Short-term placebo response in trials of patients with symptomatic osteoarthritis: differences between hip and knee.

BACKGROUND: In placebo-controlled RCT of symptomatic treatment in osteoarthritis (OA) the extent of pain reduction is heterogeneous, the pooled effect size rather small. Pain reduction is typically higher in knee than in hip trials. The recommended trial duration is 3 months, but in knee OA the best treatment effect vs placebo is observed at 2 weeks. We hypothesized that the placebo response differs in knee vs hip OA. OBJECTIVE: We performed a meta-analysis to describe the time course of pain in placebo groups of trials in knee and hip OA over 3 months. METHODS: A systematic search of PubMed, MEDLINE and Google Scholar of placebo-controlled cox-2 inhibitor (coxib) RCT (from 1999 to 2007) of hip and knee OA was performed. Pain levels (visual analogue scale [VAS], Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) in the placebo groups at different measurement time points were extracted, expressed as weighted mean at weeks 2, 4, 6-8 and 12-13. RESULTS: Twenty-one studies included 3064 knee OA patients and 608 hip OA patients. For knee OA, pain (VAS) decreased from 15 mm at week 2, to 20 mm at week 6-8, and 21 mm at week 12-13. For hip OA patients, pain decreased by 12 mm, 14 mm and 14 mm, respectively. CONCLUSION: Pain decreased in both knee and hip OA patients treated with placebo at 2 weeks, but further decreases up to week 12 occurred only in knee OA, especially for pain VAS, resulting in a time dependent impact on the magnitude of treatment outcome. Primary endpoint pain should be assessed at 2-4 weeks.

[DGRh recommendations for the implementation of current security aspects in the NSAID treatment of musculoskeletal pain]. / DGRh-Empfehlungen zur Implementierung aktueller Sicherheitsaspekte in die NSAR-Therapie muskuloskelettaler Schmerzen.

NSAIDs exert their anti-inflammatory and analgesic effects by inhibition of COX­2, a key enzyme for proinflammatory prostanoid synthesis. Therapy with NSAIDs is limited by their typical gastrointestinal, cardiovascular and renal side effects, which are caused by inhibition of COX­1 (gastrointestinal toxicity), COX­2 (cardiovascular side effects) or both COX-isoenzymes (renal side effects). Appropriate prevention strategies should be employed in patients at risk. If gastrointestinal risk factors are present, co-administration of a proton pump inhibitor or misoprostol is recommended; in patients with cardiovascular risk, coxibs, diclofenac and high-dose ibuprofen should be avoided. Furthermore, drug interactions and contraindications should be considered. In patients with renal impairment (GFR < 30 ml/min) all NSAIDs must be avoided. Ulcer anamnesis is a contraindication for traditional NSAIDs. Preexisting cardio- or cerebrovascular diseases are contraindications for coxibs. Treatment decisions should be individually based with a continuous monitoring of the risk - benefit ratio and exploitation of non-pharmacological treatment options.

Recommendations for an update of the 2010 European regulatory guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis and reflections about related clinically relevant outcomes: expert consensus statement.

OBJECTIVE: The European Society on Clinical and Economic aspects of Osteoporosis and Osteoarthritis (ESCEO) organised a working group to evaluate the need for updating the current European guideline on clinical investigation of drugs used in the treatment of osteoarthritis (OA). DESIGN: Areas of potential attention were identified and the need for modifications, update or clarification was examined. Proposals were then developed based on literature reviews and through a consensus process. RESULTS: It was agreed that the current guideline overall still reflects the current knowledge in OA, although two possible modifications were identified. The first relates to the number and timing of measurements required as primary endpoints during clinical trials of symptom-relieving drugs, either drugs with rapid onset of action or slow acting drugs. The suggested modifications are intended to take into consideration the time related clinical need and expected time response to these drugs - i.e., a more early effect for the first category in addition to the maintenance of effect, a more continuous benefit over the long-term for the latter - in the timing of assessments. Secondly, values above which a benefit over placebo should be considered clinically relevant were considered. Based on literature reviews, the most consensual values were determined for primary endpoints of both symptom-relieving drugs (i.e., pain intensity on a visual analogue scale (VAS)) and disease-modifying drugs (i.e., radiographic joint-space narrowing). CONCLUSIONS: This working document might be considered by the European regulatory authorities in a future update of the guideline for the registration of drugs in OA.

Republished: Value of biomarkers in osteoarthritis: current status and perspectives.

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the 'omics' (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.

Value of biomarkers in osteoarthritis: current status and perspectives.

