OBJECTIVES:To determine the proportion of patients with rheumatoid arthritis (RA) with severe persisting pain and to identify predictive factors despite treatment-controlled disease activity. METHODS:This prospective multicentre study included outpatients with RA scheduled for escalation of anti-inflammatory treatment due to active disease and severe pain (Disease Activity Score 28 (DAS28)>3.2 and Visual Analogue Scale (VAS)>50). At week 24, patients were stratified into reference group (DAS28 improvement>1.2 or DAS28≤3.2 and VAS pain score<50), non-responders (DAS28 improvement≤1.2 and DAS28>3.2, regardless of VAS pain score) and persisting pain group (DAS28 improvement>1.2 or DAS28≤3.2 and VAS pain score≥50). The former two subgroups ended the study at week 24. The latter continued until week 48. Demographic data, DAS28-C reactive protein, VAS for pain, painDETECT Questionnaire (PD-Q) to identify neuropathic pain (NeP) and the Pain Catastrophising Scale were assessed and tested for relation to persisting pain. RESULTS:Of 567 patients, 337 (59.4%) were classified as reference group, 102 (18.0%) as non-responders and 128 (22.6%) as patients with persisting pain. 21 (8.8%) responders, 28 (35.0%) non-responders and 27 (26.5%) persisting pain patients tested positive for NeP at week 24. Pain catastrophising (p=0.002) and number of tender joints (p=0.004) were positively associated with persisting pain at week 24. Baseline PD-Q was not related to subsequent persisting pain. CONCLUSIONS:Persisting and non-nociceptive pain occur frequently in RA. Besides the potential involvement of NeP, pain catastrophising and a higher number of tender joints coincide with persisting pain.

OBJECTIVE:Somatoform disorders and functional somatic syndromes (FSS) with symptoms that are not sufficiently explained by physical or technical examination are among the most challenging underlying causes. Many different somatoform disorders and FSS have overlapping symptoms, often with pain as the most prevalent one, leading to a high burden of disease. The concept of multisomatoform disorder (MSD) has been developed to acknowledge that fact. We analyzed a group of 151 patients and 149 matched controls to identify interactions of genetic and environmental factors with a possible influence on the development of MSD.DESIGN:In a retrospective case-control study, we performed a statistical analysis on 151 patients and 149 matched controls using logistic regression and a Classification and Regression Tree (CART) analysis.RESULTS:The logistic regression analysis of genes and environmental factors demonstrated significant differences in the results of the Trier Inventory of Chronic Stress (TICS) questionnaire, the single nucleotide polymorphism rs1800955 of the dopamine receptor D4 and the single nucleotide polymorphism rs4818 of the enzyme catechol-O-methyltransferase between patients with MSD and healthy controls. The resulting decision tree of the CART analysis determined that the TICS questionnaire was able to differentiate patients and controls most accurately, followed by certain genotypes of the 5-hydroxytryptamine receptor 2A and a single nucleotide polymorphism of the enzyme catechol-O-methyltransferase.CONCLUSIONS:The results of the statistical analysis identified a gene-environmental interaction possibly leading to MSD. The resulting identifiers could be used as a reference to inform diagnostic algorithms to easier identify patients suffering from MSD.

Objective Patients suffering from chronic pain often present with multifactorial underlying conditions, sometimes without concrete pathological physical findings. Functional somatic syndromes (FSS) and somatoform disorders show a high prevalence of 8-20% and are often associated with adverse childhood experiences (ACE) and chronic stress. As many different FSS have overlapping symptoms, the concept of multisomatoform disorder (MSD) has been introduced as an encompassing concept. We hypothesize that a common neurohumoral profile is present in patients with MSD that is distinct from gender- and age-matched controls and thus provides insight into possible common underlying mechanisms. Design In 151 patients with MSD (138 females) and 149 matched controls (131 females), we determined ACE by the Childhood Trauma Questionnaire (CTQ) and chronic stress by the Trier Inventory for Chronic Stress (TICS). Furthermore, the serum levels of leptin, FSH, LH, cortisol, DHEA-S, and IGF-1 have been assessed. Results There were significant differences in the levels of leptin, FSH, IGF-1, and cortisol between patients and controls, mainly driven by female participants. Levels of leptin were significantly correlated with BMI in patients, in controls, and in the female subgroup. This correlation was exaggerated in female patients when compared to female controls. Both CTQ and TICS predicted MSD directly and indirectly through the levels of leptin. Conclusion There is evidence of a distinct neurohumoral profile in female patients with MSD when compared to matched healthy controls, similar to what has been demonstrated in other chronic pain states. The observed profile can be taken as possible evidence for a dysregulated response to chronic stress and metabolic balance as well as a state of hypocortisolism and HPA-axis dysfunction. ACE and chronic stress play a major role in the development of MSD and altered neurohumoral profile.

