Pathways Case Record: POEMS Disease

A 65-year-old woman was admitted to the hospital with six months of recurrent fluid buildup (ascites) in the abdomen requiring frequent removal of fluid. She had a history of IgA lambda gammopathy, neuropathy, leg swelling, hypothyroidism, Raynaud's Disease, splenomegaly, and lymphadenopathy.

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The fluid removed upon admission showed evidence of high serum ascites-albumin gradient (SAAG) without evidence of hepatic cirrhosis. Despite extensive laboratory and imaging workup as well as a negative fat pad biopsy, the cause of her portal hypertension was unclear. A thorough evaluation for infectious, rheumatologic, and oncology conditions was performed, and notable for her known IgA lambda gammopathy, a lymph node biopsy that showed Castleman's disease (CD), and a vascular endothelial growth factor (VEGF) level >700. A unifying diagnosis for her seemingly disparate symptoms was POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) syndrome. She met the diagnostic criteria for this condition and was started on the appropriate treatment.

The Pathways Service in the Department of Medicine at Massachusetts General Hospital was consulted and focused on two questions:

1. Why did this patient present with this constellation of symptoms?
2. Why now?

Background and Diagnosis

POEMS syndrome is a monoclonal plasma cell disorder with associated clinical features. Though polyneuropathy (malfunction of multiple peripheral nerves) is required for diagnosis, the remaining signs and symptoms vary between patients. Symptoms may include endocrine abnormalities such as hypogonadism, skin hyperpigmentation, bone changes (e.g., increased bone density, abnormal hardening), and CD (a disorder that presents with enlarged lymph nodes and uncontrolled production of lymphocytes). Through unclear mechanisms, the monoclonal plasma cell population leads to high levels of proinflammatory cytokines, including IL-6 and VEGF, which likely mediate many POEMS features.

We hypothesize that a patient's unique profile of cytokine expression ultimately determines which clinical features of POEMS syndrome develop.

Evidence that cytokines drive the features of POEMS syndrome is largely observational. One study found that POEMS patients had significantly higher levels of pro-inflammatory cytokines, including IL-6, TNFα, and IL-1β than patients with multiple myeloma (Blood). Another study detected higher IL-6 levels in active versus stable POEMS (Intern Med) and increased IL-6 levels prior to an exacerbation of POEMS symptoms (Rinsho Shinkeigaku).

Elevated VEGF is a major diagnostic criterion, highlighting the importance of VEGF in POEMS disease pathogenesis. One study showed that VEGF is elevated in POEMS but not multiple myeloma or other neurological diseases (Blood). VEGF induces angiogenesis and microvascular permeability of vascular and lymphatic endothelial cells, which can cause multiple symptoms of POEMS (e.g., peripheral edema). One case report describes a patient with profound lower extremity edema at night that resolved during the day (Intern Med). She was found to have increased VEGF when the edema symptoms were present, but as the edema resolved, VEGF levels decreased.

Several studies have proposed mechanisms linking cytokines to disease features. For instance, VEGF may drive polyneuropathy that is universal in patients with POEMS. One study used an intraneural injection of VEGF in a rat model to show that VEGF increased microvascular permeability to cause endoneurial edema (Rinsho Shinkeigaku). They propose that this permeability enables neurotoxic serum proteins such as complement factors and thrombin to then cross the blood-nerve barrier and cause neuronal injury. Another study showed that VEGF is highly expressed in the blood vessels of nerves in POEMS, leading to histopathologic findings of basal lamina thickening and endothelial cell proliferation (Brain). They also found that high peripheral nerve VEGF was associated with more severe nerve damage. Fittingly, polyneuropathy was one of our patient's earliest POEMS manifestations, and she had an extremely high VEGF level.

We next considered how cytokines may drive less common disease features in patients with POEMS. The lymph node biopsy in our patient showed CD, a rare POEMS manifestation that has been linked to IL-6 expression. CD describes a group of lymphoproliferative disorders characterized by swollen lymph nodes and abnormal plasma cell numbers. Studies have shown high IL-6 expression, which promotes B-cell maturation, within CD lymph nodes (Blood). On this admission, our patient also presented with recurrent ascites requiring paracentesis (ascites fluid removal) due to portal hypertension. Portal hypertension is a rare disease feature but has been previously described in POEMS (Rev Esp Enferm Dig, Advances in Digestive Medicine, BMC Hematol). VEGF is a likely culprit and has been shown to exacerbate portal hypertension by increasing nitric oxide production, vasodilation, and promoting angiogenesis in splanchnic vessels, which may increase blood flow to the portal vein (J Cell Mol Med). Though VEGF elevation is universal in POEMS, we propose that portal hypertension may only occur in patients with pre-existing risk factors.

Given a model where plasma cell-derived cytokines drive POEMS disease features, anti-cytokine therapies should provide symptomatic relief but not cure the underlying disease. This hypothesis is supported by limited anecdotal studies. For instance, one patient treated with melphalan-dexamethasone had a good hematologic response but continued to have debilitating edema and polyneuropathy. After starting bevacizumab, the patient experienced symptom resolution within 1-2 weeks (Blood). Ultimately, the most effective therapies are similar to those used in multiple myeloma and treat the underlying plasma cell disorder (Am J Hematol).

Summary and Future Steps

Though pro-inflammatory cytokines have emerged as likely drivers of POEMS manifestation, basic mechanistic questions remain unanswered. To examine the role of gammopathy in disease pathogenesis, we propose isolating the monoclonal (or biclonal) immunoglobulin in our patient and other affected patients, then either [1] run patient sera through an affinity column that binds the relevant immunoglobulin, elute the immunoglobulin, then subject it to protein sequencing, or [2] isolate plasma cells via flow cytometry and perform genomic sequencing, which would reveal both the antibody sequence and other genetic perturbations that may drive this disorder. Once the antibody is sequenced, it can be cloned and assessed for tissue specificity by performing immunohistochemistry to assess antibody binding to prepared normal tissue specimens or subjecting the antibody to protein binding assays that systematically profile interactions with numerous potential antigens in parallel. Ideally, this could be performed for multiple patients and could potentially identify shared antigens. Finally, we propose expression profiling, via either 'bulk' or single-cell RNA sequencing, to identify downstream changes in affected tissues. If our hypothesis is correct, we may expect that patients with similar cytokine profiles also share key gene expression changes in target tissues.

In summary, POEMS represents a complex syndrome with seemingly unrelated clinical findings and considerable variability between patients. These experiments should help shed light on both the general pathophysiology of the disease and if performed with multiple patient samples, the basis of shared and unique features of each patient's presentation.

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