The future of GDD treatment: Individualized Management
A few issues have become clear with GDD and its treatment:
1. As Gd is the problem, Gd must be removed to stop the continued stimulus for host reaction.
2. Host reaction must be addressed for many individuals.
3. Cytokines are critical in the disease. Likely members of other inflammatory cells are also important, such as the early group of granulocytes and B-cells, and chronic cells such as CD34+ fibrocytes.
4. Duration of disease is specifically critical to determine treatment, at the division point of early stage disease (< 3 months) and later stage. This division point may be 6 months in a number of individuals.
What is likely:
1. Host management must be varied depending on the type of agent, the amount of GBCA administered historically, and the duration of GDD.
2. Spacing of chelation, concurrent management of host response may all need to be individually tailored.
In this blog I will address what is likely.
What is clear is within 3 months of disease onset, and likely within 6 months, the immune system is on such high alert that chelation alone will trigger massive Flare, and Flare must be offset with an extended hypersensitivity protocol drug management.
My opinion is that attention must be paid to how the individual is reacting to chelation, to see if Flare progressively decreases (what we hope for), remains the same severity, or becomes progressively worse, with each chelation. The last category is ofcourse the most problematic, as it suggests the treatment is making the patient worse.
The great majority of cases with progressively severe Flare experience this for the following reasons:
1. chelation started too early (< 3 months in general, without host treatment < 6 months).
2. chelation is administered at too short intervals (twice per week, sometimes 1 every two weeks may be too short intervals). This can be a major problem in patients within 3 months who are so keen 'to get better' that they insist on, or agree with, short interval treatment. This is likely a grave mistake in most cases.
3. hypersensitivity protocol is not concurrently employed.
4. unknown host factors, GBCA type factors (? macrocyclic).
Regarding point 2 above, the best way to think of this is as follows: the original GBCA administration is like an anaphylactic reaction to 100 bee stings. As mentioned in earlier blogs DTPA recreates a GBCA, but at approximately 1/100th the dose, so 1 bee sting. If this bee sting continues to be repeated, but now as a single bee, every 3 days or every 7 days, every time there will be a minireaction, but in some individuals this constant re-innoculation results in another major anaphylactic reaction.
So if with each chelation the patient gets progressively worse Flare, at some point chelation must stop. In many respects this depends on how severe the Flare is, but clearly at 5 chelations, each one with a slightly worse Flare, chelation must stop or be spaced at much greater intervals. Start with greater spacing unless the progressive Flares are intolerable.
If chelation is stopped, then what?
At this point host immune response must be managed. For this purpose we have developed the AMASE drug regimen. This is a work in progress. Autoimmune drug therapy should also be added in concurrently with chelation, if Flare is getting a little worse with each chelation as an adjuvant therapy,
What is the ideal host management? Based on the work of Wermuth and Jiminez, and ongoing work at Stanford, cytokine response by the individual can be determined by evaluating cytokine release either by isolated peripheral blood mononuclear cells (PBMCs) or in vivo measurement of PBMC release. There are drugs specifically targeted to various cytokines and these could be specifically used in these patients. At this early stage, looking at whole populations, TNF-alpha and IL-6 in particular go up. It is however possible to determine this more precisely for an individual.
As it is unethical to re-administer a GBCA to a patient with GDD, the best surrogate is actually the necessary treatment - chelation with DTPA, and the resultant recreation of a GBCA.
This is possible right now:
1. Cytokines can be measured pre-chelation and post-chelation.
2. See what cytokines elevate.
3. Treat the individual to block/diminish these cytokines with existing (or to be developed) DMARDS.
One additional future step. Reconstituting a GBCA with DTPA will elevate cytokines to Gd combined with DTPA, and other cytokines related to the original GBCA should probably also be elevated, but not necessarily. The most precise way to determine exactly the cytokines that increase, in individuals who received just one GBCA agent, or one type repeatedly, using the ligand of that GBCA to rechelate the patient should result in elevation of the exact cytokines that is making the patient sick - and then treat those cytokines. The exact ligand for Magnevist is DTPA, but for Multihance it is BOPTA, for Omniscan: Diamide, for Prohance: Versetamide, for Eovist/Primovist: EOB-DTPA, for Dotarem: DOTA, and Gadavist: Butrol... The ligands are short-hand for longer chemical names.
It is presently uncertain if the individuals treated too early, etc with chelation and are now worse than they were before, are permanently worse, or if it is time-limited (to 1 year for example).
What is clear with GDD is the first and most important treatment step is to never get another GBCA injection again.
It makes empirical sense that removing Gd has to be a good idea, almost always, if presence of Gd is what is making the individual sick.
In my opinion the Flare is analogous (to use a description akin to the Bee sting above) to having first become sick from rolling around in a bed of nettles (the GDD itself).. As with nettles and bee stings, TRPV1 - chemical channel responsible for the experience of burning heat in humans are responsible to a great extent, as they are to the burning feeling of GDD. Flares are like being struck by single strands of a nettle, at every couple of week intervals. These repeat beatings with a single strand of nettle is horrible, but are not permanent. Similarly, the great majority of strong Flares should not be permanent.... but host treatment is probably essential.
It seems that the cytokines most responsible may be the pro-inflammatory cytokines and not the profibrotic cytokines, explaining why Flare reactions in the majority should not be permanent. The need though is to develop an AMASE type protocol that is effective, affordable and with few side-effects. I do not think that we are there yet, but trying very hard.
Stay tuned on the latest advancements: