Gert Hein

Pain treatment of fibromyalgia by acupuncture

Abstract The lack of objective parameters makes the measurement of pain and the efficacy of pain treatment in patients with chronic pain very difficult. We performed acupuncture therapy in fibromyalgia patients and established a combination of methods to objectify pain measurement before and after therapy. The parameters corresponded to patients self-report. Twenty-nine fibromyalgia patients as defined by ACR-criteria (25 women, 4 men) with a mean age of 48.2±2.0 years and a mean disease duration of 6.1±1.0 years participated in the study. Pain levels and positive tender points were assessed using the visual analogue scale (VAS, i.e., range 0–100 mm) and dolorimetry. Serotonin and substance P levels in serum and the serotonin concentration in platelets were measured concomitantly. During acupuncture therapy no analgesic medication was allowed. The VAS scores decreased from 64.0±3.4 mm before therapy to 34.5±4.3 mm after therapy (P<0.001). Dolorimetry revealed a decreased number of tender points after therapy from 16.0±0.6 to 11.8±1.0, P<0.01. Serotonin levels decreased from 715.8±225.8 μg/1012 platelets to 352.4±47.9 μg/1012 platelets (P<0.01), whereas the serum concentration increased from 134.0±14.3 ng/ml to 171.2±14.6 ng/ml (P<0.01). Substance P levels in serum increased from 43.4±3.5 pg/ml to 66.9 ±8.8 pg/ml (P<0.01). Acupuncture treatment of patients with fibromyalgia was associated with decreased pain levels and fewer positive tender points as measured by VAS and dolorimetry. This was accompanied by decreased serotonin concentration in platelets and an increase of serotonin and substance P levels in serum. These results suggest that acupuncture therapy is associated with changes in the concentrations of pain-modulating substances in serum. The preliminary results are objective parameters for acupuncture efficacy in patients with fibromyalgia.

Identification of the receptor for advanced glycation end products in synovial tissue of patients with rheumatoid arthritis

ObjectivesGeneration of advanced glycation end products (AGE) is an inevitable process in vivo and can be accelerated under pathologic conditions such as oxidative stress, e.g. in rheumatoid arthritis (RA). This process is mediated by the AGE-specific receptor (RAGE). In this study we analysed the presence of RAGE in RA and osteoarthritic (OA) synovial tissue using immunohistology.MethodsFrozen synovial tissue samples from 11 RA patients and 12 OA patients were treated with goat anti-RAGE immunoglobulin G (IgG) and rabbit antigoat IgG. Immunostaining was visualised with streptavidin horse radish peroxidase (chromogen amino-ethyl-carbazole). Cell differentiation was performed with antibodies against CD68, CD45RO, and CD20.ResultsIn 9/11 RA and 8/12 OA synovial specimens, RAGE was detected in synovial lining, sublining, and stroma. In RA, many T cells (CD45RO+) and some macrophages (CD68+) showed positive immunostaining for RAGE, whereas B cells were mostly negative. We found no difference in staining patterns between the RA and OA samples.ConclusionsWe detected RAGE in RA and OA synovial tissue. The presence of RAGE on macrophages, T cells, and some B cells suggests its role in the pathogenesis of inflammatory joint disease.

Leflunomide in the treatment of patients with early rheumatoid arthritis—results of a prospective non-interventional study

Leflunomide is effective and well tolerated in the treatment of rheumatoid arthritis (RA), however, data on its use in early RA are scarce. This study seeks to evaluate effectiveness and safety of leflunomide in the treatment of early RA in daily practice. This prospective, open-label, non-interventional, multi-center study was carried out over 24xa0weeks including adults with early RA (≤1xa0year since diagnosis). Leflunomide treatment was according to label instructions. Three hundred thirty-four patients were included. Disease activity score in 28 joints (DAS28) response (reduction in DAS28 of >1.2 or reduction of >0.6 and a DAS28 of ≤5.1) was 71.9% at weeku200912 and 84.6% at week 24. 25.0% of patients achieved clinical remission (DAS28u2009≤u20092.6). Most frequently reported adverse drug reactions (ADR) were diarrhea (3.0%), nausea (2.4%), hypertension (1.8%), and headache (1.5%). Serious ADR were reported in four patients (1.2%). Leflunomide showed the effectiveness which was to be expected from controlled studies without revealing any new or hitherto unknown side effects. Onset of action was quick and significant improvement of disease was seen after 12xa0weeks of therapy and at even higher rates after 24xa0weeks irrespective of the use of a loading dose. Interestingly, the DAS28-remission rate achieved was similar to the rate seen with methotrexate or biologic therapy in other studies.

