Combination of B cell biomarkers as independent predictors of response in patients with rheumatoid arthritis treated with rituximab.

OBJECTIVES: Identification of B cell biomarkers predictive of response prior to therapy with rituximab (RTX) and evaluation of the efficacy of long-term treatment in patients with rheumatoid arthritis (RA). METHODS: 302 RA patients failing one TNFi were treated with two applications of 1000 mg RTX (FIRST study). During the follow-up study (ReFIRST) the patients were treated for up to three more courses if they showed measurable clinical response but RA was still active. In a substudy on 154 RA patients peripheral B cell subsets were determined by flow cytometry before starting RTX. Rheumatoid factor (RF), RF-isotypes and anti-citrullinated protein antibodies (ACPA) were also measured. RESULTS: Based on multivariate analyses patients with positive RF and normal (>lower limit) levels of CD19⁺ B cells (RF⁺CD19⁺) showed better treatment effects compared to patients who had only one or none of those parameters. Considering the RF status of the patients, analysis of B cell subpopulations yielded a correlation between higher ER rates and "double negative" CD19+CD27⁻IgD⁻ B cells. Lowest ER rates were observed for RF negative patients in combination with low numbers of CD19⁺CD27⁻IgD⁻ B cells as independent risk factors, thus defining a group with lower responses. Conversely, higher CD19⁺CD27⁻IgD⁻ B cells identified a responder group within RF negative patients. CONCLUSIONS: The data of this large biomarker study suggest that beyond RF positivity, normal levels of CD19⁺ B cells together with increased CD19⁺CD27⁻IgD⁻ B cells predict response to RTX in RA, in particular when all parameters were present.

[Janus kinase inhibitors]. / Janus-Kinase-Hemmer.

Janus protein tyrosine kinase (JAK) inhibitors are new therapeutic targets in the treatment of rheumatoid arthritis. Tofacitinib has shown good clinical efficacy in phase II and III studies with American College of Rheumatology (ACR) 20 response rates over 50% for monotherapy and in combination with methotrexate (MTX). Also the safety profile shows similar infection rates as observed with known biologicals. The crude rate of serious infection events was 3/100 patient-years. Often reported adverse events are infections of the upper respiratory tract and urogenital infections.

RF positivity has substantial influence on the peripheral memory B-cell compartment and its modulation by TNF inhibition.

OBJECTIVES: The role of B cells in rheumatoid arthritis (RA) has been well established with the advent of B-cell targeted therapies. Alterations of peripheral B-cell subsets in RA and heterogeneous modulations of the B-cell compartment under tumour necrosis factor (TNF) inhibition have been described. In this study we examined the influence of rheumatoid factor (RF) positivity on the peripheral B-cell compartment and its modulation under TNF blockade. METHODS: Consecutive patients with RA and inadequate response to methotrexate (MTX) were stratified according to RF status and a subset of them was included in a prospective study of weekly etanercept treatment. RESULTS: At baseline, RF-negative patients had a significant higher percentage of overall CD27+ B cells compared to healthy controls (HC) and RF-positive patients. In detail, RF-negative patients had 46.6% (range 15.7-86.8%) CD27+ B cells compared to 31.3% (12.9-56.9%, p = 0.026) in HC and 29.8% (19-73.3%, p = 0.04) in RF-positive patients. Within the CD27+ compartment, CD27+/immunoglobulin (Ig)D+ memory B cells were significantly increased to 26.4% (range 5.9-54.7%) in RF-negative patients compared to 14.9% (4.1-27.3%, p = 0.006) in HC and 10.5% (3.4-41.1%, p = 0.003) in RF-positive patients. During anti-TNF therapy, memory B cells increased significantly in relative and absolute numbers only in RF-negative patients. CONCLUSIONS: In RF-negative patients, we observed an enhanced frequency of peripheral memory B cells and an accumulation of pre-switch memory B cells. During anti-TNF therapy, memory B cells increased significantly only in RF-negative patients, suggesting that the peripheral memory B-cell compartment is more amenable to TNF inhibition in these patients.

[Tocilizumab. What comes after TNF-blockers in clinical routine?]. / Tocilizumab. Was kommt nach TNF-Blockern im klinischen Alltag?

Tocilizumab, a monoclonal humanized antibody against IL-6, was licensed in January 2009 in combination with Methotrexate for the treatment of adult patients with moderately to severely active rheumatoid arthritis and inadequate response to one or more DMARDs or TNF antagonists. Tocilizumab is given once every 4 weeks as a 60-min single intravenous infusion at a dosage of 8 mg/kg body weight and may be used as a monotherapy in the case of MTX or DMARD incompatibility. Clinical response is rapid and lasting according to clinical measurements such as ACR response rates or DAS28, irrespective of previous therapy. Within 2 weeks of the first infusion, inflammatory parameters such as CRP and ESR decline and the haemoglobin concentration increases. Adverse events often include mild respiratory infections, transient elevation in liver enzymes, decrease in neutrophile counts and increase in serum lipids. In 8% of patients a lipid lowering therapy needs to be initiated. Diverticulitis with perforation has been observed. Serious infections occur in the range known with other biological therapies. The radiological data show a reduced rate of joint destruction after 1 year of therapy. Long-term follow-up shows good clinical efficacy with an increasing percentage of patients with good clinical response and good safety profile.