Objective. Chronic pain is a debilitating condition of multifactorial origin, often without physical findings to explain the presenting symptoms. Of the possible etiologies of persisting painful symptoms, somatoform disorders and functional somatic syndromes (FSS) are among the most challenging, with a prevalence of 8-20%. Many different somatoform disorders and FSS have overlapping symptoms, with pain being the most prevalent one. The concept of multisomatoform disorder (MSD) has been developed to acknowledge that fact. We hypothesized that the concept of MSD will be reflected in a distinct sensory profile of patients compared with healthy controls and possibly provide insight into the type and pathophysiology of the pain commonly experienced by patients. Design. We performed comprehensive quantitative sensory testing (QST) in 151 patients and 149 matched controls. Results. There were significant differences in the sensory profiles of patients compared with controls. Patients with MSD showed a combination of tactile and thermal hypesthesia combined with mechanical and cold hyperalgesia. This was true for measurements at test and control sites, with the exception of vibration detection threshold and mechanical pain threshold. Among the observed changes, a marked sensory loss of function, as evidenced by an increase in cold detection threshold, and a marked gain of function, as evidenced by a decrease of pressure pain threshold, were most notable. There was no evidence of concurrent medication influencing QST results. Conclusions. The observed somatosensory profile of patients with MSD resembles that of patients suffering from neuropathic pain with evidence of central sensitization.

Objective. Chronic pain is a debilitating condition of multifactorial origin, often without physical findings to explain the presenting symptoms. Of the possible etiologies of persisting painful symptoms, somatoform disorders and functional somatic syndromes (FSS) are among the most challenging, with a prevalence of 8-20%. Many different somatoform disorders and FSS have overlapping symptoms, with pain being the most prevalent one. The concept of multisomatoform disorder (MSD) has been developed to acknowledge that fact. We hypothesized that the concept of MSD will be reflected in a distinct sensory profile of patients compared with healthy controls and possibly provide insight into the type and pathophysiology of the pain commonly experienced by patients. Design. We performed comprehensive quantitative sensory testing (QST) in 151 patients and 149 matched controls. Results. There were significant differences in the sensory profiles of patients compared with controls. Patients with MSD showed a combination of tactile and thermal hypesthesia combined with mechanical and cold hyperalgesia. This was true for measurements at test and control sites, with the exception of vibration detection threshold and mechanical pain threshold. Among the observed changes, a marked sensory loss of function, as evidenced by an increase in cold detection threshold, and a marked gain of function, as evidenced by a decrease of pressure pain threshold, were most notable. There was no evidence of concurrent medication influencing QST results. Conclusions. The observed somatosensory profile of patients with MSD resembles that of patients suffering from neuropathic pain with evidence of central sensitization.