Osteoarthritis affects the whole joint structure with progressive changes in cartilage, menisci, ligaments and subchondral bone, and synovial inflammation. Biomarkers are being developed to quantify joint remodelling and disease progression. This article was prepared following a working meeting of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis convened to discuss the value of biochemical markers of matrix metabolism in drug development in osteoarthritis. The best candidates are generally molecules or molecular fragments present in cartilage, bone or synovium and may be specific to one type of joint tissue or common to them all. Many currently investigated biomarkers are associated with collagen metabolism in cartilage or bone, or aggrecan metabolism in cartilage. Other biomarkers are related to non-collagenous proteins, inflammation and/or fibrosis. Biomarkers in osteoarthritis can be categorised using the burden of disease, investigative, prognostic, efficacy of intervention, diagnostic and safety classification. There are a number of promising candidates, notably urinary C-terminal telopeptide of collagen type II and serum cartilage oligomeric protein, although none is sufficiently discriminating to differentiate between individual patients and controls (diagnostic) or between patients with different disease severities (burden of disease), predict prognosis in individuals with or without osteoarthritis (prognostic) or perform so consistently that it could function as a surrogate outcome in clinical trials (efficacy of intervention). Future avenues for research include exploration of underlying mechanisms of disease and development of new biomarkers; technological development; the 'omics' (genomics, metabolomics, proteomics and lipidomics); design of aggregate scores combining a panel of biomarkers and/or imaging markers into single diagnostic algorithms; and investigation into the relationship between biomarkers and prognosis.

Evaluation of different protocols for gene transfer into non-obese diabetes/severe combined immunodeficiency disease mouse repopulating cells.

PURPOSE: Although gene transfer with retroviral vectors has shown distinct clinical success in defined settings, efficient genetic manipulation of hematopoietic progenitor cells remains a challenge. To address this issue we have evaluated different transduction protocols and retroviral constructs in the non-obese diabetes (NOD)/severe combined immunodeficiency disease (SCID) xenograft model. METHODS: An extended transduction protocol requiring 144 h of in vitro manipulation was compared to a more conventional protocol requiring 96 h only. RESULT: While pretransplantation analysis of cells transduced with a retroviral vector, expressing the enhanced green fluorescent protein (EGFP) marker gene, demonstrated significantly higher overall transduction rates for the extended protocol (33.6 +/- 2.3 vs. 22.1 +/- 3.8%), EGFP expression in CD34+ cells before transplantation (4.0 +/- 0.9 vs. 11.6 +/- 2.5%), engraftment of human cells in NOD/SCID bone marrow 4 weeks after transplantation (4.5 +/- 1.7 vs. 36.5 +/- 9.4%) and EGFP expression in these cells (0 +/- 0 vs. 11.3 +/- 2.8%) were significantly impaired. When the 96 h protocol was used in combination with the spleen focus forming virus (SFFV)/murine embryonic stem cell (MESV) hybrid vector SFbeta11-EGFP, high transduction rates for CD45+ (41.0 +/- 5.3%) and CD34+ (38.5 +/- 3.7%) cells prior to transplantation, as well as efficient human cell engraftment in NOD/SCID mice 4 weeks after transplantation (32.4 +/- 3.5%), was detected. Transgene expression was observed in B-lymphoid (15.9 +/- 2.0%), myeloid (36.5 +/- 3.5%) and CD34+ cells (10.1 +/- 1.5%). CONCLUSION: Our data show that CD34+ cells maintained in cytokines for multiple days may differentiate and loose their capacity to contribute to the haematological reconstitution of NOD/SCID mice. In addition, the SFFV/MESV hybrid vector SFbeta11-EGFP allows efficient transduction of and gene expression in haematopoietic progenitor cells.

-Glucose, insulin and C-peptide kinetics during tocolysis with oral fenoterol-. / Glukose-, Insulin- und C-Peptid-Kinetik unter Tokolyse mit oralem Fenoterol.

OBJECTIVE: The effect of oral fenoterol therapy (40 mg/day) on the kinetics of glucose, insulin and C-peptide during an oral glucose tolerance test (oGTT; 100 g glucose) was investigated in the third trimester. METHODS: 54 patients without tocolytic therapy (25 with a pathologic oGTT) were compared with 36 patients who received tocolytic therapy (18 patients with a pathologic oGTT). RESULTS: The patients with a normal or pathologic oGTT and with or without tocolytic therapy showed no significant differences in respect of the concentrations of glucose, insulin and C-peptide. During tocolytic therapy, an early increase in insulin was observed as well as slightly elevated C-peptide concentrations and a decreased C-peptide/insulin quotient.

[GnRH analogs in gynecology. Possibilities for therapeutic use]. / GnRH-Analoga in der Gynäkologie. Therapeutische Einsatzmöglichkeiten.