Soluble receptor activator of NFkappa B-ligand and osteoprotegerin in rheumatoid arthritis - relationship with bone mineral density, disease activity and bone turnover

The aim of our study was to investigate determinants of bone mineral density (BMD) measured by dual X-ray absorptiometry at the lumbar spine (BMD-LS) and at the femoral neck (BMD-FN) in patients with rheumatoid arthritis (RA) with special respect to bone resorbing proinflammatory cytokines and their physiological antagonists. In 142 RA patients the following parameters were measured in parallel with BMD: serum levels of soluble receptor activator of nuclear factor kappa-B-ligand (sRANKL), osteoprotegerin (OPG), interleukin (IL)-6, soluble glycoprotein 130 (sgp130), 25-hydroxyvitamin D3 (25OHD3), 1,25-dihydroxyvitamin D3 (1,25[OH]2D3), intact parathyroid hormone, osteocalcin, ionized calcium, renal excretion of pyridinolin and deoxypyridinolin, C-reactive protein, and erythrocyte sedimentation rate (ESR). No significant differences of sRANKL, OPG, IL-6, and spg130 were found between patients with osteoporosis (47.9% of patients), osteopenia (36.6%), and normal BMD (15.5%). However, total sRANKL was significantly higher in postmenopausal women with osteoporosis at FN than in those without (pu2009<u20090.05) and showed a negative correlation with BMD-LS in patients older than 60xa0years (pu2009=u20090.01). BMD-LS and BMD-FN (pu2009<u20090.001) and total sRANKL (pu2009<u20090.01) were negatively related with the age of the patients. Only IL-6 (positive correlation, pu2009<u20090.001) and 1,25(OH)2D3 (negative correlation, pu2009<u20090.001) but not sRANKL, OPG, and sgp130 were related to disease activity. Using multiple linear regression analysis, menopause was identified as the crucial negative determinant of BMD-LS (R2u2009=u20090.94, pu2009=u20090.001), whereas cumulative glucocorticoid dose (βu2009=u2009−0.80, pu2009=u20090.001) and ESR (βu2009=u2009−0.44, pu2009=u20090.016) were the negative determinants of BMD-FN (R2u2009=u20090.86, pu2009=u20090.001). The results indicate that influences of age and gender must be considered in investigations on the relationship between BMD and sRANKL in RA and that high serum levels of sRANKL seems to be associated with osteoporosis only in subgroups of RA patients.

sRANKL and OPG in serum and synovial fluid of patients with rheumatoid arthritis in comparison to non-destructive chronic arthritis.

