Tumor necrosis factor receptor signaling in keratinocytes triggers interleukin-24-dependent psoriasis-like skin inflammation in mice.

Psoriasis is a common chronic inflammatory skin disease with a prevalence of about 2% in the Caucasian population. Tumor necrosis factor (TNF) plays an essential role in the pathogenesis of psoriasis, but its mechanism of action remains poorly understood. Here we report that the development of psoriasis-like skin inflammation in mice with epidermis-specific inhibition of the transcription factor NF-κB was triggered by TNF receptor 1 (TNFR1)-dependent upregulation of interleukin-24 (IL-24) and activation of signal transducer and activator of transcription 3 (STAT3) signaling in keratinocytes. IL-24 was strongly expressed in human psoriatic epidermis, and pharmacological inhibition of NF-κB increased IL-24 expression in TNF-stimulated human primary keratinocytes, suggesting that this mechanism is relevant for human psoriasis. Therefore, our results expand current views on psoriasis pathogenesis by revealing a new keratinocyte-intrinsic mechanism that links TNFR1, NF-κB, ERK, IL-24, IL-22R1, and STAT3 signaling to disease initiation.

The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation.

Epidermal keratinocytes provide an essential structural and immunological barrier forming the first line of defense against potentially pathogenic microorganisms. Mechanisms regulating barrier integrity and innate immune responses in the epidermis are important for the maintenance of skin immune homeostasis and the pathogenesis of inflammatory skin diseases. Here, we show that epidermal keratinocyte-restricted deficiency of the adaptor protein FADD (FADD(E-KO)) induced severe inflammatory skin lesions in mice. The development of skin inflammation in FADD(E-KO) mice was triggered by RIP kinase 3 (RIP3)-mediated programmed necrosis (termed necroptosis) of FADD-deficient keratinocytes, which was partly dependent on the deubiquitinating enzyme CYLD and tumor necrosis factor (TNF)-TNF receptor 1 signaling. Collectively, our findings provide an in vivo experimental paradigm that regulation of necroptosis in keratinocytes is important for the maintenance of immune homeostasis and the prevention of chronic inflammation in the skin.

A function for Rac1 in the terminal differentiation and pigmentation of hair.

The small GTPase Rac1 is ubiquitously expressed in proliferating and differentiating layers of the epidermis and hair follicles. Previously, Rac1 was shown to regulate stem cell behaviour in these compartments. We have asked whether Rac1 has, in addition, a specific, stem-cell-independent function in the regulation of terminal hair follicle differentiation. To address this, we have expressed a constitutively active mutant of Rac1, L61Rac1, only in the basal epidermal layer and outer root sheath of mice possessing an epidermis-specific deletion of endogenous Rac1, which experience severe hair loss. The resulting 'rescue' mice exhibited a hair coat throughout their lives. Therefore, expression of Rac1 activity in the keratin-14-positive compartment of the skin is sufficient for the formation of hair follicles and hair in normal quantities. The quality of hair formed in rescue mice was, however, not normal. Rescue mice showed a grey, dull hair coat, whereas that of wild-type and L61Rac1-transgenic mice was black and shiny. Hair analysis in rescue mice revealed altered structures of the hair shaft and the cuticle and disturbed organization of medulla cells and pigment distribution. Disorganization of medulla cells correlates with the absence of cortical, keratin-filled spikes that normally protrude from the cortex into the medulla. The desmosomal cadherin Dsc2, which normally decorates these protrusions, was found to be reduced or absent in the hair of rescue mice. Our study demonstrates regulatory functions for Rac1 in the formation of hair structure and pigmentation and thereby identifies, for the first time, a role for Rac1 in terminal differentiation.

CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair.

Monocytes/macrophages are critical in orchestrating the tissue-repair response. However, the mechanisms that govern macrophage regenerative activities during the sequential phases of repair are largely unknown. In the present study, we examined the dynamics and functions of diverse monocyte/macrophage phenotypes during the sequential stages of skin repair. By combining the analysis of a new CCR2-eGFP reporter mouse model with conditional mouse mutants defective in myeloid cell-restricted CCR2 signaling or VEGF-A synthesis, we show herein that among the large number of inflammatory CCR2(+)Ly6C(+) macrophages that dominate the early stage of repair, only a small fraction strongly expresses VEGF-A that has nonredundant functions for the induction of vascular sprouts. The switch of macrophage-derived VEGF-A during the early stage of tissue growth toward epidermal-derived VEGF-A during the late stage of tissue maturation was critical to achieving physiologic tissue vascularization and healing progression. The results of the present study provide new mechanistic insights into CCR2-mediated recruitment of blood monocyte subsets into damaged tissue, the dynamics and functional consequences of macrophage plasticity during the sequential repair phases, and the complementary role of macrophage-derived VEGF-A in coordinating effective tissue growth and vascularization in the context of tissue-resident wound cells. Our findings may be relevant for novel monocyte-based therapies to promote tissue vascularization.

