POEMS syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Pathophysiology
POEMS syndrome is an acronym, where the 'P' stands for polyneuropathy, the 'O' for organomegaly, 'E' for endocrinopathy, 'M' for immunoglobulin (para-protein or M-protein) and 'S' for skin changes. POEMS syndrome is a para-neoplastic syndrome characterized by multi-organ system dysfunction, monoclonal plasma cell proliferation and demyelinating inflammatory polyneuropathy.[1]
Pathogenesis
Monoclonal Plasma Cell Proliferation
- POEMS syndrome is associated with plasma cell dyscrasia in which there is monoclonal proliferation of plasma cells. The plasma cells are involved in antibody production under physiological conditions via reorganization of immunolglobulin heavy and light chains.
- The lamba component of immunoglobulin light chains is thought to be overproduced in POEMS syndrome secondary to monoclonal plasma cell proliferation.
- Bone marrow studies of patients suffering from POEMS syndrome shows lymphoid aggregates rimmed by monotypic or polytypic plasma cells.
- Diffuse infiltration of light chain restricted plasma cells leads to development of predominantly sclerotic bone lesions. This is in contrast with myeloma patients where there is a predominance of lytic bone lesions. The bony lesions are primarily restricted to the axial and proximal appendicular skeleton.[2]
Cytokine Storm
- The monoclonal plasma cell proliferation in POEMS syndrome is thought to play a major role in overproduction of numerous pro-angiogenic and pro-inflammatory cytokines.
- The hypercytokinetic state induced in patients of POEMS syndrome is thought to drive the disease process. The following cytokines are overproduced:
- Interleukin 1 beta (IL-1b)
- Interleukin 6 (IL-6)
- Interleukin 12 (IL-12)
- Tumor necrosis factor alpha (TNF-Alpha)
- Vascular endothelial growth factor (VEGF)
Role of Interleukin-6 , Interleukin-12 and TNF-Alpha
- Interleukin- 6 is overproduced in patients with POEMS syndrome. IL-6 is a pro-inflammatory cytokine involved in maturation of B-cells into antibody producing plasma cells, induction of acute phase reactants and thrombopoeisis.[3][4][5] The overproduction of this cytokine may be related to some of the clinical features seen in POEMS syndrome such as gammopathy, elevated C-Reactive protein (CRP) and thrombocytosis.[6][7]
Abnormalities of Immune Response
Upregulation of VEGF production
- VEGF is a pro-angiogenic cytokine that promotes neovascularization. It is thought to be overproduced in POEMS syndrome and can serve as a marker of disease activity in these patients.
- VEGF165 is the isoform of VEGF that is overexpressed in POEMS syndrome.
- Increased VEGF could account for the organomegaly, edema, skin hemangiomata, and possibly the occasional mesangioproliferative changes found on renal biopsy.
- The mesangial proliferation and membranoproliferative glomerulonephritis (MPGN) seen in POEMS syndrome is thought to be secondary to increased production of platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), and fibroblast growth factor beta (FGF-β) have been implicated in mesangial cell proliferation. It has been suggested that FGF-β participates in the initiation, PDGF in the maintenance, and TGF-β (an inhibitory cytokine) in the resolution of the proliferation.[8]
Neovascularization and Edema
- The neovascularization induced by VEGF leads to increased vascular permeability. Since the increased production of VEGF is unchecked due to the plasma cell dyscrasia, the consequence is an unregulated extravasation of intravascular fluid into the extravascular compartment.
- As a result, there is accumulation of fluid in the extracellular compartment and the resultant edema seen in patients of POEMS syndrome.
Alteration of Blood-Nerve Barrier and Secondary Axonal Degenration
- Unregulated neovascularization also leads to disruption of the blood-nerve barrier in the peripheral nervous system (PNS), which subsequently results in endoneural edema. The edema compresses the nerves and eventually leads to secondary axonal degeneration.
While the main features of the disease have been described, the exact mechanism of the disease has remained elusive. The paraprotein alone is insufficient to explain the multi-organ features, and various cytokines produced by plasmacytoma cells have therefore been linked with the features of POEMS syndrome, specifically interleukin 1β, interleukin 6 and TNFα. There also seems to be a role of vascular endothelial growth factor, given the angiogenetic changes in many tissues.
The polyneuropathy is usually symmetrical and distal. There is a combination of demyelination and axonal damage, and sensory, motor and autonomic neurones are all affected. The typical symptoms are therefore of numbness, tingling and weakness in the feet, later affecting the legs and hands. Pain is unusual, but the weakness may eventually become severe and disabling. The autonomic neuropathy may cause excessive sweating and erectile dysfunction; hormonal changes may also contribute to the latter. It is usually the symptoms of neuropathy which prompt a person with POEMS syndrome to seek medical attention.
Myeloma is the most common plasma-cell proliferative disorder associated with POEMS syndrome, present in more than half of all cases. Most myelomas associated with POEMS syndrome are osteosclerotic, in contrast to the osteolytic bone lesions in most other myelomas. Other blood disorders occur in a significant minority of cases, including Castleman's disease, plasmacytoma and MGUS.
Associated Disorders
Possible associations included pulmonary hypertension, restrictive lung disease, a thrombotic diathesis, arthralgia, cardiomyopathy (systolic dysfunction), fever, low vitamin B12 levels and diarrhea.
References
- ↑ Aggarwal S, Goulatia RK, Sood A, Prasad K, Ahuja GK, Mitchell MJ, Kumar A (August 1990). "POEMS syndrome: a rare variety of plasma cell dyscrasia". AJR Am J Roentgenol. 155 (2): 339–41. doi:10.2214/ajr.155.2.2115264. PMID 2115264.
- ↑ Bardwick PA, Zvaifler NJ, Gill GN, Newman D, Greenway GD, Resnick DL (July 1980). "Plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes: the POEMS syndrome. Report on two cases and a review of the literature". Medicine (Baltimore). 59 (4): 311–22. PMID 6248720.
- ↑ Yoshizaki K, Nakagawa T, Kaieda T, Muraguchi A, Yamamura Y, Kishimoto T (March 1982). "Induction of proliferation and Ig production in human B leukemic cells by anti-immunoglobulins and T cell factors". J. Immunol. 128 (3): 1296–301. PMID 6799573.
- ↑ Muraguchi A, Hirano T, Tang B, Matsuda T, Horii Y, Nakajima K, Kishimoto T (February 1988). "The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells". J. Exp. Med. 167 (2): 332–44. PMC 2188837. PMID 3258006.
- ↑ Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H (October 1987). "Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells". Proc. Natl. Acad. Sci. U.S.A. 84 (20): 7251–5. PMC 299269. PMID 2444978.
- ↑ Hitoshi S, Okazawa H, Shimizu J, Suzuki K, Sakuta M (July 1991). "[A case of Crow-Fukase syndrome with increased serum interleukin-6]". Rinsho Shinkeigaku (in Japanese). 31 (7): 730–3. PMID 1786657.
- ↑ Mandler RN, Kerrigan DP, Smart J, Kuis W, Villiger P, Lotz M (June 1992). "Castleman's disease in POEMS syndrome with elevated interleukin-6". Cancer. 69 (11): 2697–703. PMID 1571900.
- ↑ "HarvardKey Login".