The introduction of infliximab and adalimumab, monoclonal antibodies against TNF-α, to induce and maintain clinical remission in patients with moderate to severe inflammatory bowel disease has generated new perspectives managing these disorders [1]. However, about a third of all CED patients in clinical studies treated with TNF-α antibodies exhibited no primary response (primary treatment failures) and up to 40% of patients, after having exhibited primary therapy response, show a decrease in efficacy with increasing duration of therapy (secondary treatment failures*) and do need multiple dose adjustments to re-induce or maintain clinical response.
by Dr J. Stein
Clinically important factors predicting treatment response include brief disease duration, a predominantly inflammatory disease course and disease involving the colon, non-smoker status and moderate to severe disease activity (overview in Yanai and Hanauer [2]). At first, the development of antibodies against infliximab in the sense of anti-drug antibodies (ADA) [3] occurring especially in patients undergoing episodic administration of IFX (36–61% of cases) [4] was proposed as the primary cause of this phenomenon. It is now considered increasingly questionable that ADA alone are responsible for therapy failure in patients treated with IFX. In fact, multiple studies have reported IFX trough levels that were either undetectable or very low despite the absence of ADA [5-7], which points to other factors that may influence the pharmacokinetics of these agents. A retrospective analysis of the ACT1 and ACT2 studies found an inverse correlation with serum albumin concentrations [8]. Albumin concentrations < 3 g/dl correlated with a significantly poorer initial response (primary non-responders). Several strategies can be undertaken in cases of loss of response: dose escalation (increasing the dose or shortening the interval), switching to another anti-TNF-α drug, or changing to other immunosuppressive drugs. The decision as to which is the best option for the management of these patients remains largely empirical. Data from studies suggests that measurement of anti-TNF-α trough levels and ADAs could be useful in therapeutic drug monitoring in IBD patients, as part of an individualized therapy. Figures 1a and 1b summarize an algorithm for the management of TNF-α antibody therapy based on currently available data. Methods used to detect anti-TNF-α drug concentrations and ADA concentrations are mainly based on enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) or less frequently EMSA (electrophoretic mobility shift assay). Compared to the more complex RIA- or EMSA- based detection methods, the most commonly used and, as a rule, easily performed enzyme-coupled immunoabsorptive assays (EIA) exhibit some limitations which are important for the timing of measurement: Since anti-TNF-α drugs are able to bind to antibodies to form immune complexes, they cannot be detected by ELISA and their presence can only be ascertained by detectable ADAs regardless of the serum levels of the anti-TNF-a drug. However, when ADAs are negative, it is important to know the levels of the anti-TNF-α drugs: if anti-TNF-α serum levels are undetectable, the result is a true negative, but if anti-TNF-α levels are detectable and ADA levels are negative, the result is considered inconclusive because it might be either a true negative result or a false negative result if the antibodies have bound to the anti-TNF-α drug. Therefore, anti-TNF-α drug concentrations should be determined when the drug levels are expected to be lowest, i.e. just before the next administration of the drug (trough level) and at the same time antibody titres are measured to enable further interpretation. When an EIA is used, the optimum trough level stands at > 4–5 μg/ml [5,8], compared with cut-off values of > 1 μg/ml with RIA [9,10].
* Defined as recurrence following initially effective remission maintenance with TNF-α antibodies.
References
1. Chaparro M, et al. Aliment Pharmacol Ther 2012; 35: 971–986.
2. Yanai H, et al. Am J Gastroenterol. 2011; 106: 685–98.
3. Baert F, et al. N Engl J Med. 2003; 348(7): 601–608.
4. Cassinotti A, et al. Pract Gastroenterol. 2010; 34:11–20.
5. Maser EA, et al. Clin Gastroenterol Hepatol. 2006; 4:1248–1254.
6. St Clair EW, et al. Arthritis Rheum. 2002; 46: 1451–9.
7. Fasanmade AA, et al. Int J Clin Pharmacol Ther. 2010; 48: 297–308.
8. Seow CH, et al. Gut. 2010; 59: 49–54.
9. Steenholdt C, et al. Scand J Gastroenterol. 2011; 46: 310–318.
10. Bendtzen K, et al. Scand J Gastroenterol. 2009; 44: 774–781.
The author
J. Stein, MD, PhD
Crohn Colitis Centre
Frankfurt, Germany
Much like do-it-yourself (DIY) hardware stores, DIY or at-home diagnostic test kits possess both benefits and drawbacks. Making a decision is tricky. It may become even more so as a host of new kits arrive on the market, some of which are aimed at potentially deadly diseases like cancers.