Gonadotropin releasing hormone (GnRH) agonists are synthetic peptide analogues of the natural gonadotropin releasing hormone with a stronger and more prolonged effect than the natural GnRH. Repeated administration of GnRH agonists induces pituitary desensitization followed by a decrease in gonadotropin secretion and estradiol synthesis. Thus reversible hypogonadotropic hypogonadism is produced. Consequently, estrogen-dependent diseases can be treated successfully with GnRH analogues. The therapeutic results obtained in patients with endometriosis, leiomyoma, pubertas praecox, and metastatic breast cancer are discussed. Furthermore the contraceptive properties of GnRH analogues, and combination treatment with HMG to induce ovulation is reviewed.

-Obstetric prognosis after pre-eclampsia, eclampsia or HELLP syndrome-. / Geburtshilfliche Prognose nach Präeklampsie, Eklampsie under HELLP-Syndrom.

Preeclampsia, eclampsia and the HELLP syndrome are serious pregnancy complications associated with increased maternal and perinatal mortality and morbidity. The question of subsequent pregnancy outcome in these patients is of great importance for the patient and the obstetrician. The risk of recurrence of hypertensive complications during subsequent pregnancy is related to the time of the onset and the clinical signs of hypertension during the first pregnancy. Patients having hypertensive pregnancies should be examined for chronic hypertension, kidney disease and other internal diseases. The recurrence risk is for preeclampsia between 19.5% and 25.9% and for eclampsia between 21.9% and 46.8%. Patients developing the disease early in pregnancy and with chronic hypertension are at higher risk. For the HELLP syndrome the risk of recurrence is between 3% and 5%. These patients should be considered to be at increased risk for obstetric complications in subsequent pregnancies and close perinatal care is indicated in subsequent pregnancies.

[The course of hypertension in pregnancy]. / Verlaufsform der Hypertonie in der Schwangerschaft.

Pregnancy-included hypertension (PIH) and chronic hypertension are the most common medical disorders during pregnancy. They are a major cause of maternal and neonatal morbidity and mortality. Therefore a correct diagnosis and the knowledge of the classification of hypertension are necessary to choose the best treatment for the mother and the child. This review presents the guidelines for the diagnosis and management of the different forms of PIH.

[Stomach cancer and pregnancy]. / Magenkarzinom und Schwangerschaft.

The symptoms of gastric carcinoma are nonspecific and uncharacteristic especially during the pregnancy. Two cases of gastric carcinoma in pregnancy are reported. In both cases the diagnosis of the malignoma was not made in an early stage. Therefore both women died within a short period after the delivery due to the metastasis of the gastric cancer. The newborns survived the complicated pregnancy and they were born spontaneously and by cesarean section. The reasons for the delayed diagnosis and the problems of this malignoma during a pregnancy are discussed based on the own observations and the published cases.

[Differential diagnosis of seizures in the peripartal period]. / Differentialdiagnostik der Krampfanfälle im peripartalen Zeitraum.

Seizures remain an important cause of maternal morbidity and mortality during pregnancy and the puerperium. Encouraged by some cases treated in our clinic (9 cases have been observed between 29. 12. 1989 and 22.5. 1991), the management of differential diagnosis in seizures are discussed in this article. Despite all possibilities of using technical apparatus for investigations, case history and clinical examination remain the basics of diagnosis with regard to paroxysm. EEG is an important, noninvasive method for judgement of cerebral function. It can be carried out continuously as a bedside-test and is extremely helpful in the differential diagnosis of eclampsia versus epilepsia. With a view to substantial defects as a possible convulsant factor, visualised examination procedures, e.g. cranial computed tomography (CCT) and magnetic resonance imaging (MRI) are available. Especially MRI has advantages in the diagnostic procedure. It could help to find the cause of cerebral structure defects and to clear the question of aetiology. Thus, a specific therapeutic procedure might become possible.

[Acute fatty liver of pregnancy]. / Akute Schwangerschaftsfettleber.

Liver diseases in pregnancy can occur as a complication of gestation or independently. Acute fatty liver of pregnancy is a rare disease of unknown etiology specifically associated to gestation. The frequency is increased in the first pregnancy, in the last trimester and in multiple pregnancies. Because of the high maternal and perinatal mortality early diagnosis is necessary for prompt termination of pregnancy. This case report is intended to facilitate the differentiation between acute fatty liver of pregnancy and other liver diseases in pregnancy. The differential diagnoses include preeclampsia, HELLP syndrome, intrahepatic cholestasis of pregnancy and acute viral hepatitis.

[Neurofibromatosis and pregnancy]. / Neurofibromatose und Schwangerschaft.

A case of neurofibromatosis (Recklinghausen's disease) in pregnancy in a 29-year-old patient is reported. The woman has had two uncomplicated pregnancies and deliveries. The lesions of the neurofibromatosis did not change during the course of the pregnancy. However, based on the few published cases it is necessary to pay attention to hypertension or an exacerbation of the neurofibromatosis.

[Pregnancy following organ transplantation]. / Schwangerschaften nach Organtransplantation.

