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 M (IgM 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.
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.
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-12 and TNF-Alpha
Albnormalities 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 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 grwoth 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.
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 diruption 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.