[Early recognition and screening consultation: a necessary way to improve early detection and treatment in rheumatology? : Overview of the early recognition and screening consultation models for rheumatic and musculoskeletal diseases in Germany]. / Früh- und Screeningsprechstunden: Ein notwendiger Weg zur besseren Frühversorgung in der internistischen Rheumatologie? : Rheumatologische Früh- und Screeningsprechstundenmodelle in Deutschland.

In order to reduce the prognostically relevant time interval between the initial manifestation of a rheumatic and musculoskeletal disease and diagnosis as well as the consecutive initiation of an appropriate treatment, several rheumatological centers in Germany have improved the access to initial rheumatologic evaluation by establishing early recognition/screening clinics at their respective sites. Corresponding models located at Altoetting·Burghausen, Bad Pyrmont, Berlin Buch, Duesseldorf, Heidelberg, Herne, Mannheim as well as supraregional/multicenter initiatives Rheuma Rapid, RhePort and Rheuma-VOR are presented in this overview along with the respective characteristics, potential advantages and disadvantages, but also first evaluation results of several models. The aim of this publication is to promote early detection of rheumatic and musculoskeletal diseases as one of the most important challenges in current rheumatology by encouraging further rheumatologic centers and practices to launch their own early recognition/screening consultation model on the basis of aspects presented herein.

[Osteoporosis-frequent comorbidity in patients with rheumatism]. / Osteoporose ­ häufige Komorbidität bei Rheumapatienten.

Osteoporosis is one of the most frequent comorbidities in inflammatory rheumatic diseases. The immune system is substantially involved in the regulation of bone homeostasis and chronic inflammatory diseases influence this equilibrium at several levels. Besides the immunologically mediated inflammatory activity, immobility and glucocorticoid treatment are further risk factors for osteoporosis. Diagnostic and therapeutic recommendations are based on the current guidelines for osteoporosis of the Governing Body on Osteoporosis (DVO). Monitoring of the risk factors and bone mineral density testing is meaningful in each patient with a newly diagnosed rheumatic disease. In the case of a T-score ≤-1.5 a specific drug treatment with bisphosphonates, teriparatide or denosumab should be started together with optimizing preventive measures, such as reduction of glucocorticoid dosage, calcium and vitamin D intake and life style modifications. The risk of osteonecrosis of the jaw (ONJ) in patients with osteoporosis is small; however, there appears to be a significant increase in multiple vertebral fractures after discontinuation of denosumab.

[Etanercept in routine German clinical practice to treat rheumatoid arthritis patients : A one-year observational study on effectiveness, safety and health economics]. / Etanercept in der klinischen Routinebehandlung von Patienten mit rheumatoider Arthritis : Eine einjährige nichtinterventionelle Studie zur Bewertung der Wirksamkeit und Sicherheit.

BACKGROUND: The efficacy and safety of the TNF­α inhibitor etanercept (ETA) as a treatment for rheumatoid arthritis (RA) is well established by randomized controlled trials. The purpose of this study was to evaluate the benefit yielded by ETA within the regular outpatient care. PATIENTS AND METHODS: This prospective non-interventional trial included patients being treated with ETA. Data concerning efficacy, safety and life quality were collected over a period of 52 weeks. Statistical evaluation was done on a solely descriptive level. RESULTS: From 329 specialized medical centres, 4945 patients were enrolled. Of all patients, 94.4% received a co-medication for RA, additionally to their treatment with ETA. At baseline, 22.1% of all patients fulfilled the criteria for functional remission according to the Funktionsfragebogen Hannover (FFbH) questionnaire (95% CI: 21.0-23.3%); at 52 weeks, functional remission rate accounted for 41.1% (last observation carried forward [LOCF], 95% CI: 39.4-42.9%). The disease activity score (DAS) DAS28 declined from 5.4 ± 1.3 (N = 4304) to 3.3 ± 1.4 (as observed; N = 2608). EuroQol EQ-5D, a measurement of health-related life quality issues, indicated an improvement on the visual analogue scale (VAS) from 53.1 ± 21.3 mm (N = 4718) at baseline to 70.0 ± 20.5 mm (as observed; N = 3036). Generally, ETA has been tolerated well. With regard to the safety profile specified by previous studies, no meaningful deviations concerning the nature, frequency or severity of adverse events were detected. CONCLUSION: Based on a large number of patients and in a treatment context that is representative of routine outpatient care in Germany, it was confirmed that patients with RA may benefit from a treatment with ETA.