Normal epidermal differentiation but impaired skin-barrier formation upon keratinocyte-restricted IKK1 ablation.

The kinase IKK1 (also known as IKKalpha) was previously reported to regulate epidermal development and skeletal morphogenesis by acting in keratinocytes to induce their differentiation in an NF-kappaB independent manner. Here, we show that mice with epidermal keratinocyte-specific IKK1 ablation (hereafter referred to as IKK1(EKO)) develop a normally differentiated stratified epidermis, demonstrating that the function of IKK1 in inducing epidermal differentiation is not keratinocyte-autonomous. Despite normal epidermal stratification, the IKK1(EKO) mice display impaired epidermal-barrier function and increased transepidermal water loss, due to defects in stratum corneum lipid composition and in epidermal tight junctions. These defects are caused by the deregulation of retinoic acid target genes, encoding key lipid modifying enzymes and tight junction proteins, in the IKK1-deficient epidermis. Furthermore, we show that IKK1-deficient cells display impaired retinoic acid-induced gene transcription, and that IKK1 is recruited to the promoters of retinoic acid-regulated genes, suggesting that one mechanism by which IKK1 controls epidermal-barrier formation is by regulating the expression of retinoic acid receptor target genes in keratinocytes.

Accuracy of retrospective pain measurement in patients with chronic pain.

The use of pain scales that refer to a past time period is thereby based on the assumption that patients accurately remember their 'average', 'greatest' and 'least' pain. The present study addresses the validity of numerical pain rating scales that refer to a past period of time (herein, the past 7 days). Routine data from 94 patients with chronic pain were retrospectively analysed. Pain questionnaire data on the greatest, least and average pain during the past week and on current pain were compared with the mean value of entries in a pain diary from the corresponding period. The retrospectively assessed average, greatest and least pain values were consistently slightly higher than the corresponding values of daily current pain measured for the studied collective of chronic pain patients. Current pain (at the time of answering the questionnaire) better represents daily currently measured pain [intraclass correlation (ICC)=0.885] than retrospective individual measurements. The greatest correlation with averaged diary data was shown by the combination of questionnaire data on average, least and current pain (ICC=0.911). The high correlations between the questionnaire and diary data support the validity of retrospective pain surveys. However, the current status influences recall. Thus, composite retrospective pain data improve with the addition of current pain.

Conservative In-Patient Treatment of Specific Back Pain Before and During the Coronavirus Disease Pandemic. / Konservative stationäre Behandlung von spezifischen Rückenschmerzen vor und während der Corona-Pandemie.

BACKGROUND: The measures taken in the coronavirus disease pandemic have had major structural and financial effects on orthopaedics and trauma surgery as many surgeries in this field. Experience Appropriate reports from non-surgical orthopaedics are not yet available. AIMS OF THE STUDY: The study aimed to provide information on the changes that occurred in a group of patients with spinal diseases undergoing conservative in-patient treatment during the coronavirus disease pandemic, with regard to the number of cases, patient structure and course of treatment. MATERIALS AND METHODS: Data from a total of 954 patients from an acute department for conservative treatment of back pain from the years 2019 and 2020 were retrospectively compared, thus allowing conclusions to be drawn about the course of in-patient conservative spinal treatment. In addition to sociodemographic data, numerical pain rating scales, scales for impairment by pain and physical function at the beginning and at the end of treatment were analysed using descriptive statistics and differentiation tests. RESULTS: The study showed a 21% reduction in the number of cases in 2020 compared with those in 2019. The patient structure has changed in terms of diagnosis groups and physical function. The values of the assessments on discharge and their pre-post differences show an almost identical pattern of treatment outcomes before and after the start of the pandemic. CONCLUSIONS: The relatively small decline in the number of in-patient admissions for the non-surgical treatment of specific spinal disorders indicates that this treatment option was also necessary in the pandemic-related crisis. With minor changes in the patient structure, comparable treatment results could be achieved.

Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation.

The lifelong self-renewal of the epidermis is driven by a progenitor cell population with high proliferative potential. To date, the upstream signals that determine this potential have remained largely elusive. Here, we find that insulin and insulin-like growth factor receptors (IR and IGF-1R) determine epidermal proliferative potential and cooperatively regulate interfollicular epidermal morphogenesis in a cell autonomous manner. Epidermal deletion of either IR or IGF-1R or both in mice progressively decreased epidermal thickness without affecting differentiation or apoptosis. Proliferation was temporarily reduced at E17.5 in the absence of IGF-1R but not IR. In contrast, clonogenic capacity was impaired in both IR- and IGF-1R-deficient primary keratinocytes, concomitant with an in vivo loss of keratin 15. Together with a reduction in label-retaining cells in the interfollicular epidermis, this suggests that IR/IGF-1R regulate progenitor cells. The expression of dominant active Rac rescued clonogenic potential of IR/IGF-1R-negative keratinocytes and reversed epidermal thinning in vivo. Our results identify the small GTPase Rac as a key target of epidermal IR/IGF-1R signalling crucial for proliferative potential and interfollicular morphogenesis.

Clinical Relevance of Changes in Pain Intensity in Patients with Specific Back Pain. / Klinische Bedeutung von Veränderungen der Schmerzstärke bei Patienten mit spezifischen Rückenschmerzen.

BACKGROUND: Pain intensity is frequently measured on the 11-point numerical pain rating scale (NRS-PI), ranging from 0 (no pain) to 10 points (worst imaginable pain). However, it is difficult to interpret the clinical importance of changes from baseline to endpoint on this instrument. OBJECTIVES: To estimate the minimal detectable change (MDC) and the minimal clinically important difference (MCID) for average pain intensity in patients with specific back pain. MATERIALS AND METHODS: Data on 1232 subjects with specific back pain from a German hospital were included in this study. A score combining the patient's (PGIC) and the physician's global impression of change (CGIC) over the in-patient length of stay was used as an external criterion. A priori, we considered the score value "slightly improved" as the MCID. MDC was calculated using the standard error of measurement (SEM) and the standard deviation (SD) of the sample. MCID was estimated by the mean value of PI-NRS change in patients who self-assess as "slightly improved", and by sensitivity/specificity analyses, computed by the receiver operating characteristic method (ROC). RESULTS: MDC was 1.77. The MCS and ROC methods consistently showed an MCID of 2 for the total sample. Both methods showed the dependence of the MCID on the initial pain: 1 for mild to moderate pain at baseline (1 - 4 NRS points), 2 for moderate to severe pain (5 - 7) and 3 - 4 for very severe to extreme pain (8 - 10). For patients with lumbosacral intervertebral disc disorders and patients in the acute phase (duration of pain < 6 weeks), the ROC method resulted in a higher limit than the MCS method. CONCLUSIONS: In order to facilitate the interpretation of changes and to take into account the patient's perspective, the global assessment of the success of treatment should be used as an anchor criterion. In addition to dealing with pain measurement, function-related and psychosocial aspects of pain symptoms should be kept in mind.

Auditing Practices of the Medical Service Regarding Hospitalizations of Patients With a Secondary Diagnosis of Obesity.

BACKGROUND: It has been observed that the Medical Service (Medizinischer Dienst, an auditing body of the German statutory health insurance system) is more likely to audit the bill for a hospitalization in a psychosomatic clinic if the patient carries a secondary diagnosis of obesity. METHODS: In an exploratory study, we retrospectively analyzed 771 datasets collected in 2019 as part of the standard documentation of acute psychosomatic hospitalizations. RESULTS: In 2019, the Medical Service audited bills for psychosomatic hospital - izations much more often in obese than in non-obese patients (odds ratio [OR] 2.499; 95% confidence interval [1.69; 3.69]). This was accounted for by a very high audit rate for patients with a secondary diagnosis of grade 3 obesity (OR = 3.972 [2.30; 6.86]). The audit categories "quality of coding" and "possible incorrect admission" were examined. CONCLUSION: Treatments of markedly obese inpatients that incurred greater expenses presumably led to a higher hospitalization audit rate as an automatic consequence of the auditing algorithms used. An unintentional statistical discrimination arose from the unjustified linkage of the audit category "quality of coding" of the secondary diagnosis (obesity) with the audit category "possible incorrect admission" with regard to the main diagnosis. Similar effects may be occurring with economically relevant secondary diagnoses in other areas of medicine as well.

