Cytokines in POEMS syndrome

(This is a very rough first draft, which is missing many articles and cytokines. Eventually, I hope to add in the rest of the information, but the evidence is unclear and sometimes contradictory, and I will probably not finish revising this soon. As always, please send me corrections, suggestions, and additions.) last revised 20 June 2015

pro-inflammatory cytokines

We learned in the 1990's that IL-6, IL-1-beta, and TNF-alpha are often (but not always) elevated in POEMS. Some researchers initially ascribed POEMS symptoms to an imbalance of pro-inflammatory over anti-inflammatory cytokines (Gherardi 1996).

We now know that IL-6 is more dominantly elevated in Castleman disease than in POEMS. In fact, one bit of evidence that the virus HHV-8 causes some (not all) cases of Castleman disease is that its genome encodes a viral homologue of human IL-6, which has some of the same effects as human IL-6. And one FDA-approved treatment for some cases of Castleman disease blocks IL-6: siltuximab (Sylvant) is a monoclonal antibody to human IL-6 (but it doesn't bind to viral IL-6). (Another treatment, tocilizumab (Actemra), is a monoclonal antibody to IL-6 receptor.) (See Fajgenbaum 2014 for a start on this literature.)

Kanai 2012 studied 27 cytokines, and found that 10 pro-inflammatory cytokines were significantly increased in 25 POEMS patients, but not in all of them.

And Keyzner 2014, studying 30 cytokines before and after autologous stem cell transplant found (among other things) that patients who experienced engraftment syndrome had lower levels of IL-1 receptor antagonist (which is anti-inflammatory).

angiogenetic cytokines

VEGF is the best documented cytokine in this group (first reported, I believe, in Watanabe 1996). It both causes new blood vessels to grow ("angiogenesis"), and also makes blood vessels leaky ("increases vascular permeability"). It probably causes the edema that's so characteristic of POEMS by increasing vascular permeability. (And it may well cause other POEMS symptoms--there's lots of speculation in the literature, but very little evidence.)

VEGF may also be involved in causing POEMS neuropathy, by reducing the barrier between blood and nerves, and thereby allowing something in that damages the nerves. Here a difference between POEMS and CIDP is important. In CIDP, nerves are usually slowed at the ends, where the blood-nerve barrier is weakest. In POEMS, the middle of the nerves is severely slowed. Perhaps that's because VEGF is (typically) high in POEMS, and not in CIDP. (See Nasu 2012.)

Because of the evidence that VEGF causes at least some POEMS symptoms, physicians have tried treating POEMS with bevacizumab (Avastin), which is a monoclonal antibody to VEGF. The few published cases haven't been promising: some patients who also received other treatments got better, while some patients died. (Sekiguchi 2013 summarizes the published evidence.) Since other treatments have much better results, it's hard to justify treating POEMS with bevacizumab. (But Sekiguchi 2013 suggests that treating very early cases of POEMS with bevacizumab may make sense.)

Yamada 2013 looked at three angiogenetic factors in POEMS, and found that VEGF, hepatocyte growth factor (HGF), and basic fibroblast growth factor (bFGF) were all elevated in POEMS. Like VEGF, HGF increases vascular permeability; unlike VEGF, bFGF decreases vascular permeability. They tested blood from three patients who were treated with bevacizumab, and found that VEGF did decrease (as expected), but bFGF and HGF did not change significantly. Perhaps, then, blocking VEGF, but not HGF (and other cytokines) allows the other cytokines to continue to cause the same problems (and for example to cause death by capillary leak syndrome).

Keyzner 2014 also found that EGF (endothelial growth factor) was higher both before before and 17 days after an autologous stem cell transplant (but often after other treatment) in POEMS patients than in patients with multiple myeloma or amyloidosis.

Scarlato 2005, on the other hand, found that erythropoietin (EPO) was low in POEMS patients--in fact, VEGF and EPO were inversely correlated.

neurotoxic substances

Kanai 2012 found that IL-12 is elevated in POEMS. We know that IL-12 is neurotoxic; perhaps it is the chemical (or one of the chemicals?) that elevated VEGF lets damage nerves.