Update of the evidence based, interdisciplinary guideline for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

BACKGROUND: Uveitis in juvenile idiopathic arthritis (JIAU) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first line therapy, and disease modifying anti-rheumatic drugs (DMARDs) are commonly used. However, treatment has not been standardized. METHODS: Interdisciplinary guideline were developed with representatives from the German Ophthalmological Society, Society for Paediatric Rheumatology, Professional Association of Ophthalmologists, German Society for Rheumatology, parents' group, moderated by the Association of the Scientific Medical Societies in Germany. A systematic literature analysis in MEDLINE was performed, evidence and recommendations were graded, an algorithm for anti-inflammatory treatment and final statements were discussed in a consensus meeting (Nominal Group Technique), a preliminary draft was fine-tuned and discussed thereafter by all participants (Delphi procedure). RESULTS: Consensus was reached on recommendations, including a standardized treatment strategy according to uveitis severity in the individual patient. Thus, methotrexate shall be introduced for uveitis not responding to low-dose (≤ 2 applications/day) topical corticosteroids, and a TNFalpha antibody (preferably adalimumab) used, if uveitis inactivity is not achieved. In very severe active uveitis with uveitis-related deterioration of vision, systemic corticosteroids should be considered for bridging until DMARDs take effect. If TNFalpha antibodies fail to take effect or lose effect, another biological should be selected (tocilizumab, abatacept or rituximab). De-escalation of DMARDs should be preceded by a period of  ≥ 2 years of uveitis inactivity. CONCLUSIONS: An interdisciplinary, evidence-based treatment guideline for JIAU is presented.

[S2e guideline: treatment of rheumatoid arthritis with disease-modifying drugs]. / S2e-Leitlinie: Therapie der rheumatoiden Arthritis mit krankheitsmodifizierenden Medikamenten.

BACKGROUND: Medication-based strategies to treat rheumatoid arthritis are crucial in terms of outcome. They aim at preventing joint destruction, loss of function and disability by early and consistent inhibition of inflammatory processes. OBJECTIVE: Achieving consensus about evidence-based recommendations for the treatment of rheumatoid arthritis with disease-modifying anti-rheumatic drugs in Germany. METHODS: Following a systematic literature research, a structured process among expert rheumatologists was used to reach consensus. RESULTS: The results of the consensus process can be summed up in 6 overarching principles and 10 recommendations. There are several new issues compared to the version of 2012, such as differentiated adjustments to the therapeutic regime according to time point and extent of treatment response, the therapeutic goal of achieving remission as assessed by means of the simplified disease activity index (SDAI) as well as the potential use of targeted synthetic DMARDs (JAK inhibitors) and suggestions for a deescalating in case of achieving a sustained remission. Methotrexate still plays the central role at the beginning of the treatment and as a combination partner in the further treatment course. When treatment response to methotrexate is inadequate, either switching to or combining with another conventional synthetic DMARD is an option in the absence of unfavourable prognostic factors. Otherwise biologic or targeted synthetic DMARDs are recommended according to the algorithm. Rules for deescalating treatment with glucocorticoids and-where applicable-DMARDs give support for the management of patients who have reached a sustained remission. DISCUSSION: The new guidelines set up recommendations for RA treatment in accordance with the treat-to-target principle. Modern disease-modifying drugs, now including also JAK inhibitors, are available in an algorithm.

Efficacy and safety of nicoboxil/nonivamide ointment for the treatment of acute pain in the low back - A randomized, controlled trial.

BACKGROUND: Until now, nonivamide/nicoboxil ointment has not been tested in a randomized trial for the treatment of acute non-specific low back pain. METHODS: This phase III randomized, double-blind, active- and placebo-controlled, multi-centre trial investigated efficacy, safety and tolerability of topical nicoboxil 2.5%/nonivamide 0.4% for treatment of acute non-specific low back pain [primary endpoint: pain intensity (PI) difference between pre-dose baseline and 8 h after the first application]. RESULTS: Patients (n = 805), 18-74 years of age were treated for up to 4 days with nicoboxil 2.5%/nonivamide 0.4%, nicoboxil 2.5%, nonivamide 0.4% or placebo ointment. Pre-dose baseline pain intensity (6.6 on a 0- to 10-point numerical rating scale) was reduced by 1.049 points with placebo, by 1.428 points with nicoboxil, by 2.252 points with nonivamide and by 2.410 points with nicoboxil/nonivamide after 8 h (p < 0.0001 for nicoboxil/nonivamide vs. placebo, nicoboxil; p = 0.4171 for nicoboxil/nonivamide vs. nonivamide). At the end of treatment, the combination provided more pronounced PI reduction (3.540 points) compared with nicoboxil (2.371, p < 0.0001), nonivamide (3.074, p = 0.0259) and placebo (1.884, p < 0.0001). Low back mobility scores on Day 1 were better for the combination compared with all other treatments (p < 0.044); on Day 2-4, scores were better than for placebo and nicoboxil (p < 0.003). Patients assessed efficacy of the combination as greater than of the comparators (p ≤ 0.0129). All treatments were tolerated well. No treatment-related serious adverse events were reported. CONCLUSION: Nicoboxil/nonivamide ointment is an effective, well-tolerated medication for the treatment of acute non-specific low back pain.