Pregnancies following organ transplantation are high-risk pregnancies for mother and fetus. There are many reports concerning pregnancies following renal transplantation whereas only few reports are published about pregnancies in recipients of liver, heart and bone marrow transplants. During the pregnancy after kidney transplantation pregnancy-induced hypertension can develop or the renal function can decrease. Risks for the fetus are prematurity, growth retardation and prenatal infections. A higher incidence of complications for mother and fetus is observed in patients with renal insufficiency or severe hypertension prior to conception. The risks can be reduced by an intradisciplinary cooperation of gynecologist, transplant specialist and paediatrician. The paediatrician. The experiences with pregnancies in women after organ transplantations in the Medical School of Hannover are analyzed and compared with the reports in the literature. The management of these patients is described on current state of knowledge.

[Pregnancies following kidney transplantation and in immunosuppression with cyclosporin A]. / Schwangerschaften nach Nierentransplantation und unter Immunsuppression mit Cyclosporin A.

From 1984 to 1987, offspring from six renal transplant-patients were delivered in the Department of Obstetrics and Gynaecology of the Medical School of Hannover. The patients received cyclosporine and cortisone as an immunosuppressive therapy during the pregnancies. All pregnancies ended with live births; in two cases, a caesarean section was performed. Serious congenital malformations of the newborns were not observed, only two newborns being small. In the blood of the newborns, the cyclosporine concentrations were between 85 and 65% of the maternal blood levels. In two patients, the kidney functions deteriorated significantly during and after pregnancy. An increase in blood pressure or a hypertonic crisis, however, did not occur.

[Risks of cesarean hysterectomy]. / Risiken der Kaiserschnitt-Hysterektomie.

From 1976 through 1984, 48 primary caesarean hysterectomies were performed in the Department of Obstetrics and Gynaecology of the Medical School of Hannover. The indications for the operation, the risk factors and the postoperative course were analysed and compared with a control group of patients with a Caesarean section. Caesarean hysterectomies had a higher incidence of excessive blood loss, blood transfusion and urinary tract injury, especially of the bladder. Based on this experience Caesarean hysterectomy should be performed if a valid indication is present. The operation cannot be recommended routinely for the purpose of sterilisation.

[Estriol and human placental lactogen as risk indicators in pregnancies of diabetic and hypertensive patients]. / Ostriol und Humanes Plazentares Laktogen als Risikoindikatoren in Schwangerschaften von Diabetikerinnen und Hypertonikerinnen.

The correlation between estriol (E3) and human placenta lactogen (HPL) and perinatal morbidity was investigated in 105 diabetic, 96 hypertensive and 96 pregnancies without diabetes and hypertension. The hormones were determined by radioimmunoassay. Only if two determinations were outside the normal range the values were accepted as pathological. In pregnancies with hypertension a decrease of E3- and HPL-concentrations was correlated to significant higher incidence of operative deliveries and pathological APGAR-Scores. In the diabetic group is the low E3-concentration of significant predictive value in respect of the pathological cardiotocography as the indication of the operative delivery, the same applies to low HPL-concentrations in the hypertension group, in the control group no significant differences could be determined relating thereto. Hypotrophic newborns in the hypertension and control group are significant more frequent, if the concentration of E3 is decreased. The same applies to decreased HPL-concentrations in every group, where the hypertension group shows the highest predictive values.

[Wilson disease and pregnancy. Review of the literature and case report]. / Morbus Wilson und Schwangerschaft. Literaturübersicht und kasuistische Mitteilung.

Wilson's disease is an autosomal recessive disorder of copper metabolism. Since the introduction of penicillamine treatment successful pregnancies have been reported. However little is known about the risks of breast feeding in patients on this medication. We describe the case of a patient suffering from Wilson's disease, who had two uncomplicated pregnancies and breast fed both children for a period of three months each. In the 22 year old gravida I para I the diagnosis of Wilson's disease had been previously made by liver biopsy and penicillamine therapy had been begun. At the time of her first presentation at our department she was 8 week pregnant. Her renal and liver function were normal. Neurologic or psychiatric symptoms were not observed. At 18 weeks the dosage of penicillamine was reduced from 900 mg/d to 750 mg/d. The course of the pregnancy remained uneventful. At 38 + 1 weeks a healthy boy of 3100 gm was delivered. 19 months later the patient presented again in the 16th week of her second pregnancy. Concerning Wilson's disease no major changes were observed, especially liver and renal function were not impaired. The dosage of penicillamin was reduced from 900 mg/d to 750 mg/d during the 21st week. The pregnancy again was uncomplicated and at 38 + 2 weeks resulted in the spontaneous deliver of a healthy boy, weighting 3940 gm. Both children were breast fed over a period of three months and with the exception of an icterus prolongatus no adverse effects were noted.