Introduction Complex regional pain syndrome (CRPS) is a complication following trauma or surgery and may be difficult to diagnose since biomarkers are lacking. Using protein array technology, we found antibodies binding to p29ING4, which we further characterized using ELISA. Methods Thirty-six sera of early-stage type 1 CRPS, 66 sera of rheumatoid arthritis (RA), 53 sera of axial spondyloarthritis (axSpA), 29 sera of psoriatic arthritis (PsA), 22 sera of patients after radial fractures (trauma control), and 100 sera of blood donors (BD) were analyzed for anti-p29ING4. We established ELISAs with 7 different antigens and using different secondary antibodies binding to IgG, IgG1, IgG2, IgG3, IgG4, IgA, and IgM, and 2 different tests to detect immune complexes (IC) of p29ING4 and IgG or IgG1. Results The highest likelihood ratios versus CRPS and trauma control were observed considering the A1-23 (sensitivity 19%, specificity 100%, LR > 19) using IgG as a secondary antibody, the A120-165 (sensitivity 17%, specificity 100%, LR = 17) using IgG as a secondary antibody and the A120-165 (sensitivity 31%, specificity 95%, LR = 6.2) using IgA as a secondary antibody. IC of p29ING4 and IgG were present in 11/36 (31%) CRPS sera, 17/64 (27%) RA sera, 13/53 (25%) SpA sera, 5/29 (17%) PsA sera, 1/22 (5%) trauma control sera, and 4/100 (4%) sera of BD. IC of p29ING4 and IgG1 were present in 14/36 (39%) CRPS sera, 19/64 (30%) RA sera, 13/53 (25%) SpA, 1/29 (3%) PsA, 2/22 (9%) trauma control, and 4/100 (4%) of the BD sera. Conclusion Due to the lack of other biomarkers of type 1 CRPS, P29ING4 autoantibodies could be helpful in its diagnostic work-up.

Arthrosen sind die häufigsten Gelenkerkrankungen weltweit und führen zu einer Verschlechterung der Gelenkfunktion sowie zu akuten, intermittierenden oder chronischen Gelenkschmerzen. Muskelschmerzen sind die häufigste Ursache für Beschwerden im Bewegungssystem.

Throughout Europe, chronic pain syndromes occur with a point prevalence of about 20%, with somatic, psychological, and social factors playing a significant role for their development. Therefore, a careful evaluation of the interaction of these factors is the decisive step for a successful therapy. New insights into pathophysiological processes associated with chronic pain have led to an increasing differentiation of drug and non-drug strategies. These strategies take individual factors into account and aim on influencing the neural network for chronic pain. The drugs used are chosen on the basis of pathophysiological findings and specific drug effects. Adjunctive agents are often used in the management of chronic pain. Knowledge of anti-allodynic and anti-hyperalgesic drugs such as antidepressants and anticonvulsants increases continuously and is therefore presented in more detail in the present study.

Kernaussagen Chronischer Schmerz ist multifaktoriell. Eine effiziente Arzt-Patienten-Kommunikation ist der Schlüssel zum erfolgreichen Schmerzmanagement. Kenntnisse der Schmerzphysiologie sollten Basis der Behandlungsentscheidungen sein. Der Einsatz der Medikamente sollte nach pathophysiologischen Erkenntnissen und spezifischen Medikamentenwirkungen erfolgen. Das Wissen über antihyperalgetische Wirkstoffe, wie z. B. Antidepressiva und Antikonvulsiva, nimmt beständig zu. Das Verständnis des Teufelskreises „chronischer Schmerz“ in der pharmakologischen Schmerzbehandlung ist wichtig. Ziel sollte eine mechanismenorientierte Schmerztherapie sein, die an die individuellen Bedürfnisse des Patienten angepasst wird.

INTRODUCTION:The etiology of multisomatoform disorder (MSD) is still largely unknown, but genetic factors seem to have an influence on pathogenesis. Pain is a major symptom of MSD and polymorphisms of different proinflammatory cytokines have been found associated with pain in former studies. Therefore, we presumed that cytokine polymorphisms could also be associated with MSD. PATIENTS AND METHODS:Groups of 148 MSD patients with pain as the leading clinical symptom and 149 age and gender matched healthy controls participated in this study. Nine cytokine polymorphisms were genotyped and statistically analyzed for associations with MSD. RESULTS:Allelic and genotypic associations were found for rs16944 (interleukin 1β), rs1800629 (tumor necrosis factor) and rs909253 (lymphotoxin α). After correcting for multiple testing, the association of rs1800629 with MSD remained significant. The rare A-allele was correlated with MSD (p=0.007). DISCUSSION:Since the common G-allele of rs1800629 (TNFα) occurs much more often in the control group than in the MSD group it is assumed to be protective. Being carrier of the A-allele seems to be a risk factor for MSD.

Anhand eines Fallbeispiels wird dargestellt, wie ein ambulantes, interdisziplinäres Behandlungskonzept etabliert und erfolgreich umgesetzt werden kann.