Ascertaining minimal clinically meaningful changes in symptoms of depression rated by the 15-item Centre for Epidemiologic Studies Depression Scale.

RATIONALE, AIMS AND OBJECTIVES: In clinical practise and in clinical studies on depression it is important to estimate whether changes in symptomatology measured by self-rating instruments are, in fact, clinically relevant. Therefore, the aim of the study was to estimate the clinical relevance of changes on the 15-item version of the Centre for Epidemiologic Studies Depression Scale (CES-D-15) based on the concept of the minimal clinically important difference (MCID). METHODS: Data was acquired from 4781 patients with depression symptoms from a German psychosomatic hospital who have been assessed using the CES-D-15 before and after treatment. Threshold values representing the MCID were estimated on the basis of mean change scores and sensitivity/specificity analyses. Patients' global impression of change, clinical (therapists') global impression of change and change in impairment severity were used as external anchor criteria. RESULTS: On average, the MCID was represented by a reduction of approximately 11 points in the CES-D-15, irrespective of age, gender, type of treatment and first or secondary diagnosis. However, higher baseline scores in the CES-D-15 required larger changes of raw values to represent a clinically important difference. CONCLUSIONS: Anchor-based values are suggested here as an estimation of the clinical relevance of changes in the CES-D-15. Thus, instead of relying solely on effect sizes, the evaluation of treatment outcomes should be supplemented by reporting the percentage of patients who have reached the MCID. Further examinations to verify our results in other patient populations and with other types of anchor criteria will be needed.

ALX4 dysfunction disrupts craniofacial and epidermal development.

Genetic control of craniofacial morphogenesis requires a complex interaction of numerous genes encoding factors essential for patterning and differentiation. We present two Turkish families with a new autosomal recessive frontofacial dysostosis syndrome characterized by total alopecia, a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, hypogonadism, callosal body agenesis and mental retardation. Using homozygosity mapping, we mapped the entity to chromosome 11p11.2-q12.3 and subsequently identified a homozygous c.793C-->T nonsense mutation in the human ortholog of the mouse aristaless-like homeobox 4 (ALX4) gene. This mutation is predicted to result in a premature stop codon (p.R265X) of ALX4 truncating 146 amino acids of the protein including a part of the highly conserved homeodomain and the C-terminal paired tail domain. Although the RNA is stable and not degraded by nonsense-mediated RNA decay, the mutant protein is likely to be non-functional. In a skin biopsy of an affected individual, we observed a hypomorphic interfollicular epidermis with reduced suprabasal layers associated with impaired interfollicular epidermal differentiation. Hair follicle-like structures were present but showed altered differentiation. Our data indicate that ALX4 plays a critical role both in craniofacial development as in skin and hair follicle development in human.

Impact of Rac1 and Cdc42 signaling during early herpes simplex virus type 1 infection of keratinocytes.

Keratinocytes of the skin or mucosa are the primary entry portals for herpes simplex virus type 1 (HSV-1) in vivo. We hypothesized that dynamics of cell motility and adhesion contribute to the initial steps of HSV-1 infection of epithelial cells, and thus, we investigated the impact of Rac1 and Cdc42, which serve as key regulators of actin dynamics. Measurement of endogenous Rac1 and Cdc42 in the human keratinocyte cell line HaCaT indicated temporary changes in activity levels of Rac1/Cdc42 upon HSV-1 infection. Overexpression of Rac1/Cdc42 mutants in HaCaT cells demonstrated a decrease of infection efficiency with constitutively active Rac1 or Cdc42, while dominant-negative Rac1 had no effect. Accordingly, we addressed whether the absence of Rac1 and/or Cdc42 influenced infection, and we performed RNA interference studies. Both in HaCaT cells and in primary human keratinocytes, reduction of Rac1 and/or Cdc42 did not suppress infection. When mouse epidermis was infected ex vivo, we observed early HSV-1 infection in basal keratinocytes. Similar results were obtained upon infection of mouse epidermis with a keratinocyte-restricted deletion of the rac1 gene, indicating no inhibitory effect on HSV-1 infection in the absence of Rac1. Our results suggest that HSV-1 infection of keratinocytes does not depend on pathways involving Rac1 and Cdc42 and that constitutively active Rac1 and Cdc42 have the potential to interfere with HSV-1 infectivity.