[Anti-CD20 therapy in rheumatoid arthritis]. / Anti-CD20-Therapie bei rheumatoider Arthritis.

The anti-CD20 antibody Rituximab was the first B-cell-specific therapy approved for the treatment of rheumatoid arthritis patients. The basis for its approval in 2006 was the REFLEX study, which examined the administration of 1000 mg Rituximab at 2-week intervals combined with Methotrexat compared with placebo in patients with poor response to TNF-inhibitors in terms of all relevant clinical parameters. Radiological data show that Rituximab is capable of effectively arresting joint destruction. The treatment was well tolerated. The most common side effect, seen in up to 35% of patients, was infusion reactions, particularly during initial Rituximab administration. This could be reduced by approximately 30% with the use of steroid premedication. The serious infection rate in this randomised trial was slightly increased compared with the placebo group, as would also be expected for other biologicals. Data on re-treatment is currently available for up to five treatments and show sustained and/or improved efficacy with continued good tolerance.

[B-cell-targeted therapy in the treatment of autoimmune diseases]. / B-Zell-gerichtete Therapie bei Autoimmunerkrankungen.

In recent years a growing body of evidence suggests a more central role for B-cells in the pathogenesis of several autoimmune diseases, apart from being the precursors of autoantibody-producing plasma cells. B-lymphocytes play an important role in the pathogenesis of various autoimmune diseases. In particular, the introduction of rituximab, a depleting antibody targeting CD20+ B cells and its clinical efficacy in rheumatoid arthritis, systemic lupus erythematosus, vasculitis and multiple sclerosis has stimulated further B-cell-targeted therapies. Other biologicals targeting CD20 are under clinical investigation. New strategies include targeting further B-cell surface markers such as CD22, as well as blocking B-cell-activating factors or their receptors.

Post-mortem histopathological investigations of the bone marrow in forensic medicine: an important issue for both the forensic and clinical pathologist.

In the forensic literature only a few scientific reports are dealing with series of histopathological bone marrow (BM) investigations, mainly concerning changes after drug abuse and alcoholic consumption. In a period of 13 years (1995-2008) we routinely investigated 225 BM specimens from anterior iliac crests taken at forensic autopsies if the cause of death was unclear or vague, septicaemia was suspected or known, in cases of presumed haemorrhagic diathesis or bleeding tendencies, spleens were found to be enlarged or intoxications were suspected or proofed. In 78 cases (34.66%) abnormal histopathologic changes were found. Forty of those revealed neoplastic, mainly haematological diseases, which were unknown during lifetime. Referring to our findings, extraction of post-mortem BM specimens for histopathological investigations should become an essential issue for both the forensic and clinical pathologist.

Genetics of infantile seizures with paroxysmal dyskinesia: the infantile convulsions and choreoathetosis (ICCA) and ICCA-related syndromes.

The relationship between paroxysmal movement disorders (PD: paroxysmal dyskinesia) and epilepsy continues to present a challenging problem. Attacks of PD and epileptic seizures have several characteristics in common: both are paroxysmal in nature with a tendency to spontaneous remission, and a subset of PD responds well to anticonvulsants. In 1997, description of the ICCA (infantile convulsions and choreoathetosis) syndrome and linkage to chromosome 16p12-q12 provided the first genetic evidence for common mechanisms shared by benign infantile seizures and PD. The chromosome 16 ICCA locus is by far the most frequently involved in such associations as well as in pure forms of benign infantile seizures. The ICCA region at the pericentromeric area of chromosome 16 shows complicated genomic architecture and the ICCA gene still remains unknown. Genetic studies focusing on PD with or without epilepsy have led to the identification of other genes linked to chromosomes 2q35 and 10q22. Alterations of ion channel and ion pump subunits could provide a simple, albeit probably non-unique, explanation for the pathophysiology of the link between epilepsy and PD. The aim of this review is to update genetic aspects of infantile epileptic seizures and PD and their association in the context of ICCA and ICCA related syndromes.

[Acute monarthritis]. / Differenzialdiagnostik der akuten Monarthritis.

Common causes of acute monarthritis are osteoarthritis, an acute attack of gout or other crystal arthropathies in older patients or a reactive arthritis or gonococcal arthritis in younger patients. The differential diagnosis should primarily rule out septic arthritis. An arthrocentesis with a microbiological work up and a fresh specimen should be prepared for the diagnosis of crystal arthropathies and if an infectious origin is suspected or if nothing remarkable was found during the primary examination. Further diagnosis und therapy should be performed by a specialist.

Isolation of Gordonia terrae from a patient with catheter-related bacteraemia.

