This is in response to Sandy's request the other day that I clarify my post under the heading of "Differential expression patterns of cytokines in complex regional pain syndrome."

To begin with, a "pro-inflammatory cytokine" is any number of protein messengers that trigger an inflammatory response. (And for a more precise definition of cytokine, see the online mondofacto medical dictionary at http://www.mondofacto.com/facts/dict...ion=look+it+up)

One, such pro-inflammatory cytokine that has been identified as, among other things, an independent risk of death from cardiac artery disease (CAD), in some but not all studies, is something called Interleukin-6 or IL-6. Now, in 2005, a paper came out finding relatively high levels of IL-6 in the cerebral spinal fluids of CRPS patients. Changes in Cerebrospinal Fluid Levels of Pro-inflammatory Cytokines in CRPS, Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzmann RJ, Pain, 2005; 116: 213-219, free full text at http://www.rsds.org/2/library/articl.../alexander.pdf

As you might imagine, this got a lot of people excited. On a referral from a rheumatologist I saw a year later that the Mayo Clinic, I went packing to Johns Hopkins in the thirds week of October, 2006 to try to get into a large trial of an anti-IL-6 drug, only to have cold water thrown in my face: first the trial was at that time only open to people with defined rheumatological conditions, and CRPS wasn't one of them, and, more importantly, while it was believed the link between IL-6 and, for instance, CAD was quite high, it's role in CRPS was described to me as "iffy," notwithstanding the 2005 article of Alexander, et al. And, sure enough, a month later out came the epub of a second study by essentially the same group of authors reporting somewhat less robust results:

Changes in immune and glial markers in the CSF of patients with Complex Regional Pain Syndrome, Alexander GM, Perreault MJ, Reichenberger ER, Schwartzman RJ, Brain Behav Immun., 2007 Jul; 21(5): 668-76. Epub 2006 Nov 28.

Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. guillermo.alexander@drexelmed.edu

Complex Regional Pain Syndrome is a severe chronic pain condition characterized by sensory, autonomic, motor and dystrophic signs and symptoms. The pain in CRPS is continuous, it worsens over time, and it is usually disproportionate to the severity and duration of the inciting event. This study compares cerebrospinal fluid (CSF) levels of pro- and anti-inflammatory cytokines, chemokines and several biochemical factors (glial fibrillary acidic protein (GFAP), the nitric oxide metabolites (nitrate plus nitrite), the excitatory amino acid neurotransmitter glutamate, calcium, total protein and glucose) in patients afflicted with CRPS to levels found in patients suffering with other non-painful or painful conditions. The aim of the study is to determine the degree of involvement of glial cells and immune system mediators in the pathophysiology of CRPS. There was no elevation or reduction of a CSF marker that was specific for CRPS patients. However, there were several patterns of markers that could be helpful in both elucidating the mechanisms involved in the disease process and supporting the diagnosis of CRPS. The most common pattern was found in 50% (11 out of 22) of the CRPS patients and consisted of; elevated IL-6, low levels of IL-4 or IL-10, increased GFAP or MCP1 and increases in at least two of the following markers NO metabolites, calcium or glutamate. The results from this and other similar studies may aid in elucidating the mechanisms involved in the pathophysiology of CRPS. A better understanding of these mechanisms may lead to novel treatments for this very severe, life-altering illness.

PMID: 17129705 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/1...ubmed_RVDocSum

(I'm guessing that someone at Johns Hopkins was familiar with follow up study by Alexander et al, before it was posted online.)

It was against this background, and other related studies, that Differential expression patterns of cytokines in complex regional pain syndrome, Uceyler N, Eberle T, Rolke R, Birklein F, Sommer C, Pain, 2007;132:195–205, free full text at http://www.rsds.org/2/library/articl...erle_Rolke.pdf came out, finding in part that:

We found elevated levels of pro-inflammatory cytokines and reduced levels of anti-inflammatory cytokines in patients with CRPS. Specifically, mRNA levels of the pro-inflammatory cytokines TNF and IL-2 and serum IL-2 protein levels were elevated, and mRNA levels of the anti-inflammatory cytokines IL-4 and IL-10 were reduced. TGFb1 protein levels were also lower in patients with CRPS. Taken together, these findings show a pro-inflammatory cytokine profile in our patients with CRPS. [Emphasis added.]

