem that internal medicine is not only an intellectually, but also a physically, demanding job.

The delayed-type hypersensitivity reaction is dependent on IL-8. Inhibition of a tuberculin skin reaction by an anti-IL-8 monoclonal antibody.

Cell-mediated immune reactions are essential to our immune response toward foreign organisms such as microorganisms, or in the response toward foreign tissue Ags, as seen in the rejection of allogeneic transplanted organs. Similar reactions form the basis for the development and the progression of delayed-type hypersensitivity (DTH) reactions. We found that the alpha-chemokine IL-8 plays an important pathophysiologic role for the development of a DTH reaction because infusion of a neutralizing anti-IL-8 mAb (WS-4) was able to suppress the development of a tuberculin skin reaction in rabbits, as judged by histologic, biochemical, and clinical examinations. Thus, the number of neutrophil granulocytes and lymphocytes at the site of tuberculin injection was decreased considerably, and the clinical signs of inflammation were suppressed almost completely at 24 h after intracutaneous injection of tuberculin, as judged by the size of the infiltrates. In contrast, we did not see any effect on the visible erythema of the skin. We found that the tissue content of myeloperoxidase (MPO), reflecting the number of infiltrating neutrophils, was lowered significantly. Furthermore, immunohistochemical analysis confirmed that IL-8 immunoreactivity is actually enhanced in the skin of positive tuberculin reactions. The results indicate that IL-8 plays an important role for the early accumulation of leukocytes in the skin and for the clinical signs of a DTH reaction.

Expression of monocyte chemotactic and activating factor (MCAF) in skin related cells. A comparative study.

A significant proportion of the infiltrating cells in several inflammatory skin diseases, including psoriasis and allergic contact dermatitis, are monocytes. Additionally, it is known that the cytokine monocyte chemotactic and activating factor (MCAF) can be produced by several cell types present in the skin, suggesting a significant role for MCAF in the accumulation of monocytes during immunological and inflammatory skin reactions. We have recently developed a precise method for quantification of the amount of a specific mRNA species in a given sample and have used this technique to compare specific MCAF mRNA amounts in cultures of human keratinocytes, dermal fibroblasts, endothelial cells, and monocytes, after stimulation with interleukin 1 alpha (IL-1 alpha) for 6 h. Endothelial cells produced very high, monocytes and fibroblasts intermediate, and keratinocytes low amounts of MCAF mRNA. We have also performed time course studies of MCAF mRNA levels in the four cell types. Our findings suggest that the regulation of MCAF mRNA expression in these cells parallels the regulation of the lymphocyte and neutrophil chemotactic factor interleukin 8.

Localization of interleukin-1 alpha, type 1 interleukin-1 receptor and interleukin-1 receptor antagonist in the synovial membrane and cartilage/pannus junction in rheumatoid arthritis.

Using monoclonal antibodies and immunohistochemical techniques we have investigated the presence and distribution of interleukin-1 alpha (IL-1 alpha), type 1 IL-1 receptor (IL-1R1) and of interleukin-1 receptor antagonist (IL-1ra) in synovial tissue from 18 rheumatoid arthritis (RA) and eight osteoarthritis (OA) patients and in eight normal synovial tissue samples. IL-1 alpha and IL-1R1 were found in all of the samples examined. In RA, there were a large number of synovial cells expressing IL-1 alpha and IL-1R1, with 85 and 90% positive cells in the lining layer, 45 and 80% in the interaggregate area, and 90% of the vascular endothelial cells. In the lymphoid aggregates, 20% of the cells contained IL-1 alpha and 70% expressed IL-1R1. IL-1 alpha and IL-1R1 expressing cells showed a similar distribution in OA synovial membrane, but there was a smaller number of positive cells in the deeper area; and the staining intensity was lower. In contrast to IL-1 alpha and IL-1R1, IL-1ra was found only in 10/18 RA, 5/8 OA and 2/8 normal tissue samples. IL-1ra was detected in 35% of RA and 45% OA lining layer cells; 25% RA and 35% OA vascular endothelium; 10% RA and 15% OA interstitial cells and 30% cells in RA lymphoid aggregate. The staining intensity in both RA and OA tissues was comparably low. The presence of IL-1ra in RA and OA tissues was confirmed by Northern blot analysis for IL-1ra mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Localization of tumor necrosis factor receptors in the synovial tissue and cartilage-pannus junction in patients with rheumatoid arthritis. Implications for local actions of tumor necrosis factor alpha.