Tumor immune escape by the loss of homeostatic chemokine expression.

The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)-Ras-MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo, precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR-Ras signaling pathways in keratinocyte-derived malignancies. In vitro, exogenous stimulation of the EGFR-Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.

Pathogenic role for skin macrophages in a mouse model of keratinocyte-induced psoriasis-like skin inflammation.

Psoriasis is a common skin disease, the pathogenesis of which has not yet been resolved. In mice, epidermis-specific deletion of inhibitor of NF-kappaB (IkappaB) kinase 2 (IKK2) results in a skin phenotype that mimics human psoriasis in several aspects. Like psoriasis, this skin disease shows pronounced improvement when mice are treated with a TNF-neutralizing agent. We have found previously that this phenotype does not depend on the presence of alphabeta T lymphocytes. In order to evaluate contributions of other immune cell populations to the skin disease, we selectively eliminated macrophages and granulocytes from the skin of mice with epidermis-specific deletion of IKK2 (K14-Cre-IKK2fl/fl mice). Elimination of skin macrophages by subcutaneous injection of clodronate liposomes was accompanied by inhibition of granulocyte migration into the skin and resulted in a dramatic attenuation of psoriasis-like skin changes. The hyperproliferative, inflammatory skin disease in K14-Cre-IKK2fl/fl mice was a direct consequence of the presence of macrophages in the skin, as targeted deletion of CD18, which prevented accumulation of granulocytes but not macrophages, did not lead to major changes in the phenotype. Targeted deletion of the receptor for IFN-gamma revealed that the pathogenesis of the skin disease does not depend on classical IFN-gamma-mediated macrophage activation. Our results demonstrate that in mice epidermal keratinocytes can initiate a hyperproliferative, inflammatory, IFN-gamma-independent, psoriasis-like skin disease whose development requires essential contributions from skin macrophages but not from granulocytes or alphabeta T lymphocytes.

Activated macrophages are essential in a murine model for T cell-mediated chronic psoriasiform skin inflammation.

The CD18 hypomorphic (CD18hypo) PL/J mouse model clinically resembling human psoriasis is characterized by reduced expression of the common chain of beta2 integrins (CD11/CD18) to only 2-16% of WT levels. Previously we found that this chronic psoriasiform skin inflammation also depends on the presence of CD4+ T cells. Herein we investigated the role of macrophages in this CD18hypo mouse model. Activated macrophages were significantly increased in lesional skin as well as in inflamed skin draining lymph nodes (DLNs) of affected CD18hypo mice and were identified as being an important source of TNF-alpha in vivo. Both depletion of macrophages and neutralization of TNF-alpha resulted in a significant alleviation of psoriasiform skin inflammation. As monocyte chemotactic protein 1 was enhanced in lesional skin of affected CD18hypo mice, we intradermally injected recombinant murine monocyte chemotactic protein-1 (rJE/MCP-1) alone or in combination with rTNF-alpha into the skin of healthy CD18hypo mice. Only simultaneous injection of rJE/MCP-1 and rTNF-alpha, but neither substance alone, resulted in the induction of psoriasiform skin inflammation around the injection sites with recruitment and activation of macrophages. Collectively, our data suggest that maintenance of psoriasiform skin inflammation critically depends on efficient recruitment and activation of macrophages with sufficient release of TNF-alpha.

Rac1 is crucial for hair follicle integrity but is not essential for maintenance of the epidermis.

Rac1 is a small GTPase that regulates the actin cytoskeleton but also other cellular processes. To investigate the function of Rac1 in skin, we generated mice with a keratinocyte-restricted deletion of the rac1 gene. Rac1-deficient mice lost nearly all of their hair within a few weeks after birth. The nonpermanent part of mutant hair follicles developed constrictions; lost expression of hair follicle-specific keratins, E-cadherin, and alpha6 integrin; and was eventually removed by macrophages. The permanent part of hair follicles and the sebaceous glands were maintained, but no regrowth of full-length hair follicles was observed. In the skin of mutant mice, epidermal keratinocytes showed normal differentiation, proliferation, cell-cell contacts, and basement membrane deposition, demonstrating no obvious defects of Rac1-deficient epidermis in vivo. In vitro, Rac1-null keratinocytes displayed a strong spreading defect and slightly impaired adhesion. These data show that Rac1 plays an important role in sustaining the integrity of the lower part of hair follicles but not in maintenance of the epidermis.