[Diagnosis and treatment of Lyme arthritis. Recommendations of the Pharmacotherapy Commission of the Deutsche Gesellschaft für Rheumatologie (German Society for Rheumatology)]. / Diagnostik und Therapie der Lyme-Arthritis. Empfehlungen der Kommission Pharmakotherapie der DGRh.

These guidelines summarize the current evidence for diagnosis and treatment of Lyme arthritis and the most frequent skin manifestations of Borrelia burgdorferi infections. Lyme arthritis is a monoarticular or oligoarticular form of arthritis that typically involves the knee. A positive enzyme-linked immunosorbent assay (ELISA) for IgG antibodies should be followed by an IgG immunoblot. A positive PCR test from synovial fluid adds increased diagnostic certainty. Serum positivity for antibodies to Borrelia burgdorferi without typical symptoms does not justify antibiotic treatment. Oral antibiotic treatment for erythema migrans is recommended using doxycycline, 200 mg once per day for 10-21 days, alternative choices are amoxicillin, cefuroxime and azithromycin. For children below 8 years of age, amoxicillin is recommended.Lyme arthritis can usually be successfully treated with orally administered antimicrobial agents. Doxycycline, 1 × 200 or 2 × 100 mg for 30 days is the antibiotic agent of choice. Amoxicillin (3 × 500-1000 mg) can be alternatively chosen. Patients who have persistent or recurrent joint swelling after a recommended course of oral antibiotic therapy should be treated intravenously. In this situation, ceftriaxone at 2 g per day for 14-21 days is recommended. There is no evidence to recommend long-term and combined treatments.

Association of extended interleukin-10 promoter haplotypes with disease susceptibility and manifestations in German patients with systemic lupus erythematosus.

OBJECTIVES: Associations of interleukin-10 (IL-10) promoter single nucleotide polymorphisms (SNPs) and their haplotypes with systemic lupus erythematosus (SLE) are unclear. We extended the analysis of established proximal IL-10 promoter haplotypes to a more distal SNP with functional capacity. METHODS: Two hundred and ten German caucasian SLE patients fulfilling the ACR criteria and 160 ethnically, age and sex matched controls were genotyped for IL-10 -2849 G > A, -1082 A > G, -819 T > C and -592 C > A. Haplotypes were reconstructed via a mathematical model, then allele and haplotype distributions were compared between patients and controls and patients with different disease manifestations. RESULTS: We detected at -2849, -1082, -819 and -592 the four predominant haplotypes GGCC (22% in patients vs. 29% in controls), AGCC (24% vs. 21%), GACC (30% vs. 25%) and GATA (24% vs. 24%). GGCC was underrepresented in SLE patients, suggesting a protective effect (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.48-0.94). AGCC was found significantly more frequently in patients with pathognomonic anti-dsDNA antibodies (26% vs. 15%; OR 1.98, 95% CI 1.04-3.75). As compared to patients with glomerulonephritis type V (WHO classification), the presumptive IL-10 high producer allele -2849 G was found significantly more often in patients with GN type III/IV (93% vs. 60%; OR 8.7, 95% CI 1.59-47.15). CONCLUSION: Our data confirm that the complexity of the IL-10 promoter evokes the need for a meticulous analysis of its haplotypic structure in order to specify disease associations, particularly under functional aspects, thereby shedding light on the pathophysiology of SLE.

[German 2012 guidelines for the sequential medical treatment of rheumatoid arthritis. Adapted EULAR recommendations and updated treatment algorithm]. / S1-Leitlinie der DGRh zur sequenziellen medikamentösen Therapie der rheumatoiden Arthritis 2012. Adaptierte EULAR-Empfehlungen und aktualisierter Therapiealgorithmus.