The aim of this study was to investigate sRANKL and OPG levels in serum and synovial fluid (SF) and to evaluate their relations in patients with RA in comparison to those with non-erosive arthritis (NEA). The study included 45 unselected RA patients with knee joint effusions and 27 patients with knee joint effusions because of NEA. Serum and SF samples were investigated isochronously. OPG and sRANKL were measured by ELISA assays. In RA, sRANKL levels were higher in serum than in SF (Pxa0=xa00.007). In contrast, the NEA revealed higher sRANKL in SF compared to the serum (Pxa0=xa00.001). Though in RA the average levels of sRANKLser were 5.6 times and of sRANKLsyn 1.5 times higher than in NEA, the differences were not significant. The free (unbound) OPG in SF was not significantly different in RA compared to NEA. Also in serum, the measured free OPG was only slightly higher in RA. There were no significant differences between RA and NEA concerning ESR and CRP. Significant correlations could be found between sRANKLsyn and CRP (rxa0=xa00.453; Pxa0=xa00.005) as well as ESR (rxa0=xa00.362; Pxa0=xa00.033) in RA. Nearly a positive correlation was evident also between sRANKLsyn and CRP in NEA (rxa0=xa00.520; Pxa0=xa00.08). RA and NEA differ in particular concerning their power and intensity to destruct the juxtaarticular bone. This is the most remarkable finding of this study, that in RA a high part of sRANKL seems to be OPG bound and cleared by the blood stream, but the sRANKL neutralizing capacity of produced OPG in opposite to NEA is not sufficient to prevent osteoclast activation and bone destruction in the RA joint.

Hypercalcemia in rheumatoid arthritis: relationship with disease activity and bone metabolism

To investigate the relationship between ionized calcium and disease activity, parameters of bone metabolism and bone mineral density (BMD) at the lumbar spine (BMD-LS) and the femoral neck (BMD-FN) measured by dual X-ray absorptiometry in rheumatoid arthritis (RA). In 146 patients with RA, the following parameters were investigated: serum levels of ionized calcium, total calcium, vitamin D metabolites 25-hydroxyvitamin D3 (25D3) and 1,25-dihydroxyvitamin D3 (1,25D3), intact parathyroid hormone (iPTH), interleukin-6, osteocalcin, erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP); renal excretion of pyridinolin (PYD)- and desoxypyridinolin (DPD)-crosslinks. A total of 30.1% of the patients were hypercalcemic (ionized calcium >1.30xa0mmol/l). In comparison with normocalcemic patients, those with hypercalcemia had significantly higher ESR (P<0.01) and CRP values (P<0.05) and significantly lower serum levels of both iPTH (P<0.01) and 1,25D3 (P<0.05) and a significantly lower BMD-LS (P<0.05). The results indicate that a substantial part of RA patients is hypercalcemic. Hypercalcemia is associated with high disease activity and may contribute to suppression of PTH secretion and vitamin D hormone synthesis. High levels of ionized calcium may be a reflection of disease-activity-related systemic bone loss, and could be a predictor of BMD at the lumbar spine in RA.

Diagnosis of Large-Vessel Vasculitis by [18F] Fluorodeoxyglucose–Positron Emission Tomography

A 57-year-old previously healthy woman presented with a history of fever for 6 months, weight loss of 20 kg, and dry cough. Ambulatory antibiotic treatment failed to improve her symptoms. On physical examination (blood pressure, 100/60 mm Hg; heart rate, 64 bpm), she appeared tired, was pale, but was not in acute distress. Lungs and heart appeared normal on auscultation. The abdomen was soft and not tender with normal bowel sounds. The neurological examination was unremarkable. Abnormal laboratory studies included an elevated serum C-reactive protein level (142.1 mg/L; normal 120 mm the first hour; normal, 7 to 12 mm/h), decreased hemoglobin concentration (5.0 mmol/L; normal, 8.7 to 10.9 mmol/L), and proteinuria (1.7 g/24 h; normal <0.1 g/24 h). Results of other laboratory studies, including leukocyte count with differentials, serum chemistry, liver function test, antinuclear antibody, anti–double-stranded DNA, rheumatoid factor, cryoglobulins, complement, …

Orbital inflammatory pseudotumor due to hypersensitivity vasculitis and mononeuritis multiplex in a patient with atypical, cANCA-positive Wegener's granulomatosis