A comparison of mycophenolate mofetil with ciclosporine for the treatment of chronic plaque-type psoriasis.

AIMS: To compare the efficacy of ciclosporine (CsA) versus mycophenolate mofetil (MMF) in psoriasis, a randomized trial was conducted. METHODS: A prospective multicenter randomized open-label clinical trial was performed to compare two parallel groups of patients with chronic plaque psoriasis undergoing different treatments. Therefore, a total of 54 patients with psoriasis were randomly assigned to treatment with either CsA (2.5 mg/kg body weight) or MMF (2 g daily) for 12 weeks, and the drug doses were adjusted according to response. The psoriasis area and severity index (PASI) was used to assess the clinical severity of psoriasis. The primary outcome of this trial was the time to disease relapse. Safety, PASI scores and psoriasis disability index (PDI) were assessed as secondary outcome. RESULTS: There was no difference in time to disease relapse between the two groups. After 12 weeks of treatment, the mean PASI score (+/-SD) decreased from 24.6 +/- 11.1 to 6.6 +/- 7.3 in the CsA group (n = 27) and from 22.4 +/- 9.2 to 10.6 +/- 6.7 in the MMF group (n = 27; p = 0.02). The side effects, time to remission and PDI were similar in both groups. CONCLUSIONS: After 12 weeks, CsA demonstrated a significantly superior efficacy in psoriasis compared to MMF.

[Evaluation of Inpatient Conservative Management of Acute, Subacute, and Chronic Back Pain]. / Evaluation einer stationären nicht operativen Behandlung von akuten, subakuten und chronischen Rückenschmerzen.

BACKGROUND: Backache is very common in the German population. It is a common reason for people to seek medical advice and specific back pain programs have been developed. The intention of this study is to evaluate the short and long term effects of conservative management of back pain in a German general hospital. Outcomes of interest were pain intensity, interference in daily functions, physical functioning and health related quality of life. PATIENTS AND METHODS: We examined 1010 patients with acute, subacute and chronic back pain, admitted to inpatient nonsurgical interventional therapy in a German hospital between July 2013 and July 2015. Outcomes were assessed at the end of the inpatient treatment and at 3, 6 and 12 months follow-up, using Numerical Rating Scales (NRS) for pain and daily function, the Hannover Ability Questionnaire for Measuring Back Pain-Related Functional Limitations (FFbH - R) and the German Version of the EuroQol Questionnaire (EQ-5D) for measuring health-related quality of life. The baseline questionnaire also included questions on the risk of developing long-term disability following back pain (HKF-R 10) for acute and subacute cases and the Mainz Pain Staging System (MPSS) for patients with chronic back pain. The return rate was 54% after 3 months, 38% after 6 months and 27% at 12 months follow-up. The results from the follow-up measurements (T2 - T5) were compared to the pre-treatment results (T1). Because of missing or insufficiently normal distributions nonparametric paired Wilcoxon tests were used to test differences over time for each variable. Level of significance was adjusted for multiple testing. In addition, effect sizes were computed to estimate the clinical relevance of statistically significant results. RESULTS: Pain intensity and impact of pain on daily function were significantly lower at the end of the inpatient treatment (T2). The results remained largely stable at the 3, 6 and 12 month follow-ups. Significant improvements were found in physical functioning and health-related quality of life. These improvements were maintained equally at the 3, 6 and 12 month follow-ups. In consequence, working ability increased during the follow-up period. Calculated effect sizes showed large effects for pain intensity, interference and quality of life (r = 0.51 to 0.85) and predominately moderate effects (r = 0.45 to 0.62) for physical functioning at all measurement points. The percentage of patients who had an operation due to continuing back pain after conservative treatment was 7.8, 9.9, and 12.3 at the 3, 6, and 12 month follow-ups, respectively. CONCLUSION: Persistent effects of inpatient conservative treatment of back pain were found for all outcome variables. The specific approach appears to be effective in conservative treatment programs of back pain. In the end, it's not about the alternative of surgery or conservative treatment for back pain. Treatment has to be coordinated with the patient in terms of participative decisions.