Following the EULAR recommendations published in 2010 German guidelines for the medical treatment of rheumatoid arthritis were developed based on an update of the systematic literature search and expert consensus. Methotrexate is the standard treatment option at the time of diagnosis, preferably in combination with low dose glucocorticoids. Combined disease-modifying antirheumatic drugs (DMARD) therapy should be considered in patients not responding within 12 weeks. Treatment with biologicals should be initiated in patients with persistent high activity no later than 6 months after conventional treatment and in exceptional situations (e.g. early destruction or unfavorable prognosis) even earlier. If treatment with biologicals remains ineffective, changing to another biological is recommended after 3-6 months. In cases of long-standing remission a controlled reduction of medical treatment can be considered.

[Biologicals 2012]. / Biologika 2012.

Therapy with biologicals for the management of rheumatic diseases has improved treatment options and dramatically increased expectations of patients and doctors. Remission is a reasonable therapeutic aim, as well as inhibition of progression of structural damage. In 2012, five TNF-α inhibitors and four other biologicals targeted against Il-1, IL-6, B-lymphocytes and cell-cell interaction, have become available. Safety data for biological therapy are reassuring, based on a large amount of study data and data collected from national registries. The most important side-effect is a slightly increased tendency to infections (up to doubled in the first treatment year, depending on other factors such as previous infections and comorbidities). An increased risk for cancer (with the exception of preliminary data supporting a possible increase of skin cancer) has not been observed for patients treated with anti-TNF-α. Screening for tuberculosis as well as completing of vaccinations is necessary before starting treatment.

Cerebral mechanisms of experimental hyperalgesia in fibromyalgia.

The present study examined the hyperresponsiveness of the central nervous system in patients with fibromyalgia syndrome (FMS) related to mechanical hyperalgesia. The goals were to differentiate between increased pain ratings and hyperalgesia related either to peripheral or to central sensitization and to correlate with cerebral activation pattern. Seventeen patients and 17 healthy controls were examined, placing an experimental incision in the right volar forearm and causing tonic pain. Experimental pain, primary and secondary hyperalgesia were assessed during the time course of the experimental pain, and the changes in hyperalgesia were correlated to brain activation (functional magnetic resonance imaging). Patients with FMS experienced the experimental pain during the time course as more painful than healthy controls (F(score) = 3.93, p(score) = 0.008). While they did not present a different course of primary hyperalgesia (F(score) = 1.01, p(score) = 0.40), they did show greater secondary hyperalgesia (F(score) = 5.45, p(score) = 0.004). In patients with FMS, the cerebral pattern corresponding to secondary hyperalgesia was altered. The activity in the dorsolateral prefrontal cortex was inversely correlated with secondary hyperalgesia in healthy controls (R = -0.34 p = 0.005); in patients, this correlation was disrupted (R = 0.19 p = 0.12). These findings point to an alteration of pain transmission at the central level in FMS (e.g., loss of inhibition) and might be related to changes in cerebral-midbrain-spinal mechanisms of pain inhibition.

Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

Uveitis in juvenile idiopathic arthritis (JIA) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first-choice therapy, and immunosuppression is commonly used. However, treatment has not been standardized. Representatives from the German Ophthalmological Society, Society for Childhood and Adolescent Rheumatology, and the German Society for Rheumatology reached consensus on a standardized treatment strategy according to disease severity in the individual patient. The recommendations were based on a systematic literature analysis in MEDLINE and consensus expert meetings. Evidence and recommendations were graded, and an algorithm for anti-inflammatory treatment and final statements confirmed in a Delphi method. An interdisciplinary, evidence-based treatment guideline for JIA uveitis is presented.

[Recommendations of the German rheumatology society on the use of tocilizumab in rheumatoid arthritis]. / Empfehlungen der Deutschen Gesellschaft für Rheumatologie zum Einsatz von Tocilizumab bei der rheumatoiden Arthritis (Februar 2010).

The humanized anti-IL-6 receptor monoclonal antibody tocilizumab (TCZ) represents a new therapy approach for moderately severe to severe cases of rheumatoid arthritis (RA). The IL-6 concentration in the synovial fluid and peripheral circulation of patients with RA is elevated. TCZ recognises the IL-6 binding site of human IL-6R and blocks the IL-6 signaling pathway. TCZ is capable of correcting a multitude of pathological processes in RA, as has been shown in a number of studies. TCZ treatment should be combined with methotrexate. If the latter cannot be administered, TCZ can also be used as a monotherapy. The recommended dose is 8 mg/kg once every 4 weeks; the minimum dose per infusion is 480 mg. Close monitoring, in particular for infectious complications, is necessary. Clinical effects of TCZ are usually seen several weeks following initiation of therapy. If no significant clinical response is seen within 6 months, TCZ therapy should be ceased.