The growth in the DIY kit market is driven by a combination of several factors:
Many kit developers are beginning to see easier opportunities in the developing world, especially in large emerging countries such as Brazil, India and China. All these have a rising number of affluent consumers, accompanied by lifestyle changes which heighten the risk of diseases such as diabetes or AIDS. At the same time, medical regulations are more lax than in the West; for example, it is not impossible that kits are packaged differently, without the visible labels which warn that a specific test is not (yet) approved by health regulators.
What is common to both the West and large emerging markets, as far as DIY test kits go, is the Internet. Not only does the Net allow consumers to become aware of new tests, but it also provides them a channel for access to vendors, credit card payments and delivery by mail order. As a follow-on, some DIY kit producers are working to provide encrypted transfer of data and access to the test results, again over the Internet.
No one doubts the utility of DIY kits in areas such as ovulation and pregnancy testing. Most physicians also agree that the monitoring of chronic diseases is far better served by emerging DIY diagnostic technologies. For example, a relatively new test for patients taking the anticoagulant warfarin does away with the need for weekly visits to a physician – to ensure that their blood is neither too thick to cause a stroke, nor too thin to be life threatening in case of a wound or high blood pressure. This is also the case for at-home diabetes tests, which permit day-to-day modifications in insulin intake. Blood pressure too, it is now accepted, needs to be monitored throughout the day to give a true reading, rather than once at a doctor’s.
However, there are several areas where healthcare professionals are apprehensive about the growth in DIY tests, and are likely to remain so for some time. This is mainly because even state-of-the-art DIY technology has an approximately 10% risk of error. While the psychological impact of a false positive – which has a similar error level to false negatives in most DIY tests – can be serious, a false negative on a major allergy, urinary tract or yeast infection, or for that matter, HIV, would be devastating.
One of the fastest-paced developments in clinical laboratories has been in the area of quality control (QC) systems. Its driver has been the increase in the performance and sophistication of QC software, which has progressively tightened benchmarks for acceptable standards. On the plus side, improved QC systems clearly help a laboratory to serve the needs of patients more efficiently. Less clear is the latest, paradigm-shifting QC guideline known as EP-23; it is so far restricted to the US (where it originates), but is likely to have a major impact on Europe.
Quality control in a lab concerns routine operational and technical activities to verify that a particular test is conducted correctly. The main aim of QC software has been to ensure the validity of both test methodology and results, to define and set acceptable SDs (standard deviations), and to correct errors if they occur (ideally before they do so), or flag them as such.
There is a wide variety of software for laboratory QC. Market leaders such as Westgard and Bio-Rad supply end-to-end solutions. Other vendors provide application specific software, for example Hematronix’s Real-Time and Quantimetrix’s Quantrol Online for monitoring performance against peers, Boston Biomedica’s AccuChart for infectious disease testing, etc.
Staff challenges
The capability of the staff who run laboratory tests is a major issue, but this has long been attended to – in terms of accreditation of study programmes and training courses as well as requirements for continuing education to stay abreast of developments in the field. In the US, the Clinical Laboratory Improvement Amendments Act (1988) legally ensures that laboratory staff have to be up to the mark.
On the other hand, staffing has recently begun posing another set of problems. This is because many laboratory personnel who ushered in the IT era have begun to retire. In spite of high levels of unemployment, finding an adequately qualified pool of new recruits is proving to be a major problem in the US. [1]
As with any other core systems software, QC has been in perpetual evolution – a result of ever-changing regulations and market forces. Even the most intuitive and adaptive software requires people, experienced people, to tweak and adapt the programs in order to get them to work well and deliver the best results within a particular environment. QC is no exception.
The need for qualified personnel is set to increase dramatically as US laboratories shift away from the current system of equivalent QC to risk-based analysis, which is based on a more scientifically rigorous methodology. The US has decided to completely abandon equivalent QC in favour of a new risk-based analysis system, known as EP-23.