Some matrix metalloproteinases have also been shown to be elevated in POEMS (Michizono 2001). VEGF causes these to increase. And there's evidence that they can cause demyelinating neuropathy.

Other chemicals have been proposed as possible neurotoxic substances, including complements and thrombins (Watanabe 1998).


(This is just a list of the article I mentioned explicitly above; many other articles have studied cytokines in POEMS.)
Fajgenbaum 2014
Fajgenbaum DC, van Rhee F, Nabel CS. 'HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy'. Blood 123 #19 (8 May 2014) 2924-2933.
Gherardi 1996
Gherardi RK, L Belec, M Soubrier, D Malapert, M Zuber, JP Viard, L Intrator, JD Degos, FJ Authier. 'Overproduction of proinflammatory cytokines imbalanced by their antagonists in POEMS syndrome'. Blood 87#4 (15 Feb 1996) 1458-65
Kanai 2012
Kanai K, Sawai S, Sogawa K, Mori M, Misawa S, Shibuya K, Isose S, Fujimaki Y, Noto Y, Sekiguchi Y, Nasu S, Nakaseko C, Takano S, Yoshitomi H, Miyazaki M, Nomura F, and Kuwabara S. 'Markedly upregulated serum interleukin-12 as a novel biomarker in POEMS syndrome'. Neurology 79 (2012) 575-582.
Keyzner 2013
Keyzner A, D'Souza A, Lacy M, Gertz M, Hayman S, Buadi F, Kumar S, Dingli D, Engebretson A, Tong C, Dispenzieri A. 'Low levels of interleukin-1 receptor antagonist (IL-1RA) predict engraftment syndrome after autologous stem cell transplantation in POEMS syndrome and other plasma cell neoplasms.' Biology of blood and marrow transplantation 2013 Sep;19(9):1395-8. doi: 10.1016/j.bbmt.2013.06.012.
Michizono 2001
Michizono K, Umehara F, Hashiguchi T, Arimura K, Matsuura E, Watanabe O, Fujimoto N, Okada Y, Osame M. 'Circulating levels of MMP-1, -2, -3, -9, and TIMP-1 are increased in POEMS syndrome.' Neurology 2001 Mar 27;56(6):807-10.
Nasu 2012
Nasu S, Misawa S, Sekiguchi Y, Shibuya K, Kanai K, Fujimaki Y, Ohmori S, Mitsuma S, Koga S, Kuwabara S. 'Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy.' Journal of neurology, neurosurgery, & psychiatry 2012 May;83(5):476-9. doi: 10.1136/jnnp-2011-301706.
Scarlato 2005
Scarlato M; Previtali SC; Carpo M; Pareyson D; Briani C; Del Bo R; Nobile-Orazio E; Quattrini A; Comi GP. 'Polyneuropathy in POEMS syndrome: role of angiogenic factors in the pathogenesis.' Brain : a journal of neurology 2005 Aug; 128(Pt) 8: 1911-20.
Sekiguchi 2013
Sekiguchi Y, Misawa S, Shibuya K, Nasu S, Mitsuma S, Iwai Y, Beppu M, Sawai S, Ito S, Hirano S, Nakaseko C, Kuwabara S. 'Ambiguous effects of anti-VEGF monoclonal antibody (bevacizumab) for POEMS syndrome.' Journal of neurology, neurosurgery, & psychiatry 2013 Dec;84(12):1346-8. doi: 10.1136/jnnp-2012-304874.
Watanabe 1996
Watanabe O, Arimura K, Kitajima I, Osame M, Maruyama I. 'Greatly raised vascular endothelial growth factor (VEGF) in POEMS syndrome.' Lancet 1996 Mar 9;347(9002):702.
Watanabe 1998
Watanabe O, Maruyama I, Arimura K, Kitajima I, Arimura H, Hanatani M, Matsuo K, Arisato T, Osame M. 'Overproduction of vascular endothelial growth factor/vascular permeability factor is causative in Crow-Fukase (POEMS) syndrome.' Muscle & nerve 1998 Nov;21(11):1390-7.

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