[Recommendations on therapy using interleukin-1beta-blocking agents]. / Empfehlungen zur Therapie mit Interleukin-1beta-blockierenden Wirkstoffen.

In Germany, the only available interleukin-1beta (IL-1beta) blocking agent is anakinra (ANR) (as of August 2009) which is given subcutaneously at a dosage of 100 mg/day (adults) and 1-2 mg/kg body weight/day (maximum 100 mg/day) (children), respectively. Based on published data and clinical experience the German Society of Rheumatology (Deutsche Gesellschaft für Rheumatologie) recommends the following indications for ANR: (1) Rheumatoid arthritis, if treatment with two DMARDs (one of the two being methotrexate, MTX) for at least 6 months has failed. (2) Adult-onset and juvenile-onset Still's disease (systemic juvenile idiopathic arthritis) in the case of insufficient response to glucocorticoids or inadequate long-term dosage, as well as failure of a conventional DMARD, usually MTX. For both indications the treatment should be supervised and documented by a rheumatologist or paediatric rheumatologist. Cryopyrin-associated periodic syndromes (CAPS) are recommended as an additional treatment option for IL-1 blocking therapy. The efficacy of the fusion protein rilonacept (RIC) and the monoclonal antibody canakinumab in the treatment of CAPS has been proven by randomized, placebo-controlled trials. In the US, RIL was recently approved by the FDA for the treatment of CAPS under the "Orphan Drug Status".

[Leg ulcer in mixed connective tissue disease. Resolution during sitaxsentan therapy]. / Unterschenkelulzera bei Sharp-Syndrom. Abheilung unter Sitaxentan.

Leg ulcers may result in serious morbidity in patients with connective tissue diseases and Raynaud's phenomenon (RP). We describe a 35-year-old woman with mixed connective tissue disease who suffered from leg ulcers refractory to iloprost. When the patient was treated with the selective endothelin A receptor antagonist sitaxsentan for pulmonary arterial hypertension, the ulcers improved within 4 weeks and resolved completely thereafter. In addition, severity of RP ameliorated markedly. Further evaluation of sitaxsentan in patients with connective tissue diseases suffering from ischemic skin ulcers is required.

Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine versus etanercept alone in patients with rheumatoid arthritis: a double-blind randomised 2-year study.

OBJECTIVE: To determine the efficacy and safety of etanercept and etanercept plus sulfasalazine versus sulfasalazine in patients with rheumatoid arthritis (RA) despite sulfasalazine therapy. METHODS: Patients were randomly assigned to etanercept (25 mg twice weekly; sulfasalazine was discontinued at baseline), etanercept plus sulfasalazine (unchanged regimen of 2-3 g/day) or sulfasalazine in a double-blind, randomised, 2-year study in adult patients with active RA despite sulfasalazine therapy. Efficacy was assessed using the American College of Rheumatology criteria, disease activity scores (DAS) and patient-reported outcomes (PRO). RESULTS: Demographic variables and baseline disease characteristics were comparable among treatment groups; mean DAS 5.1, 5.2 and 5.1 for etanercept (n = 103), etanercept plus sulfasalazine (n = 101) and sulfasalazine (n = 50), respectively. Withdrawal due to lack of efficacy was highest with sulfasalazine (26 (52%) vs 6 (6%) for either etanercept group, p<0.001). Patients receiving etanercept or etanercept plus sulfasalazine had a more rapid initial response, which was sustained at 2 years, than those receiving sulfasalazine: mean DAS 2.8, 2.5 versus 4.5, respectively (p<0.05); ACR 20 response was achieved by 67%, 77% versus 34% of patients, respectively (p<0.01) Overall, PRO followed a similar pattern; a clinically significant improvement in health assessment questionnaire was achieved by 76%, 78% versus 40% of patients, respectively (p<0.01). Commonly reported adverse events occurring in the etanercept groups were injection site reactions and pharyngitis/laryngitis (p<0.01). CONCLUSION: Etanercept and etanercept plus sulfasalazine are efficacious for the long-term management of patients with RA. The addition of etanercept or substitution with etanercept should be considered as treatment options for patients not adequately responding to sulfasalazine.