The etiology of multisomatoform disorder (MSD) is largely unknown, but an influence of genetic factors is likely. Since pain is a major component of MSD and dopamine as well as serotonin are involved in pain pathways, genes of the dopaminergic and serotonergic system are promising candidate genes and we assumed that polymorphisms could be associated with MSD. One hundred forty-nine patients with MSD and 149 age- and gender-matched healthy controls participated in this study. DNA from all participants was genotyped for 22 single nucleotide polymorphisms (SNPs) within genes of the dopaminergic and serotonergic system by polymerase chain reaction, a restriction enzyme analysis, and pyrosequencing. The distribution of SNP alleles, genotypes, and haplotypes was compared between patients and controls. Neither an allelic nor a genotypic association was found for any individual SNP, but testing for a haplotypic association revealed that a haplotype of the serotonergic genes HT(1B) and HT(1D) indicated a lower risk. However, this statistically insignificant protective effect became highly significant on the background of two DAT1 haplotypes. Interestingly, if these two DAT1 haplotypes are analyzed without considering the serotonergic genes as confounders, they are significantly associated with an enhanced risk. Taking into account observations from recent publications, this apparent contradiction might be explained with the complex interaction of the dopaminergic and serotonergic systems. To conclude, our results reveal an involvement of polymorphisms in dopaminergic and serotonergic genes in the etiology of MSD in patients of German descent, but their exact role in MSD requires further investigation.

Many extracellular factors sensitize nociceptors. Often they act simultaneously and/or sequentially on nociceptive neurons. We investigated if stimulation of the protein kinase C epsilon (PKCε) signaling pathway influences the signaling of a subsequent sensitizing stimulus. Central in activation of PKCs is their transient translocation to cellular membranes. We found in cultured nociceptive neurons that only a first stimulation of the PKCε signaling pathway resulted in PKCε translocation. We identified a novel inhibitory cascade to branch off upstream of PKCε, but downstream of Epac via IP3‐induced calcium release. This signaling branch actively inhibited subsequent translocation and even attenuated ongoing translocation. A second ‘sensitizing’ stimulus was rerouted from the sensitizing to the inhibitory branch of the signaling cascade. Central for the rerouting was cytoplasmic calcium increase and CaMKII activation. Accordingly, in behavioral experiments, activation of calcium stores switched sensitizing substances into desensitizing substances in a CaMKII‐dependent manner. This mechanism was also observed by in vivo C‐fiber electrophysiology corroborating the peripheral location of the switch. Thus, we conclude that the net effect of signaling in nociceptors is defined by the context of the individual cell's signaling history.

Chronische Schmerzen treten europaweit mit einer Punktprävalenz von etwa 20% häufig auf. Dabei kommt es auf dem Boden neuroplastischer Vorgänge zu einer erhöhten synaptischen Übertragungsstärke im schmerzverarbeitenden System. Diese zentrale Sensibilisierung kann als eigenständige Erkrankung gelten. Bei ihrer Entstehung spielen somatische, psychologische und soziale Faktoren in gleichberechtigter Verwobenheit eine bedeutsame Rolle. Aus diesem Grund ist eine sorgfältige Evaluation des Zusammenspiels dieser Faktoren der entscheidende Schritt für eine erfolgreiche Therapie. Idealerweise führen multimodale Ansätze zu einem erfolgreichen Therapieergebnis. Dabei sind häufig eine hohe Behandlungsdichte und viel Behandlungszeit notwendig und die Schmerzlinderung ist nicht das einzige oder erste Ziel, sondern vielmehr die erfolgreiche Integration der Symptomatologie. Neue Erkenntnisse über pathophysiologische Vorgänge, die mit chronischen Schmerzen assoziiert sind, haben zu einer zunehmenden Ausdifferenzierung medikamentöser und nicht medikamentöser Strategien geführt, die individuelle Faktoren berücksichtigen und auf die Beeinflussung des neuronalen Netzwerkes abzielen, in dem die chronischen Schmerzen codiert sind. Künftig könnten Therapieentscheidungen an neu identifizierten Biomarkern ausgerichtet werden. Definition !