The complex clinical picture of side effects to biologicals

Biologicals are proteins used as drugs. Biologicals target clearly defined molecular structures, being part of established pathogenetic pathways. Therefore, their focused mode of action seems to render them superior to classic small molecular drugs regarding "off-target" adverse drug reactions (ADR). Nevertheless, the increasing use of biologicals for the treatment of different diseases has revealed partially unexpected adverse reactions. The often direct interaction of a biological with the immune system provides a clue to most side effects, which have consequently been subclassified, based on pathogenetic principles, into 5 subtypes named alpha, beta, gamma, delta, and epsilon, reflecting overstimulation (high cytokine values, type alpha), hypersensitivity (type beta), immune deviation (including immunodeficiency, type gamma), cross-reactivity (type delta), and nonimmune mediated side effects (type epsilon). This article presents typical clinical manifestations of these subtypes of ADR to biologicals, proposes general rules for treating them, and provides a scheme for a thorough allergological workup. This approach should help in future handling of these often very efficient drugs.

Etiology and pathogenesis of adverse drug reactions

In clinical routine, adverse drug reactions (ADR) are common, and they should be included in the differential diagnosis in all patients undergoing drug treatment. Only part of those ADR are immune-mediated hypersensitivity reactions and thus true drug allergies. Far more common are non-immune-mediated ADR, e.g. due to the pharmacological properties of the drug or to the individual predisposition of the patient (enzymopathies, cytokine dysbalance, mast cell hyperreactivity). In true drug allergiesT cell- and immunoglobulin E (lgE)-mediated reactions dominate the clinical presentation. T cell-mediated ADR usually have a delayed appearance and include skin eruptions in most cases. Nevertheless, it should not be forgotten that they may involve systemic T cell activation and thus take a severe, sometimes lethal turn. Clinical danger signs are involvement of mucosal surfaces, blistering within the exanthematous skin areas and systemic symptoms, e.g. fever or malaise. Drug presentation via antigen-presenting cells to T cells can either involve the classical pathway of haptenization of endogenous proteins or be directly mediated via noncovalent binding to immune receptors (MHC molecules or T cell receptors), the so-called p-i concept. Flare-up reactions during the acute phase of T cell-mediated ADR should not be mistaken for true drug allergies, as they only occur in the setting of a highly activated T cell pool. IgE-mediated ADR are less frequent and involve mast cells and/or basophils as peripheral effector cells. Recent data suggest that certain patients with drug allergy have a preexistent sensitization although they have never been exposed to the culprit drug, probably due to cross-reactivity. Thus, allergic drug reactions on first encounter are possible. In general, the extent of cross-reactivity is higher in IgE-compared to T cell-mediated ADR. Based on a specific ethnic background and only for severe T cell-mediated ADR to certain drugs, a strong HLA association has been established recently.

Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV.

Tyrosine kinase inhibitors (TKI) have changed the natural course of chronic myeloid leukemia (CML). With the advent of second-generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM). 1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years, 965 patients (64%) still received IM. At 10 years, progression-free survival was 82%, overall survival 84%, 59% achieved MR(5), 72% MR(4.5), 81% MR(4), 89% major molecular remission and 92% MR(2) (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR(5). Eight-year probabilities of adverse drug reactions (ADR) were 76%, of grades 3-4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800 mg and IM 400 mg+IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.Leukemia advance online publication, 13 March 2015; doi:10.1038/leu.2015.36.

Space debris attitude simulation - ιOTA (In-Orbit Tumbling Analysis)

Today, there is little knowledge on the attitude state of decommissioned intact objects in Earth orbit. Observational means have advanced in the past years, but are still limited with respect to an accurate estimate of motion vector orientations and magnitude. Especially for the preparation of Active Debris Removal (ADR) missions as planned by ESA’s Clean Space initiative or contingency scenarios for ESA spacecraft like ENVISAT, such knowledge is needed. ESA's “Debris Attitude Motion Measurements and Modelling” project (ESA Contract No. 40000112447), led by the Astronomical Institute of the University of Bern (AIUB), addresses this problem. The goal of the project is to achieve a good understanding of the attitude evolution and the considerable internal and external effects which occur. To characterize the attitude state of selected targets in LEO and GTO, multiple observation methods are combined. Optical observations are carried out by AIUB, Satellite Laser Ranging (SLR) is performed by the Space Research Institute of the Austrian Academy of Sciences (IWF) and radar measurements and signal level determination are provided by the Fraunhofer Institute for High Frequency Physics and Radar Techniques (FHR). The In-Orbit Tumbling Analysis tool (ιOTA) is a prototype software, currently in development by Hyperschall Technologie Göttingen GmbH (HTG) within the framework of the project. ιOTA will be a highly modular software tool to perform short-(days), medium-(months) and long-term (years) propagation of the orbit and attitude motion (six degrees-of-freedom) of spacecraft in Earth orbit. The simulation takes into account all relevant acting forces and torques, including aerodynamic drag, solar radiation pressure, gravitational influences of Earth, Sun and Moon, eddy current damping, impulse and momentum transfer from space debris or micro meteoroid impact, as well as the optional definition of particular spacecraft specific influences like tank sloshing, reaction wheel behaviour, magnetic torquer activity and thruster firing. The purpose of ιOTA is to provide high accuracy short-term simulations to support observers and potential ADR missions, as well as medium-and long-term simulations to study the significance of the particular internal and external influences on the attitude, especially damping factors and momentum transfer. The simulation will also enable the investigation of the altitude dependency of the particular external influences. ιOTA's post-processing modules will generate synthetic measurements for observers and for software validation. The validation of the software will be done by cross-calibration with observations and measurements acquired by the project partners.