I would agree with all that Adrian and especially so about the claimed 95% specificity.
We pretty much do exactly what you do.
Regards
Ian Barlow
Path Links
-----Original Message-----
From: Clinical biochemistry discussion list [mailto:[log in to unmask]] On Behalf Of Heaps Adrian (RNL) North Cumbria University Hospitals
Sent: 04 March 2016 10:06
To: [log in to unmask]
Subject: Re: NICE guideline NG35
I have been in discussion with the manufacturers and our haematologists on this matter for some time and we will not be dropping urine BJP. We have a large myeloma cohort and an elderly patient population and we've been using the SFLC assay in combination with urine and serum SEP/immunofixation for just over 10 years (at this moment the light chain assay can be requested by GPs). We have a number of examples of light chain myelomas/AL amyloid cases presenting with only renal failure that would have been missed if we weren't still analysing urines; this is because of the continued antigen excess failures on the light chain analysers where false negatives occur due to prozone when the involved light chain is at a very high concentration. In cases where no light chain band is present in the serum electrophoresis (as is often the case due to their short serum half-life) and we don't have any previous light chain results these are missed by the SFLC/SEP-only algorithm.
To take this into account the manufacturers have recommended to me that if we were to stop testing urines then ALL new patients having their light chains measured for the first time (so every GP request in the context of "back ache" or "osteoporosis" or "off their feet") should have a second, off-line manual dilution antigen excess check for both kappa and lambda chains. This effectively doubles the reagent cost of an already expensive assay and is an admission by the manufacturer's that the assay has a problem with false negatives cause by antigen-excess. The manufacturers have certainly improved their detection methods for prozone in the last few years but it is certainly not faultless and we see a patient who would be missed by the SEP/SFLC-only algorithm about once every couple of months: we then dutifully send the serum to the manufacturer for further investigation. Obviously missing AL-amyloid or light chain myeloma patients is not acceptable.
One of the arguments from the manufacturers of the SFLC assay is that the light chain assay is more cost-effective compared to the manually intensive urine EP/fix assays> but we use a fully automated electrophoresis /immunofixation system operated by MLAs/ATOs and therefore the cost of a urine EP is about 20% of the cost of the light chain assay so that doesn't apply to us. Another argument is poor concordance in GPs providing urine samples for BJP> this is a local education issue and as my predecessor has shown; continued "positive reinforcement" can resolve this issue. Also it's straightforward to create an algorithm in most LIMS that can automatically request one where it's not been sent. I personally think this is a bit of a non-argument.
Dependent on the outcome of an ongoing clinical audit we would aim to continue using urine and serum EP for our first line screening algorithm in primary care and remove SLFC assays from GP requesting due to the vast numbers of false alarms it creates> abnormal SFLC concentration or ratio absolutely does NOT have a 95% specificity for the diagnosis of plasma cell disorders in this area and our army of resident haematologists continually contacted by worried GPs would agree with this statement. Instead we plan to take a novel approach with the SFLC assay being reflexed by us in the context of any high index of suspicion patients (Hypercalcaemia, Renal insufficiency, Anaemia, Elevated plasma viscosity, Bone lesions, Peripheral neuropathy, Recurrent infections, suppressed Igs, Abnormal SEP/UEP etc) or requested in clinic by specialists (renal medicine and haematology). We are also looking into whether GPs could request SFLC on behalf of a "named haematologist" after phone consultations for high index of suspicion patients.
I believe the SFLC assay has had a very positive impact on both diagnosis and monitoring of certain plasma cell dyscrasias but until the cost is reduced and the antigen excess problem is completely resolved I don't think it should be replacing urine BJP screening entirely. I have been in discussion with a number of experts on this subject and the feeling is that this new NICE guideline has jumped the gun with regards to using the SLFC assay as a first line screen in place of urines. Ultimately these are only "guidelines" and it's our responsibility to provide a diagnostic service that's appropriate for our local populace.
I am keenly anticipating the results of a large diagnostic utility and health economics study (DEC study) on exactly this topic currently being performed in Oxford.