The point I was trying to make when I compared the Uceyler et al study of 2007 with Systemic inflammatory mediators in post-traumatic complex regional pain syndrome (CRPS I) - longitudinal investigations and differences to control groups, Schinkel C, Scherens A, Köller M, Roellecke G, Muhr G, Maier C., Eur J Med Res. 2009 Mar 17; 14(3):130-5, was that the latter, and far more ambitious study - which had hoped to find a distinct pattern of change in cytokine expressions, as the disease went from the acute to chronic stage - instead only found a handful of changes in CRPS patient from controls (notably finding no significant change in the levels of either IL-2 or IL-6, in which the Uceyler and Alexander groups, respectively, found significant changes) and concluding instead:

Although clinically appearing as inflammation in acute stages, local rather than systemic inflammatory responses seem to be relevant in CRPS. Variable results from different studies might be explained by unpredictable intermittent release of mediators from local inflammatory processes into the blood combined with high interindividual variabilities. A clinically relevant difference to various control groups was not notable in this pilot study. Determination of systemic inflammatory parameters is not yet helpful in diagnostic and follow-up of CRPS I.

Now, at first blush, it looks like the authors as saying "pattern, what pattern?" But having given it some consideration, I'm starting to think that their findings tell a new story altogether.

Now this is not to say that there is no evidence of an inflammatory response in acute cases of CRPS, where the 2009 study by Schinkel et al apparently found statistically significant differences in between acute cases, on the one hand and chronic cases on the other hand, in the levels of IL-12, Substance P (a protein found in the brain and spinal cord that is associated with some inflammatory processes in the joints), and Tumor Necrosis Factor-Alpha, a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction, and is among other things the key mediator of septic shock in response to infection. But the sole statistically significant difference that was found between patients with chronic CRPS and healthy volunteers that Schinkel et al found was with respect to something called calcitonin gene-related peptide (CGRP).

Now, it turns out that CGRP is far from uninteresting. As I posted last night on the "Botox" thread, when I ran a Wikipedia search on CGRP, it noted, among other things, that:

It is the most potent peptide vasodilator and can function in the transmission of pain [fn. 2: Brain SD, Williams TJ, Tippins JR, Morris HR, MacIntyre I (1985), "Calcitonin gene-related peptide is a potent vasodilator," Nature 313 (5997): 54–6] [fn. 3: McCulloch, J., et al. (1986), "Calcitonin gene-related peptide: Functional role in cerebrovascular regulation," Proc Natl Acad Sci USA 83: 5731–5735, abstract at http://www.pnas.org/content/83/15/5731] . . . . CGRP receptors are found throughout the body suggesting that the protein may modulate a variety of physiological functions in all major systems (eg, respiratory, endocrine, gastrointestinal, immune, and cardiovascular). Increased levels of CGRP have been reported in migraine and Temporomandibular joint disorder patients as well as a variety of other diseases such as cardiac failure, hypertension, and sepsis.

Regulation of the calcitonin gene related peptide (CGRP) gene is in part controlled by the expression of the mitogen-activated protein kinases (MAPK) signaling pathway, cytokines such as TNFα and iNOS. 5HT1 agonists such as sumatriptan increase intracellular calcium which cause decreases in CGRP promoter activity. Botulinum toxin type A is able to prevent stimulated release of CGRP through the cleavage of SNAP-25 protein [fn. 15: Durham, P., R. Cady, and R. Cady (2004), "Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy," Headache 44 (1): 35–42, abstract at http://www3.interscience.wiley.com/j...RY=1&SRETRY=0]. Receptor antagonists such as telcagepant, which is in phase III from Merck Pharmaceuticals, also has promise in limiting the effects of CGRP [fn. 16: Tepper, S.J. and M.J. Stillman (2008), "Clinical and preclinical rationale for CGRP-receptor antagonists in the treatment of migraine," Headache 48 (8): 1259–68, abstract at http://www3.interscience.wiley.com/j...4225/abstract] [Citations partially omitted; emphasis added.]

http://en.wikipedia.org/wiki/Calcito...elated_peptide

Bottom line: there may well be a single and quite specific inflammatory aspect to chronic CRPS, but there's no reason that I can see in the literature to believe that those agents which tend to reduce most acute inflammation will necessarily have any effect on it.

I hope this clarification is helpful.

Mike