ObjectiveWe report on a 60-year-old woman with a retro-orbital pseudotumor and polyneuropathy. The retro-orbital inflammation was histologically diagnosed as hypersensitivity vasculitis (HV). As cytoplasmatic antineutrophilic cytoplasmatic antibody (cANCA) and anti-proteinase-3 antibody were detected, the differential diagnosis also included atypical Wegeners granulomatosis. Hypersensitivity vasculitis is defined as small-vessel vasculitis mediated by the deposition of immune complexes (Arthus reaction) after exposure to various agents such as drugs, toxins, and infections. Since an inflammatory retro-orbital pseudotumor due to HV has not previously been reported, the following case is presented.Methods and main outcome measuresMagnetic resonance imaging (MRI) revealed retro-orbital infiltrate without granuloma. Histology from an orbital biopsy confirmed HV. Electromyography was used for the diagnosis of polyneuropathy. Serum investigation indicated erythrocyte sedimentation rate (ESR) >100xa0mm/h, C-reactive protein (CRP) 223xa0mg/l, antinuclear antibodies 1:80, and cANCA 100xa0U/ml.ResultsThe bilateral orbital pseudotumor, polyneuropathy, and serum levels of inflammation reactants (ESR and CRP) improved from therapy with corticosteroids (1xa0g of methylprednisolone initially) and azathioprine (150xa0mg/day).ConclusionsBecause of cANCA and anti-proteinase-3 antibody positivity, this case can be viewed more as an atypical Wegeners granulomatosis than a systemic HV. The causal variety of inflammatory orbital pseudotumor, including HV and different therapeutic consequences, requires histological differentiation from usual orbital pseudotumors.

Clinical Manifestation of POEMS Syndrome with Features of Connective Tissue Disease

Abstract: The POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome is a rare plasma cell disease with multiorgan involvement and varying clinical manifestations. We report a 38-year-old man who presented with scleroderma-like skin changes of the hands and feet, sicca and Raynaud’s syndrome, pleural effusions, glomerulopathy, polyneuropathy, hepatosplenomegaly and lymphadenopathy. Steroid treatment was started on the assumption of a connective tissue disease and led to a temporary improvement. During the further course of the disease, hypothyreosis, monoclonal gammopathy and osteosclerotic bone lesions were detected, leading to the diagnosis of POEMS syndrome. This case emphasises the need to consider POEMS syndrome as a differential diagnosis in patients with signs of connective tissue disease and polyneuropathy.

Einfluss von Bisphosphonaten auf die entzündliche Gelenkdestruktion bei rheumatoider Arthritis und in Arthritismodellen

In context with the increasing evidence for the significance of osteoclastic bone resorption mediated by the RANKL-RANK-OPG system in the pathogenesis of postmenopausal, glucocorticoid-induced and inflammation-associated osteoporosis as well as in joint destruction in rheumatoid arthritis (RA), there is an increasing interest in the combination of anti-inflammatory and anti-osteoclastic therapies in RA. Because of their suppressive effects on both osteoclastic bone resorption and inflammation due to inhibitory effects on the secretion of pro-inflammatory cytokines and matrix metalloproteinases, bisphosphonates are implicated to be a useful adjuvant therapy in RA. Furthermore, these substances are relatively cheap and have only few side effects. The effects of various bisphosphonates on inflammation, joint destruction and periarticular bone resorption were investigated in different animal models of RA and also in some small studies in RA patients. In various animal models, a suppressive effect of different non-amino- and aminobisphosphonates on periarticular bone resorption was found. But the results with respect to the inhibition of joint and cartilage destruction and inflammation are inconsistent. Newly developed, highly potent aminobisphosphonates such as zoledronate have been shown to inhibit articular bone erosion not only in animal models but also in RA. The assessment of data from animal models is difficult because various bisphosphonates were administered in different doses in heterogeneous animal models with a partly different pathogenesis. Furthermore, the effects of bisphophonates on bone and joint destruction were investigated using different methods or combinations of these methods. Data from animal models and from RA patients have shown that the doses of bisphosphonates necessary for the suppression of inflammation and joint destruction are significantly higher than those needed for the inhibition of osteoclastic bone resorption. It is not clear whether or not these relatively high bisphosphonate doses may result in an oversuppression of bone turnover. The effects of various bisphosphonates on joint destruction and inflammation in RA and animal models of RA are reviewed systematically and discussed in this contribution.