Adrian
Dr Adrian Heaps BSc MSc PhD FRCPath
Consultant Clinical Scientist / Head of Service (Immunology) Department of Virology & Immunology Cumberland Infirmary Newtown Road Carlisle Cumbria
CA2 7HY
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The NCUHT Pathology Handbook can be found here
-----Original Message-----
From: Clinical biochemistry discussion list [mailto:[log in to unmask]] On Behalf Of Salter Simon (ROYAL FREE LONDON NHS FOUNDATION TRUST)
Sent: 03 March 2016 10:10
To: [log in to unmask]
Subject: Re: NICE guideline NG35
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I think it is a poorly worded way of recommending that SLCH should be used first line. We are planning on going down that route at the Royal Free with SLCH for GPs rather than urine immunofixation/electrophoresis.
The full guideline has the evidence on which it was based: http://www.nice.org.uk/guidance/ng35/evidence/full-guideline-2306487277
Diagnostic accuracy of laboratory tests for suspected plasma cell disorders
Serum protein electrophoresis (SPE)
Evidence from 4 studies including 4888 patients (McTaggart et al 2013, Hill et al 2006, Piehler et al 2008 and Vermeersch et al 2008) suggests serum protein electrophoresis has sensitivity 85% [95%C.I. 75% – 92%] and specificity of 95% [95%C.I. 85% – 98%] for the diagnosis of plasma cell disorders.
Serum free light chain (sFLC) analysis
Evidence from of 4 studies including 4888 patients (McTaggart et al 2013, Hill et al 2006, Piehler et al 2008 and Vermeersch et al 2008) suggests serum free light chain ratio outside the normal range has sensitivity of 47% [33% – 60%] and specificity of 95% [85% – 99%] for the diagnosis of plasma cell disorders.
Combined SPE and sFLC
Evidence from 3 studies including 4054 patients (McTaggart et al 2013, Hill et al 2006, Piehler et al 2008) suggests that combining serum free light chain analysis with serum protein electrophoresis, improves sensitivity for the diagnosis of plasma cell disorders with a pooled estimate of 94% [72% – 99%]. In this strategy patients with a negative serum protein electrophoresis test would go on to have a serum free light chain test.
-----Original Message-----
From: Clinical biochemistry discussion list [mailto:[log in to unmask]] On Behalf Of Hart, Tanya
Sent: 02 March 2016 15:02
To: [log in to unmask]
Subject: Re: NICE guideline NG35
Our FLC reagent suppliers are not interpreting it as advice to use FLCs as a first line screen for everyone. I think the guideline is unclear on this. However I've just noticed that the NICE website itself says:
"This guideline covers adults (aged 16 years and over):
- who are referred to secondary care with suspected myeloma
- with newly diagnosed or relapsed myeloma (including high‑risk myeloma and primary plasma cell leukaemia)."
http://www.nice.org.uk/guidance/ng35/chapter/Context
I'm not really sure what is meant by using FLCs to 'confirm the presence of a paraprotein'. I'm also surprised that the guideline claims that an abnormal FLC ratio has 95% specificity for diagnosis of plasma cell disorders.
Tanya
Dr Tanya Hart
Clinical Scientist
Department of Clinical Biochemistry
Poole and Royal Bournemouth Hospitals
-----Original Message-----
From: Clinical biochemistry discussion list [mailto:[log in to unmask]] On Behalf Of McTaggart Malcolm (SHREWSBURY AND TELFORD HOSPITAL NHS TRUST)
Sent: 02 March 2016 14:19
To: [log in to unmask]
Subject: NICE guideline NG35
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Dear All
Section 1.2 of this new guideline on 'myeloma: diagnosis and management' states 'use serum protein electrophoresis and serum-free light chain assay to confirm the presence of a paraprotein'. Should this be interpreted as: all myeloma screens should have serum electrophoresis and sFLC analysis? Or since most myeloma screens are negative is it not going that far given the use of the word 'confirm'. Perhaps it means sFLC should be done at least if an abnormality is detected in one of the other tests?
Best wishes,
Malcolm
Malcolm McTaggart
Senior Clinical Scientist
Biochemistry, Pathology
Shrewsbury and Telford Hospital NHS Trust
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