Equivalent versus risk-based QC
Standard operating procedures (and inbuilt IT system capabilities) for equivalent QC usually entailed running controls just once a month. In case of an aberration, the entire month load of patients (or over 8% of the annual total) needed to be recalled, samples retaken and tests rerun. Scheduling the re-tests alongside a current batch almost invariably led to capacity bottlenecks, which could then spill over into the subsequent months. Risk-based analysis is meant to do away with such contingencies.
Nevertheless, risk-based analysis also means more complex software, and more human intervention. It requires identifying potential error sources in a test or device, and implementing (external or ‘wet’) controls to reduce the risk. Meanwhile, the pathways to implement EP-23 remain somewhat nebulous. Proponents of risk-based analysis, on their part, acknowledge its complexity, but argue that the costs of error in equivalent QC far outweigh the latter, not only in terms of re-running tests but in case of wrong diagnosis.
EP-23 will drive need for skilled lab staff
Clearly, EP-23 will rely heavily on experienced laboratory personnel. The Clinical and Laboratory Standards Institute (CLSI), the US professional society mandated with establishing EP-23, notes: [2]
“The decision of how the laboratory performs its risk assessment to develop a quality control plan (QCP) will be up to the laboratory director. Some tests analysed on the same analyser may have risks of error so similar that they can be grouped on the same QCP, with only minor additions or deletions for individual tests, while other tests on the same analyser may have significantly greater, or lesser, risks and need a completely different approach to a QCP.” It also acknowledges that there “is no specific format that is required for the presentation of a QCP.”
In an official presentation on EP-23 by the Centers for Disease Control, [3] CLSI goes on to add: “Labs will receive guidance to enable them to develop effective, cost-efficient QC protocols that will ensure appropriate application of local regulatory requirements based on the technologies selected by the lab and reflective of the lab’s unique environmental aspects. Labs will receive guidance to develop QC processes and procedures to reduce negative impact of test system’s limitation, while considering laboratory environmental/operator factors like personnel competency, temperature, storage conditions, clinical use of test results, etc.”
In such a scenario, a looming shortage of qualified personnel would hardly help.
Large laboratories clearly have an edge in being ready for a shift to EP-23, since they can afford to recruit specialist consultants to manage the changeover. For their smaller counterparts, the outlook is likely to be very different.
Europe and EP-23
The impact of EP-23 on Europe remains to be seen. At present, the EU has made no official comment, in spite of the inevitable issues which could arise, for example within the framework of the International Conference for Harmonization (ICH).
Part of the reason for its nonchalance may simply lie in the fact that there is no similar European laboratory QC standard, like EP-23. Indeed, several EU countries have their own national systems covering QC in laboratories – for example Belgium’s Directive pratique pour la mise en place d’un système qualité dans les laboratoires agréés dans le cadre de l’INAMI, France’s Guide de bonne exécution des analyses de biologie clinique, and Britain’s CPA Manual for Laboratory Accreditation.
On its part, European standard EN 45001, currently recommended for laboratories, is far broader in scope than EP-23. It covers not only QC but technical competence, human resources, organizational structure, document management and much more. It is also based on the international ISO Guide 25. ISO 25 is currently under revision, and is due to replace EN 45001.
US proponents for globalizing EP-23 note that its inspiration too lies in the accepted ISO standard, 14971. Between the sweeping generalities of EN 45001 and the different national systems in place for lab QC, it may be hard to argue that EP-23 could be a good path forward for Europe too.
References
1. http://www.healthcareitnews.com/
news/lab-staff-shortages-call-better-point-care-diagnostics
2. http://www.clsi.org/Content/NavigationMenu/Education/EP23QA/EP23_Q_A.htm
3. http://wwwn.cdc.gov/cliac/pdf/Addenda/cliac0908/Addendum%20N.pdf
by Dr Petraki Munujos Systemic vasculitides are a group of inflammatory idiopathic clinical syndromes usually classified by the size of the vessels being affected. Among them, the small vessels vasculitides show clear associations with the presence in the patients sera of antibodies directed against cytoplasmic antigens of neutrophils (ANCA).
November 2024
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