OBJECTIVE: We have previously described the location of tumor necrosis factor alpha (TNF alpha)-producing cells in synovial tissue and cartilage-pannus junction in rheumatoid arthritis (RA). To further understand the local actions of TNF alpha, we investigated the expression of TNF receptors (TNF-R) on cells in the same compartments in patients with RA. METHODS: The expression of both p55 TNF-R and p75 TNF-R was determined using alkaline phosphatase-conjugated mouse anti-alkaline phosphatase (APAAP) and double immunofluorescence staining techniques with monoclonal antibodies. RESULTS: In RA synovial membrane, both p55 TNF-R and p75 TNF-R were detectable in up to 90% of the cells in the lining layer, and were demonstrated on cells in deeper layers of the membrane, including vascular endothelial cells. Cells in lymphoid aggregates expressed both TNF-R, but with a predominant expression of p75 receptor. At the cartilage-pannus junction, the majority of pannus cells, especially those invading cartilage, expressed both the p55 and the p75 TNF-R. Sequential section and double immunofluorescence staining showed that the TNF-R-expressing cells were in the vicinity of TNF alpha-containing cells, and some TNF alpha-containing cells also expressed TNF-R. TNF-R-expressing cells were also detected in osteoarthritic and normal synovial tissue, but in smaller numbers and at a lower intensity. CONCLUSION: These results provide histologic evidence that both p55 TNF-R and p75 TNF-R are expressed by a variety of cell types in RA synovial tissue, reflecting the fact that a wide range of cells are potential targets for TNF alpha in this tissue. This study further supports the hypothesis that TNF alpha plays a major role in the pathogenesis of RA.

Quantitative determination of IL-1 alpha-induced IL-8 mRNA levels in cultured human keratinocytes, dermal fibroblasts, endothelial cells, and monocytes.

The presence of the leukocyte chemotactic cytokine interleukin 8 (IL-8) in psoriatic scales and in epidermal tissue overlying allergic patch test reactions suggests a role for this cytokine in certain inflammatory skin diseases. IL-8 can be produced by several cell types present in the skin. Their relative potentials for IL-8 expression has, however, not yet been studied, due to the lack of convenient methods for quantitative comparison of specific mRNA amounts in different cell types. Using a new method for quantification, we compared specific IL-8 mRNA amounts in cultures of keratinocytes, dermal fibroblasts, endothelial cells, and monocytes, stimulated with interleukin 1 alpha (IL-1 alpha). Endothelial cells produced very high, fibroblasts and monocytes intermediate, and keratinocytes low amounts of IL-8 mRNA. We also studied the time course of IL-8 mRNA levels in the four cell types following IL-1 alpha stimulation, and found a clear difference both in onset and stability of the response. We discuss the different strength of the response at different time points in the cell types analyzed in relation to their possible role in regulation of the normal response to stimulation.

[The clientele of physiotherapists in private practice]. / Privatpraktiserende fysioterapeuters klientel.

The aim of the study was to describe sociomedical characteristics of physiotherapy patients. A material of 466 patients answered questions about personal and social data and their disease. Women were significantly more frequent in the material than men (p less than 0.001). The following groups were underrepresented compared to the background population calculated by X2: 1) boys 0-9 years, 2) girls 0-19 years, 3) women more than 80 years old, 4) officials, 5) unskilled workers and 6) unemployed. The following groups were overrepresented: 1) women 30-39 years, 2) women 60-79 years, 3) pensioners and persons receiving public assistance and 4) students. More than half of the symptoms were located to the head-neck or back-thorax-loin. The cause was most often primarily somatic (46%), while 25% had an occupational genesis.

[Factors of significance for short or prolonged duration of physiotherapeutic treatment from private practicing physiotherapists]. / Faktorer af betydning for kortog langvarigt behandlingsforløb hos privatpraktiserende fysioterapeut.

The aim of the study was to determine factors of importance for the duration of treatment of physiotherapy patients. A material of 363 patients answered questions about personal and social data and their disease. The following was related to prolonged treatment (greater than 47 days): 1) young, unmarried students. There was twice as many boys as girls. 2) Patients with psychosomatic disease. The ratio between men and women was 1, and the main symptom was headache. 3) Patients with generalized disease. This study did not reveal whether prolonged treatment is due to an ineffective treatment or whether other factors are of importance. However, we doubt the effect of physiotherapy in patients with psychosomatic disease.