A cornyeform bacterium was isolated from a blood culture from a 24-year-old man with familial hypertrophic non-obstructive cardiomyopathy, chronic abuse of anabolic steroids and prior admission to hospital because of clinical signs of sepsis. 16S rRNA gene analysis unambiguously identified Gordonia terrae.

[Role of DNA microarrays in the diagnosis of pleural exudates: a feasibility study]. / Apport des puces à ADN dans le diagnostic étiologique des pleurésies: étude de faisabilité

INTRODUCTION: Establishing the cause of exudative pleural effusions is sometimes difficult, especially in the context of possible malignant pleural mesothelioma (MPM). Therefore, the development of new biological tools is necessary. The aim of this study was to determine the feasibility and the diagnostic contribution of genomic analysis of cells contained in pleural fluid, using DNA microarray techniques. METHODS: Patients with pleural effusion requiring diagnostic thoracocentesis were eligible to participate in the study. Five hundred mls of pleural fluid were then collected. RNA was extracted from pleural fluid cells and its integrity was assessed. Gene expression was studied using pangenomic DNA microarrays. RESULTS: Seventeen patients were included (4 MPM, 8 secondary malignant pleurisies, 5 benign pleurisies). Three patients offered fully exploitable samples. Taking into account the results of control experiments, gene expression study from pleural fluid was reproducible. The comparison of samples showed significant differences in gene expression. Samples from 14 patients were not exploitable because of RNA degradation. CONCLUSIONS: Gene expression study of cells from pleural fluid is feasible but remains difficult, essentially in relationship with RNA weakness.

Lethal brain abscess due to the fungus Scedosporium apiospermum (teleomorph Pseudallescheria boydii) after a near-drowning incident: case report and review of the literature.

A 39-year-old healthy man developed a brain abscess weeks after a near-drowning incident. Scedosporium apiospermum, the anamorph of Pseudallescheria boydii, was isolated from the abscess. The patient died 153 days after the accident despite antifungal therapy. We discuss the role of antifungals and review the literature for comparable cases.

Finding of a skeleton in the Altaussee Lake--a forensic odyssey.

Divers found several human bones in a lake in central Austria. As signs of blunt force trauma to the skull were detectable and one of the possible perpetrators still was alive, exact medico-legal examination was necessary. Age of the person and time since death were estimated. The residues of possible brain tissue underwent histological examination. Two of the three missing persons could be excluded, one of them using mitochondrial DNA analysis. Any pending legal proceedings could be avoided as a result of our examinations.

Rare fatal vascular complication of transsphenoidal surgery.

We report the case of a 61-year-old man, who underwent transsphenoidal surgery for a pituitary macroadenoma. The presence of tough fibrous septa dividing the tumour permitted only a partial resection. Progressive loss of consciousness soon after surgery occurred, an emergency CT scan showed no evidence of haemorrhage. Twenty hours later, MRI revealed compression of both internal carotid arteries with arrest of arterial flow resulting in stroke by an enlarged haemorrhagic mass consistent with a pituitary apoplexy. On the second postoperative day, the patient died as a result of this extensive stroke. The mechanisms of this rare complication after transsphenoidal surgery are theorized and the sensitivity of imaging methods is discussed.

Fatal truck-bicycle accident involving dragging for 45 km.

Vehicle-bicycle accidents with subsequent dragging of the rider over long distances are extremely rare. The case reported here is that of a 16-year-old mentally retarded bike rider who was run over by a truck whose driver failed to notice the accident. The legs of the victim became trapped by the rear axle of the trailer and the body was dragged over 45 km before being discovered under the parked truck. The autopsy revealed that the boy had died from the initial impact and not from the dragging injuries which had caused extensive mutilation. The reports of the technical expert and the forensic pathologist led the prosecutor to drop the case against the truck driver for manslaughter.

Sudden death from myocardial contusion following an isolated blunt force trauma to the chest.

Cardiac contusion is a common concomitant injury in blunt, non-penetrating chest trauma and is mostly a benign disorder which remains undiagnosed. In the case presented, a young man sustained a single blunt trauma to the chest from falling pieces of a wooden wheel and died at the scene. Among other findings, the autopsy revealed a circumscribed detachment of the coronary arteries on the anterior side of the heart. The most unusual findings were lacerations of the vessel wall layers in these areas which could already be seen at the autopsy and were proven by histological examination.

Cytogenetic study of six cases of radiation-induced meningiomas.

It is known that, following radiotherapy, secondary cancer may occur after a long latent period. Few cytogenetic studies have been reported on tumors of the central nervous system occurring after radiotherapy. We report the cytogenetic study of six cases of radiation-induced meningiomas. In all cases, we observed the same chromosome abnormality, der(1)(1qter-->1p11::22q12-->22pter). SKY and CGH techniques allowed us to identify the chromosomal abnormalities. We suggest that a gene localized on 1p13 is involved in radiation-induced meningiomas.